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{{CMG}}; {{AE}} {{HK}}, {{ARK}}
{{Alzheimer's disease}}
{{Alzheimer's disease}}


==Overview==
==Overview==
Alzheimer disease (AD), is a progressive [[Neurodegenerative disease|neurodegenerative disorder]]. The dysfunction of [[Amyloid precursor protein|amyloid precursor protien]] ([[Amyloid precursor protein|APP]]) [[metabolism]] and the resulting build up of of Aβ [[peptides]] and their aggregation in the form of [[senile plaques]] in the brain [[parenchyma]] of individuals have been considered pivotal for [[neurodegeneration]] in the disease. [[Cognitive impairment]] in patients with AD is closely associated with [[synaptic]] loss in the [[neocortex]] and [[limbic system]]. In [[familial]] forms of AD, [[Mutation|mutations]] result in an increased Aβ production or aggregation, in sporadic AD, failure of the clearance mechanisms might play a key role. Loss of mature [[neurons]] and alterations in [[neural]] [[Progenitor cell|progenitor cells]] (NPCs) in areas such as the [[dentate gyrus]] (DG) of the [[hippocampus]] have been found to be responsible for manifestations of AD. On [[gross pathology]], [[Temporal lobe|temporal]] [[atrophy]] ([[hippocampus]] in particular), dilation of [[lateral ventricles]] and [[third ventricle]] are characteristic findings of Alzheimer's disease. The [[microscopic]] [[histopathological]] features of alzheimer's disease consist [[neurofibrillary tangles]], [[senile plaques]], [[neuronal]] loss, and with or without [[cerebral amyloid angiopathy]].


Alzheimer's disease develops from the loss of [[neurons]] and [[synapses|synaptic connections]]. There exist at least three major hypotheses that aim to describe the mechanism of how Alzheimer's disease proliferates in the [[brain]].
==Pathophysiology==
Alzheimer disease (AD), is a progressive [[neurodegenerative]] disorder. The dysfunction of [[Amyloid precursor protein|amyloid precursor protien]] ([[Amyloid precursor protein|APP]]) [[metabolism]] and the resulting build up of of Aβ [[peptides]] and their aggregation in the form of [[senile plaques]] in the [[brain]] [[parenchyma]] of individuals have been considered pivotal for [[neurodegeneration]] in the disease. There is also an accumulation of [[intracellular]] [[neurofibrillary tangles]] that consist of hyperphosphorylated [[tau protein]] and a profound loss of [[basal forebrain]] [[cholinergic]] [[neurons]] that innervate the [[hippocampus]], and the [[neocortex]].<div style="-webkit-user-select: none;">
<div style="-webkit-user-select: none;">
===Triggers===
The following factors lead to the development of Alzheimer's dementia:


==Pathogenesis==
*[[Genetics|Genetic]] factors
*Environmental factors
*[[Chromosomal]] factors


[[Image:Alzheimer's disease - MRI.jpg|left|150x200px|frame|[[MRI]] images of a normal aged brain (right) and an Alzheimer's patient's brain (left). In the Alzheimer brain, atrophy is clearly seen.]]
===Pathogenesis===
The [[pathogenesis]] of Alzheimer's dementia (AD) can be explained by four [[pathological]] processes. The processes involved in the development of AD and their [[molecular]] basis is as follows:<ref name="pmid20413653">{{cite journal |vauthors=Crews L, Masliah E |title=Molecular mechanisms of neurodegeneration in Alzheimer's disease |journal=Hum. Mol. Genet. |volume=19 |issue=R1 |pages=R12–20 |year=2010 |pmid=20413653 |pmc=2875049 |doi=10.1093/hmg/ddq160 |url=}}</ref><ref name="pmid30135715">{{cite journal |vauthors=Weller J, Budson A |title=Current understanding of Alzheimer's disease diagnosis and treatment |journal=F1000Res |volume=7 |issue= |pages= |date=2018 |pmid=30135715 |pmc=6073093 |doi=10.12688/f1000research.14506.1 |url=}}</ref>
====(i) [[Neuronal]] loss====


At a [[macroscopic]] level, AD is characterized by loss of [[neuron]]s and [[synapse]]s in the [[cerebral cortex]] and certain subcortical regions. This results in gross [[atrophy]] of the affected regions, including [[degeneration]] in the [[temporal lobe]] and [[parietal lobe]], and parts of the [[frontal cortex]] and [[cingulate gyrus]].<ref name="pmid12934968">{{cite journal |author=Wenk GL |title=Neuropathologic changes in Alzheimer's disease |journal=Journal of Clinical Psychiatry |volume=64 Suppl 9 |issue= |pages=7–10 |year=2003 |pmid=12934968 |doi=}}</ref>
*[[Neurogenesis]] is a complex process characterized by several progressive steps, including [[neural]] progenitor cell (NPC) [[proliferation]], migration, [[differentiation]] ([[cell]] fate commitment) and [[maturation]], including growth and [[synapse]] formation
Three major hypotheses exist to explain the cause of the disease, though other possible explanations also exist.
