Alzheimers Disease: Recent Advances



Ritu Arora, Anshika Mittal, Rita Kakkar



Ritu Arora, Anshika Mittal, Rita Kakkar, Computational Chemistry Group, Department of Chemistry, University of Delhi, Delhi-110 007, India

Correspondence to: Rita Kakkar, Computational Chemistry Group, Department of Chemistry, University of Delhi, Delhi-110 007, India


Telephone: +91-1127666313       

Fax: +91-27666605

Received: June 5, 2015                    

Revised: August 8, 2015

Accepted: August 12, 2015

Published online: September 22, 2015



These days our society is combating against a neurodegenerative disease called Alzheimers disease which is an age-related dementia. The concern has become graver as the disease may not be a necessary outcome in the oldest old and may even thrive in an age of thirties or forties. Alzheimers impairs a persons cognitive ability and gradually leads to loss of bodily functions, making them dependent on others. Plaques and tangles are the two prime hallmarks in the disease progression. Their escalation in the cortex gradually causes shriveling up of the brain. Unfortunately, the neurodegenerative changes are irreversible and no treatment can retard the progression of the disease. New therapeutic interventions related to Alzheimers disease are needed to be explored in order to apprehend the order of its occurrence and retard its progression.


Key words: Dementia; AD; Neurodegeneration; Progression; Clinical symptoms; Protein aggregation; Apoptosis; Amyloid plaques; Neuroinflammation; Preventions; Biomarkers


Arora R, Mittal A, Kakkar R. Alzheimers Disease: Recent Advances. Journal of Biochemistry and Molecular Biology Research 2015; 1(3): 87-104 Available from: URL:



Alzheimers disease (AD)[1,2,3] is one of the most recurrent types of dementia which accounts for around 60-80 % of the cases of dementia[4]. Dementia is a blanket term used to describe any brain disease that impairs a persons cognitive ability i.e. memory, behaviour and ability to think clearly[5]. The other forms of dementia include Parkinsons disease[6], Huntingtons disease[7], Lewy body dementia[8], vascular dementia[9], Creutzfeldt-Jakob disease[10], frontotemporal dementia, progressive supranuclear palsy[11,12] and normal pressure hydrocephalus[13].

    The different forms of dementia run counter in terms of the distinct pattern of symptoms and abnormalities in the brain. Alzheimers Association published the definitions of the various forms of dementia, suggesting overlapping features in them[14,15]. Dementia is neurodegenerative in nature and the associated conditions develop due to malfunctioning or death of nerve cells (called neurons) in the brain which may become more common with age. In AD, which is an age-related dementia, the neurodegenerative changes in brain gradually cause loss of basic bodily functions like speaking, walking and swallowing and, ultimately, prove to be fatal. It is a progressive ailment i.e. the degeneration in the structure and chemistry of the brain increases over time.

    Cognitive aging and AD were explored in a review[16]. It was suggested that the latter is critical to genetics and previous brain injuries and, although more prevalent in the aging population, it is not a necessary outcome only in the oldest old. Some believe environmental and intergenerative approaches can better incorporate existent world ecological and psychosocial models of health to recalibrate the study of the disease[17]. Additionally, factors like education[18], diet, exercise and cognitive stimulation all seem to make Alzheimers more likely.

    AD was first identified more than 100 years ago by a German psychiatrist and neuropathologist Alois Alzheimer and was named after him[19,20,21]. Despite its long history, the research into its characteristics, pathophysiology, diagnosis, prevention, risk factors, management and treatment has gained impetus only in the last few years. In spite of the wealth of research that has been reported during these years, the changes in the brain that stimulate the development of Alzheimers and their order of occurrence largely remain a moot question. Therefore, this work is dedicated to review AD, the most common dementia in aging population, and to compile the recent advances in its ongoing research.


Onset of Alzheimers disease

The categorization of AD is generally based on the differences in age of its onset and can be broadly classified as early-onset and late-onset AD. It can also be categorized as familial and sporadic AD on the basis of differences in the genetic cause[22]. Neurologists generally have a belief that both have similar overall sequence of symptoms and increasing impairments.


Early-onset alzheimer's

Less than 10% of all AD subjects are pinpointed with the disease before age 65; this is referred to as early-onset alzheimers. This is an uncommon form of AD, known to develop in a persons 30s, 40s, and 50s (and very scarcely in the late 20s). Ironically, early-onset AD patients are often not included in drug studies because of the young age. Approximately 13% of the cases of early-onset alzheimers are familial AD[23], that is, known to be entirely inherited. People with Downs syndrome[24] or other autosomal-dominant inheritance are particularly at a risk for this form of AD. There are even the rarest of rare cases of non-familial early-onset AD that thrive in people of 30s or 40s.


Late-onset alzheimer's

Late-onset alzheimers is the most prevalent type of AD which accounts for about the rest 90% of the cases, and usually occurs after age 65. Late-onset AD strikes almost half of all people over the age of 85 and may or may not be hereditary. Late-onset dementia is also called sporadic AD[25], in which genetic and environmental differences may act as risk factors, exclusive of autosomal-dominant inheritance. The disease can also be associated with a genetically defected chromosome 14, to which late-onset AD is not related.


Clinical Symptoms of Alzheimers disease

The 2011 proposed criteria and guidelines for diagnosis of AD[26-29] suggest that AD begins 20 years or more before the occurrence of symptoms referred as the preclinical stage of AD or asymptomatic stage of AD. People seem to be free of any symptom but toxic changes start occurring in the brain by this time. Since there is no effective treatment to delay onset or prevent the disease, the focus has now shifted to identify and treat AD during the long preclinical stage.

The destruction to nerve cells and tissues starts from the cerebral cortex. It is the region of the brain responsible for high-level brain functions such as consciousness, memory, language, reading and intelligence, which starts shriveling up. According to the results[30], AD patients oral reading is marked by reduction of speech and articulation rates, high number and proportion of pauses, and poor effectiveness of phonation time. All parts of the visual system may be affected, including the optic nerve and the retina[31].

    The area of the cortex, mainly hippocampus, which is responsible for the formation of the new memory, begins to shrink[32], leading to short term memory loss, the first warning signs of cognitive loss, demarcated as the early stage of AD. The condition is sometimes more pronounced with mild cognitive impairment (MCI). MCI, also called prodromal stage of AD, is the transition stage between preclinical stage and early AD. A trend of a slight increase of cerebral blood flow in both hippocampi and the posterior cingulate gyrus has been noticed in MCI patients with a decrease in AD patients[33]. The MCI stage of the disease is detected through cognitive tasks like the mini-mental state examination and computerized screening instruments[34]. At this stage of the disease, memory deficit becomes serious enough to be noticed by the subject or other people but at the same time does not hamper daily life or independent function.

    Progression of Alzheimers aggravates memory loss and evidently impairs other cognitive abilities, such as reasoning or judgment, vision, language and word-finding, leading to dementia. Memory loss and confusion grow worse, and people begin to have problems identifying family and friends. They may have difficulty to grasp new things, perform daily tasks or manage with new situations.

    People are often diagnosed in the dementia stage[26]. The incidence of dementia and AD is considered to be associated with neuropsychiatric symptoms[35] and therapeutically targeting the latter might retard the conversion of MCI to dementia. Behavioral or non-pharmacologic treatment may represent another effort towards reduction of dementia risk in AD patients[36,37]. A study revealed the existence of a poor perception of emotions in AD subjects[38]. A distinct pattern was observed in visual and auditory-verbal perception, whereas only the verbal modality seems to be relatively preserved. Thus, strengthening of emotional prosody can be used as a communication support between the patient and care-givers.

    Problem of apathy, hallucinations, paranoia and delusions[39] make the patients more impulsive. These symptoms occur in approximately 50% of AD patients, indicative of a more severe phenotype. The risk for psychosis in AD is genetically mediated, as revealed by studies on familial aggregation of AD and psychosis[40]. Baseline inferior temporal and supramarginal cortical thinning are predictive of worsening apathy and hallucination over time[41]. Actigraphy can prove to be a fruitful complementary measurement in the clinical diagnosis of apathy related to AD[42]. Delusions are clinically and neurobiologically related to memory deficits but partially. Likewise hallucination, delusion in AD, is linked with dysfunctioning of specific frontal and temporal cortex[43].

    Then, in the early stages of AD, the alterations in plaques and deposition of tau proteins start taking place. A dramatically high loss of nerve cell and synapse are identified hallmarks of Alzheimers brain abnormalities, which are suspected to be caused due to senile (neuritic) plaques and tangles. Plaques are formed when abnormal clusters of protein pieces called amyloid-beta (A) clump up together between neurons. Plaques and/or tangles may destroy vital cell transport system and hinder cell-to-cell signaling at synapses. Post-mortem results of the human hippocampus, and the CA1 region in 3xTg-AD mice revealed that these alterations are administered by hippocampus[44].

    The progression of AD is studied using the patterns in which these plaques and tangles are spread through the cortex. The basis for these changes is unknown, but preferably a combination of factors commences common biochemical and physiologic pathways that finally lead to nerve cell dysfunction and death[45]. In the advanced stage of AD, plaques and tangles escalate throughout the brain, and brain tissues shrivel dramatically. Patients have the highest levels of A peptide and neurofibrillary tangles in this stage. They become bedridden and cannot communicate, completely becoming dependent on care-takers.


Alzheimers Pathogenecity and Therapeutic Perspective

1. Genetics

Apolipoprotein E4 (APOE4) genotype is the profound genetic risk factor for late-onset AD. On chromosome 19, the APOE gene has three common alleles: ɛ2, ɛ3 and ɛ4. Apolipoprotein E (APOE) 4 alleles escalate the risk for late-onset AD and mitigate the age of AD onset[46]. Cohorts with at least one APOE ɛ2 provide some protection against AD and show better performance on neuropsychological measures as compared to those without an ɛ2 allele[47]. On the other hand, APOE ɛ3 may play a neutral role in the disease i.e. neither increasing nor decreasing the risk[48]. The findings of Yang et al[49]. suggest that bone marrow transplants-derived APOE3-expressing cells may have better ability to reduce the behavioral and neuropathological changes in experimental AD as compared to those that express APOE4.

    Sherva et al[50] reported the first genome-wide association study to investigate the rate of cognitive decline in a sample of AD subjects with longitudinal measures of cognition. Their data suggested the association of SPON1, a protein-coding gene, with the interindividual variability existing in the AD trajectories. The gene product plausibly binds to amyloid precursor protein (APP) inhibiting its cleavage by -secretase.

    Neurodegeneration and AD might be advanced by chronically elevated level of the RCAN1-1 protein[51]. The methionine/valine polymorphism in the PRNP gene harbors the vulnerability of the disease[52]. Tiedt et al[53] recognized a new mutation in a male patient with early onset familial AD, which resulted in the deletion of a leucine at codon 174 of PSEN1. DNA sequencing[54] exhibited a heterozygous nucleotide transition (c.824C > T) in exon 8 of PSEN1, leading to change in alanine to valine at codon 275 (Ala275Val). Another gene family TREML2 may also foster risk alleles for AD; mainly the genes, TREM2-p.R47H and TREML2-p.S144G are associated with increased and reduced risk for AD, respectively.[55] Coding variations in ADAM10 have also been reviewed in familial AD[56]. A recent meta-analysis of 74,046 individuals identified 11 new susceptibility loci for AD and discussed some already known loci, which include CASS4, CELF1, FERMT2, HLA-DRB5, INPP5D, MEF2C, NME8, PTK2B, SORL1, ZCWPW1, SlC24A4, CLU, PICALM, CR1, BIN1, MS4A, ABCA7, EPHA1, and CD2AP[57].

    Green et al[58] observed the combined effects of two Alzheimers risk alleles, APOE-4 and CLU-C, which decrease brain activity in the medial temporal lobe, a brain area affected early in AD. They used assays which are known to track an early AD intervention, executive attention assays during functional magnetic resonance imaging (fMRI) in young adults, pointing to the necessity for establishing early biomarkers of increased AD risk. The TT allele of progranulin polymorphism rs5848 is also related with increased chances of AD, suggestive of the significant role of progranulin gene in AD progression[59,60]. Single nucleotide polymorphisms were not found to be related to AD as probed in a Polish population[61].


2. Protein Aggregation

Aggregation of protein plays an important role in pathogenesis of most of the neurodegenerative diseases, including AD. In the process of protein aggregation[62], a monomeric unit interacts with another monomeric unit of the same protein forming dimers, oligomers and even multimers. This is accompanied with conformational changes in the 3-D structure of the protein and formation of beta-strands. In such a way, the size of aggregates keeps on increasing and this is normally taken care by complex cellular quality control mechanisms of the body. However, under certain adverse circumstances, like high protein concentration, complex interactions with other peptidic chains or specific cellular environment, an undesirable subset of protein may aggregate intracellularly or extracellularly[63].

    In order to stabilize the aggregated structures, the interaction between beta-strands and beta-sheets takes place, leading to extracellular precipitation of insoluble amyloid fibrils or senile plaques within beta-sheets, subsequently causing neurotoxicity[64,65]. The formation of amyloid plaques is one of the two types of protein aggregation in the brain that characterizes AD pathology and the other is intracellular neurofibrillary tangles. Neurofibrillary tangles are composed of highly phosphorylated forms of the microtubule-associated tau protein[66]. Tau proteins are often found in close proximity to amyloid deposits[67,68] and have been suggested as vital mediators of amyloid plaque induced neurotoxicity.

    Currently, AD is defined by the regional presence of neuritic plaques and neurofibrillary tangles in the brain along with the deposition of A aggregation. Hence, it is justified to speculate that any kind of event that is capable of kicking off the biophysical process of tau and A aggregation results into AD[69]. The following topics under this section describe a number of recent studies related to the two major AD pathologies - amyloid and tau hypotheses supported with a brief framework of the biochemistry involved.


2.1 Formation of Amyloid Plaques C Amyloid Hypothesis

Long before enzymes appeared, amyloid plaques have been believed to catalyze metabolic reactions of life[70]. Amyloid plaques are found in the extracellular region and are basically composed of a ~4 kDa protein, specifically A protein. A protein is the primitive component of the amyloid plaques formed in the brain tissues of AD patients[71]. The exact mechanism of toxicity of amyloidogenic proteins is not yet known. In a recent structure-function study of amyloid pores in AD[72], it was found that monomers adopt the U-shaped, -strand-turn--strand pattern as a usual feature of beta amyloid organization.

    As per in vivo and in vitro studies, A deposits are toxic to hippocampal and cortical neurons[64,73,74]. Amyloidogenic proteins, characterized by their ability to form fibrillar aggregates with -sheet configurations, also play an important role in several other neurodegenerative diseases. A larger A burden is found in the brain of living early-onset AD cohorts as compared to late-onset AD cohorts[75], which is in agreement with those from postmortem studies. The indirect proportionality between A burden and age-at-onset is possibly related with aging-associated decline of brain or cognitive reserve and with aging-associated increase of brain susceptibility. On the other hand, Castello and Soriano[76] suggested that accumulation of A is neither necessary nor sufficient to initiate pathogenesis in sporadic AD.

    A is produced by the action of two aspartyl proteases, - and -secretases on amyloid precursor protein (APP)[77-79]. Firstly, -secretase cleaves APP to generate the N-terminal of the protein, which is then followed by the action of -secretases to release A[80,81]. There are two basic forms of A which depend on the number of amino acid residues produced, which is either A40 or A42. The other minor fragments of peptides, A37 and A38 have also been identified and analyzed by liquid chromatography-MS and immunochemical methods[82].

    A consistent increase in the levels of A42 is comparably more common than its counterpart, A40. A short-lived increase in the amount of A42 is observed in cohorts with major head injury, a recognized AD risk factor[83]. An elevated proportion of the 42-amino acid form is enough for progression of early-onset AD but this is not the case for the more common sporadic forms of AD. In autosomal-dominant familial AD, deposition of amyloidogenic protein elevates with AD-causing mutations within presenilin (PS), especially PS1 and PS2 genes and APP[84]. Inherited mutations in PS1 and PS2 increase the ratio of A42 to A40, which leads to very early and hostile forms of AD.

