https://www.scientificarchives.

com/journal/journal-of-experimental-neurology

Journal of Experimental Neurology Review Article

Alzheimer’s Disease: A Brief Review

Samantha McGirr#, Courtney Venegas#, Arun Swaminathan*

University of Nebraska Medical Center, Omaha, NE, USA
#
Both authors contributed equally to this review
*Correspondence should be addressed to Arun Swaminathan; [email protected]

Received date: June 07, 2020, Accepted date: July 10, 2020

Copyright: © 2020 McGirr S, et al. This is an open-access article distributed under the terms of the Creative Commons
Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author
and source are credited.

Abstract
Introduction: Alzheimer’s disease (AD) is the most common cause of dementia globally and imposes a growing burden on
healthcare systems.

Historical background: Alois Alzheimer reported the first case of AD in 1907, describing “particular changes in cortical cell
clusters” on brain biopsy and attributing the patient’s behavioral changes to these lesions.

Pathogenesis: AD is a complex, multifactorial, neurodegenerative disease implicating the interactions of one’s genetic makeup,
education, age, and environment. Currently the most accepted theory for the development of AD is the amyloid cascade hypothesis,
which attributes clinical signs/symptoms to the overwhelming presence of amyloid beta (Ab) peptides, leading to increased deposition
into amyloid plaques and the eventual result of neuronal damage.

Presentation: The most common presentation of those with AD involves an elderly individual with gradual decline in memory
centered cognitive decline.

Testing: Though AD remains a clinical diagnosis, imaging such as fluorodeoxyglucose positron emission tomography (PET) and
amyloid PET and biomarkers in cerebrospinal fluid (CSF) can be helpful in evaluating some patients.

Histology: The histology of AD is composed primarily of extracellular amyloid plaques consisting of misfolded Ab peptides and
intracellular neurofibrillary tangles consisting of hyperphosphorylated tau. Eventually, these lead to gross anatomical findings of
atrophy diffusely.

Treatment: Current pharmaceutical treatment available for AD include cholinesterase inhibitors as well as memantine. Other aims
include increasing one’s cognitive reserve and providing a nutritional approach to prevent or slow the progression of disease.

Future Directions: Most therapeutics in development are intended to achieve disease modification by targeting amyloid plaques
or neurofibrillary tangles of tau. There is increasing focus on identifying and prophylactically treating patients with preclinical AD
and individuals with risk factors for cognitive decline.

Introduction older with dementia are estimated to be $305 billion in

2020 [2].
The worldwide prevalence of dementia is estimated to
be over 45 million people. Alzheimer’s disease (AD) is the The neuropathology of AD consists of extracellular beta-
most common cause of dementia, responsible for 60-80% amyloid plaque depositions and intracellular neurofibrillary
of cases [1]. An estimated 5.8 million Americans ages 65 tangles of hyperphosphorylated tau. AD remains a clinical
and older have AD, a number which could grow to 13.8 diagnosis, although cerebrospinal fluid (CSF) and positron
million by 2050. As the number of people suffering from AD emission tomography (PET) biomarkers can increase
increases, so does the economic burden of care. Payments diagnostic accuracy [3]. Current treatments, including
for healthcare and hospice services for Americans 65 and cholinesterase inhibitors and memantine, improve quality

J Exp Neurol. 2020

Volume 1, Issue 3 89
McGirr S, Venegas C, Swaminathan A. Alzheimer’s Disease: A Brief Review. J Exp Neurol. 2020;1(3): 89-98.

of life but do not modify or slow the disease course. Current AD histopathology reveals intraneuronal neurofibrillary
research aims to treat underlying pathology of active AD lesions made up of tau proteins. Tau proteins are mainly
as well as identify and stage interventions in those with found in neurons and are involved in the assembly and
preclinical, or asymptomatic, AD. stabilization of the neuronal microtubule network. Tau
protein becomes pathological when the phosphorylation
Historical Background regulation becomes unchecked and hyperphosphorylated
tau proteins polymerize into filaments and become
Alois Alzheimer, a German physician, reported the neurofibrillary tangles. This leads to malfunction of the
first case of Alzheimer’s disease in 1907 [4]. He first saw structural and regulatory actions of the cytoskeleton and
Auguste Deter, a 51-year-old woman, in 1901. Auguste’s then leads to abnormal morphology, axonal transport,
husband Karl brought her to a mental hospital after she and synaptic function of neurons, thus leading to
began exhibiting unusual behavior, including hiding neurodegeneration [12].
items, threatening neighbors, and accusing her husband
of adultery. She also lost the ability to do daily activities These prior theories paved the way to the widely accepted
such as cooking and housework. Auguste came under hypothesis for the pathogenesis of AD: the amyloid cascade
Alzheimer’s care at a mental hospital in Frankfurt. There hypothesis. This theory attributes clinical sequelae of the
he observed and recorded her behavioral patterns: she disease to the overproduction or decreased clearance of
could speak but not write her own name, she could name amyloid beta (Ab) peptides, which then leads to increased
objects such as a pencil but not the food she was eating, deposition of Ab, furthermore, leading to neuronal damage
she was polite sometimes but loud and offensive at other (Figure 1). The length of Ab varies depending on the
times. He diagnosed Auguste with “presenile dementia” posttranslational cleavage pattern of the transmembrane
[5]. amyloid precursor protein (APP). Ab is generated by
cleavage of APP via either b- or g-secretases, resulting in
Upon her death in 1906, Alzheimer’s biopsy of her the infamous insoluble Ab fibrils [13]. Two main types
brain revealed diffuse cortical atrophy and “particular of Ab polymers play a direct role in the pathology of AD:
changes in cortical cell clusters” [6]. Alzheimer described Ab40 and Ab42. Ab40/Ab42 then oligomerizes, travels
plaques and tangles of nerve fibers which researchers to synaptic clefts, and interferes with synaptic signaling.
would identify in the 1980’s as beta amyloid plaques and These eventually further polymerize into insoluble
neurofibrillary tangles of tau [7,8]. That year, Alzheimer amyloid fibrils that aggregate into amyloid plaques [14].
gave a presentation on Auguste at a German psychiatry Within the plaques, Ab peptides in b-sheet conformation
conference, asserting these cortical lesions to be the cause
of her symptoms. He published a research paper the next
year, and a psychiatry textbook in 1910 named the disorder
‘Alzheimer’s disease.’