*Initial [[synaptic]] injury is followed by [[neuronal]] loss accompanied by [[astrogliosis]] and [[Microglial cell|microglial]] [[cell proliferation]].<ref name="pmid2531723">{{cite journal |vauthors=Beach TG, Walker R, McGeer EG |title=Patterns of gliosis in Alzheimer's disease and aging cerebrum |journal=Glia |volume=2 |issue=6 |pages=420–36 |year=1989 |pmid=2531723 |doi=10.1002/glia.440020605 |url=}}</ref><ref name="pmid2531723">{{cite journal |vauthors=Beach TG, Walker R, McGeer EG |title=Patterns of gliosis in Alzheimer's disease and aging cerebrum |journal=Glia |volume=2 |issue=6 |pages=420–36 |year=1989 |pmid=2531723 |doi=10.1002/glia.440020605 |url=}}</ref>
*[[Cognitive impairment]] in patients with AD is closely associated with [[synaptic]] loss in the [[neocortex]] and [[limbic system]]<ref name="pmid2360787">{{cite journal |vauthors=DeKosky ST, Scheff SW |title=Synapse loss in frontal cortex biopsies in Alzheimer's disease: correlation with cognitive severity |journal=Ann. Neurol. |volume=27 |issue=5 |pages=457–64 |year=1990 |pmid=2360787 |doi=10.1002/ana.410270502 |url=}}</ref><ref name="pmid1789684">{{cite journal |vauthors=Terry RD, Masliah E, Salmon DP, Butters N, DeTeresa R, Hill R, Hansen LA, Katzman R |title=Physical basis of cognitive alterations in Alzheimer's disease: synapse loss is the major correlate of cognitive impairment |journal=Ann. Neurol. |volume=30 |issue=4 |pages=572–80 |year=1991 |pmid=1789684 |doi=10.1002/ana.410300410 |url=}}</ref>
*Increase in [[neurogenesis]] in the brains of AD patients may be related to [[Glial cells|glial]] and [[vasculature]]-associated changes as suggested by an increase in [[neurogenic]] markers<ref name="pmid16814555">{{cite journal |vauthors=Boekhoorn K, Joels M, Lucassen PJ |title=Increased proliferation reflects glial and vascular-associated changes, but not neurogenesis in the presenile Alzheimer hippocampus |journal=Neurobiol. Dis. |volume=24 |issue=1 |pages=1–14 |year=2006 |pmid=16814555 |doi=10.1016/j.nbd.2006.04.017 |url=}}</ref>
*Loss of mature [[neurons]] and alterations in [[neural]] progenitor cells (NPCs) in areas such as the [[dentate gyrus]] (DG) of the [[hippocampus]] have been found to be responsible for manifestations of AD


===Cholinergic hypothesis===
====(ii) Aggregation of [[Extracellular|extra-cellular]] [[Amyloid beta|amyloid β]] (Aβ)====
<div style="-webkit-user-select: none;">
*[[Amyloid precursor protein]] ([[Amyloid precursor protein|APP]]) is [[Physiological|physiologically]] present in normal [[Brain|brains]]
*It is [[Proteolytic|proteolytically]] processed by α-, β-, and γ-secretases<ref name="pmid2504495">{{cite journal |vauthors=Selkoe DJ |title=Amyloid beta protein precursor and the pathogenesis of Alzheimer's disease |journal=Cell |volume=58 |issue=4 |pages=611–2 |year=1989 |pmid=2504495 |doi= |url=}}</ref><ref name="pmid2949367">{{cite journal |vauthors=Tanzi RE, Gusella JF, Watkins PC, Bruns GA, St George-Hyslop P, Van Keuren ML, Patterson D, Pagan S, Kurnit DM, Neve RL |title=Amyloid beta protein gene: cDNA, mRNA distribution, and genetic linkage near the Alzheimer locus |journal=Science |volume=235 |issue=4791 |pages=880–4 |year=1987 |pmid=2949367 |doi= |url=}}</ref>
*In [[familial]] forms of AD, mutations result in an increased Aβ production or aggregation, in sporadic AD, failure of the clearance mechanisms might play a key role