    The main constituents of A plaques, A40 and A42, associate to form abnormal extracellular deposits of amorphous aggregates and aggregated forms (protofibrils and fibrils)[85]. Fibrillary aggregates of A may enhance the effect of oligomers and protofibrils by creating mechanical barriers for diffusion, sprouting and migration of cells in brain parenchyma[69]. However, Walsh and Selkoe have shown that A dimers and trimers have more neuronal toxic effect and synaptic loss as compared to fibrillary proteins[86]. Since A seems to be the main culprit in the AD pathology and A oligomers are the roots of neurotoxicity in AD[87,88], the amyloid hypothesis has become the major focus of much AD research. The amyloid pathology can be targeted either by inhibiting the enzymatic action of one of the secretases (- and -secretase) or by removal of A deposits using antibodies[89].

    The carboxyl-terminal cleavage of APP to form isoforms of A40 and A42 results from -secretase activity. Many potent small molecules have been developed to inhibit -secretase to reduce the formation of A40 and A42[90-94], but, unfortunately, -secretase not only targets APP, the main precursor of A, but also cleaves Notch receptors, which are crucially important for normal growth[95,96]. Besides, potent -secretase inhibitors have several side effects like serious immunological and gastrointestinal problems[97]. Such drawbacks have directed researchers towards the development of -secretase modulators[98]. The function of these modulators is to either specifically cleave APP without affecting Notch cleavage or modify the cleavage of APP by -secretase to favor the production of A40 over that of A42[99-104]. Such drugs include non-steroidal anti-inflammatory drugs (NSAIDs) such as ibuprofen[34] and drugs that interact with the ATP-binding cassette of PS1 near the active site of the enzyme[105].

    The serious target-related side effects of -secretase have aroused interest in the possibility of targeting -secretase for AD treatment. It is worth mentioning here that the activity of a single protease, -secretase 1 (BACE1) is involved in -secretase cleavage of APP[81,106-109] and inhibition of BACE1 activity has no serious target-related issues[110]. BACE1 inhibitors can block A production, retard the cascade of amyloid pathology and prevent AD related memory deficits in mice brain[111-114]. However, the struggle is still on to seek effective BACE1 inhibitors that are active in CNS. The problem lies in the large active site of BACE1, which calls for identification of large molecules as potent BACE1 inhibitors. Such heavy molecular weight molecules usually have poor blood brain permeability and are rarely stable. Some studies[115-124] also suggest the role of BACE1 in cleavage of alternative substrates like 2,6-sialyltransferase, interleukin-1 receptor II, P-selectin glycoprotein ligand-1, APLP2, lipoprotein and voltage-gated sodium channels, and these may play physiological roles in humans. Despite the aforementioned drawbacks to the approach of secretase inhibition, -secretase inhibitors, -secretase modulators and -secretase inhibitors continue to actively follow as drug targets for AD therapy in the hope that the concluding benefits might outweigh the risks[63].

    The second approach to address the A menace is to target the degradation of the aggregated protein or the aggregates. For this purpose, immune system manipulation is the sought after therapeutic approach for AD to dramatically improve cognitive deficits and/ or reduce A and plaque pathology. Although the desired results have been obtained on passive transfer of A-specified antibodies in APP-transgenic mice, clinical trials on humans were stopped due to the development of sterile meningocephalitis in a subset of individuals[125]. However, A immunotherapies still have hope as monoclonal A antibodies, since the humanized monoclonal antibody, bapineuzumab (bapi), from the Élan-Wyeth pharmaceutical company significantly delayed cognitive decline in some cohorts[126]. Immunotheraupists also believe that the approved treatment for immune deficiencies and autoimmune disorders can be effectively used in A clearance and cognitive improvement in AD patients[127,128].

    The intracellular A might also play a central role in the pathophysiology of the disease. Although the A plaques are extracellular lesions, they may mediate their toxic effects inside the neuron if soluble oligomers are the principal toxic species[63,129]. Most of the A is excreted from the cell through the secretory pathway. On the contrary, there are evidences that intracellular A plays an important role in AD pathology. The disease-related isoform of A, A42, appears to be more vulnerable to intracellular accumulation relative to A40. Intracellular A mounts more frequently in the highly-affected region of the Alzheimers brain, i.e. entorhinal cortex and hippocampus[130].

    The aggregation of amyloidogenic proteins damages brain mitochondria, which causes neuronal dysfunction. Mitochondrial beta-amyloid plays a critical role in the development of AD as it binds to beta-amyloid-binding alcohol dehydrogenase, a mitochondrial enzyme[131]. It also induces oxidative stress[132] leading to increase in the levels of lipid peroxidation products. This may trigger neurodegeneration by causing oxidative dysfunction of essential energy-related complexes in mitochondria[133].

    The intracellular A gets bound to heme groups in mitochondrial membranes impairing electron transport chain and loss of respiratory function. The experimental affirmation of such oxidative stress leads to the basis for treatment of AD with antioxidants[134]. Also, the profound genetic risk factor, 4 allele of APOE4, elevates intracellular A[135] whereas increased synaptic activities reduce it[136]. A immunotherapy can be used to address the reduction of intracellular A[137,138].

    Also, Memantine combined with vitamin D may avert degeneration of nerve fibers triggered by A[139] and can be applied to prevent the onset of AD. Memantine is accepted for treatment of moderate to severe AD. Recently, proline-rich polypeptide-1 was tested as a neuroprotective agent on A25-35 animal model of AD and was concluded to be one of the effective preventive agents to fight against neurodegenerative disorders[140].

    Interestingly, an executable mathematical language, Maude was used to write a computational model to simulate and logically analyze the system it models. The amyloid hypothesis was used as the basis of the AD model[141]. On analyzing the model, it was found that A regulation can be interrupted through the interaction of pathological processes such as cerebrovascular insufficiency, oxidative stress, and inflammation. Lately, what experiments and computer simulations can offer us about A and its link to AD has been reviewed[142]. In order to understand this link, the usage of computational techniques to study the A conformational properties are encouraged, keeping in mind the challenges and limitations inherent to the current set of experimental techniques.


2.2 Formation of Neurofibrillary Tangles C Tau Hypothesis

The neurofibrillary tangles of tau protein observed in AD brains are likely to have been deposited after changes in A metabolism and initial plaque formation[143-145]. Discovery of tau protein goes back to some 40 years. The normal functioning of the neurons is dependent on tau protein as it stabilizes microtubules by promoting tubulins assembly. Microtubules, a major component of the neuronal cytoskeleton, is responsible for normal morphology and gives structural support to the nerve cells[146]. Tau protein that can regulate tubulins assembly into microubules is in the phoshorylated form. The coordinated action of kinases and phosphatases on tau protein further assists the tubulins assembly[147-148]. Under AD pathological conditions, abnormal phosphorylation of tau protein takes place. This limits the binding capacity of tubulins to disorganize microtubules. Also, self polymerization and aggregation of tau into paired helical filaments[149] progressively leads to formation of neurofibrillary tangles inside the neurons[150-152]. A-like biophysical mechanism of protein aggregation is applied for the production of tau-derived neurofibrillary changes (neuropil threads, neurofibrillary tangles, neuritic plaques). Like the toxicity of A, toxic intermediates of tau (oligomers and fibrillary tau protein) cause toxicity at the cell biological level.

    New perspectives on the role of tau in AD and its therapeutic implications have been actively pursued in a review[153]. In AD, tau protein fails to keep the cytoskeleton well assembled in the axonal process as it fails to bind to microtubules. This abnormality is advanced by prominent modifications in the conformation of the tau native structure and tau misfoldings[154-156]. Abnormal post-translational modifications seem to be the main reason of this abnormality[157,158]. In Alzheimers, fibril inclusions start from the entorhinal cortex, progressively damage the hippocampus, and ultimately the neocortex[159]. As these regions of brain are essential for learning and memory, progression of tangles pathology is victimized with cognitive loss[160]. The density of neurofibrillary tangles distributed along the entorhinal cortex, hippocampus and neocortex has been correlated with the degree of dementia in AD[161].

    The nonfunctionality of tau protein has been proposed to be caused due to abnormal phosphorylation, also called hyperphosphorylated state. Accumulation of post-translationally phosphorylated tau proteins takes place early in neurons, even prior to formation of neurofibrillary tangles. In the hyperphosphorylated state, the tau protein is deprived of its biological activity. In AD, the hyperphosphorylation[162,163] might be a result of upregulation of tau kinases[164] like GSK- 3, cAMP-dependent protein kinase, cyclin-dependent kinase 5, and calcium/ calmodulin-dependent kinase II and/ or downregulation of tau phosphatases, which include PP1, PP2A, PP2B, and PP2C[165]. It has been proposed that tau hyperphosphorylation occurs prior to its cleavage[166,167] and formation of neurofibrillary tangles follows tau cleavage[168]. The former has been confirmed by in vitro studies of ethanol-induced neuronal apoptosis in the developing mouse brain[167,169]. The other proposed reasons for the loss of normal functioning of the tau protein can be acetylation, nitration, glycation, truncation, ubiquitination and conformational changes[154,170-179].

    Tau hyperphosphorylation and misfolding take place both at presynaptic and postsynaptic terminals. The abnormal post-translationally modified tau is enriched in synaptoneurosomal fractions. The accumulation of hyperphosphorylation tau oligomers at human AD synapses is associated with increased ubiquitinated substrates and proteasome components that may disrupt synapses in AD[180]. Besides this, considerable hyperphosphorylation and misfolding of synaptic tau take place amongst non-demented elderly, signifying synapse to be one of the first subcellular compartments affected by tauopathy[181].

    In a healthy neuron, over ten-fold excess of tau is in the microtubule bounded form[182,183]. On the other hand, in AD affected neurons, hyperphosphorylated tau does not bind to tubulins, which leads to disintegration of microtubules. The disintegration of microtubules affects the neuronal transport system and affects the distribution of mitochondria. The disrupted distribution of mitochondria in the peripheral region of axon can decrease glucose levels, lipid metabolism and synthesis of ATP and loss of Ca2+ homeostasis[184], leading to a neuronal degeneration state called dying back of axons. Synapses are also dependent on mitochondria for the energy required for its regular functioning[185] and tau protein abnormalities interrupt mitochondria from providing energy to synapses causing synaptic loss[186].

    Tau proteolytic cleavage can be considered as another possible mechanism that may promote tau protein aggregation[187-189]. Unfortunately, the enzyme that is associated with the proteolytic cleavage of tau is not clearly known. Some findings suggest association of aberrant proteolysis even with programmed cell death[190,191]. The correlation of apoptosis and associated caspases with the neurodegenerative process in AD shows the proliferation of apoptotic cells in the protein aggregation prone areas of the brain[192-194]. Caspases, the cystein proteases, cleave ASP residue in the canonical consensus sequence on the carboxyl terminal of molecule. Caspase enzymes, especially caspase3, participate in a proteolytic cascade to kill cells via apoptosis[195]. They also play a vital role in A-induced neuronal apoptosis[196] and are activated in apoptotic neurons in AD[197].

    Tau is also found in the cerebrospinal fluid (CSF)[198] and increased level of tau is an AD biomarker. There are numerous pathways that have been hypothesized to explain the presence of tau in the CSF. Tau might have passively released from dead or dying tangle-bearing neurons or actively secreted and transferred between neurons through synapse[199]. Although the intercellular transfer of tau is of great interest and vital in tau pathology, the exact mechanism of neuronal internalization of tau remains a moot question. However, it is often hypothesized that the mechanism depends upon the nature of the tau intermediate involved, say monomers[200,201], small soluble oligomers[202] or aggregates[203]. In AD, the elevated levels of tau phosphorylated on T181 has been found in human CSF[204], suggesting that tau phosphorylation may be modified extracellularly.

Since it is now understood that the progression of tau pathology in AD is marked by interneuronal transfer of tau, suppressing this transfer may have an impact on AD pathology. Also, tau pathology causes synaptic loss and subsequent cell death; thus AD-related cognitive decline may be improved by preventing intercellular tau transfer. The therapeutic strategies implemented in this context are blocking tau release, reducing tau accumulation or extracellular oligomerization or preventing uptake of tau by neighboring neurons[199].


3 Cholinergic Deficiency

Some of the demential neuropsychiatric symptoms, such as hyperactivity, depression, apathy and psychosis, may render central cholinergic deficiency syndrome[205,206]. Cholinergic deficiency syndrome is the reduction in the synthesis of a neurotransmitter, acetylcholine[207], which is a well-known feature associated with AD[208]. The acetylcholinesterase enzyme is involved in the breakdown of acetylcholine by hydrolyzing it. The accessibility of acetylcholine can be increased by using acetylcholinesterase inhibitors which inhibit the acetylcholinesterase from hydrolyzing acetylcholine. Tacrine, rivastigmine, donepezil and galantamine are the four approved acetylcholinesterase inhibitors[209,210], but none of these can delay or halt the disease progression. In fact, for half of the AD subjects with milder forms of the disease, these drugs remained effective for just 6-12 months[211]. Therefore, the researchers are more interested in targeting A and tau proteins[187,212,213] and BACE[214].

    An endogenous neurotrophic-factor protein, termed as nerve growth factor (NGF) has a potential to restore function and to avoid degenerating cholinergic neurons in AD, but offers a long-standing delivery obstacle. Recently, ten AD patients were successfully administered with genetically engineered gene-therapy vector adeno-associated virus serotype 2 delivering NGF (AAV2-NGF [CERE-110]) to the nucleus basalis of Meynert[215]. The latter was found to be safe and well-tolerated for two years without any evidence of accelerated decline.


4. Apoptosis

For proper functioning and to maintain constant size of proliferative tissues, it is necessary for the older cells to die and make way for new cells. Apoptosis, a stereotyped sequence of biochemical and morphological changes, leads to programmed cell death without adversely influencing its neighbors[216]. Hence, it is also frequently called programmed cell death[217]. In contrast to proliferative tissues, neurons of an organism need to stay alive for the whole lifetime as they are responsible for maintaining the function of cells with neuronal circuits. Unfortunately, excessive death of neurons may take place, resulting in disease or injury. For example, Alzheimers disease involves the death of hippocampal and cortical neurons[216].

    Necrosis and apoptosis are two ways by which cell death can occur. Apoptosis is a programmed, smooth and tightly regulated physiological method required for maintaining a balance between cell division and cell death. In contrast to this, necrosis results in quick disruption of the cellular mechanism and non-physiological disintegration of the cells. A combination of both apoptosis and necrosis may occur in contributing to neurodegeneration in AD. Both may overlap or occur sequentially[217].

    Occurrence of apoptosis in Alzheimers came into the picture in 1993 when two research teams, Carl Cotman's at the University of California, Irvine, and Gianluigi Forloni's at the Institute of Pharmacological Research in Milan, Italy, showed that A, which accumulates in the brains of patients suffering from AD, leads to the death of cultured neurons by apoptosis[218]. There have been many other hints regarding occurrence of apoptosis in AD[197,219-223].

    Apoptosis leads to the cleavage of the AD associated vital proteins, APP and presenilins, which are also commonly referred to as cell death substrates, as the process ultimately results in cell death­[224]. Presenilin mutations also disturb calcium homeostatsis in the endoplasmic reticulum such that neurons are sensitized to apoptosis and excitotoxicity[225].

    Activity of the apoptosis-associated family of cysteine proteases named caspases[226], has been found in neurons related with amyloid deposits in the brains of people suffering from AD[216]. Gervais et al[196] suggested that APP is cleaved by capsases. They proposed that this may be an early event that facilitates the production of A, suggesting the strong link that apoptic cell death might have with deposition of A. The predominant site where this proteolysis mediated by caspase occurs is within the cytoplasmic tail of APP. The cleavage occurs in hippocampal neurons in vivo, which is followed by acute excitotoxic or ischemic brain. Based on sequence homology, the caspases family of proteases is classified into three subfamilies: caspase-1 (ICE), caspase-2 (ICH-1), and caspase-3 (CPP32).[226] As already mentioned, Caspase-3 shows a marked elevation in neurons that are dying in Alzheimers disease, implying caspase-3 to be the predominant caspase involved in APP cleavage[196]. Caspase activation is thus a prerequisite of apoptosis[217]. Different cellular substrates for caspases have been described. For example, an essential cellular protein, ICAD, which is an inhibitor of caspase-activated deoxyribonuclease (CAD or DFF45), is cleaved by caspase, which actually begins DNA fragmentation[227]. Capases attack the main essential structures of the cell by cutting off contacts with surrounding cells, reorganizing cytoskeleton, shutting down replication and repair of DNA, interrupting splicing, disrupting nuclear structure and disintegrating cells into apoptotic bodies[228]. Caspase activation may also involve signaling pathways such as apoptotic triggers like toxins, death receptors like Fas/CD95 and intracellular stress conditions[217].