The clinical diagnostic criteria for AD were standardized

in the U.S. in 1984 [9]. They were revised in 2011 and
2018 to create separate diagnoses for the preclinical, mild
cognitive impairment (MCI) and dementia stages of AD
and to recognize the role of biomarkers in AD diagnosis
[10,11].

Pathogenesis
AD is a complex, multifactorial, neurodegenerative
disease, resulting from complicated interactions of one’s
genetic makeup, education, age, and environment. Many
hypotheses have laid the foundation to gain understanding
of the etiology of the disease, with one of the oldest being
the cholinergic hypothesis. This hypothesis is based upon
the fact that AD patients show reduction in activity of
choline acetyltransferase and acetylcholinesterase in the
cerebral cortex compared with the normal brain [12]. Post-
mortem brain tissue from patients with AD confirmed
the reduced neurotransmitter pathway activity, revealing
that degeneration of cholinergic neurons and loss of
cholinergic neurotransmission significantly contributes
to the cognitive impairment seen in those with AD [12].
The Tau hypothesis has also been proposed, considering Figure 1: The amyloid (Aβ) cascade hypothesis [12].

J Exp Neurol. 2020

Volume 1, Issue 3 90
McGirr S, Venegas C, Swaminathan A. Alzheimer’s Disease: A Brief Review. J Exp Neurol. 2020;1(3): 89-98.

polymerize into structurally distinct forms, including elderly adults without the history of familial AD. APOE
fibrillar, protofibers and polymorphic oligomers. It is the is associated with an approximately three-fold risk of
deposition of these plaques diffusely throughout the brain developing AD if one copy is present, and there is an eight-
that lead to microglial activation, cytokine release, reactive fold risk if two copies are present [16]. These plus other
astrocytosis, and an overall inflammatory response. These major influencing genes for SAD are listed in Table 1 and 2.
structural changes lead to synaptic and neuronal loss and
eventual gross cerebral atrophy [12]. On the other hand, Genes Involved in Pathogenesis of AD Abbreviations
should APP be processed by a-secretase in the healthy
adult, soluble b-amyloid is produced, which has been Amyloid Precursor Protein gene APP
linked to play a role in neuronal plasticity/survival, is
protective against excitotoxicity, is important for early Presenilin gene PS
CNS development, and has been shown to be important
for promoting synapse formation [15]. Apolipoprotein E gene APOE

Clusterin gene n/a

The genetics of AD should also be considered to
play an influential role in the pathogenesis, alongside Complement Receptor 1 gene n/a
inflammation, apoptosis, and plaque buildup. In fact,
the APP gene located on 21q21, mentioned above, was Phospholipids Bind to Clathrin
the first discovered causative gene of AD [13]. Advances PICALM
Protein gene
in genetic research have identified two distinct forms of
AD: Familial Alzheimer’s Disease (FAD) and Sporadic CH25H,
Alzheimer Disease (SAD), with the latter making up the Cholesterol Metabolism gene ABCAL, and
majority of cases. Important advances in the 1990s and CH24H
early 2000s revealed that FAD is the result of autosomal
dominant mutations in APP, PSEN1 and PSEN2 genes, Sterol O-acyltransferase gene SOAT1
located on chromosome 21, 14, and 1, respectively [12,16].
Prostaglandin-endoperoxide Synthase
More specifically, PSEN1 and PSEN2 contain the necessary Ptgs2
2 gene
amino acid residues required for the catalytic active site of
gamma-secretase. Certain mutations of these genes lead to Angiotensin-Converting Enzyme gene n/a
increased production of Ab peptide and neurodegeneration
[12]. Far more commonly, the genetic risk factor for SAD SLC26A38 gene n/a
was identified as the type e4 allele on chromosome 19,
of the gene for apolipoprotein E (APOE), a low-density Table 1: A list of several genes that play a major influential
lipoprotein carrier resides. APOE is present in roughly 50- role for the development of Sporadic Alzhemer’s Disease
60% of patients with AD compared to 20-25% in healthy (SAD) [17].