*Aβ [[oligomers]] are responsible for the [[Synapses|synapto]]-toxic effects of Aβ<ref name="pmid15182223">{{cite journal |vauthors=Walsh DM, Selkoe DJ |title=Oligomers on the brain: the emerging role of soluble protein aggregates in neurodegeneration |journal=Protein Pept. Lett. |volume=11 |issue=3 |pages=213–28 |year=2004 |pmid=15182223 |doi= |url=}}</ref>


The oldest major hypothesis is the ''[[cholinergic]] hypothesis'', which proposes that AD is caused by reduced synthesis of the [[neurotransmitter]] [[acetylcholine]].  Most currently available drug therapies in Alzheimer's are based on this theory, although the medications that treat [[acetylcholine]] deficiency only affect symptoms of the disease and will neither halt nor reverse the progression of AD.<ref name="pmid16644763">{{cite journal |author=Walker LC, Rosen RF |title=Alzheimer therapeutics-what after the cholinesterase inhibitors? |journal=Age Ageing |volume=35 |issue=4 |pages=332–335 |year=2006 |pmid=16644763 |doi=10.1093/ageing/afl009}}</ref>
'''Constitutive (non[[amyloidogenic]]) pathway'''
The [[cholinergic]] hypothesis has not maintained widespread support in the face of this evidence, although cholinergic effects have been proposed to initiate large-scale aggregation,<ref name="pmid15236795">{{cite journal |author=Shen ZX |title=Brain cholinesterases: II. The molecular and cellular basis of Alzheimer's disease |journal=Medical Hypotheses |volume=63 |issue=2 |pages=308–321 |year=2004 |pmid=15236795 |doi=10.1016/j.mehy.2004.02.031}}</ref> leading to generalized neuroinflammation.<ref name="pmid12934968">{{cite journal |author=Wenk GL |title=Neuropathologic changes in Alzheimer's disease |journal=Journal of Clinical Psychiatry |volume=64 Suppl 9 |issue= |pages=7–10 |year=2003 |pmid=12934968 |doi=}}</ref> In 1991 the [[amyloid beta|amyloid]] hypothesis was proposed,<ref name="pmid1763432">{{cite journal |author=Hardy J, Allsop D |title=Amyloid deposition as the central event in the aetiology of Alzheimer's disease |journal=Trends Pharmacol. Sci. |volume=12 |issue=10 |pages=383–8 |year=1991 |pmid=1763432 |doi=10.1016/0165-6147(91)90609-V }}</ref> while research after 2000 is also centered on [[tau protein]]s. The two positions differ insofar as one states that the [[tau protein]] abnormalities initiate the disease cascade, while the other states that [[amyloid beta]] (Aβ) deposits are the causative factor in the disease.<ref name="pmid11801334">{{cite journal |author=Mudher A, Lovestone S |title=Alzheimer's disease-do tauists and baptists finally shake hands? |journal=Trends in Neuroscience |volume=25 |issue=1 |pages=22–26 |year=2002 |pmid=11801334 | doi=10.1016/S0166-2236(00)02031-2 }}</ref>  Other changes, including congophilic amyloid angiopathy, oxidative changes, neuronal loss, and [[inflammation]] are also associated with Alzheimer's disease.


===Amyloid hypothesis===
*In the constitutive pathway, [[proteolysis]] of [[Amyloid precursor protein|APP]] by α- and γ-secretases results in nonpathogenic fragments (sAPPα and α-[[C-terminal end|C-terminal]] fragment)


[[Image:Amyloid-plaque formation-big.jpg|left|50x100px|frame|Enzymes act on the APP (amyloid precursor protein) and cut it into fragments. The beta-amyloid fragment is crucial in the formation of senile plaques in AD.]]