    Mutations in presenilins alter -secretase cleavage of APP at the C terminus of A. In one pathway, presenilin mutations increase production of A directly, which induces apoptosis and activation of caspase. Caspase cleavage of APP further facilitates greater A production, resulting in a vicious cycle that involves apoptosis and A generation. In the second pathway, presenilin mutations first activate caspase which cleaves APP and results in increased A production. Both pathways relate apoptosis and caspase activation with increased generation of A[224].

    Changes in expression of apoptosis-related genes like the Bcl-2 family of regulator proteins, Par- 4 and DNA damage response genes and increased DNA damage have also been found to be linked to accumulation of amyloid deposits in AD brains[216]. Bcl-2 of the Bcl-2 family of regulator proteins is anti-apoptotic, whereas some, like Bax, Bad, and Bak, are pro-apoptotic in their function. For the survival of individual neurons, balance of pro-apoptotic (Bax, Bak and Bad) and anti-apoptotic (Bcl-2 and Bcl-xL) proteins may be essential. Neurons that have high levels of Bak and Bad, and normal or low levels of Bcl-2 and Bcl-xL die, while increased levels of Bcl-2 and Bcl-xL inhibit apoptosis[226].

    Another major pathway that leads to activation of caspase is the release of cytochrome c from mitochondria. Assembly of apoptosome, a large proteinaceous complex made up of an oligomer of Apaf-1 and procaspase-9, is controlled by cytochrome c in the cytosol. When this complex is formed, caspase-9 is activated, which further activates other caspases[229]. It lies in the space between the outer and inner membranes of mitochondria, where cytochrome c resides in healthy cells. It has been proposed that members of the Bcl2 family, such as Bad, Bak, Bax and Bid, cause cytochrome-c release[230,231]. These proteins have been reported to form pores in the outer membrane through which diffusion of cytochrome c occurs[232]. In fact, other apoptotic proteins and several caspases and apoptosis-inducing factor might also translocate from mitochondria to the cytosol[229]. Apart from activating caspase and inducing apoptosis, release of cytochrome c may also result in loss of oxidative phosphorylation and production of reactive oxygen species, which may lead to cell death[233,234].

    The clarification of the mechanism of apoptosis promises to the discovery of therapeutic drugs that would help in prevention and therapy of AD[217]. In recent years, much attention has been devoted to identify drugs that control apoptosis, but the results have been unsatisfactory. Thus, it is necessary to find novel targets for the same[235].


5 Neuroinflammation

Inflammation or inflammatory response is an inherent part of the bodys defense mechanisms to fight against numerous threats, including injuries and infections. Inflammations could be of three types: inflamm-aging, metaflammation and peripheral inflammation. Inflamm-aging is a term used to describe a condition when the immune system runs amiss with age, damaging aged tissues. Sometimes the response may be less protective and more harmful due to a low-grade and chronic form of inflammation called metainflammation. Inflammation may also exist due to damages affecting nerves, causing peripheral inflammation.

    These inflammations can contribute to the AD onset by increasing the toxic levels of A protein[236]. It is believed to be caused by malfunctioning of blood brain barrier transporters, which then fails to push the accumulated A proteins from the brain into the blood. These evidences suggest that proinflammatory cytokines, the cell signalling proteins which promote systematic inflammation, should be considered as therapeutic targets or relevant biomarkers in psychiatric disorders[237,238].

    Neuroinflammatory and neuroregenerative processes occur in the early stages of AD pathology[239]. In advanced stages of AD, neocortex exhibits upregulation of inflammatory mediators. This takes place as a regenerative response to the deposition of amyloidogenic proteins. A is considered as a foreign substance by the immunity system of the body which in turn generates anti-A antibodies. The removal of A by anti-A antibodies leads to clearance of the A deposits with subsequent reduction of the dystrophic neurites as found in transgenic APP mice.

    NSAIDs tamper inflammation by inhibiting the main mediators of CNS neuroinflammation such as cyclooxygenase-mediated signaling pathways including prostaglandins. Since neuroinflammation has become an important pathological hallmark of AD, NSAIDs are associated with reduced incidence of AD[240], but their administration has adverse cardiovascular side-effects. Thus more targeted exploitation of downstream prostaglandin signaling pathways must be addressed to prevent or therapeutically intervene AD[241].

    A two-photon excitation microscopy displays that infiltrated neutrophils in the brain migrate to brain A plaques[242]. The study suggests a possible influence of these immune cells on the progression of AD, especially in relation to brain inflammation. Fingolimod, a new oral immunosuppressant used to treat a neuroinflammatory disease, multiple sclerosis, may provide therapeutic effects in patients with AD, by up-regulating neuronal brain-derived neurotophic factor[243].

    Antidiabetic drugs affect brain metabolism like neuroinflammation and neuroregeneration. This suggests the contribution of these drugs to the evolution of disease modifying treatments for neurodegenerative diseases[236]. Ginseng Rb1 is also found to reverse the changes in a number of direct or indirect hippocampal neuroinflammation markers, indicating that this could be a potential way to develop anti-aging drugs[244].


6 Miscellaneous

Insulin, a key factor of diabetic pathogenesis, is involved in essential pathways of learning and memory in CNS and thus contributes to the development and progression of AD in aging patients with diabetes[245]. In early sporadic AD pathology, abnormal brain glucose metabolism and insulin signaling have been reported to play a crucial role[246]. Over two-third of AD cohorts were clinically indentified with impairment of glucose. It is hypothesized[247] that AD, clinically and pathologically, presents a metabolic form of diabetes on the brain and would also contribute to the pancreatic and beta-cells degeneration, leading to diabetes. Using a positron emission tomography (PET) probe of regional glucose utilization in the brain, it was suggested that severe energy deficiency for preclinical AD and MCI patients is consistent with the progression of AD[248].

    Malfunction in the iron biomineralization undertaken by ferritin may be a pivotal factor in development of AD[249]. The amount of nanocrystals of magnetite (Fe3O4) intrinsically found in the human brains is generally increased in the Alzheimers brain[250].

    Correia et al[251] carried out thorough research in autopsy brain tissues from AD cohorts, AD animals and other cellular models. They found that multiple malfunctioning takes place in mitochondria during the course of the disease. The mitochondria isolated from lymphocytes of patients with MCI have been found to undergo an increase in oxidative stress. On correlation with varying levels of a number of vitamin E components, an increase in oxidative stress markers in the peripheral system was observed[252]. This may potentially reflect brain damage and can also serve as a potential biomarker in AD pathogenesis.



The potential misconceptions related to risk and protective factors can be targeted with tailored educational endeavors. It was found in a study that older and middle-aged adults are concerned about their AD risk status and believe that initiatives can be taken to reduce disease risk[253]. At present, there is no effective preventive measure for AD that comes with a definitive affirmation to support these measures. Since global studies of measures to avert the onset of AD or its delay have often produced inconsistent results, the focus has now shifted to environmental proteomics associated to the disease[254].


1. Environmental Factors

Environmental factors such as ingestion of metals like lead[255], iron and zinc[256] may also be associated with the development or progression of AD. An imbalance in the levels of redox transition metals, especially iron, copper, and other trace metals has been pinpointed by current evidences[257]. They are present at higher levels in subjects with AD and Parkinson disease while with other neurodegenerative disorders, copper, zinc, aluminum, and manganese are involved.

    Aluminium is a neurotoxicant, which hastens brain aging but its extensively studied role in the etiology of AD is still debated[258]. Some mechanisms contributing to Al-induced neurobehavioral toxicity are noted in a review[259]. Metal ions, particularly copper(II), may contribute to the formation of amyloid plaques and neurofibrillary tangles[260-262], which are the core pathological hallmarks of AD.


2. Diet

The role of nutrition in regulating AD is not certain, though a lower risk of AD is associated with a Mediterranean-type diet, coffee and moderate alcohol consumption[263]. A Mediterranean diet and/or a food combination, such as Souvenaid, seem to be the most effective approaches with the least possible side effects to mitigate the progression of AD[264]. Epidemiologically, combination supplements rich in antioxidant vitamins may also reduce the risk of AD. Retinoids, vitamin A-related compounds, reveal to be capable therapeutic targets for AD treatment because of their capability to affect the vital components of disease such as plaque formation, cholinergic transmission, APOE expressions, cholesterol content and inflammatory environment of the brain[265]. On the other hand, soy food consumption may lead to the increasing incidence of AD and other dementias[266]. Additionally, vitamin D[267] and vitamin E related compounds[268] such as - and -tocopherols are also associated with health risks.


3. Others

The risk factors of AD onset differ enormously between the sexes. Women are more prone to the development of AD than men and also more likely to be informal caregivers for someone with AD or related dementias[15]. This entry focuses on the role of ovarian steroid hormones, especially estrogens and progesterone, and their contributions to womens neurological health[269]. As reviewed by Li and co-workers[270], brain estradiol, a localized female sex hormone, has emerged as a therapeutic target for preventing brain disorders and neurodegeneration. The benefits of estrogen replacement therapy for cognitive functions and AD prevention, especially in postmenopausal women, warrant attention. The biology of sex differences in cognitive function is needed to be perceived in detail to provide insight into AD prevention and development of personalized, gender-specific medicine[271].

    AD pathogenesis is associated with immoderate exposure to electromagnetic fields from electrical grids, excessive alcohol intake, hyperhomocysteinaemia, hypertension, hyperinsulinaemia and chronic anaemia[263]. A higher risk of AD is associated with pesticides, smoking, traumatic brain injury, obesity and high cholesterol levels in middle age. Along with the well-known clinical and lifestyle risk factors, personality traits such as self-discipline and depression are also associated with AD incidence[272].


AD Biomarkers

1. Current Biomarkers

Early treatment of AD patients may contribute to a small delay in their institutionalization, resulting in notable cost savings[273]. To improve both the diagnostic and prognostic accuracy of AD and to differentiate it from other types of neurodegenerative dementia, the clinical symptoms and signs are combined with biomarkers[274].

    Throughout the review, a number of known biomarkers have already been discussed. These neurochemical indicators provide a reliable assessment of the disease and thus need a summarization. Prior to the escalation of pathological changes, they must be effectively diagnosed. Trzepacz et al[275] showed that MRI[276] and amyloid PET neuroimaging[277] are the best combination of biomarker modalities for predicting conversion of MCI to AD.

    The definitive diagnosis of AD is only through brain biopsy or autopsy. Since CSF is in direct contact with the brain, the molecular composition of CSF can also be a useful source of information for diagnosing AD and other neurological disorders. CSF levels of A40, A42, total tau (t-tau) and phosphorylated tau (p-tau) usually form a part of the clinicians tool for accurate AD diagnosis. Soluble A oligomers are also one of the diagnostic tools, as they are more synaptotoxic for AD relative to A aggregates. Gene mutation in presenilins and APP is a genetic predisposition to early-onset AD and can be a good predictor of the same.

    Different phosphorylation epitopes, mainly tau181, can be detected by different immunochemical methods. MCI to AD transition can be distinguished from stable MCI with 90% and 100% sensitivity and selectivity respectively, with the help of t-tau. On the other hand, p-tau181 shows a 80% sensitivity and 92% specificity to discriminate AD from healthy cohorts[278]. Thus, p-tau reveals a higher specificity than t-tau for diagnosing AD as compared to other types of dementia. Also, several kinases and phosphatses, especially cdk5 and Gsk3, involved in the hyperphosphorylation modifications, characterize AD.

    Upregulation of the brains innate immune response is another prime marker for neuronal degeneration in AD, which results in inflammatory processes. Besides CSF, amyloid and tau pathologies are ubiquitous in blood, saliva, skin and extra brain tissues, and have moderately promising diagnostic values[278]. Now, let us discuss certain new potential biomarkers that have emerged to predict the risk of AD progression.


2 New Potential Biomarkers

The typical findings of established and new MRI procedures in healthy aging, MCI, and AD are well documented[279-281]. Increased cortical phase shift in AD patients demonstrated on 7-tesla T2*-weighted MRI is a contemporary biomarker for AD, which may manifest amyloidogenesis in the early stages[282]. Using multitask learning algorithms, Zhou et al[283] analyzed MRI and cerebrospinal fluid data of the temporal patterns of biomarkers in disease progression. They found that cortical thickness average of left middle temporal, left and right entorhinal, and white matter volume of left hippocampus play crucial role in predicting Alzheimer's disease Assessment Scale cognitive subscale (ADAS-Cog) at any stage of the disease progression. ADAS-Cog[284] is one of the cognitive measures designed for clinical evaluation of cognitive status of the AD patients.

    Welling et al[285] postulated that antimicrobial peptides (AMPs) may be labeled as a marker to target pathogens that play a role in aggregation of A in the brain. AMPs can effectively penetrate infected cells and tissues beyond many endothelial barriers, including blood brain barrier. So, cerebral infections caused by environment influences such as viral or chronic bacterial infections can be detected and diagnosed by AMPs.

    Bada and co-workers[286] took the challenge to find the biomarkers of early-onset familial AD, a boon to young healthy individuals at risk of AD. Alzheimers has been associated with oxidative stress. Lymphocytes from young, healthy persons carrying at least one APOE4 allele, the strongest known single genetic risk factor for AD, were considered. It was found that lymphocytes suffered from reductive stress rather than oxidative, i.e., lower oxidized glutathione and P-p38 levels and higher expression of enzymes involved in antioxidant mechanism, such as glutamylcysteinyl ligase and glutathione peroxidase. On the other hand, in the full fledged AD, the antioxidant mechanism probably gets exhausted, the situation is reversed and oxidative stress occurs. The findings of Badas group provided an insight into the early events of AD progression that may help to find biomarkers of Alzheimers at its very early stages.

    The largest multiplexed plasma protein study till date for AD markers describes some novel protein associations, and also validates some previously identified ones[287]. Prostate-specific antigen complexed to 1-antichymotrypsin, pancreatic prohormone, clusterin, and fetuin B were found to be the strongest association of protein levels with AD. Their findings provide strong affirmation that quantities of these plasma proteins are truly associated with AD.

    MicroRNAs (miRNAs), endogenous small RNAs of 21C25 nucleotides, post-transcriptionally regulate gene expressions. Recently, circulating miRNAs have been reported as potential new biomarkers for neurodegenerative diseases and processes affecting the central nervous system[288]. The study was carried out to investigate the potential role of serum miRNAs as diagnostic biomarkers for AD. Their results indicated that serum miR-125b may act as a fruitful noninvasive biomarker for AD. Due to the easy availability of blood serum from AD patients, the phospholipid alterations occurring in serum can be investigated as promising biomarkers for diagnosis of AD[289]. These alterations are indicative of membrane breakdown processes in pathogenesis of AD.

    Labeling tissue transglutaminase (tTG) as a biochemical marker for AD can be misleading[290]. In another report[291], the results of Wolff and co-workers were criticized on the basis of the experimental conditions taken into account by them and the overwhelming evidence in the literature which reports tTG to be a promising biochemical marker of AD. Extracellular vesicles may also play a role in initiation and progression of AD. Both normal and pathological cells release extracellular vesicles which help in getting rid of unwanted cellular substances. These vesicles are even functional in intercellular communication like exchange of messenger RNAs, noncoding RNAs, and proteins between healthy and/or pathological cells[292]. Perceiving the significance of the role played by extracellular vesicles in AD initiation and progression, may help in the discovery of new potential biomarkers.

    A novel concept of specific immune-sensing application on the controlled silanized surface was proposed to quantify the biomarkers of AD in biological fluids[293]. The method employed grafting of the antibodies involved in the detection of AD biomarkers over the silanized surface followed by evaluation of biological activity using fluorescence microscopy. Machine learning methodologies are also used to predict cognitive and disease states form neuroimaging data[294]. The progression of disease associated with aging, such as AD, is characterized by gradual and continuous changes in the shape of the brain.

    Most of the contemporary shape analysis studies in AD and related dementia perform statistics on the specific region of interests, already clinically known to be affected. Recently, a multivariate analysis of diffeomorphic transformations of the whole brain was presented[295]. The complex anatomical changes were related with neuropsychological responses, such as clinical measures of cognitive abilities, logical memory, audio-verbal learning, and measures of executive functions. The proposed methodology may discover new patterns of shape changes in the human brain that can help in envisaging progress of disease in neurological disorders.