Gene Proposed mechanism of dysfunction contributing to pathogenesis in Alzheimer’s disease

Defects in synaptic development and neuronal migration [18], A-beta peptide synthesis defects
APP
[19]
PSEN 1 / 2 Altered gamma-secretase activity resulting in elevated amyloid beta-42 levels [20]
Lipid and cholesterol dysmetabolism, synaptic inflammation, impaired clearance of amyloid
APOE – epsilon 4
beta-42, LDL receptor impairment [21-24]
CLU Deposition and metabolism of amyloid beta-42 [25]

ABCA7 Immune mediated and lipid metabolic response alterations [26]

CR1 Aggravated senile plaque formation [27]

CD33 Influences microglia mediated clearance of amyloid beta-42 [28]

MS4A Dysregulation of intracellular calcium concentration [29]

EPHA1 Axonal guidance changes [30]

SORL1, BIN,
Alterations in lipid metabolism [31]
CD2AP, PICALM
Table 2: A list of relevant genes involved in pathogenesis of Alzheimer’s disease.

J Exp Neurol. 2020

Volume 1, Issue 3 91
McGirr S, Venegas C, Swaminathan A. Alzheimer’s Disease: A Brief Review. J Exp Neurol. 2020;1(3): 89-98.

Figure 2: “Neuronal dysfunction and cell death are responsible for the development of Alzheimer’s disease.
Accumulating evidence suggests that abnormally elevated tau hyperphosphorylation, pathogenic Aβ oligomers,
and mitochondrial dysfunction cooperate to drive the neuronal dysfunction and cell death that underlie cognitive
impairment. Although the amyloid hypothesis supports that neurotoxic Aβ primarily induces tau pathology, other
proteolytic fragments of the human APP including sAPPβ, N-APP, and AICD, also appear to contribute to tau
alterations. In addition, aging, which is tightly associated with mitochondrial dysfunction, can serve as the most
significant nongenetic risk factor for Alzheimer’s disease” [32].

Clinical Presentation more apparent and widespread, eventually impacting

activities of daily living. The decline in two or more areas,
The most common presentation of AD is that of an elderly including memory, language, executive and visuospatial
individual with an insidious progression of cognitive function, personality, and behavior that lead to the loss of
decline, most centered around memory loss. Declines in the ability to perform instrumental and basic ADL’s point
non-memory aspects of cognition including word-finding, towards the diagnosis of AD dementia [33]. For those that
vision/spatial issues, impaired reasoning or judgment, do survive to the late stages of AD, death is often due to
are also seen in early stages. At this time, patients meet consequences of the disease itself as well as increased
criteria for mild cognitive impairment [33]. Almost all vulnerability to falls, pressure sores, and infections,
patients diagnosed with AD also have neuropsychiatric ultimately leading to an average of 8 years from diagnosis
symptoms during some stage of their disease, of which to death [35]. Tools considered useful for clinical detection
depression and apathy are the most dominant early on. of AD include global cognitive screens, such as the MMSE
Verbal and physical aggression are frequently observed and MOCA, and more specific tests of memory impairment
throughout all stages. As the disease progresses, delusions, like the five-word test. More formal diagnosis can be done
hallucinations, and aggression are more often seen and by specialists, such as neuropsychologists [36].
additionally, circadian sleep-wake rhythms are more
exaggerated as compared to those with normal aging [34]. FAD tends to have the typical presentation mentioned
As the disease progresses, cognitive difficulties become above, although at a much earlier age. Some PSEN1

J Exp Neurol. 2020

Volume 1, Issue 3 92
McGirr S, Venegas C, Swaminathan A. Alzheimer’s Disease: A Brief Review. J Exp Neurol. 2020;1(3): 89-98.

mutations are associated with other features of disease, with MCI showed similar diagnostic accuracy between
including seizures, spastic paresis, and myoclonus [33]. CSF and amyloid PET biomarkers and no improvement
There are rarer forms of AD that present atypically, when combining them [46]. Thus, the choice between CSF
including posterior cortical atrophy, logopenic primary and amyloid PET biomarkers can be based on availability,
progressive aphasia, and frontal variant AD [35]. Posterior cost, patient preference and other factors such as patient
cortical atrophy tends to present with progressive loss suitability for radiation or lumbar puncture.
of higher visual functions, such as diminished ability to
interpret, locate, or reach for objects via visual guidance. Currently, there are no blood biomarkers routinely used to
A decreased ability of numeracy, literacy, and praxis diagnose AD. Only a small fraction of brain proteins enters
may also be present in this variant of the disease [37]. the bloodstream, and these proteins are diluted by plasma
Logopenic primary progressive aphasia presents more with proteins such as albumin and IgG, making them difficult
language disturbance focus, characterized by slow word to measure quantitatively. Additionally, brain proteins in
retrieval, word finding difficulties, and impaired sentence plasma may be degraded or metabolized, so that plasma
repetition, while motor speech, grammar, and single-word levels would not reflect real-time changes in the brain [47].
comprehension are spared [38]. The frontal variant of AD Nonetheless, several plasma proteins are being examined
presents with stereotyped behaviors, progressive apathy/ as potential noninvasive biomarkers of AD. Plasma tau is
behavior disinhibition, and executive dysfunction [39]. one such protein. One study with prospective and cross-
These variant presentations are important to address, but sectional cohorts found higher plasma tau to be associated
more than likely, they do result in the more global and with AD, but with significant overlap in levels of healthy
typical picture of memory loss and dementia caused by AD controls [48]. Another potential blood marker is the
over the course of time. axonal neurofilament light (NFL) protein. A prospective
study found high correlation between plasma NFL and
Testing CSF NFL, and high diagnostic accuracy of plasma NFL in
patients with AD versus controls [49]. However, plasma
AD remains a clinical diagnosis and is reliant on a NFL is also increased in other neurological diseases
detailed history, cognitive assessment and physical exam. such as frontotemporal dementia, limiting its utility for
Structural imaging is also an important component of differential diagnosis of AD [50]. Finally, despite the utility
the assessment for AD. Atrophy of the medial temporal of CSF Ab42 as a biomarker, plasma Ab42 has not shown
lobes on magnetic resonance imaging (MRI) is considered to be predictive of AD development in patients with MCI.
a diagnostic marker for the mild cognitive impairment Unlike NFL, there is a lack of correlation between levels
stage of AD [40]. Similarly, hypometabolism in the of Ab42 in CSF and plasma, possibly due to the release of
parieto-temporal association area, posterior cingulate Ab42 in plasma from peripheral tissues [51].
and precuneus on fluorodeoxyglucose PET imaging is
associated with AD [41]. Histology