'''[[Amyloidogenic]] pathway'''


Alzheimer's disease has been identified as a [[protein folding|protein misfolding]] disease, or [[proteopathy]], due to the accumulation of abnormally folded A-beta and tau proteins in the brains of AD patients.<ref name="pmid14528050">{{cite journal |author=Hashimoto M, Rockenstein E, Crews L, Masliah E |title=Role of protein aggregation in mitochondrial dysfunction and neurodegeneration in Alzheimer's and Parkinson's diseases |journal=Neuromolecular Medicine |volume=4 |issue=1–2 |pages=21–36 |year=2003 |pmid=14528050 |doi=10.1385/NMM:4:1-2:21}}</ref>  The ''[[amyloid beta|amyloid]] hypothesis'' postulates that amyloid beta (Aβ) deposits are the fundamental cause of the disease.<ref name="pmid1763432">{{cite journal
*In the [[amyloidogenic]] pathway, [[proteolysis]] of APP by β-secretase and γ-secretase gives rise to a mixture of Aβ [[peptides]] with different lengths. There are two major Aβ species: Aβ1–40 (90%) and Aβ1–42 (10%). The Aβ1–42 fragments are more aggregation-prone and are predominantly present in [[amyloid plaques]] in [[Brain|brains]] of AD patients.<ref name="pmid26312828">{{cite journal |vauthors=Van Cauwenberghe C, Van Broeckhoven C, Sleegers K |title=The genetic landscape of Alzheimer disease: clinical implications and perspectives |journal=Genet. Med. |volume=18 |issue=5 |pages=421–30 |year=2016 |pmid=26312828 |pmc=4857183 |doi=10.1038/gim.2015.117 |url=}}</ref>
|author=Hardy J, Allsop D
*Abnormal accumulation of Aβ is the result of an imbalance between the levels of Aβ production, aggregation and clearance.
|title=Amyloid deposition as the central event in the aetiology of Alzheimer's disease
*Aβ clearance is mediated by [[proteolytic]] [[enzymes]] such as [[neprilysin]], [[Chaperone (protein)|chaperone]] [[molecules]] such as [[Apolipoprotein E|apoE]], [[Lysosomal enzymes|lysosomal]] (e.g. [[autophagy]]) and non-lysosomal pathways (e.g. [[proteasome]])<ref name="pmid12769185">{{cite journal |vauthors=Bendiske J, Bahr BA |title=Lysosomal activation is a compensatory response against protein accumulation and associated synaptopathogenesis--an approach for slowing Alzheimer disease? |journal=J. Neuropathol. Exp. Neurol. |volume=62 |issue=5 |pages=451–63 |year=2003 |pmid=12769185 |doi= |url=}}</ref>
|journal=Trends Pharmacol. Sci.
*[[Nerve]] damage as described under '[[neuronal]] loss', might result from the conversion of normally non-toxic monomers to toxic [[oligomers]] of Aβ [[peptides]]<ref name="pmid15182223">{{cite journal |vauthors=Walsh DM, Selkoe DJ |title=Oligomers on the brain: the emerging role of soluble protein aggregates in neurodegeneration |journal=Protein Pept. Lett. |volume=11 |issue=3 |pages=213–28 |year=2004 |pmid=15182223 |doi= |url=}}</ref><ref name="pmid11926821">{{cite journal |vauthors=Volles MJ, Lansbury PT |title=Vesicle permeabilization by protofibrillar alpha-synuclein is sensitive to Parkinson's disease-linked mutations and occurs by a pore-like mechanism |journal=Biochemistry |volume=41 |issue=14 |pages=4595–602 |year=2002 |pmid=11926821 |doi= |url=}}</ref><ref name="pmid10392577">{{cite journal |vauthors=Selkoe DJ |title=Translating cell biology into therapeutic advances in Alzheimer's disease |journal=Nature |volume=399 |issue=6738 Suppl |pages=A23–31 |year=1999 |pmid=10392577 |doi= |url=}}</ref>
|volume=12