Unfortunately, the damages caused to the brain cannot be reversed with ongoing treatments and the disease is incurable. At this time, there is no treatment to slow down the rate of progression of the disease. So, it was necessary to have new insights into the pathophysiology of AD. Courageous efforts, cooperation and endurable management are needed to perceive the incredibly complex AD, as aging population forms an important part of our society. With increase in the lifespan, the number of patients with cognitive diseases is only going to increase, and unless steps are taken right now to slow down the progress of age-related diseases, AD may take on epidemic proportions.



The authors have no conflicts of interest to declare.



1    Alois A. Über eine eigenartige Erkrankung der Hirnrinde [About a peculiar disease of the cerebral cortex]. Allgemeine Zeitschrift fur Psychiatrie und Psychisch-Gerichtlich Medizin 1907; 64:146C148. (German)     

2    Alois A. About a peculiar disease of the cerebral cortex. Alzheimer Dis Assoc Disord 1987; 1: 3C8. PMID: 3331112    

3    Ulrike M, Konrad M. Alzheimer: The Life of a Physician and the Career of a Disease. New York, Columbia Press, 2003   

4    Alzheimer's Association. 2012 Alzheimer's disease facts and figures. Alzheimers Dement 2012; 8: 131-168. PMID: 22404854    

5    Khan ZU, Martn-Montañez E, Navarro-Lobato I, Muly EC. Memory deficits in aging and neurological diseases. Prog Mol Biol Transl Sci 2014; 122: 1-29. PMID: 24484696   

6    Parkinson J. An essay on the shaking palsy. 1817. J Neuropsychiatry Clin Neurosci 2002; 14: 223-236. PMID: 11983801   

7    Huntington G. (1872) On Chorea. In: Med. Surgical Reporter: A Weekly Journal, (Philadelphia: Butler, S.W.) 26: 317C321   

8    Kosaka K, Oyanagi S, Matsushita M, Hori A. Presenile dementia with Alzheimer-, Pick- and Lewy-body changes. Acta Neuropathol 1976; 36: 221C233. PMID: 188300   

9    Battistin L, Cagnin A. Vascular cognitive disorder. A biological and clinical overview. Neurochem. Res 2010; 35: 1933C1938. PMID: 21127967   

10   Meggendorfer FZ. Klinische und genealogische Beobachtungen bei einem Fall von spastischer Pseudosklerose Jakobs. Neurol Psychiatry 1930; 128: 337C41. DOI: 10.1007/BF02864269   

11   Richardson JC, Steele J, Olszewski J. Supranuclear ophthalmoplegia, pseudobulbar palsy, nuchal dystonia and dementia. A clinical report on eight cases of "heterogenous system degeneration". T Am Neurol Assoc 1963; 88: 25C9. PMID: 14272249    

12   Steele JC, Richardson JC, Olszewski J. Progressive supranuclear palsy. A heterogeneous degeneration involving the brain stem, basal ganglia and cerebellum with vertical gaze and pseudobulbar palsy, nuchal dystonia and dementia. Arch Neurol 1964; 10: 333C59. PMID: 14107684   

13   Adams RD, Fisher CM, Hakim S, Ojemann RG, Sweet WH. Symptomatic occult hydrocephalus with "normal" cerebrospinal-fluid pressure. A treatable syndrome. N Eng J Med 1965; 273: 117C126. PMID: 14303656    

14   Alzheimers Association. 2013 Alzheimer's disease facts and figures. Alzheimers Dement 2013; 9: 208-245. PMID: 23507120         

15   Alzheimer's Association. 2014 Alzheimer's disease facts and figures. Alzheimers Dement 2014; 10: e47-e92. PMID: 24818261         

16   Rice DM. Alzheimer's and mind- brain problems. In: Calculus of Thought. Academic Press, Elsevier, 2014: 175-195.       

17   Whitehouse PJ. The end of Alzheimers disease-From biochemical pharmacology to ecopsychosociology: A personal perspective. Biochem. Pharmacol 2014; 88: 677-681. PMID: 24304687       

18   Shpanskaya KS, Choudhury KR., Hostage C Jr, Murphy KR, Petrella JR, Doraiswamy PM. Educational attainment and hippocampal atrophy in the Alzheimer's disease neuroimaging initiative cohort. J Neuroradiol 2014; In Press. PMID: 24485897    

19   Cipriani G, Dolciotti C, Picchi L, Bonuccelli U. Alzheimer and his disease: a brief history. Neurol Sci 2011; 32: 275-9. PMID: 21153601           

20   Dahm R. Alzheimers discovery. Curr. Biol.2006; 16: R906-910.          

21   Filley CM. Alzheimer's disease. In: Encyclopedia of the Neurological Sciences. 2nd ed. Academic Press, Elsevier, 2014: 120-121.  

22   Pressman P, Rabinovici GD. Alzheimer, Alois. In: Encyclopedia of the Neurological Sciences. Academic Press, Elsevier 2014: 122-127.        

23   Campion D. Early-onset autosomal dominant Alzheimer disease: prevalence, genetic heterogeneity, and mutation spectrum. Am J Hum Genet 1999; 65: 664C670. DOI: 10.1086/302553       

24   Olson MI, Shaw CM. Presenile dementia and Alzheimer's disease in mongolism. Brain 1969; 92: 147. PMID: 4237656           

25   Braak H, Del Tredici K. Where, when, and in what form does sporadic Alzheimer's disease begin? Curr Opin Neurol 2012; 25: 708C14. PMID: 23160422   

26   Albert MS, DeKosky ST, Dickson D, Dubois B, Feldman HH, Fox NC, Gamst A, Holtzman DM, Jagust WJ, Petersen RC, Synder PJ, Carrillo MC, Thies B, Phelps CH. The diagnosis of mild cognitive impairment due to Alzheimer's disease: recommendations from the National Institute on Aging-Alzheimer's Association workgroups on diagnostic guidelines for Alzheimer's disease. Alzheimers Dement 2011; 7: 270C9. PMID: 21514249    

27   Jack CR, Albert MS, Knopman DS, McKhann GM, Sperling RA, Carrillo MC, Thies B, Phelps CH. The diagnosis of dementia due to Alzheimers disease: Recommendations from the National Institute on Aging-Alzheimers Association workgroups on diagnostic guidelines for Alzheimers disease. Alzheimers Dement 2011; 7: 257C62. DOI: 10.1016/j.jalz.2011.03.005         

28   McKhann GM, Knopman DS, Chertkow H, Hyman BT, Jack CR, Kawas CH, Klunk WE, Koroshetz WZ, Manly JJ, Mayeux R, Mohs RC, Morris JC, Rossor MN, Scheltens P, Carrillo MC, Thies B, Weintraub S, Phelps CH. The diagnosis of dementia due to Alzheimers disease: Recommendations from the National Institute on Aging-Alzheimers Association workgroups on diagnostic guidelines for Alzheimer's disease. Alzheimers Dement 2011; 7: 263C9. DOI:  

29   Sperling RA, Aisen PS, Beckett LA, Bennett DA, Craft S, Fagan AM, Iwatsubo T, Jack CR Jr, Kaye J, Montine TJ, Park DC, Reiman EM, Rowe CC, Siemers E, Stern Y, Yaffe K, Carrillo MC, Thies B, Morrison-Bogorad M, Wagster MV, Phelps CH. Toward defining the preclinical stages of Alzheimer's disease: recommendations from the National Institute on Aging-Alzheimer's Association workgroups on diagnostic guidelines for Alzheimer's disease. Alzheimers Dement 2011; 7: 280C92. PMID: 21514248    

30   Martnez-Snchez F, Meiln JJG, Garca-Sevilla J, Carro J, Arana JM. Oral reading fluency analysis in patients with Alzheimer disease and asymptomatic control subjects. Neurologa 2013; 28: 325-331. PMID: 23046975          

31   Tzekov R, Mullan M. Vision function abnormalities in Alzheimer disease. Surv Opthalmol 2014; 59: 414-433. PMID: 24309127

32   Engmann O, Hortobgyi T, Thompson AJ, Guadagno J, Troakes C, Soriano S, Al-Sarraj S, Kim Y, Giese KP. Cyclin-dependent kinase 5 activator p25 is generated during memory formation and is reduced at an early stage in Alzheimer's disease. Biol Psychiatry 2011; 70:159C168. PMID: 21616478          

33   Hauser T, Schönknecht P, Thomann PA, Gerigk L, Schröder J, Henze R, Radbruch A, Essig M. Regional cerebral perfusion alterations in patients with mild cognitive impairment and Alzheimer disease using dynamic susceptibility contrast MRI. Acad Radiol 2013; 20: 705-11. PMID: 23664398

34   Harrison J. Cognitive approaches to early Alzheimer's disease diagnosis. Med Clin North Am 2013; 97: 425-438. PMID: 23642579        

35   Rosenberg PB, Mielke MM, Appleby BS, Oh ES, Geda YE, Lyketsos CG. The association of neuropsychiatric symptoms in MCI with incident dementia and Alzheimer disease. Am J Geriatr Psychiatry 2013; 21: 685-695. PMID: 23567400       

36   Hahn EA, Wang H-X, Andel R, Fratiglioni L. A change in sleep pattern may predict Alzheimer disease. Am J Geriatr Psychiatry 2013; 22: 1262-1271. PMID: 23954041    

37   Koppel J, Goldberg TE, Gordon ML, Huey E, Davies P, Keehlisen L, Huet S, Christen E, Greenwald BS. Relationships between behavioral syndromes and cognitive domains in Alzheimer disease: the impact of mood and psychosis. Am J Geriatr Psychiatry 2012; 20: 994-1000. PMID: 22048323      

38   Gatignol P, Aubert-Garaïalde O, Rousseau T. Perception of emotions in Alzheimer disease. Ann Phys Rehabil Med 2011; 54: 248.        

39   Zahodne LB, Ornstein K, Cosentino S, Devanand DP, Stern Y. Longitudinal relationships between Alzheimers disease progression and psychosis, depressed mood and agitation/aggression. Am J Geriatr Psychiatry 2013; In Press. PMID: 23871118       

40   Murray PS, Kumar S, DeMicheleCSweet MAA, Sweet RA. Psychosis in Alzheimers Disease. Biol Psychiatry 2014; 75: 542-552. DOI:        

41   Donovan NJ., Wadsworth LP, Lorius N, Locascio JJ, Rentz DM, Johnson KA, Sperling RA, Marshall GA, Alzheimer Disease Neuroimaging Initiative. Regional cortical thinning predicts worsening apathy and hallucinations across the Alzheimer disease spectrum. Am J Geriatr Psychiatry 2014; 22: 1168-1179. PMID: 23890751         

42   Zeitzer JM, David R, Friedman L, Mulin E, Garcia R, Wang J, Yesavage JA, Robert PH, Shannon W. Phenotyping apathy in individuals with Alzheimer disease using functional principal component analysis. Am J Geriatr Psychiatry 2013; 21: 391-397. PMID: 23498386  

43   Sultzer DL, Leskin LP, Melrose RJ, Harwood DJ, Narvaez TA, Ando TK, Mandelkern MA. Neurobiology of delusions, memory, and insight in Alzheimer disease. Am J Geriatr Psychiatry 2014; 22: 1346-55. DOI: 10.1016/j.jagp.2013.06.005. 

44   Orta-Salazar E, Feria-Velasco A, Medina-Aguirre GI, Daz-Cintra S. Morphological analysis of the hippocampal region associated with an innate behaviour task in the transgenic mouse model (3xTg-AD) for Alzheimer disease. Neurologa 2013; 28: 497-502. PMID: 23972735      

45   Sack GH. Chemistry of Alzheimer disease. In: Encyclopedia of Biological Chemistry. 2nd ed. Academic Press, Elsevier, 2013: 473-479.     

46   Strittmatter WJ, Saunders AM, Schmechel D, Pericak-Vance M, Enghild J, Salvesen GS, Roses AD. Apolipoprotein E: high-avidity binding to beta-amyloid and increased frequency of type 4 allele in late-onset familial Alzheimer disease. Proc Natl Acad Sci U S A 1993; 90:1977C1981. PMID: 8446617         

47   Bonner-Jackson A, Okonkwo O, Tremont G, Alzheimers disease neuroimaging initiative. Apolipoprotein E ɛ2 and functional decline in amnestic mild cognitive impairment and Alzheimer disease. Am J Geriatr Psychiatry 2012; 20: 584-593. PMID: 21685781

48   de-Almada BV, de-Almeida LD, Camporez D, de-Moraes MV, Morelato RL, Perrone AM, Belcavello L, Louro ID, de-Paula F. Protective effect of the APOE-e3 allele in Alzheimer's disease. Braz J Med Biol Res 2012; 45: 8-12. PMID: 22068907

49   Yang Y, Cudaback E, Jorstad NL, Hemingway JF, Hagan CE, Melief EJ, Li X, Yoo T, Khademi SB, Montine KS, Montine TJ, Keene CD. APOE3, but not APOE4, bone marrow transplantation mitigates behavioral and pathological changes in a mouse model of Alzheimer disease. Am J Pathol 2013; 183: 905-917. PMID: 23831297       

50   Sherva R, Tripodis Y, Bennett DA, Chibnik LB, Crane PK., de Jager PL, Farrer LA, Saykin AJ, Shulman JM, Naj A, Green RC. Genome-wide association study of the rate of cognitive decline in Alzheimer's disease. (2014) Alzheimers Dement 2014; 10: 45-52. PMID: 23535033         

51   Ermak G, Davies KJA. Chronic high levels of the RCAN1-1 protein may promote neurodegeneration and Alzheimer disease. Free Radic Biol Med 2013; 62: 47-51. PMID: 23369757         

52   He J, Li X, Yang J, Huang J, Fu X, Zhang Y, Fan H. The association between the methionine/valine (M/V) polymorphism (rs1799990) in the PRNP gene and the risk of Alzheimer disease: an update by meta-analysis. J Neurol Sci 2013; 326: 89-95. PMID: 23399523            

53   Tiedt HO, Lueschow A, Winter P, Mller U. Previously not recognized deletion in presenilin-1 (p.Leu174del.) in a patient with early-onset familial Alzheimer's disease. Neurosci Lett 2013; 544: 115-118. DOI: 10.1016/j.neulet.2013.03.056         

54   Luedecke D, Becktepe JS, Lehmbeck JT, Finckh U, Yamamoto R, Jahn H, Boelmans K. A novel presenilin 1 mutation (Ala275Val) as cause of early-onset familial Alzheimer disease. Neurosci Lett 2014; 566:115-119. PMID: 24582897

55   Benitez BA, Jin SC, Guerreiro R, Graham R, Lord J, Harold D, Sims R, Lambert JC, Gibbs JR, Bras J, Sassi C, Harari O, Bertelsen S, Lupton MK, Powell J, Bellenguez C, Brown K, Medway C, Haddick PCG, van der Brug MP, Bhangale T, Ortmann W, Behrens T, Mayeux R, Pericak-Vance MA, Farrer LA, Schellenberg GD, Haines JL, Turton J, Braae A, Barber I, Fagan AM, Holtzman DM, Morris JC, Williams J, Kauwe JS, Amouyel P, Morgan K, Singleton A, Hardy J, Goate AM, Cruchaga C. Missense variant in TREML2 protects against Alzheimer's disease. Neurobiol Aging 2014; 35: 1510.e19-1510.e26. DOI:          

56   Cai G, Atzmon G, Naj AC, Beecham GW, Barzilai N, Haines JL, Sano M, Pericak-Vance M, Buxbaum JD. Evidence against a role for rare ADAM10 mutations in sporadic Alzheimer disease. Neurobiol Aging 2012; 33: 416-417. PMID: 20381196      

57   Lambert JC, et al. Meta-analysis of 74,046 individuals identifies 11 new susceptibility loci for Alzheimer's disease. Nat Genet 2013; 45: 1452C8. PMID 24162737.