In 2012, the Food and Drug Administration approved the Amyloid plaques and neurofibrillary tangles are the
first beta-amyloid tracer, florbetapir, for use in PET scans cardinal features of Alzheimer histopathology. The
of suspected Alzheimer’s patients. In one study, florbetapir amyloid plaques consist of extracellular accumulations
PET imaging was shown to have a 92% sensitivity and 100% of misfolded Ab sheets consisting of 40 or 42 amino
specificity for detecting moderate to frequent plaques in acids (Ab40 and Ab42), the two by-products of amyloid
patients with an autopsy within 2 years of the scan [42]. precursor protein metabolism [33]. Amyloid plaques are
The amyloid PET tracers florbetaben and flutemetamol located extracellularly, and initially develop in the basal,
have also been approved and show similar sensitivity temporal, and orbitofrontal cortex of the brain, and later
and specificity [43]. However, amyloid PET scans have progress to involve the neocortex, hippocampus, amygdala,
had limited clinical impact due to lack of insurance diencephalon, and basal ganglia. These aggregates of Ab
reimbursement, and they are currently used primarily in trigger the formation of neurofibrillary tangles (NFS),
research trials. which are composed mostly of hyperphosphorylated
tau protein. These NFS are found in the locus coeruleus
Biomarkers in CSF further support a diagnosis of AD. and transentorhinal and entorhinal areas of the brain.
The biomarker profile of AD is increased total tau (T-tau) In the last critical stage, these histopathological entities
and phosphorylated tau (P-tau) and decreased amyloid- are spread to the hippocampus and neocortex [14].
beta (Ab42). This biomarker pattern can also predict Additionally, neuropil threads, dystrophic neurites,
which subjects with MCI are likely to progress to AD associated astrogliosis, microglial activation and evidence
[44]. Amyloid PET and the CSF marker Ab42 show a of amyloid angiopathy are also common findings [33].
concordance of around 90% across several studies [45]. Histology images of Alzheimer’s Disease is illustrated in
One longitudinal study of healthy elderly and patients Figures 3 and 4.

J Exp Neurol. 2020

Volume 1, Issue 3 93
McGirr S, Venegas C, Swaminathan A. Alzheimer’s Disease: A Brief Review. J Exp Neurol. 2020;1(3): 89-98.

Figure 3: A representation of the basic histology of Alzheimer’s Disease, consisting of intracellular neurofibrillary
tangles composed of hyperphosphorylated tau and extracellular collections of misfolded Aβ peptide forming amyloid
plaques [52].

Treatment symptoms of AD [36]. Preventing, halting, or slowing

down the progression of AD with nutrition has been a
Currently, treatment for Alzheimer’s disease does not topic of much research in Alzheimer’s today. Antioxidants,
impact the progression or underlying pathology of the omega-3 fatty acids, B vitamins, folate, medium chain
disease. However, with medication and other therapies, triglycerides, and combination medical foods, are just
steps are taken to increase the quality of life of those with a few of the avenues of which are being studied. For
AD. Current therapeutics are based off the Cholinergic instance, the variable actions inherent in any given
Theory, which attributes a decrease in cholinergic antioxidant, such as reducing oxidized membrane lipids,
neurotransmission to a decline in cognitive function [12]. limiting damage to nucleic acids, and influencing strep
At present, there are two classes of pharmacologic therapy kinase pathways, may alter the pathways of cellular injury
available for AD: cholinesterase inhibitors (donepezil, that lead to the positive benefits of having them in the diet
rivastigmine, and galantamine) and memantine, which has of someone with AD [53]. Research has also demonstrated
activity as both a non-competitive N-methyl-D-aspartate Vitamin E to prevent AD-like changes in the brains of
receptor antagonist and a dopamine agonist [3]. The AD genetic models of mice, and other clinical trials have
cholinesterase inhibitors are approved for use in patients shown an increase in median survival in patients with
with mild, moderate, or severe AD dementia as well as AD who were treated with selegiline (15 mg twice daily)
Parkinson’s disease dementia. Memantine is approved for and α-tocopherol (1000 IU twice daily) [53]. Several large
use in patients with moderate to severe AD who may also scale clinical trials have also looked into omega-3 fatty
have difficulty with alertness and attention. acids, one of which being the MIDAS study which found
that 900 mg of daily docosahexaenoic acid (DHA) led to a
Other aims of treatment look to modifiable risk factors 7 year age improvement in cognition over 24 weeks when
in one’s overall health and “cognitive reserve” including compared to placebo. This study and many more point to
cardiovascular/lifestyle factors, such as a healthy diet DHA’s potential direct effects on neurodegeneration in
and plenty of physical exercise, as well as cognitive AD as well as its overarching reduction in cerebrovascular
engagement. Cognitive reserve refers to the ability to disease [53]. To discuss DHA even further, a randomized
fend off pathologic insult, meaning the ability to engage control trial looked at the effect of omega-3 fatty acids had
alternate synaptic pathways or cognitive strategies to cope on B vitamin function. To preface, inadequate B vitamin
with the pathology of AD. By improving one’s physical status alone leads to the accumulation of homocysteine, a
wellbeing and mental reserve, this may delay clinical non-essential amino acid, that when elevated is recognized