*Changes in [[glutamate receptors]] and increased excitability; [[mitochondrial]] dysfunction; [[lysosomal]] failure and alterations in signaling pathways related to [[synaptic]] plasticity, [[neuronal]] [[cell]] death and [[neurogenesis]] have been proposed as the [[molecular]] mechanisms leading to the development of Alzeimer's dementia (AD)<ref name="pmid11689468">{{cite journal |vauthors=Lin H, Bhatia R, Lal R |title=Amyloid beta protein forms ion channels: implications for Alzheimer's disease pathophysiology |journal=FASEB J. |volume=15 |issue=13 |pages=2433–44 |year=2001 |pmid=11689468 |doi=10.1096/fj.01-0377com |url=}}</ref><ref name="pmid20177970">{{cite journal |vauthors=Nakamura T, Lipton SA |title=Redox regulation of mitochondrial fission, protein misfolding, synaptic damage, and neuronal cell death: potential implications for Alzheimer's and Parkinson's diseases |journal=Apoptosis |volume=15 |issue=11 |pages=1354–63 |year=2010 |pmid=20177970 |pmc=2978885 |doi=10.1007/s10495-010-0476-x |url=}}</ref><ref name="pmid16914867">{{cite journal |vauthors=Nixon RA, Cataldo AM |title=Lysosomal system pathways: genes to neurodegeneration in Alzheimer's disease |journal=J. Alzheimers Dis. |volume=9 |issue=3 Suppl |pages=277–89 |year=2006 |pmid=16914867 |doi= |url=}}</ref>
|issue=10
|pages=383–88
|year=1991
|month=October
|pmid=1763432
}}</ref><ref name="pmid11801334">{{cite journal
|author=Mudher A, Lovestone S
|title=Alzheimer's disease-do tauists and baptists finally shake hands?
|journal=Trends Neurosci.
|volume=25
|issue=1
|pages=22–26
|year=2002
|month=January
|pmid=11801334
}}</ref>  
[[Plaques]] are made of a small [[peptide]] (39 to 43 amino acid residues) called [[beta-amyloid]] (also A-beta or Aβ), a [[protein]] fragment snipped from a larger protein called [[amyloid precursor protein]] (APP). APP is a [[transmembrane protein]]; which means that it sticks through the neuron's membrane; and is believed to help neurons grow, survive and repair themselves after injury.<ref name="pmid16822978">{{cite journal |author=Priller C, Bauer T, Mitteregger G, Krebs B, Kretzschmar HA, Herms J |title=Synapse formation and function is modulated by the amyloid precursor protein |journal=Journal of Neuroscience |volume=26 |issue=27 |pages=7212–7221 |year=2006 |pmid=16822978 |doi=10.1523/JNEUROSCI.1450-06.2006}}</ref><ref name="pmid12927332">{{cite journal |author=Turner PR, O'Connor K, Tate WP, Abraham WC |title=Roles of amyloid precursor protein and its fragments in regulating neural activity, plasticity and memory |journal=Prog. Neurobiology |volume=70 |issue=1 |pages=1–32 |year=2003 |pmid=12927332 |doi=}}</ref> In AD, APP is divided by [[enzymes]] such as [[gamma-secretase]] and [[BACE1]] through a mechanism called [[proteolysis]].<ref name="pmid15787600">{{cite journal |author=Hooper NM |title=Roles of proteolysis and lipid rafts in the processing of the amyloid precursor protein and prion protein |journal=Biochemical Society Transactions |volume=33 |issue=Pt 2 |pages=335–338 |year=2005 |pmid=15787600 |doi=10.1042/BST0330335}}</ref> One of these fragments is [[beta-amyloid]]. Beta-amyloid fragments (amyloid fibrils) outside the cell form clumps that deposit outside neurons in dense formations known as [[senile plaques]].<ref name="pmid15004691">{{cite journal |author=Ohnishi S, Takano K |title=Amyloid fibrils from the viewpoint of protein folding |journal=Cellular Molecular Life Sciences |volume=61 |issue=5 |pages=511–524 |year=2004 |pmid=15004691 |doi=10.1007/s00018-003-3264-8}}</ref><ref name="pmid15184601">{{cite journal |author=Tiraboschi P, Hansen LA, Thal LJ, Corey-Bloom J |title=The importance of neuritic plaques and tangles to the development and evolution of AD |journal=Neurology |volume=62 |issue=11 |pages=1984–1989 |year=2004 |pmid=15184601 |doi=}}</ref>