58   Green AE, Gray JR, DeYoung CG, Mhyre TR, Padilla R, Dibattista AM, William Rebeck G. A combined effect of two Alzheimer's risk genes on medial temporal activity during executive attention in young adults. Neuropsychologia 2014; 56: 1-8. PMID: 24388797            

59   Fenoglio C, Galimberti D, Cortini F, Kauwe JSK, Cruchaga C, Venturelli E, Villa C, Serpente M, Scalabrini D, Mayo K, Piccio LM, Clerici F, Albani D, Mariani C, Forloni G, Bresolin N, Goate AM, Scarpini E. Rs5848 variant influences GRN mRNA levels in brain an peripheral mononuclear cells in patients with alzhiemer's disease. J Alzheimers Dis 2009; 18: 603C612. PMID: 19625741             

60   Sheng J, Su L, Xu Z, Chen G. Understanding the role of progranulin in Alzheimer's disease Gene 2014; 542: 141-145. DOI: 10.1038/nm.3712              

61   Klimkowicz-Mrowiec A, Sado M, Dziubek A, Dziedzic T, Pera J, Szczudlik A, Słowik A. Lack of association of CR1, PICALM and CLU gene polymorphisms with Alzheimer disease in a Polish population. Neurol Neurochir Pol 2013; 47: 157-160. PMID: 23650005           

62   Nolting B. Protein folding kinetics: biophysical methods. 2nd ed. Berlin: Springer Verlag, 1999: 95-123.

63   Aguzzi A, OConnor T. Protein aggregation diseases: pathogenicity and therapeutic perspectives. Nature Rev 2010; 9: 237-248. PMID: 20190788

64   Pike CJ, Walencewicz AJ, Glabe CG, Cotman CW. In vitro aging of beta-amyloid protein causes peptide aggregation and neurotoxicity. Brain Res. 1991; 563: 311C314. PMID: 1786545

65   Deshpande A, Mina E, Glabe C, Busciglio J. Different conformations of amyloid beta induce neurotoxicity by distinct mechanisms in human cortical neurons. J Neurosci 2006; 26: 6011C6018. PMID: 16738244

66   Goedert M, Spillantini MG & Crowther RA. Tau proteins and neurofibrillary degeneration. Brain Pathol 1991; 1: 279C86. PMID: 1669718         

67   Wood JG, Mirra SS, Pollock NJ, Binder LI. Neurofibrillary tangles of Alzheimer disease share antigenic determinants with the axonal microtubule-associated protein tau (). Proc Natl Acad Sci USA 1986; 83: 4040C4043. PMID: 2424015.

68   Kosik KS, Joachim CL, Selkoe DJ. Microtubule-associated protein tau () is a major antigenic component of paired helical filaments in Alzheimer disease. Proc Natl Acad Sci USA 1986; 83: 4044C4048. PMID: 224016

69   Thal DR, Fändrich M. Protein aggregation in Alzheimers disease: A and and their potential roles in the pathogenesis of AD. Acta Neuropathol 2015; 129: 163C165. DOI: 10.1007/s00401-015-1387-2

70   Barras C. Alzheimers molecules may have powerful early life. New Scientist 2014; 221: 12.     

71   Glenner GG, Wong CW. Alzheimer's disease: initial report of the purification and characterization of a novel cerebrovascular amyloid protein. Biochem Biophys Res Commun 1984; 120: 885. PMID: 6375662                       

72   Arce FT, Jang H, Connelly L, Ramachandran S, Kagan BL, Nussinov R, Lal R. StructureCFunction Studies of Amyloid Pores in Alzheimers Disease as a Case Example of Neurodegenerative Diseases. In: Bio-nanoimaging Protein Misfolding and Aggregation Academic Press, Elsevier, 2014: 397-408.                

73   Busciglio J, Lorenzo A, Yankner BA. Methodological variables in the assessment of beta amyloid neurotoxicity. Neurobiol Aging 1992; 13: 609C612. PMID: 1461350

74   Pike CJ, Burdick D, Walencewicz AJ, Glabe CG, Cotman CW. Neurodegeneration induced by beta-amyloid peptides in vitro: the role of peptide assembly state. J Neurosci 1993; 13: 1676C1687. PMID: 8463843

75   Choo IH, Lee DY, Kim JW, Seo EH, Lee DS, Kim YK, Kim SG, Park SY, Woo JI, Yoon EJ. Relationship of amyloid- burden with age-at-onset in Alzheimer disease. Am J Geriatr Psychiatry 2011; 19: 627-634. PMID: 21709608               

76   Castello MA, Soriano S. On the origin of Alzheimers disease. Trials and tribulations of the amyloid hypothesis. Ageing Res Rev 2014; 13: 10-12. DOI: 10.1016/j.arr.2013.10.001         

77   Haass C, Schlossmacher MG, Hung AY, Vigo-Pelfrey C, Mellon A, Ostaszewski BL, Lieberburg I, Koo EH, Schenk D, Teplow DB, Selkoe DJ. Amyloid beta-peptide is produced by cultured cells during normal metabolism. Nature 1992; 359: 322C325. PMID: 1383826

78   Seubert P, et al. Isolation and quantification of soluble Alzheimers beta-peptide from biological fluids. Nature 1992; 359: 325C7. PMID: 1406936

79   Shoji M, Golde TE, Ghiso J, Cheung TT, Estus S, Shaffer LM, Cai XD, McKay DM, Tintner R, Frangione B, Younkin SG. Production of the Alzheimer amyloid beta protein by normal proteolytic processing. Science 1992; 258: 126C9. PMID: 1439760

80   Cai H, Wang Y, McCarthy D, Wen H, Borchelt DR, Price DL, Wong PC. BACE1 is the major beta-secretase for generation of Abeta peptides by neurons. Nat Neurosci 2001; 4: 233C234. PMID: 11224536

81   Vassar R, Bennett BD, Babu-Khan S, Kahn S, Mendiaz EA, Denis P, Teplow DB, Ross S, Amarante P, Loeloff R, Luo Y, Fisher S, Fuller J, Edenson S, Lile J, Jarosinski MA, Biere AL, Curran E, Burgess T, Louis JC, Collins F, Treanor J, Rogers G, Citron M. Beta-secretase cleavage of Alzheimers amyloid precursor protein by the transmembrane aspartic protease BACE. Science 1999; 286: 735C741. PMID: 10531052

82   Tang BL, Kumar R. Biomarkers of mild cognitive impairment and Alzheimers disease. Annals of the Academy of Medicine Singapore 2008; 37: 406C410. PMID: 18536828

83   Raby CA, Morganti-Kossmann MC, Kossmann T, Stahel PF, Watson MD, Evans LM, Mehta PD, Spiegel K, Kuo YM, Roher AE, Emmerling MR. Traumatic brain injury increases beta-amyloid peptide 1-42 in cerebrospinal fluid. J Neurochem 1998; 71: 2505C2509. PMID: 9832149

84   Waring SC, Rosenberg RN. Genome-wide association studies in Alzheimer disease. Arch Neurol 2008; 65: 329C34. PMID: 18332245     

85   Querfurth HW, LaFerla FM. Alzheimers disease. N Engl J Med 2010, 362: 329-344. PMID: 20107219

86   Walsh DM, Selkoe DJ. Oligomers on the brain: the emerging role of soluble protein aggregates in neurodegeneration. Science 2002, 295: 1852-1858. PMID: 15182223

87   Bucciantini M, Giannoni E, Chiti F, Baroni F, Formigli L, Zurdo J, Taddei N, Ramponi G, Dobson CM, Stefani M. Inherent toxicity of aggregates implies a common mechanism for protein misfolding diseases. Nature 2002. 416: 507-511. PMID: 11932737

88   Dominici R, Finazzi D, Zoia CP, Frasca GM, Tremolizzo L, Ida Biunno. Protein aggregation and toxicity in Alzheimers and Parkinson disease review. Alz Dis Res J; 4: 285-300.

89   Irvine GB, El-Agnaf OM, Shankar GM, Walsh DM. Protein Aggregation in the Brain: The Molecular Basis for Alzheimers and Parkinsons Diseases. Mol Med 2008; 14: 451-64. PMID: 18368143

90   Dovey HF, John V, Anderson JP, Chen LZ, de Saint Andrieu P, Fang LY, Freedman SB, Folmer B, Goldbach E, Holsztynska EJ, Hu KL, Johnson-Wood KL, Kennedy SL, Kholodenko D, Knops JE, Latimer LH, Lee M, Liao Z, Lieberburg IM, Motter RN, Mutter LC, Nietz J, Quinn KP, Sacchi KL, Seubert PA, Shopp GM, Thorsett ED, Tung JS, Wu J, Yang S, Yin CT, Schenk DB, May PC, Altstiel LD, Bender MH, Boggs LN, Britton TC, Clemens JC, Czilli DL, Dieckman-McGinty DK, Droste JJ, Fuson KS, Gitter BD, Hyslop PA, Johnstone EM, Li WY, Little SP, Mabry TE, Miller FD, Audia JE. Functional -secretase inhibitorsreduce -amyloid peptide levels in brain. J Neurochem 2001; 76: 173C181. PMID: 11145990

91   Barten DM, Guss VL, Corsa JA, Loo A, Hansel SB, Zheng M, Munoz B, Srinivasan K, Wang B, Robertson BJ, Polson CT, Wang J, Roberts SB, Hendrick JP, Anderson JJ, Loy JK, Denton R, Verdoorn TA, Smith DW, Felsenstein KM. Dynamics of -amyloid reductions in brain, cerebrospinal fluid, and plasma of Camyloid precursor protein transgenic mice treated with a -secretase inhibitor. J Pharmacol Exp Ther 2005; 312: 635C643. PMID: 15452193

92   Best JD, Jay MT, Otu F, Ma J, Nadin A, Ellis S, Lewis HD, Pattison C, Reilly M, Harrison T, Shearman MS, Williamson TL, Atack JR. Quantitative measurement of changes in amyloid- (40) in the rat brain and cerebrospinal fluid following treatment with the -secretase inhibitoLY-411575 [N2-[(2S)-2-(3,5-difluorophenyl)-2-hydroxyethanoyl]-N1-[(7S)-5-methyl-6-oxo-6,7-dihydro-5Hdibenzo[b,d]azepin-7-yl]-l-alaninamide]. J Pharmacol Exp Ther 2005; 313: 902C908. PMID: 15743924

93   Siemers ER, Quinn JF, Kaye J, Farlow MR, Porsteinsson A, Tariot P, Zoulnouni P, Galvin JE, Holtzman DM, Knopman DS, Satterwhite J, Gonzales C, Dean RA, May PC. Effects of a -secretase inhibitor in a randomized study of patients with Alzheimer disease. Neurology 2006; 66: 602C604. PMID: 16505324

94   Liu Q, Waltz S, Woodruff G, Ouyang J, Israel MA, Herrera C, Sarsoza F, Tanzi RE, Koo EH, Ringman JM, Goldstein LS, Wagner SL, Yuan SH. Effect of potent -secretase modulator in human neurons derived from multiple presenilin 1-induced pluripotent stem cell mutant carriers. JAMA Neurol 2014; 71: 1481-1489. PMID: 25285942

95   Wong PC, Zheng H, Chen H, Becher MW, Sirinathsinghji DJ, Trumbauer ME, Chen HY, Price DL, Van der Ploeg LH, Sisodia SS. Presenilin 1 is required for Notch1 and DII1 expression in the paraxial mesoderm. Nature 1997; 387: 288C292. PMID: 9153393

96   Shen J, Bronson RT, Chen DF, Xia W, Selkoe DJ, Tonegawa S. Skeletal and CNS defects in Presenilin-1-deficient mice. Cell 1997; 89: 629C639. PMID: 9160754

97   Wong GT, Manfra D, Poulet FM, Zhang Q, Josien H, Bara T, Engstrom L, Pinzon-Ortiz M, Fine JS, Lee HJ, Zhang L, Higgins GA, Parker EM. Chronic treatment with the -secretase inhibitor LY-411, 575 inhibits -amyloid peptide production and alters lymphopoiesis and intestinal cell differentiation. J Biol Chem 2004; 279: 12876C12882. PMID: 14709552

98   Crump CJ, Johnson DS, Li YM. Development and Mechanism of -Secretase Modulators for Alzheimer Disease. Biochemistry 2013; 52: 3197-3216. PMID: 23614767

99   Sherrington R, Rogaev EI, Liang Y, Rogaeva EA, Levesque G, Ikeda M, Chi H, Lin C, Li G, Holman K, Tsuda T, Mar L, Foncin JF, Bruni AC, Montesi MP, Sorbi S, Rainero I, Pinessi L, Nee L, Chumakov I, Pollen D, Brookes A, Sanseau P, Polinsky RJ, Wasco W, Da Silva HA, Haines JL, Perkicak-Vance MA, Tanzi RE, Roses AD, Fraser PE, Rommens JM, St George-Hyslop PH. Cloning of a gene bearing missense mutations in early-onset familial Alzheimers disease. Nature 1995; 375: 754C760. PMID: 7596406

100 Levy-Lahad E, Wasco W, Poorkaj P, Romano DM, Oshima J, Pettingell WH, Yu CE, Jondro PD, Schmidt SD, Wang K, Crowley AC, Fu YH, Guenette SY, Galas D, Nemens E, Wijsman, EM, Bird TD, Schellenberg GD, Tanzi RE. Candidate gene for the chromosome 1 familial Alzheimers disease locus. Science 1995; 269: 973C977. PMID: 7638622

101 Rogaev EI, Sherrington R, Rogaeva EA, Levesque G, Ikeda M, Liang Y, Chi H, Lin C, Holman K, Tsuda T, Mar L, Sorbi S, Nacmias B, Placentent S, Amaducci L, Chumakov I, Cohen D, Lannfelt L, Fraser PE, Rommens JM, St George-Hyslop PH. Familial Alzheimers disease in kindreds with missense mutations in a gene on chromosome 1 related to the Alzheimers disease type 3 gene. Nature 1995; 376: 775C778. PMID: 7651536

102 Duff K, Eckman C, Zehr C, Yu X, Prada CM, Perez-tur J, Hutton M, Buee L, Harigaya Y, Yager D, Morgan D, Gordon MN, Holcomb L, Refolo L, Zenk B, Hardy J, Younkin S. Increased amyloid-42(43) in brains of mice expressing mutant presenilin 1. Nature 1996; 383: 710C713. PMID: 8878479

103 Lemere CA, Lopera F, Kosik KS, Lendon CL, Ossa J, Saido TC, Yamaguchi H, Ruiz A, Martinez A, Madrigal L, Hincapie L, Arango JC, Anthony DC, Koo EH, Goate AM, Selkoe DJ, Arango JC. The E280A presenilin 1 Alzheimer mutation produces increased A 42 deposition and severe cerebellar pathology. Nature Med 1996; 2: 1146C1150. PMID: 8837617

104 Citron M, Westaway D, Xia W, Carlson G, Diehl T, Levesque G, Johnson-Wood K, Lee M, Seubert P, Davis A, Kholodenko D, Motter R, Sherrington R, Perry B, Yao H, Strome R, Lieberburg I, Rommens J, Kim S, Schenk D, Fraser P, St George Hyslop P, Selkoe DJ. Mutant presenilins of Alzheimers disease increase production of 42-residue amyloid-protein in both transfected cells and transgenic mice. Nature Med 1997; 3: 67C72. PMID: 8986743

105 Fraering PC, Ye W, LaVoie MJ, Ostaszewski BL, Selkoe DJ, Wolfe MS. -Secretase substrate selectivity can be modulated directly via interaction with a nucleotide-binding site. J Biol Chem 2005; 280: 41987C41996. PMID: 16236717

106 Hussain I, Powell D, Howlett DR, Tew DG, Meek TD, Chapman C, Gloger IS, Murphy KE, Southan CD, Ryan DM, Smith TS, Simmons DL, Walsh FS, Dingwall C, Christie G. Identification of a novel aspartic protease (Asp 2) as -secretase. Mol. Cell Neurosci 1999; 14: 419C427. PMID: 10656250

107 Lin X, Koelsch G, Wu S, Downs D, Dashti A, Tang J. Human aspartic protease memapsin 2 cleaves the -secretase site of -amyloid precursor protein. Proc Natl Acad Sci USA 2000; 97: 1456C1460. PMID: 10677483

108 Sinha S, Anderson JP, Barbour R, Basi GS, Caccavello R, Davis D, Doan M, Dovey HF, Frigon N, Hong J, Jacobson-Croak K, Jewett N, Keim P, Knops J, Lieberburg I, Power M, Tan H, Tatsuno G, Tung J, Schenk D, Seubert P, Suomensaari SM, Wang S, Walker D, Zhao J, McConlogue L, John V. Purification and cloning of amyloid precursor protein -secretase from human brain. Nature 1999; 402: 537C540. PMID: 10591214