J Exp Neurol. 2020

Volume 1, Issue 3 94
McGirr S, Venegas C, Swaminathan A. Alzheimer’s Disease: A Brief Review. J Exp Neurol. 2020;1(3): 89-98.

as a modifiable risk factor for AD and other dementias. Several therapeutics are also in development to target
This goes along with the results of the VITACOG trial, tau, which is downstream of amyloid and thought to be the
which showed that B vitamin supplement in elderly adults direct cause of AD symptoms. Although tau accumulates
with mild cognitive impairment slowed the rate of brain intracellularly, several in vivo and in vitro studies have
atrophy both globally and regionally [54]. And so it makes shown tau can move from one neuron to another in a
sense that the group that was randomized to B vitamin “prion-like” spread, suggesting a possible therapeutic
treatment (folic acid and vitamins B6 and B12) showed target [60]. LMTX, a selective inhibitor of tau protein
that B vitamins plus an omega-3 level in the upper range aggregation, failed to show cognitive improvement in AD
of normal interacted to slow cognitive decline, basically patients compared to placebo in a Phase III trial, but a
sumizing that elevated omega-3 acids alone significantly separate Phase II/III trial was started to test a lower dose
enhanced the cognitive effect of B vitamins [54]. of the drug [61]. Several anti-tau antibodies are in early
clinical testing, as are at least two active tau vaccines
Novel treatments for AD today are based off multi- designed to stimulate antibody production in AD patients
faceted strategies and are currently under investigation [62].
via clinical trials. There are three trials currently ongoing,
including gantenerumab, crenezumab, and aducanumab Given the underwhelming results of therapeutics
as immunotherapy approaches, which aim to effectively against amyloid and tau, drug development has shifted
clear the Ab aggregates [55]. Other future targets for its focus to the “pre-dementia” space, including patients
with preclinical AD and individuals with risk factors for
treatment include targeting mitochondrial dysfunction,
cognitive decline. A large number of therapeutic trials
targeting excitotoxicity and misfolding protein
with private and public funding are underway in high-risk
aggregations via novel acetylcholinesterase inhibitors or
asymptomatic individuals, including carriers of genetic
NMDA-Receptor Antagonists, targeting autophagy, and
mutations and those with amyloid-positive PET scans or
targeting neuroinflammation, to name a few [55]. Links
elevated biomarkers [63]. Data from these trials in the next
have also been made regarding the gut microbiota and AD,
several years may provide insight into which interventions,
and further research regarding dysbiosis and worsening
if any, can slow or halt the onset of symptomatic AD.
disease are being investigated for other novel treatment
approaches [56].
Ethical Standards
Future Directions This review article was written in a manner consistent
with ethical and scientific guidelines regarding research
The majority of therapeutics in development target the and publication.
two hallmark pathologies of AD: beta-amyloid plaques
and neurofibrillary tangles of tau. As of February 2019, the Contributions
pipeline of AD drugs includes 132 agents, with 96 (73%)
intended to achieve disease modification. Of these, 38 Both Samantha McGirr and Courtney Venegas, fourth
have amyloid as a primary or combination target, and 17 year medical students, were equally involved in the
have tau as a primary or combination target [57]. research and writing of this paper. Dr. Swaminathan,
Neurologist at UNMC who contributed to and edited the
One class of therapeutics against amyloid, monoclonal published review, supervised them both.
antibodies, is intended to facilitate amyloid removal from
the brain. Data have so far failed to show improvement in References
clinical symptoms despite significant reductions in amyloid
load. However, one antibody which had previously failed 1. Crous-Bou M, Minguillón C, Gramunt N, Molinuevo
futility analyses in Phase III trials later showed positive JL. Alzheimer’s disease prevention: from risk factors to
results in a subset of patients. The antibody, aducanumab, early intervention. Alzheimer’s Research & Therapy. 2017
is directed against both amyloid fibrils and soluble Dec 1;9(1):71.
oligomers, and its manufacturer Biogen plans to apply for
FDA approval in 2020 [58]. Another set of therapeutics 2. Alzheimer’s Association. 2020 Alzheimer’s disease
inhibit the enzyme that cleaves the beta-amyloid protein facts and figures. Alzheimer’s & Dementia. 2020 Mar 10;
from its precursor, amyloid precursor protein (APP). 16(3):391-460.
These drugs against the beta-site APP-cleaving enzyme 3. Weller J, Budson A. Current understanding
1 (BACE-1) have similarly led to reductions in amyloid of Alzheimer’s disease diagnosis and treatment.
levels but produce worse cognitive decline in AD patients F1000Research. 2018;7.
compared to placebo. The results indicate BACE-1 activity
may be important in preserving normal synaptic function 4. Alzheimer A. Uber eine eigenartige Erkrankung der
[59]. Hirnrinde. Zentralbl. Nervenh. Psych. 1907;18:177-9.