The amyloid hypothesis is compelling because the gene for the amyloid beta precursor (APP) is located on [[chromosome 21]], and patients with [[trisomy 21]] ([[Down Syndrome]]) who thus have an extra [[gene dosage|gene copy]] almost universally exhibit AD-like disorders by 40&nbsp;years of age.<ref name="pmid16904243">{{cite journal
|author=Nistor M, Don M, Parekh M, Sarsoza F, Goodus M, Lopez GE, Kawas C, Leverenz J, Doran E, Lott IT, Hill M, Head E
|title=Alpha- and beta-secretase activity as a function of age and beta-amyloid in Down syndrome and normal brain
|journal=Neurobiol. Aging
|volume=28
|issue=10
|pages=1493–506
|year=2007
|pmid=16904243
|doi=10.1016/j.neurobiolaging.2006.06.023
}}</ref><ref name="pmid15639317">{{cite journal |author=Lott IT, Head E |title=Alzheimer disease and Down syndrome: factors in pathogenesis |journal=Neurobiology of Aging |volume=26 |issue=3 |pages=383–389 |year=2005 |pmid=15639317 |doi=10.1016/j.neurobiolaging.2004.08.005}}</ref> It should be noted further that [[ApoE4]], the major genetic risk factor for AD, leads to excess amyloid build-up in the brain before AD symptoms arise. Thus, Aβ deposition precedes clinical AD.<ref name="pmid7566000">{{cite journal
|author=Polvikoski T, Sulkava R, Haltia M, Kainulainen K, Vuorio A, Verkkoniemi A, Niinistö L, Halonen P, Kontula K
|title=Apolipoprotein E, dementia, and cortical deposition of beta-amyloid protein
|journal=New England Journal of Medicine
|volume=333
|issue=19
|pages=1242–1247
|year=1995
|pmid=7566000
|doi=10.1056/NEJM199511093331902
}}</ref> It is known that some types of inherited AD involve only mutations in the APP gene (although this is not the most common type—others involve genes for "pre-senilin" proteins which process APP and may also have still-unknown functions).<ref>{{cite web |url=http://ghr.nlm.nih.gov/condition=alzheimerdisease |title=Alzheimer disease |publisher=US National Library of Medicine |date=2008-04-25 |accessdate=2008-05-02}}</ref> However, another strong support for the amyloid hypothesis, which looks at Aβ as the common initiating factor for Alzheimer's disease, is that [[Genetically modified organism|transgenic]] mice solely expressing a mutant human APP gene develop fibrillar [[amyloid plaques]].<ref>Beta-amyloid precursor protein
* {{cite journal
|author=Games D, Adams D, Alessandrini R, Barbour R, Berthelette P, Blackwell C, Carr T, Clemens J, Donaldson T, Gillespie F
|title=Alzheimer-type neuropathology in transgenic mice overexpressing V717F beta-amyloid precursor protein
|journal=Nature
|volume=373
|issue=6514
|pages=523–527
|year=1995
|pmid=7845465
|doi=10.1038/373523a0
}}
* {{cite journal |author=Masliah E, Sisk A, Mallory M, Mucke L, Schenk D, Games D |title=Comparison of neurodegenerative pathology in transgenic mice overexpressing V717F beta-amyloid precursor protein and Alzheimer's disease |journal=Journal of Neuroscience |volume=16 |issue=18 |pages=5795–5811 |year=1996 |pmid=8795633 |doi=}}
* {{cite journal
|author=Hsiao K, Chapman P, Nilsen S, Eckman C, Harigaya Y, Younkin S, Yang F, Cole G
|title=Correlative memory deficits, Abeta elevation, and amyloid plaques in transgenic mice
|journal=Science
|volume=274
|issue=5284
|pages=99–102
|year=1996
|pmid=8810256
|doi = 10.1126/science.274.5284.99
}}</ref>