109 Yan R, Bienkowski MJ, Shuck ME, Miao H, Tory MC, Pauley AM, Brashier JR, Stratman NC, Mathews WR, Buhl AE, Carter DB, Tomasselli AG, Parodi LA, Heinrikson RL, Gurney ME. Membrane-anchored aspartyl protease with Alzheimers disease -secretase activity. Nature 1999; 402: 533C537. PMID: 10591213

110 Luo Y, Bolon B, Kahn S, Bennett BD, Babu-Khan S, Denis P, Fan W, Kha H, Zhang J, Gong Y, Martin L, Louis JC, Yan Q, Richards WG, Citron M, Vassar R. Mice deficient in BACE1, the Alzheimers -secretase, have normal phenotype and abolished -amyloid generation. Nature Neurosci 2001; 4: 231C232. PMID: 11224535

111 Ohno M, Sametsky EA, Younkin LH, Oakley H, Younkin SG, Citron M, Vassar R, Disterhoft JF. BACE1 deficiency rescues memory deficits and cholinergic dysfunction in a mouse model of Alzheimers disease. Neuron 2004; 41: 27C33. PMID: 14715132

112 Ohno M, Cole SL, Yasvoina M, Zhao J, Citron M, Berry R, Disterhoft JF, Vassar R. BACE1 gene deletion prevents neuron loss and memory deficits in 5XFAD APP/PS1 transgenic mice. Neurobiol Dis 2007; 26: 134C145. PMID: 17258906

113 Laird FM, Cai H, Savonenko AV, Farah MH, He K, Melnikova T, Wen H, Chiang HC, Xu G, Koliatsos VE, Borchelt DR, Price DL, Lee HK, Wong PC. BACE1, a major determinant of selective vulnerability of the brain to amyloid- amyloidogenesis, is essential for cognitive, emotional, and synaptic functions. J Neurosci 2005; 25: 11693C11709. PMID: 16354928

114 McConlogue L, Buttini M, Anderson JP, Brigham EF, Chen KS, Freedman SB, Games D, Johnson-Wood K, Lee M, Zeller M, Liu W, Motter R, Sinha S. Partial reduction of BACE1 has dramatic effects on Alzheimer plaque and synaptic pathology in APP transgenic mice. J Biol Chem 2007; 282: 26326C26334. PMID: 17616527

115 Hu X, Hicks CW, He W, Wong P, Macklin WB, Trapp BD, Yan R. Bace1 modulates myelination in the central and peripheral nervous system. Nature Neurosci 2006; 9: 1520C1525. PMID: 17099708

116 Kim DY, Carey BW, Wang H, Ingano LA, Binshtok AM, Wertz MH, Pettingell WH, He P, Lee VM, Woolf CJ, Kovacs DM. BACE1 regulates voltage-gated sodium channels and neuronal activity. Nature Cell Biol 2007; 9: 755C764. PMID: 17576410

117 Kitazume S, Nakagawa K, Oka R, Tachida Y, Ogawa K, Luo Y, Citron M, Shitara H, Taya C, Yonekawa H, Paulson JC, Miyoshi E, Taniguchi N, Hashimoto Y. In vivo cleavage of 2,6-sialyltransferase by Alzheimer -secretase. J Biol Chem 2005; 280: 8589C8595. PMID: 15364953

118 Kuhn PH, Marjaux E, Imhof A, De Strooper B, Haass C, Lichtenthaler SF. Regulated intramembrane proteolysis of the interleukin-1 receptor II by -, -,and -secretase. J Biol Chem 2007; 282: 11982C11995. PMID: 17307738

119 Li Q, Sudhof TC. Cleavage of amyloid- precursor protein and amyloid- precursor-like protein by BACE 1. J Biol Chem 2004; 279: 10542C10550. PMID: 14699153

120 Lichtenthaler SF, Dominguez DI, Westmeyer GG, Reiss K, Haass C, Saftig P, De Strooper B, Seed B. The cell adhesion protein P-selectin glycoprotein ligand-1 is a substrate for the aspartyl protease BACE1. J Biol Chem 2003; 278: 48713C48719. PMID: 14507929

121 Pastorino L, Ikin AF, Lamprianou S, Vacaresse N, Revelli JP, Platt K, Paganetti P, Mathews PM, Harroch S, Buxbaum JD. BACE (-secretase) modulates the processing of APLP2 in vivo. Mol Cell Neurosci 2004; 25: 642C649. PMID: 15080893

122 vonArnim CA, Kinoshita A, Peltan ID, Tangredi MM, Herl L, Lee BM, Spoelgen R, Hshieh TT, Ranganathan S, Battey FD, Liu CX, Bacskai BJ, Sever S, Irizarry MC, Strickland DK, Hyman BT. The low density lipoprotein receptor-related protein (LRP) is a novel -secretase (BACE1) substrate. J Biol Chem 2005; 280: 17777C17785. PMID: 15749709

123 Willem M, Dewachter I, Smyth N, Van Dooren T, Borghgraef P, Haass C, Van Leuven F. -Site amyloid precursor protein cleaving enzyme 1 increases amyloid deposition in brain parenchyma but reduces cerebrovascular amyloid angiopathy in aging BACE x APP[V717I]double-transgenic mice. Am J Pathol 2004; 165: 1621C1631. PMCID: PMC1618675

124 Wong HK, Sakurai T, Oyama F, Kaneko K, Wada K, Miyazaki H, Kurosawa M, De Strooper B, Saftig P, Nukina N. Subunits of voltage-gated sodiumchannels are novel substrates of -site amyloid precursor protein-cleaving enzyme (BACE1) and -secretase. J Biol Chem 2005; 280: 23009C23017. PMID: 15824102

125 Senior K. Dosing in phase II trial of Alzheimers vaccine suspended. Lancet Neurol 2002; 1: 3. PMID: 12849527

126 Gura, T. Hope in Alzheimers fight emerges from unexpected places. Nature Med 2008; 14: 894. PMID: 18776868

127 Dodel RC, Du Y, Depboylu C, Hampel H, Frölich L, Haag A, Hemmeter U, Paulsen S, Teipel SJ, Brettschneider S, Spottke A, Nölker C, Möller HJ, Wei X, Farlow M, Sommer N, Oertel WH. Intravenous immunoglobulins containing antibodies against -amyloid for the treatment of Alzheimers disease. J Neurol Neurosurg Psychiatry 2004; 75: 1472C1474. PMID: 15377700

128 Relkin NR, Szabo P, Adamiak B, Burgut T, Monthe C, Lent RW, Younkin S, Younkin L, Schiff R, Weksler ME. 18-Month study of intravenous immunoglobulin for treatment of mild Alzheimer disease. Neurobiol Aging 2008; 30: 1728C1736. PMID: 18294736

129 Glabe CG. Structural classification of toxic amyloidoligomers. J. Biol. Chem. 2008; 283: 29639C29643. PMID: 18723507

130 Gouras GK, Tsai J, Naslund J, Vincent B, Edgar M, Checler F, Greenfield JP, Haroutunian V, Buxbaum JD, Xu H, Greengard P, Relkin NR. Intraneuronal A42 accumulation in human brain. Am J Pathol 2000; 156: 15C20. PMID: 10623648

131 Yao J, Du H, Yan S, Fang F, Wang C, Lue LF, Guo L, Chen D, Stern DM, Gunn Moore FJ, Xi CJ, Arancio O, Yan SS. Inhibition of amyloid-beta (Abeta) peptide-binding alcohol dehydrogenase-Abeta interaction reduces Abeta accumulation and improves mitochondrial function in a mouse model of Alzheimer's disease. J Neurosci 2011; 31: 2313-2320. PMID: 21307267                

132 Butterfield DA, Swomley AM, Sultana R. Amyloid -Peptide (1C42)-Induced Oxidative Stress in Alzheimer Disease: Importance in Disease Pathogenesis and Progression. Antioxid Redox Signal 2013; 19: 823-835. doi: 10.1089/ars.2012.5027           

133 Hardas SS, Sultana R, Clark AM, Beckett TL, Szweda LI, Murphy MP, Butterfield DA. Oxidative modification of lipoic acid by HNE in Alzheimer disease brain. Redox Biol 2013; 1: 80-85. PMID: 24024140                

134 Loret al, Giraldo E, Viña J. Is antioxidant therapy effective to treat Alzheimers disease? Free Radicals Antioxidants 2011; 1: 8-14. DOI: 10.5530/ax.2011.4.3              

135 Zerbinatti CV, Wahrle SE, Kim H, Cam JA, Bales K, Paul SM, Holtzman DM, Bu G. Apolipoprotein E and low density lipoprotein receptor-related protein facilitate intraneuronal A42 accumulation in amyloid model mice. J Biol Chem 2006; 281: 36180C36186. PMID: 17012232

136 Tampellini D, Rahman N, Gallo EF, Huang Z, Dumont M, Capetillo-Zarate E, Ma T, Zheng R, Lu B, Nanus DM, Lin MT, Gouras GK. Synaptic activity reduces intraneuronal A, promotes APP transport to synapses, and protects against A-related synaptic alterations. J Neurosci 2009; 29: 9704C9713. PMID: 19657023

137 Arbel M, Solomon B. Immunotherapy for Alzheimers disease: attacking amyloid- from the inside. Trends Immunol 2007; 28: 511C513. PMID: 17981084

138 Kitazawa M, Vasilevko V, Cribbs DH, LaFerla FM. Immunization with amyloid- attenuates inclusion body myositis-like myopathology and motor impairment in a transgenic mouse model. J Neurosci 2009; 29: 6132C6141. PMID: 19439591

139 Annweiler C, Brugg B, Peyrin JM, Bartha R, Beauchet O. Combination of memantine and vitamin D prevents axon degeneration induced by amyloid-beta and glutamate. Neurobiol Aging 2014; 35: 331-335. PMID:24011542       

140 Yenkoyan K, Safaryan K, Chavushyan V, Meliksetyan I, Navasardyan G, Sarkissian J, Galoyan A, Aghajanov M. Neuroprotective action of proline-rich polypeptide-1 in -amyloid induced neurodegeneration in rats. Brain Res Bull 2011; 86: 262-271.              

141 Anastasio TJ. Data-driven modeling of Alzheimer disease pathogenesis. J Theor Biol 2011; 290: 60-72. PMID: 21920373            

142 Nasica-Labouze J, Nguyen PH, Sterpone F, Berthoumieu O, Buchete NV, Cot S, De Simone A, Doig AJ, Faller P, Garcia A, Laio A, Li MS, Melchionna S, Mousseau N, Mu Y, Paravastu A, Pasquali S, Rosenman DJ, Strodel B, Tarus B, Viles JH, Zhang T, Wang C, Derreumaux P. Amyloid Protein and Alzheimer's Disease: When Computer Simulations Complement Experimental Studies. Chem Rev 2015; 115: 3518-63. PMID: 25789869

143 Hardy J, Selkoe DJ. The amyloid hypothesis of Alzheimer's disease: progress and problems on the road to therapeutics. Science 2002; 297: 353. PMID: 12130773         

144 Götz J, Chen F, van Dorpe J, Nitsch RM. Formation of neurofibrillary tangles in P301 l tau transgenic mice induced by Abeta 42 fibrils. Science 2001; 293: 1491C1495. PMID: 11520988

145 Lasagna-Reeves CA, Castillo-Carranza DL, Guerrero-Muoz MJ, Jackson GR, Kayed R. Preparation and characterization of neurotoxic tau oligomers. Biochemistry 2010; 49: 10039C10041. PMID: 21047142

146 Kosik KS. The molecular and cellular biology of tau. Brain Pathol 1993; 3: 39C43. PMID: 8269082

147 Mandelkow EM, Biernat J, Drewes G, Gustke N, Trinczek B, Mandelkow E. Tau domains, phosphorylation,and interactions with microtubules. Neurobiol  Aging 1995; 16: 355C363. PMID: 7566345

148 Liu F, Iqbal K, Grundke-Iqbal I, Rossie S, Gong CX. Dephosphorylation of tau by protein phosphatase 5: impairment in Alzheimers disease. J Biol Chem 2005; 280: 1790C1796. PMID: 15546861

149 Mandelkow EM, Mandelkow E. Tau Protein and Alzheimer's Disease. Neurobiol Aging 1994; 15: S85-S86. PMID: 7700470

150 Garc´ıa-Sierra F, Ghoshal N, Quinn B, Berry RW, B´ınder LI. Conformational changes and truncation oftau protein during tangle evolution in Alzheimers disease. J Alz Dis 2003; 5: 65C77. PMID: 12719624

151 Ghoshal N, Garca-Sierra F, Fu Y, Beckett LA, Mufson EJ, Kuret J, Berry RW, Binder LI. Tau-66: evidence for a novel tau conformation in Alzheimers disease. J Neurochem 2001; 77: 1372C1385. PMID: 11389188

152 Ghoshal N, Garca-Sierra F, Wuu J, Leurgans S, Bennett DA, Berry RW, Binder LI. Tau conformational changes correspond to impairments of episodic memory in mild cognitive impairment and Alzheimers disease. Exp Neurol 2002; 177: 475C493. PMID: 12429193

153 Medina M, Avila J. New perspectives on the role of tau in Alzheimer's disease. Implications for therapy. Biochem Pharmacol 2014; 88: 540-547. DOI: 10.1016/j.bcp.2014.01.013            

154 Carrell RW, Gooptu B. Conformational changes and diseaseCserpins, prions and Alzheimers. Curr Opin Struct Biol 1998; 8: 799C809. PMID: 9914261

155 Fox N, Harvey RJ, Rossor MN. Protein folding, nucleation phenomena and delayed neurodegeneration in Alzheimers disease. Rev Neurosci 1998; 7: 21C28. PMID: 8736676

156 Hyman BT, Augustinack JC, Ingelsson M. Transcriptional and conformational changes of the tau moleculein Alzheimers disease. Biochim Biophys Acta 2005; 1739: 150C157. PMID: 15615634

157 Martin L, Latypova X, Terro F. Post-translational modifications of tau protein: implications for Alzheimers disease. Neurochem Int 2011; 58: 458C471. PMID: 21215781

158 Soto C. Alzheimers and prion disease as disorders of protein conformation: implications for the design of novel therapeutic approaches. J Mol Med (Berl) 1999; 77: 412C418. PMID: 104226190

159 Braak H, Braak E. Neuropathological stageing of Alzheimer-related changes. Acta Neuropathol. 1991; 82: 239C259. PMID: 1759558

160 Nelson PT, Alafuzoff I, Bigio EH, Bouras C, Braak H, Cairns NJ, Castellani RJ, Crain BJ, Davies P, Del Tredici K, Duyckaerts C, Frosch MP, Haroutunian V, Hof PR, Hulette CM, Hyman BT, Iwatsubo T, Jellinger KA, Jicha GA, Kövari E, Kukull WA, Leverenz JB, Love S, Mackenzie IR, Mann DM, Masliah E, McKee AC, Montine TJ, Morris JC, Schneider JA, Sonnen JA, Thal DR, Trojanowski JQ, Troncoso JC, Wisniewski T, Woltjer RL, Beach TG: Correlation of Alzheimer disease neuropathologic changes with cognitive status: a review of the literature. J Neuropathol Exp Neurol 2012; 71: 362C381. PMID: 22487856

161 Arriagada PV, Growdon JH, Hedley-Whyte ET, Hyman BT. Neurofibrillary tangles but not senile plaques parallel duration and severity of Alzheimers disease. Neurology 1992; 42: 631C639. PMID: 1549228

162 Trojanowski JQ, Lee VMY. Phosphorylation of paired helical filament tau in Alzheimers disease neurofibrillary lesions: focusing on phosphatases. FASEB J 1995; 9: 1570C1576. PMID: 8529836

163 Bue L, Bussire T, Bue-Scherrer V, Delacourte A, Hof PR. Tau protein isoforms, phosphorylation and role in neurodegenerative disorders. Brain Res Brain Res Rev 2000; 33: 95C130. PMID: 10967355

164 Gong CX, Iqbal K. Hyperphosphorylation of microtubule-associated protein tau: a promising therapeutic target for Alzheimer disease. Curr Med Chem 2008; 15: 2321C2328. PMID: 18855662

165 Avila J, Lucas JJ, P´erez M, Hern´andez F. Role of tau protein in both physiological and pathological conditions. Physiol Rev 2004; 84: 361C384. PMID: 15044677

166 Mondrag ´on-Rodr´ıguez S, Basurto-Islas G, Santa-Maria I, Mena R, Binder LI, Avila J, Smith MA, Perry G, Garca-Sierra F. Cleavage and conformational changes of tau protein follow phosphorylation during Alzheimers disease. Int J Exp Pathol 2008; 89: 81C90. doi: 10.1111/j.1365-2613.2007.00568.x