J Exp Neurol. 2020

Volume 1, Issue 3 95
McGirr S, Venegas C, Swaminathan A. Alzheimer’s Disease: A Brief Review. J Exp Neurol. 2020;1(3): 89-98.

5. Yang HD, Kim DH, Lee SB, Young LD. History of 17. Chen YG. Research progress in the pathogenesis of
Alzheimer’s Disease. Dementia and Neurocognitive Alzheimer’s disease. Chinese Medical Journal. 2018 Jul
Disorders. 2016 Dec 1;15(4):115-21. 5;131(13):1618.

6. Soria Lopez JA, Gonzalez HM, and Leger GC. Chapter 18. Priller C, Bauer T, Mitteregger G, Krebs B, Kretzschmar
13 – Alzheimer’s disease. Handbook of Clinical Neurology HA, Herms J. Synapse formation and function is
2019; 167: 231-255. modulated by the amyloid precursor protein. Journal of
Neuroscience. 2006 Jul 5;26(27):7212-21.
7. Glenner GG, Wong CW. Alzheimer’s disease: initial
report of the purification and characterization of a 19. Nilsberth C, Westlind-Danielsson A, Eckman CB,
novel cerebrovascular amyloid protein. Biochemical Condron MM, Axelman K, Forsell C, et al. The’Arctic’APP
and Biophysical Research Communications. 1984 May mutation (E693G) causes Alzheimer’s disease by enhanced
16;120(3):885-90. Aβ protofibril formation. Nature Neuroscience. 2001
Sep;4(9):887-93.
8. Brion JP, Couck AM, Passareiro E, Flament-Durand
J. Neurofibrillary tangles of Alzheimer’s disease: an 20. Schellenberg GD, Bird TD, Wijsman EM, Orr HT,
immunohistochemical study. Journal of Submicroscopic Anderson L, Nemens E, et al.. Genetic linkage evidence for
Cytology. 1985 Jan 1;17(1):89-96. a familial Alzheimer’s disease locus on chromosome 14.
Science. 1992 Oct 23;258(5082):668-71.
9. McKhann G, Drachman D, Folstein M, Katzman R,
Price D, Stadlan EM. Clinical diagnosis of Alzheimer’s 21. Mahley RW, Weisgraber KH, Huang Y. Apolipoprotein
disease: Report of the NINCDS-ADRDA Work Group* E: structure determines function, from atherosclerosis to
under the auspices of Department of Health and Human Alzheimer’s disease to AIDS. Journal of Lipid Research.
Services Task Force on Alzheimer’s Disease. Neurology. 2009 Apr 1;50(Supplement):S183-8.
1984 Jul 1;34(7):939-44.
22. Herz J, Chen Y, Masiulis I, Zhou L. Expanding
functions of lipoprotein receptors. Journal of Lipid
10. McKhann GM, Knopman DS, Chertkow H, Hyman
Research. 2009 Apr 1;50(Supplement):S287-92.
BT, Jack Jr CR, Kawas CH, et al. The diagnosis of dementia
due to Alzheimer’s disease: recommendations from the 23. Zhong N, Weisgraber KH. Understanding the
National Institute on Aging-Alzheimer’s Association association of apolipoprotein E4 with Alzheimer disease:
workgroups on diagnostic guidelines for Alzheimer’s clues from its structure. Journal of Biological Chemistry.
disease. Alzheimer’s & Dementia. 2011 May;7(3):263-9. 2009 Mar 6;284(10):6027-31.
11. Jack Jr CR, Bennett DA, Blennow K, Carrillo MC, 24. Verghese PB, Castellano JM, Garai K, Wang Y, Jiang
Dunn B, Haeberlein SB, et al. NIA-AA research framework: H, Shah A, et al. ApoE influences amyloid-β (Aβ) clearance
toward a biological definition of Alzheimer’s disease. despite minimal apoE/Aβ association in physiological
Alzheimer’s & Dementia. 2018 Apr;14(4):535-62. conditions. Proceedings of the National Academy of
Sciences. 2013 May 7;110(19):E1807-16.
12. Barage SH, Sonawane KD. Amyloid cascade
hypothesis: Pathogenesis and therapeutic strategies in 25. Nuutinen T, Suuronen T, Kauppinen A, Salminen A.
Alzheimer’s disease. Neuropeptides. 2015 Aug 1;52:1-8. Clusterin: a forgotten player in Alzheimer’s disease. Brain
Research Reviews. 2009 Oct 1;61(2):89-104.
13. Shao W, Peng D, Wang X. Genetics of Alzheimer’s
disease: From pathogenesis to clinical usage. Journal of 26. Ramirez LM, Goukasian N, Porat S, Hwang KS,
Clinical Neuroscience. 2017 Nov 1;45:1-8. Eastman JA, Hurtz S, Wang B, Vang N, Sears R, Klein
E, Coppola G. Common variants in ABCA7 and MS4A6A
14. Tiwari S, Atluri V, Kaushik A, Yndart A, Nair M. are associated with cortical and hippocampal atrophy.
Alzheimer’s disease: pathogenesis, diagnostics, and Neurobiology of Aging. 2016 Mar 1;39:82-9.
therapeutics. International Journal of Nanomedicine.
2019;14:5541. 27. Chibnik LB, Shulman JM, Leurgans SE, Schneider JA,
Wilson RS, Tran D, et al. CR1 is associated with amyloid
15. Šerý O, Povová J, Míšek I, Pešák L, Janout V. Molecular plaque burden and age-related cognitive decline. Annals
mechanisms of neuropathological changes in Alzheimer’s of Neurology. 2011 Mar;69(3):560-9.
disease: a review. Folia Neuropathologica. 2013;51(1):1-9.
28. Bradshaw EM, Chibnik LB, Keenan BT, Ottoboni L,
16. Bondi MW, Edmonds EC, Salmon DP. Alzheimer’s Raj T, Tang A, Rosenkrantz LL, Imboywa S, Lee M, Von
disease: past, present, and future. Journal of the Korff A, Morris MC. CD33 Alzheimer’s disease locus:
International Neuropsychological Society: JINS. 2017 altered monocyte function and amyloid biology. Nature
Oct;23(9-10):818. Neuroscience. 2013 Jul;16(7):848-50.