If damage from [[Aβ]] is the primary initiating cause of AD, the exact mechanism has not been elucidated. The traditional formulation of the amyloid hypothesis points to the [[cytotoxicity]] of mature aggregated amyloid fibrils.<ref name="pmid2218531">{{cite journal |author=Yankner BA, Duffy LK, Kirschner DA |title=Neurotrophic and neurotoxic effects of amyloid beta protein: reversal by tachykinin neuropeptides |journal=Science |volume=250 |issue=4978 |pages=279–282 |year=1990 |pmid=2218531 |doi=10.1126/science.2218531 }}</ref> The most [[neurotoxic]] form of [[amyloid]] are the soluble [[oligomers]] and intermediate amyloids; the severity of cognitive defect in AD correlates with oligomeric level in [[brain tissue]]. It is also known that [[Aβ]] selectively builds up in the [[mitochondria]] of samples from the [[brains]] of humans with AD, as well as in [[mitochondria]] from transgenic mice with APP genes. In both cases, it inhibits certain mitochondrial enzyme functions and exhibits a similar decrease in glucose utilization in neurons to the one which is a known characteristic of AD. This process may also lead to the formation of damaging [[reactive oxygen species]], [[calcium]] influx, and [[apoptosis]]. Mechanisms which involve direct damage from [[Aβ]] before it forms fibrils and [[plaques]] also address the issue that [[neuronal]] damage is not correlated as well with [[plaques]], since in this model it is not the plaques themselves which cause the major damage, but rather the precursor [[Aβ]] protein directly, via another mechanism.<ref name="pmid17424907">{{cite journal|author=Chen, X, Yan, SD|title=Mitochondrial Aβ: A Potential Cause of Metabolic Dysfunction in Alzheimer's Disease. |journal=IUBMB Life|volume=58|issue=12|pages=686-694|year=2006|pmid=17424907|doi=10.1080/15216540601047767}}</ref>
Again, deposition of amyloid plaques does not correlate well with neuron loss.<ref name="pmid15039236">{{cite journal
|author=Schmitz C, Rutten BP, Pielen A, ''et al''
|title=Hippocampal neuron loss exceeds amyloid plaque load in a transgenic mouse model of Alzheimer's disease
|journal=Am. J. Pathol.
|volume=164
|issue=4
|pages=1495–1502
|year=2004
|month=April
|pmid=15039236
|pmc=1615337
}}</ref>


===Tau hypothesis===
====(iii) [[CDK5]] pathway====
<gallery>
Image:TAU HIGH.JPG|Microscopy image of a neurofibrillary tangle, conformed by hyperphosphorylated tau protein.
Image:TANGLES HIGH.jpg|In Alzheimer's disease, changes in tau protein lead to the disintegration of microtubules in brain cells.
</gallery>
The observation that [[amyloid plaques]] do not correlate with neuron loss supports the ''tau hypothesis''. The ''tau hypothesis'' supports the idea that [[tau protein]] abnormalities initiate the disease cascade.<ref name="pmid11801334"/>  AD is also considered a [[tauopathy]] due to abnormal aggregation of the [[tau protein]]. Healthy neurons have an internal support structure, or [[cytoskeleton]], partly made up of structures called [[microtubules]]. These microtubules act like tracks, guiding nutrients and molecules from the body of the cell down to the ends of the [[axon]] and back. A special kind of protein, tau, makes the microtubules stable through a process named [[phosphorylation]] and is therefore called a [[microtubule-associated protein]].<ref name="pmid17604998">{{cite journal |author=Hernández F, Avila J |title=Tauopathies |journal=Cellular Molecular Life Sciences |volume=64 |issue=17 |pages=2219–2233 |year=2007 |pmid=17604998 |doi=10.1007/s00018-007-7220-x}}</ref> In AD, tau is changed chemically, becoming [[Hyperphosphorylation|hyperphosphorylated]].