167 Saito M, Chakraborty G, Mao RF, Paik SM, Vadasz C, Saito M. Tau phosphorylation and cleavage in ethanol induced neurodegeneration in the developing mouse brain. Neurochem Res 2010; 35: 651C659. PMID: 20049527

168 Rohn TT, Rissman RA, Davis MC, Kim YE, Cotman CW, Head E. Caspase-9 activation and caspase cleavage of tau in the Alzheimers disease brain. Neurobiol  Dis 2002; 11: 341C354. PMID: 12505426

169 Zhang Q, Zhang Y, Sun A. Truncated tau at D421 is associated with neurodegeneration and tangle formation in the brain of Alzheimer transgenic models. Acta Neuropathol 2009; 117: 687C697. PMID: 19190923

170 Kolarova M, Garc´ıa-Sierra F, Bartos A, Ricny J, Ripova D. Structure and Pathology of Tau Protein in Alzheimer Disease. Int J Alzheimers Dis 2012; 2012: 73152. PMID: 22690349

171 Grundke-Iqbal I, Iqbal K, Tung YC, Quinlan M, Wisniewski HM, Binder LI. Abnormal phosphorylation of the microtubule-associated protein (tau) in Alzheimer cytoskeletal pathology. Proc Natl Acad Sci U S A. 1986; 83: 44913C4917. PMID: 3088567

172 Mondrag ´on-Rodr´ıguez S, Basurto-Islas G, Binder LI, Garc´ıa-Sierra F. Conformational changes and cleavage; arethese responsible for the tau aggregation in Alzheimersdisease? Future Neurol 2009; 4: 39C53. doi:10.2217/14796708.4.1.39

173 Binder LI, Guillozet-Bongaarts AL, Garcia-Sierra F, Berry RW. Tau, tangles, and Alzheimers disease. Biochim Biophys Acta 2005; 1739: 216C223. PMID: 15615640

174 Kuhla B, Haase C, Flach K, Lth HJ, Arendt T, Mnch G. Effect of pseudophosphorylation and cross-linking by lipid peroxidation and advanced glycation end product precursors on tau aggregation and filament formation. J Bio Chem 2007; 282: 6984C6991. PMID: 17082178

175 Wischik CM, Novak M, Edwards PC, Klug A, Tichelaar W, Crowther RA. Structural characterization of the core of the paired helical filament of Alzheimer disease. Proc Natl Acad Sci USA 1988; 85: 4884C4888. PMCID: PMC280541

176 Perry G, Mulvihill P, Fried A, Smith HT, Grundke-Iqbal I, Iqbal K. Immunochemical properties of ubiquitin conjugates in the paired helical filaments of Alzheimer disease. J Neurochem 1989; 52: 1523C1528. PMID: 2468737

177 Reynolds MR, Berry RW, Binder LI. Site specific nitration and oxidative dityrosine bridging of the protein by peroxynitrite: implications for Alzheimers disease. Biochemistry 2005; 44: 1690C1700. PMID: 15683253

178 Gamblin TC, Chen F, Zambrano A, Abraha A, Lagalwar S, Guillozet al, Lu M, Fu Y, Garcia-Sierra F, LaPointe N, Miller R, Berry RW, Binder LI, Cryns VL. Caspase cleavage of tau: linking amyloid and neurofibrillary tangles in Alzheimers disease. Proc Natl Acad Sci USA 2003; 100: 10032C10037. PMID: 12888622

179 Min SW, Cho SH, Zhou Y, Schroeder S, Haroutunian V, Seeley WW, Huang EJ, Shen Y, Masliah E, Mukherjee C, Meyers D, Cole PA, Ott M, Gan L. Acetylation of tau inhibits its degradation and contributes to tauopathy. Neuron 2010; 67: 953C966. PMID: 20869593

180 Tai HC, Serrano-Pozo A, Hashimoto T, Frosch MP, Spires-Jones TL, Hyman BT. The synaptic accumulation of hyperphosphorylated tau oligomers in Alzheimer disease is associated with dysfunction of the ubiquitin-proteasome system. Am J Pathol 2012; 181: 1426-35. PMID: 22867711

181 Tai HC, Wang BY, Serrano Pozo A, Frosch MP, Spires-Jones TL, Hyman BT. Frequent and symmetric deposition of misfolded tau oligomers within presynaptic and postsynaptic terminals in Alzheimers disease. Acta Neuropathol Commun 2014; 2: 146. PMID: 25330988

182 Iqbal K, Liu F, Gong CX, Alonso Adel C, Grundke-Iqbal I. Mechanisms of tau-induced neurodegeneration. Acta Neuropathol 2009; 118: 53C69. PMID: 19184068

183 Khatoon S, Grundke-Iqbal I, Iqbal K. Levels of normal and abnormally phosphorylated tan in different cellular and regional compartments of Alzheimer disease and control brains, FEBS Letters, vol. 351, no. 1, pp. 80C84, 1994. PMID: 8076698

184 Futerman AH, Banker GA. The economics of neurite outgrowthCthe addition of new membrane to growing axons. Trends Neurosci 1996; 19: 144C149. PMID: 8658598

185 Kopeikina KJ, Carlson GA, Pitstick R, Ludvigson AE, Peters A, Luebke JI, Koffie RM, Frosch MP, Hyman BT, Spires-Jones TL. Tau accumulation causes mitochondrial distribution deficits in neurons in a mouse model of tauopathy and in human Alzheimer's disease brain. Am J Pathol 2011; 179: 2071-2082. PMID: 21854751            

186 Scheff SW, Neltner JH, Nelson PT. Is synaptic loss a unique hallmark of Alzheimer's disease? Biochem Pharmacol 2014; 88: 517-528. PMID: 24412275                 

187 Wischik CM, Harrington CR, Storey JM. Tau-aggregation inhibitor therapy for Alzheimer's disease. Biochem Pharmacol 2014; 88: 529−539. PMID: 24361915

188 Wischik CM, Novak, Thøgersen HC, Edwards PC, Runswick MJ, Jakes R, Walker JE, Milstein C, Roth M, Klug A. Isolation of a fragment of tau derived from the core of the paired helical filament of Alzheimer disease. Proc Natl Acad Sci U S A. 1988; 85: 4506C4510. PMCID: PMC280459

189 Novak M, Kabat J, Wischik CM. Molecular characterization of the minimal protease resistant tau unit of the Alzheimers disease paired helical filament. EMBO J 1993; 12: 365C370. PMCID: PMC4133214

190 Rohn TT, Rissman RA, Head E, Cotman CW. Caspase activation in the Alzheimers disease brain: tortuous and torturous. Drug News Perspect 2002; 15: 549C557. PMID: 12677194

191 De La Monte SM, Sohn YK, Wands JR. Correlates of p53- and Fas (CD95)-mediated apoptosis in Alzheimers disease. J Neurol Sci 1997; 152: 73C83. PMID: 9395128

192 Stadelmann C, Deckwerth TL, Srinivasan A, Bancher C, Brck W, Jellinger K, Lassmann H. Activation of caspase-3 in single neurons and autophagic granules of granulovacuolar degeneration in Alzheimers disease: evidence for apoptotic cell death, American Journal of Pathology 1999; 155: 1459C1466. PMID: 10550301

193 Rohn TT, Head E, Su JH, Anderson AJ, Bahr BA, Cotman CW, Cribbs DH. Correlation between caspase activation and neurofibrillary tangle formation in Alzheimers disease. Am J Pathol 2001; 158: 189C198. PMID: 11141492

194 Nagy Z, Esiri MM. Apoptosis-related protein expression in the hippocampus in Alzheimers disease. Neurobiol Aging 1997; 18: 565C571. PMID: 9461054

195 Cryns V, Yuan J. Proteases to die for. Genes and Development 1998; 12: 1551C1570. PMID: 9620844

196 Gervais FG, Xu D, Robertson GS, Vaillancourt JP, Zhu Y, Huang J, LeBlanc A, Smith D, Rigby M, Shearman MS, Clarke EE, Zheng H, Van Der Ploeg LH, Ruffolo SC, Thornberry NA, Xanthoudakis S, Zamboni RJ, Roy S, Nicholson DW. Involvement of caspases in proteolytic cleavage of Alzheimers amyloid- precursor protein and amyloidogenic A peptide formation. Cell 1999; 97: 395C406. PMID: 10319819

197 Smale G, Nichols NR, Brady DR, Finch CE, Horton WE. Evidence for apoptotic cell death in Alzheimers disease. Exp Neurol 1995; 133: 225C 230. PMID: 7544290

198 Arai H, Terajima M, Miura M, Higuchi S, Muramatsu T, Machida N, Seiki H, Takase S, Clark CM, Lee VM, Trojanowski JQ, Sasaki H: Tau in cerebrospinal fluid: a potential diagnostic marker in Alzheimers disease. Ann Neurol 1995; 38: 649C652. PMID: 7574462

199 Pooler AM, Polydoro M, Wegmann S, Nicholls SB, Spires-Jones TL, Hyman BT. Propagation of tau pathology in Alzheimer's disease: identification of novel therapeutic targets. Alzheimer's Res Ther 2013; 5: 49. PMID: 24152385

200 Yamada K, Cirrito JR, Stewart FR, Jiang H, Finn MB, Holmes BB, Binder LI, Mandelkow EM, Diamond MI, Lee VM, Holtzman DM: In vivo microdialysis reveals age-dependent decrease of brain interstitial fluid tau levels in P301S human tau transgenic mice. J Neurosci 2011; 31: 13110C13117. PMID: 21917794

201 Karch CM, Jeng AT, Goate AM. Extracellular tau levels are influenced by variability in tau that is associated with tauopathies. J Biol Chem 2012; 287: 42751C42762. PMID: 23105105

202 Frost B, Jacks RL, Diamond MI: Propagation of tau misfolding from the outside to the inside of a cell. J Biol Chem 2009; 284: 12845C12852. PMID: 19282288

203 Lasagna-Reeves CA, Castillo-Carranza DL, Sengupta U, Guerrero-Munoz MJ, Kiritoshi T, Neugebauer V, Jackson GR, Kayed R: Alzheimer brain-derived tau oligomers propagate pathology from endogenous tau. Sci Rep 2012; 2: 700. PMID: 23050084

204 Vanmechelen E, Vanderstichele H, Davidsson P, Van Kerschaver E, Van Der Perre B, Sjogren M, Andreasen N, Blennow K. Quantification of tau phosphorylated at threonine 181 in human cerebrospinal fluid: a sandwich ELISA with a synthetic phosphopeptide for standardization. Neurosci Lett 2000; 285: 49C52. PMID: 10788705

205 Lanari A, Amenta F, Silvestrelli G, Tomassoni D, Parnetti L. Neurotransmitter deficits in behavioural and psychological symptoms of Alzheimer's disease. Mech Ageing Dev 2006; 127: 158C165. PMID: 16297434

206 Pinto T, Lanctôt KL, Herrmann N. Revisiting the cholinergic hypothesis of behavioral and psychological symptoms in dementia of the Alzheimers type. Ageing Res Rev 2011; 10: 404C 412. PMID: 21292041       

207 Suryanarayanan A. Acetylcholine. In: Encyclopedia of Toxicology. 3rd ed. Academic Press, Elsevier, 2014: 49-50.     

208 Francis PT, Palmer AM, Snape M, Wilcock GK. The cholinergic hypothesis of Alzheimer's disease: A review of progress. J Neurol Neurosurg Psychiatry 1996; 66: 137-147.    

209 Pohanka M. Cholinesterases, a target of pharmacology and toxicology. Biomed Pap Olomouc 2011; 155: 219C229. PMID: 22286807     

210 Pohanka M, Pavlis O. Tacrine can suppress immune response to tularemia in BALB/c mouse model. J Applied Biomedicine 2013; 11: 187-193. DOI 10.2478/v10136-012-0021-z      

211 Tan CC, Yu JT, Wang HF, Tan MS, Meng XF, Wang C, Jiang T, Zhu XC, Tan LJ. Efficacy and safety of donepezil, galantamine, rivastigmine, and memantine for the treatment of Alzheimer's disease: a systematic review and meta-analysis. Alzheimers Dis 2014; 41: 615−631. PMID: 24662102

212 Doig AJ, Derreumaux P. Inhibition of protein aggregation and amyloid formation by small molecules. Curr Opin Struct Biol 2015; 30C: 50−56. PMID: 25559306

213 Jiang L, Liu C, Leibly D, Landau M, Zhao M, Hughes MP, Eisenberg DS. Structure-based discovery of fiber-binding compounds that reduce the cytotoxicity of amyloid beta. Elife 2013; 2: e00857. PMID: 23878726

214 Yan R, Vasser R. Targeting the secretase BACE1 for Alzheimer's disease therapy. Lancet Neurol 2014; 13: 319−329. PMID: 24556009

215 Rafii MS, Baumann TL, Bakay RAE, Ostrove JM, Siffert J, Fleisher AS, Herzog CD, Barba D, Pay M, Salmon DP, Chu Y, Kordower JH, Bishop K, Keator D, Potkin S, Bartus RT. A phase1 study of stereotactic gene delivery of AAV2-NGF for Alzheimer's disease. Alzheimers Dement 2014; 10: 571-581. PMID: 24411134         

216 Mattson MP. Apoptosis in neurodegenerative disorders. Nat Rev Mol Cell Biol 2000; 1: 120-9. PMID: 11253364

217 Behl C. Apoptosis and Alzheimer's disease. J Neural Transm 2000; 107: 1325-44. PMID: 11145007 

218 Barinaga M. Is Apoptosis Key in Alzheimer's Disease? Science 1998; 281: 1303-1304. PMID: 9735049

219 Li WP, Chan WY, Lai HW, Yew DT. Terminal dUTP nick end labeling (TUNEL) positive cells in the different regions of the brain in normal aging and Alzheimer patients. J Mol Neurosci 1997; 8: 75-82. PMID: 9188038

220 Su JH, Anderson AJ, Cummings BJ, Cotman CW. Immunohistochemical evidence for apoptosis in Alzheimer's disease. Neuroreport 1994; 5: 2529-33. PMID: 7696596

221 Lassmann H, Bancher C, Breitschopf H, Wegiel J, Bobinski M, Jellinger K, Wisniewski HM. Cell death in Alzheimer's disease evaluated by DNA fragmentation in situ. Acta Neuropathol 1995; 89: 35-41. PMID: 7709729

222 Cotman CW, Anderson AJ. A potential role for apoptosis in neurodegeneration and Alzheimer's disease. Mol Neurobiol 1995; 10:19-45. PMID:7598831

223 Troncoso JC, Sukhov RR, Kawas CH, Koliatsos VE. In situ labeling of dying cortical neurons in normal aging and in Alzheimer's disease: correlations with senile plaques and disease progression. J Neuropathol Exp Neurol 1996; 55:1134-42. PMID: 8939196

224 Tanzi RE. Caspases land on APP: One small step for apoptosis, one giant leap for amyloidosis? Nature Neuroscience 1999; 2: 585-586. doi:10.1038/10133

225 Mattson MP, Chan SL. Dysregulation of cellular calcium homeostasis in Alzheimer's disease: bad genes and bad habits. J Mol Neurosci 2001; 17: 205-24. PMID:11816794

226 Shimohama S. Apoptosis in Alzheimers disease - an update. Apoptosis 2000; 5: 9-16. PMID:11227497

227 Enari M, Sakahira H, Yokoyama H, Okawa K, Iwamatsu A, Nagata S. A caspase-activated DNase that degrades DNA during apoptosis, and its inhibitor ICAD. Nature 1998; 391: 43-50. PMID: 9422506

228 Thornberry NA, Lazenbnik Y. Capsases: enemies within. Science 1998; 281:1313-1316. PMID: 9721091

229 Goldstein JC, Waterhouse NJ, Juin P, Evan GI, Green DR. The coordinate release of cytochrome c during apoptosis is rapid, complete and kinetically invariant. Nat Cell Biol 2000; 2:156-62. PMID:10707086

230 Kennedy SG, Kandel ES, Cross TK, Hay N. Akt/Protein kinase B inhibits cell death by preventing the release of cytochrome c from mitochondria. Mol Cell Biol 1999; 19: 5800C5810. PMID: 10409766