J Exp Neurol. 2020

Volume 1, Issue 3 96
McGirr S, Venegas C, Swaminathan A. Alzheimer’s Disease: A Brief Review. J Exp Neurol. 2020;1(3): 89-98.

29. Karch CM, Jeng AT, Nowotny P, Cady J, Cruchaga 42. Clark CM, Pontecorvo MJ, Beach TG, Bedell BJ,
C, Goate AM. Expression of novel Alzheimer’s disease risk Coleman RE, Doraiswamy PM, et al. Cerebral PET
genes in control and Alzheimer’s disease brains. PloS one. with florbetapir compared with neuropathology at
2012 Nov 30;7(11):e50976. autopsy for detection of neuritic amyloid-β plaques: a
prospective cohort study. The Lancet Neurology. 2012
30. Wang HF, Tan L, Hao XK, Jiang T, Tan MS, Liu Y, Zhang Aug 1;11(8):669-78.
DQ, Yu JT, Alzheimer’s Disease Neuroimaging Initiative.
Effect of EPHA1 genetic variation on cerebrospinal fluid 43. Yeo JM, Waddell B, Khan Z, Pal S. A systematic review
and neuroimaging biomarkers in healthy, mild cognitive and meta-analysis of 18F-labeled amyloid imaging in
impairment and Alzheimer’s disease cohorts. Journal of Alzheimer’s disease. Alzheimer’s & Dementia: Diagnosis,
Alzheimer’s Disease. 2015 Jan 1;44(1):115-23. Assessment & Disease Monitoring. 2015 Mar 1;1(1):5-13.

31. Naj AC, Jun G, Beecham GW, Wang LS, Vardarajan BN, 44. Hampel H, Bürger K, Teipel SJ, Bokde AL, Zetterberg
Buros J, et al. Common variants at MS4A4/MS4A6E, CD2AP, H, Blennow K. Core candidate neurochemical and
CD33 and EPHA1 are associated with late-onset Alzheimer’s imaging biomarkers of Alzheimer’s disease. Alzheimer’s &
disease. Nature Genetics. 2011 May;43(5):436-41. Dementia. 2008 Jan 1;4(1):38-48.

32. Jeong S. Molecular and cellular basis of 45. Blennow K, Mattsson N, Schöll M, Hansson O,
neurodegeneration in Alzheimer’s disease. Molecules and Zetterberg H. Amyloid biomarkers in Alzheimer’s
Cells. 2017 Sep 30;40(9):613. disease. Trends in Pharmacological Sciences. 2015 May
1;36(5):297-309.
33. Lane CA, Hardy J, Schott JM. Alzheimer’s disease. The
46. Palmqvist S, Zetterberg H, Mattsson N, Johansson
European Journal of Neurology. 2018 Jan;25(1):59-70.
P, Minthon L, Blennow K, et al, Alzheimer’s Disease
34. Lyketsos CG, Carrillo MC, Ryan JM, Khachaturian AS, Neuroimaging Initiative, Swedish BioFINDER Study
Trzepacz P, Amatniek J, et al. Neuropsychiatric Symptoms Group. Detailed comparison of amyloid PET and CSF
biomarkers for identifying early Alzheimer disease.
in Alzheimer’s Disease. Alzheimers & Dementia. 2011
Neurology. 2015 Oct 6;85(14):1240-9.
Sep;7(5):532-9.
47. Blennow K, Zetterberg H. Biomarkers for Alzheimer’s
35. Eratne D, Loi SM, Farrand S, Kelso W, Velakoulis
disease: current status and prospects for the future.
D, Looi JC. Alzheimer’s disease: clinical update on
Journal of Internal Medicine. 2018 Dec;284(6):643-63.
epidemiology, pathophysiology and diagnosis. Australasian
Psychiatry. 2018 Aug;26(4):347-57. 48. Mattsson N, Zetterberg H, Janelidze S, Insel PS,
Andreasson U, Stomrud E, et al. Plasma tau in Alzheimer
36. Aisen PS, Cummings J, Jack CR, Morris JC, Sperling disease. Neurology. 2016 Oct 25;87(17):1827-35.
R, Frölich L, et al. On the path to 2025: understanding the
Alzheimer’s disease continuum. Alzheimer’s Research & 49. Mattsson N, Andreasson U, Zetterberg H, Blennow
Therapy. 2017 Dec 1;9(1):60. K. Association of plasma neurofilament light with
neurodegeneration in patients with Alzheimer disease.
37. Crutch SJ, Schott JM, Rabinovici GD, Murray JAMA Neurology. 2017 May 1;74(5):557-66.
M, Snowden JS, van der Flier WM, et al. Consensus
classification of posterior cortical atrophy. Alzheimer’s & 50. Rohrer JD, Woollacott IO, Dick KM, Brotherhood E,
Dementia. 2017 Aug;13(8):870-84. Gordon E, Fellows A, et al. Serum neurofilament light chain
protein is a measure of disease intensity in frontotemporal
38. Oh MJ, Kim S, Park YH, Suh J, Yi S. Early Onset dementia. Neurology. 2016 Sep 27;87(13):1329-36.
Alzheimer’s Disease Presenting as Logopenic Primary
Progressive Aphasia. Dementia and Neurocognitive 51. Hansson O, Zetterberg H, Vanmechelen E,
Disorders. 2018 Jun 1;17(2):66-70. Vanderstichele H, Andreasson U, Londos E, et al.
Evaluation of plasma Aβ40 and Aβ42 as predictors of
39. Villain N, Dubois B. Alzheimer’s disease including conversion to Alzheimer’s disease in patients with mild
focal presentations. InSeminars in neurology. Thieme cognitive impairment. Neurobiology of Aging. 2010 Mar
Medical Publishers. 2019; p. 213-26. 1;31(3):357-67.

40. Frisoni GB, Fox NC, Jack CR, Scheltens P, Thompson 52. Silbert LC. Does statin use decrease the amount of
PM. The clinical use of structural MRI in Alzheimer Alzheimer disease pathology in the brain?. Neurology.
disease. Nature Reviews Neurology. 2010 Feb;6(2):67-77. 2007 Aug 28;69(9):E8-11.

41. Kato T, Inui Y, Nakamura A, Ito K. Brain 53. Swaminathan A, Jicha GA. Nutrition and prevention
fluorodeoxyglucose (FDG) PET in dementia. Ageing of Alzheimer’s dementia. Frontiers in Aging Neuroscience.
Research Reviews. 2016 Sep 1;30:73-84. 2014 Oct 20;6:282.

J Exp Neurol. 2020

Volume 1, Issue 3 97
McGirr S, Venegas C, Swaminathan A. Alzheimer’s Disease: A Brief Review. J Exp Neurol. 2020;1(3): 89-98.

54. Oulhaj A, Jernerén F, Refsum H, Smith AD, de Jager 60. DeVos SL, Corjuc BT, Oakley DH, Nobuhara CK,
CA. Omega-3 fatty acid status enhances the prevention Bannon RN, Chase A, et al. Synaptic tau seeding precedes
of cognitive decline by B vitamins in mild cognitive tau pathology in human Alzheimer’s disease brain.
impairment. Journal of Alzheimer’s Disease. 2016 Jan Frontiers in Neuroscience. 2018 Apr 24;12:267.
1;50(2):547-57.
61. Gauthier S, Feldman HH, Schneider LS, Wilcock GK,
55. Van Bulck M, Sierra-Magro A, Alarcon-Gil J, Perez- Frisoni GB, Hardlund JH, et al. Efficacy and safety of tau-
Castillo A, Morales-Garcia JA. Novel approaches for aggregation inhibitor therapy in patients with mild or
the treatment of Alzheimer’s and Parkinson’s disease. moderate Alzheimer’s disease: a randomised, controlled,
International Journal of Molecular Sciences. 2019 double-blind, parallel-arm, phase 3 trial. The Lancet. 2016
Jan;20(3):719. Dec 10;388(10062):2873-84.

56. Jiang C, Li G, Huang P, Liu Z, Zhao B. The gut 62. Jadhav S, Avila J, Schöll M, Kovacs GG, Kövari
microbiota and Alzheimer’s disease. Journal of Alzheimer’s E, Skrabana R, et al. A walk through tau therapeutic
Disease. 2017 Jan 1;58(1):1-5. strategies. Acta Neuropathologica Communications. 2019
Dec 1;7(1):22.
57. Cummings J, Lee G, Ritter A, Sabbagh M, Zhong K.
Alzheimer’s disease drug development pipeline: 2019. 63. Aisen P, Touchon J, Amariglio R, Andrieu S, Bateman
Alzheimer’s & Dementia: Translational Research & Clinical R, Breitner J, et al. EU/US/CTAD task force: lessons
Interventions. 2019 Jan 1;5:272-93. learned from recent and current Alzheimer’s prevention
trials. The Journal of Prevention of Alzheimer’s Disease.
58. Schneider L. A resurrection of aducanumab for 2017;4(2):116.
Alzheimer’s disease. The Lancet Neurology. 2020 Feb
1;19(2):111-2.

59. Knopman DS. Lowering of amyloid-beta by β-secretase

inhibitors—some informative failures. The New England
Journal of Medicine. 2019 Apr 11;380(15):1476-1478.

J Exp Neurol. 2020

Volume 1, Issue 3 98