231 Finucane DM, Bossy-Wetzel E, Waterhouse NJ, Cotter TG, Green DR. Bax-induced caspase activation and apoptosis via cytochrome c release from mitochondria is inhibitable by Bcl-xL. J Biol Chem 1999; 274: 2225C2233. PMID: 9890985

232 Basañez G, Nechushtan A, Drozhinin O, Chanturiya A, Choe E, Tutt S, Wood KA, Hsu Y, Zimmerberg J, Youle RJ. Bax, but not Bcl-xL, decreases the lifetime of planar phospholipid bilayer membranes at subnanomolar concentrations. Proc Natl Acad Sci USA 1999; 96: 5492C5497. PMID: 10318911

233 Green DR, Reed JC. Mitochondria and apoptosis. Science 1998; 281: 1309C1312. PMID: 9721092

234 Trachootham D, Lu W, Ogasawara MA, Valle NRD, Huang P. Redox regulation of cell survival. Antioxid Redox Signal 2008; 10: 1343-1374. PMCID: PMC2932530

235 Ghavami S, Shojaei S, Yeganeh B, Ande SR, Jangamreddy JR, Mehrpour M, Christoffersson J, Chaabane W, Moghadam AR, Kashani HH, Hashemi M, Owji AA, Łos MJ. Autophagy and apoptosis dysfunction in neurodegenerative disorders. Prog Neurobiol 2014; 112: 24-49. PMID: 24211851

236 Patrone C, Eriksson O, Lindholm D. Diabetes drugs and neurological disorders: new views and therapeutic possibilities. Lancet Diabetes Endocrinol 2014; 2: 256-262. DOI: 10.1016/S2213-8587(13)70125-6              

237 Michaud M, Balardy L, Moulis G, Gaudin C, Peyrot C, Vellas B, Cesari M, Nourhashemi F. Proinflammatory cytokines, aging, and age-related diseases. J Am Med Dir Assoc 2013; 14: 877-882. PMID: 23792036              

238 Stuart MJ, Baune BT. Chemokines and chemokine receptors in mood disorders, schizophrenia, and cognitive impairment: a systematic review of biomarker studies. Neurosci Biobehav Rev 2014; 42: 93-115. PMID: 24513303         

239 Hoozemans JJM, Veerhuis R, Rozemuller JM, Eikelenboom P. Neuroinflammation and regeneration in the early stages of Alzheimers disease pathology. Int J Devl Neuroscience 2006; 24: 157C165. DOI: 10.1016/j.ijdevneu.2005.11.001        

240 Wyss-coray T, Rogers J. Inflammation in Alzheimer disease-a brief review of the basic science and clinical literature. Cold Spring Harb Perspect Med 2012; 2: a006346. PMID: 22315714               

241 Cudaback E, Jorstad NL, Yang Y, Montine TJ, Keene CD. Therapeutic implications of the prostaglandin pathway in Alzheimer's disease. Biochem Pharmacol 2014; 88: 565C572. PMID: 24434190         

242 Baik SH, Cha MY, Hyun YM, Cho H, Hamza B, Kim DK, Han SH, Choi H, Kim K H, Moon M, Lee J, Kim M, Irimia D, Mook-Jung I. Migration of neutrophils targeting amyloid plaques in Alzheimer's disease mouse model. Neurobiol Aging 2014; 35: 1286-1292. PMID: 24485508                

243 Fukumoto K, Mizoguchi H, Takeuchi H, Horiuchi H, Kawanokuchi J, Jin S, Mizuno T, Suzumura A. Fingolimod increases brain-derived neurotrophic factor levels and ameliorates amyloid -induced memory impairment. Behav Brain Res 2014; 268: 88-93. PMID: 24713151       

244 Wang Y, Liu J, Zhang Z, Bi P, Qi Z, Zhang C. Anti-neuroinflammation effect of ginsenoside Rbl in a rat model of Alzheimer disease. Neurosci Lett 2011; 487: 70-72. PMID: 20933058    

245 Ferreira ST, Clarke JR, Bomfim TR, De Felice FG. Inflammation, defective insulin signaling, and neuronal dysfunction in Alzheimer's disease. Alzheimers Dement 2014; 10: S76-S83. PMID: 24529528               

246 Correia SCI, Santos RX, Perry G, Zhu X, Moreira PI, Smith MA. Insulin-resistant brain state: the culprit in sporadic Alzheimer's disease? Ageing Res Rev 2011; 10: 264-273. DOI: 10.1016/j.arr.2011.01.001                

247 Tang J, Pei Y, Zhou G. Effects of body mass index-related disorders on cognition: preliminary results. Exp Gerontol 2013; 48: 744-750.        

248 Swomley AM, Förster S, Keeney JT, Triplett J, Zhang Z, Sultana R, Butterfield DA. Abeta, oxidative stress in Alzheimer disease: evidence based on proteomics studies. BBA C Mol Basis Dis 2014; 1842: 1248-1257. PMID: 24120836                 

249 Størmer FC. Is there a link between type 2 diabetes, Alzheimer, magnetite and memory loss? Med Hypotheses 2014; 82: 401. PMID: 24398163          

250 Pankhurst Q, Hautot D, Khan N, Dobson J. Increased levels of magnetic iron compounds in Alzheimer's disease. J Alzheimer Dis 2008; 13: 49C52. PMID: 18334756     95

251 Correia SC, Santos RX, Cardoso S, Carvalho C, Candeias E, Duarte AI, Plcido AI, Santos MS, Moreira PI. Alzheimer disease as a vascular disorder: Where do mitochondria fit? Exp Gerontol 2012; 47: 878-886. PMID: 22824543

252 Sultana R, Baglioni M, Cecchetti R, Cai J, Klein J B, Bastiani P, Ruggiero C, Mecocci P, Butterfield DA. Lymphocyte mitochondria: toward identification of peripheral biomarkers in the progression of Alzheimer disease. Free Radic Biol Med 2013; 65: 595-606. PMID: 23933528       

253 Roberts JS, McLaughlin SJ, Connell CM. Public beliefs and knowledge about risk and protective factors for Alzheimer's disease. Alzheimers Dement 2014; In Press. PMID: 24630852       

254 Demartini DR, Schilling LP, da Costa, JC & Carlini CR. Alzheimer's and Parkinson's diseases: an environmental proteomic point of view. J. Proteomics 2014; 104: 24-36. PMID: 24751585       

255 Bakulski KM, Rozek LS, Dolinoy DC, Paulson HL, Hu H. Alzheimer's disease and environmental exposure to lead: the epidemiologic evidence and potential role of epigenetics. Curr Alzheimer Res 2012; 9: 563-73. PMID: 22272628        

256 Shcherbatykh I, Carpenter DO. The role of metals in the etiology of Alzheimer's disease. J Alzheimers Dis 2007; 11: 191-205.PMID: 17522444      

257 Jellinger KA. The relevance of metals in the pathophysiology of neurodegeneration, pathological considerations. Int Rev Neurobiol 2013; 110: 1-47. PMID: 24209432     

258 Stephen CB. The neurotoxicity of environmental aluminium is still an issue. Toxicology 2014; 315: 1-7. PMID: 20553758    

259 Yokel RA. Aluminium. In: Encyclopedia of the Neurological Sciences. Academic Press, Elsevier, 2014: 116-119.        

260 James SA, Volitakis I, Adlard PA, Duce JA, Masters CL, Cherny RA, Bush AI. Elevated labile Cu is associated with oxidative pathology in Alzheimer disease. Free Radic Biol Med 2012; 52: 298-302. PMID: 22080049      

261 Jones CE, Abdelraheim SR, Brown DR, Viles JH. Preferential Cu2+ coordination by His96 and His111 induces beta-sheet formation in the unstructured amyloidogenic region of the prion protein. J Biol Chem 2004; 279: 32018-27. PMID: 15145944    

262 Ma Q, Li Y, Du J, Liu H, Kanazawa K, Nemoto T, Nakanishi H, Zhao Y. Copper binding properties of a tau peptide associated with Alzheimer's disease studied by CD, NMR, and MALDI-TOF MS. Peptides 2006; 27: 841-849. PMID: 16225961           

263 Campdleacreu J. Parkinson disease and Alzheimer disease: environmental risk factors. Neurologia 2014; 29: 541-549. PMID: 22703631

264 Shah R. The role of nutrition and diet in Alzheimer disease: a systematic review. J Am Med Dir Assoc 2013; 14: 398-402. PMID: 23419980        

265 Sodhi RK, Singh N. Retinoids as potential targets for Alzheimer's disease. Pharmacol Biochem Behav 2014; 120: 117-123. PMID:24582848       

266 Roccisano D, Henneberg M, Saniotis A. A possible cause of Alzheimer's dementia - industrial soy foods. Med Hypotheses 2014; 82: 250-254. DOI: 10.1016/j.mehy.2013.11.033           

267 Annweiler C, Herrmann FR, Fantino B, Brugg B, Beauchet O. Vitamin D supplements: a novel therapeutic approach for Alzheimer patients. Cogn Behav Neurol 2012; 25: 121-127. doi: 10.3389/fphar.2014.00006        

268 Morris MC, Schneider JA, Li H, Tangney CC, Nag S, Bennett DA, Honer WG, Barnes LL. Brain tocopherols related to Alzheimer's disease neuropathology in humans. Alzheimers Dement 2014; In Press. PMID: 24589434          

269 Gore AC. Neurology of women's health In: Encyclopedia of the Neurological Sciences. Academic Press, Elsevier, 2014: 779-783.         

270 Li R, Cui J, Shen Y. Brain sex matters: estrogen in cognition and Alzheimer's disease. Mol Cell Endocrinol 2014; 389: 13-21. PMID: 24418360       

271 Li R, Singh M. Sex differences in cognitive impairment and Alzheimer's disease. Front Neuroendocrin 2014; 35: 385-403. PMID: 24434111         

272 Terracciano A, Sutin AR, An Y, O'Brien RJ, Ferrucci L, Zonderman AB, Resnick SM. Personality and risk of Alzheimer's disease: new data and meta-analysis. Alzheimers Dement 2014; 10: 179-186. PMID: 23706517        

273 Geldmacher DS, Kirson NY, Birnbaum HG, Eapen S, Kantor E, Cummings AK, Joish VN. Implications of early treatment among Medicaid patients with Alzheimer's disease. Alzheimers Dement 2014; 10: 214C224. PMID: 23643457         

274 Sutphen CL, Fagan AM, Holtzman DM. Neurodegenerative dementias: Connecting psychiatry and neurology through a shared neurobiology. Biol Psychiatry 2014; 75: 520-526. DOI:     

275 Trzepacz PT, Yu P, Sun J, Schuh K, Case M, Witte MM, Hochstetler H, Hake A. Comparison of neuroimaging modalities for the prediction of conversion from mild cognitive impairment to Alzheimer's dementia. Neurobiol Aging 2014; 35: 143-151. PMID: 23954175     

276 Brown GG. (2013) Magnetic resonance imaging as a tool for modeling drug treatment of CNS disorders: Strengths and Weaknesses. In: Translational Neuroimaging pp 23-57, McArthur, R. A. (Ed.) Academic Press, Elsevier.         

277 Schmidt ME, Matthews D, Andrews R, Mosconi L. Positron Emission Tomography in Alzheimer Disease: Diagnosis and Use as Biomarker Endpoints. In: Translational Neuroimaging, Academic Press, Elsevier, 2013: 131-174.    

278 Chintamaneni M, Bhaskar M. Biomarkers in Alzheimers Disease: A Review. International Scholarly Research Network ISRN Pharmacology 2012. doi:10.5402/2012/984786

279 Lockau H, Jessen F, Fellgiebel A, Drzezga A. Structural and Functional Magnetic Resonance Imaging. PET Clinics 2013; 8: 407-430. DOI:         

280 Novak G, Einstein SG Structural magnetic resonance imaging as a biomarker for the diagnosis, progression, and treatment of Alzheimer disease. In: Translational Neuroimaging. Academic Press, Elsevier, 2013: 87-129.               

281 Teipel SJ, Grothe M, Lista S, Toschi N, Garaci FG, Hampel H. Relevance of magnetic resonance imaging for early detection and diagnosis of Alzheimer disease. Med Clin North Am 2013; 97: 399-424. PMID: 23642578         

282 Rooden SV, Versluis MJ, Liem MK, Milles J, Maier AB, Oleksik AM, Webb AG, Mark A, van Buchem, van der Grond J. Cortical phase changes in Alzheimer's disease at 7T MRI: A novel imaging marker. Alzheimers Dement 2014; 10: e19-e26. DOI: 10.1016/j.jalz.2013.02.002      

283 Zhou J, Liu J, Narayan VA, Ye J. Modeling disease progression via multi-task learning. Neuroimage 2013; 78: 233-248. PMID: 23583359       

284 McGleenon BM, Dynan KB, Passmore AP. Acetylcholinesterase inhibitors in Alzheimers disease. J Clin Pharmacol 1999; 48: 471C480. DOI: 10.1046/j.1365-2125.1999.00026.x          

285 Welling MM, Nabuurs RJA, van der Weerd L. Potential role of antimicrobial peptides in the early onset of Alzheimer's disease. Alzheimers Dement 2014; In Press. DOI: 10.1016/j.jalz.2013.12.020.

286 Bada MC, Giraldo E, Das F, Alonso D, Lainez JM, Lloret A, Viña J. Reductive stress in young healthy individuals at risk of Alzheimer disease. Free Radic Biol Med 2013; 63: 274-9. PMID: 23665394

287 Sattlecker M, Kiddle SJ, Newhouse S, Proitsi P, Nelson S, Williams S, Johnston C, Killick R, Simmons A, Westman E, Hodges A, Soininen H, Kłoszewska I, Mecocci P, Tsolaki M, Vellas B, Lovestone S, Richard JBD. Alzheimer's disease biomarker discovery using SOMAscan multiplexed protein technology. Alzheimers Dement 2014; 10: 724C734. PMID: 24768341         

288 Tan L, Yu JT, Liu QY, Tan MS, Zhang W, Hu N, Wang YL, Sun L, Jiang T, Tan L. Circulating miR-125b as a biomarker of Alzheimer's disease. J Neurol Sci 2014; 336: 52-56. PMID: 24139697

289 Gonzlez-Domnguez R, Garca-Barrera T, Gmez-Ariza JL. Combination of metabolomic and phospholipid-profiling approaches for the study of Alzheimer's disease. J Proteomics 2014; 104: 37-47. PMID: 24473279 

290 Wolf J, Jäger C, Morawski M, Lachmann I, Schönknecht P, Mothes T, Arendt T. Tissue transglutaminase in Alzheimer's disease - facts and fiction: a reply to "Tissue transglutaminase is a biochemical marker for Alzheimer's disease". Neurobiol Aging 2014; 35: e5-e9. PMID: 24300236

291 Wilhelmus MMM, Drukarch B. Tissue transglutaminase is a biochemical marker for Alzheimer's disease. Neurobiol Aging 2014; 35: e3-e4. DOI:

292 Candelario KM, Steindler DA. The role of extracellular vesicles in the progression of neurodegenerative disease and cancer. Trends Mol Med 2014; 20: 368-374. PMID: 24835084 

293 Ammar M, Smadja C, Giang Thi Phuong L, Azzouz M, Vigneron J, Etcheberry A, Taverna M, Dufour-Gergam E. A new controlled concept of immune-sensing platform for specific detection of Alzheimer's biomarkers. Biosens Bioelectron 2013; 40: 329-335. PMID: 22981833

294 Weiner MW, Veitch DP, Aisen PS, Beckett LA, Cairns NJ, Green RC, Harvey D, Jack CR, Jagust W, Liu E, Morris JC, Petersen RC, Saykin AJ, Schmidt ME, Shaw L, Siuciak JA, Soares H, Toga AW, Trojanowski JQ. The Alzheimers disease neuroimaging initiative: a review of papers published since its inception. Alzheimers Dement 2012; 8: S1CS68. PMID: 22047634                    

295 Singh N, Fletcher PT, Preston JS, King RD, Marron JS, Weiner MW, Joshi S. Quantifying anatomical shape variations in neurological disorders. Med Image Anal 2014; 18: 616-633. PMID: 24667299      


Peer reviewer: Se Bok Jang, Professor, Department of Molecular Biology, College of Natural Sciences, Pusan National University, Jangjeon-dong, Geumjeong-gu, Busan 609-735, Republic of Korea.



  • There are currently no refbacks.