In the tau hypothesis, hyperphosphorylated tau begins to pair with other threads of tau and they become tangled up together inside [[nerve cell]] bodies in masses known as [[neurofibrillary tangles]].<ref name="pmid1669718">{{cite journal |author=Goedert M, Spillantini MG, Crowther RA |title=Tau proteins and neurofibrillary degeneration |journal=Brain Pathology |volume=1 |issue=4 |pages=279–286 |year=1991 |pmid=1669718 | doi=10.1111/j.1750-3639.1991.tb00671.x }}</ref> When this happens, the microtubules disintegrate, collapsing the neuron's transport system. This may result first in malfunctions in communication between [[neurons]] and later in the death of the cells.<ref name="pmid17127334">{{cite journal |author=Chun W, Johnson GV |title=The role of tau phosphorylation and cleavage in neuronal cell death |journal=Frontiers of Bioscience |volume=12 |pages=733–756 |year=2007 |pmid=17127334}}</ref>
*[[CDK5]] is the predominant CDK found in the [[brain]], is expressed heavily in neurons and plays a key part in [[synaptic]] integrity and [[neuronal]] development
Both [[amyloid plaques]] and [[neurofibrillary tangle]]s are clearly visible by [[microscopy]] in AD brains.<ref name="pmid15184601">{{cite journal |author=Tiraboschi P, Hansen LA, Thal LJ, Corey-Bloom J |title=The importance of neuritic plaques and tangles to the development and evolution of AD |journal=Neurology |volume=62 |issue=11 |pages=1984–1989 |year=2004 |pmid=15184601 |doi=}}</ref> Plaques are dense, mostly [[insoluble]] deposits of amyloid-beta [[protein]] and [[cell]]ular material outside and around neurons. Tangles are insoluble twisted fibers that build up inside the nerve cell. Though many older people develop some plaques and tangles, the brains of AD patients have them to a much greater extent and in different brain locations.<ref name="pmid8038565">{{cite journal |author=Bouras C, Hof PR, Giannakopoulos P, Michel JP, Morrison JH |title=Regional distribution of neurofibrillary tangles and senile plaques in the cerebral cortex of elderly patients: a quantitative evaluation of a one-year autopsy population from a geriatric hospital |journal=Cerebral Cortex |volume=4 |issue=2 |pages=138–150 |year=1994 |pmid=8038565 |doi =10.1093/cercor/4.2.138 }}</ref>
*Increased activation of [[CDK5]]/[[P35 (gene)|p35]]/p25 has been linked to the [[pathogenesis]] of [[neurodegenerative diseases]] such as AD
*[[CDK5]] may mediate changes in [[neurogenesis]] in AD via aberrant [[phosphorylation]] of [[CDK5]] substrates, which include [[cytoskeletal]] ([[Neurofilament|neurofilaments]], [[Nestin (protein)|nestin]]), [[synaptic]] [[Protein|proteins]] ([[synapsin]])<ref name="pmid8702879">{{cite journal |vauthors=Matsubara M, Kusubata M, Ishiguro K, Uchida T, Titani K, Taniguchi H |title=Site-specific phosphorylation of synapsin I by mitogen-activated protein kinase and Cdk5 and its effects on physiological functions |journal=J. Biol. Chem. |volume=271 |issue=35 |pages=21108–13 |year=1996 |pmid=8702879 |doi= |url=}}</ref>


===Alternative hypotheses===
====(iv) Formation of intraneuronal [[neurofibrillary tangles]] ([[tau protein]] accumulation)====


Recent research supports the previously obscure theory that [[Herpes_simplex#Alzheimer.27s_disease|Herpes simplex]] virus type 1 plays a role as a possible cause of AD in people carrying the susceptible versions of the [[Apolipoprotein E|apoE]] gene.<ref name=Itzhaki2008>{{cite journal |author=Wozniak MA, Mee AP, Itzhaki RF |title=Herpes simplex virus type 1 DNA is located within Alzheimer's disease amyloid plaques |journal=J Pathol. |volume=217 |issue=1 |pages=131–8 |year=2009 |month=January |pmid=18973185 |doi=10.1002/path.2449 |url=http://www3.interscience.wiley.com/journal/121411445/abstract}}</ref>
*Aβ is involved in [[Tau protein|tau]] deposition in AD [[pathogenesis]] and leads to the conversion of tau from a normal to a [[toxic]] state, but there is also evidence that toxic [[Tau protein|tau]] increases Aβ [[toxicity]] via a [[positive feedback loop]]
As [[HSV-1]] is not a new virus, consideration of additional factors will be needed to explain the increase
*A [[protein]] that functionally links Aβ to [[Tau protein|tau]] is [[Fyn (biochemistry)|fyn]]. This [[cytosolic]] [[tyrosine kinase]] positively regulates [[NMDA receptor|N-methyl-D-aspartate (NMDA) receptor]] activity and has been shown to be targeted to [[postsynaptic]] sites in [[dendrites]] by [[Tau protein|tau]], which binds [[Fyn (biochemistry)|fyn]]<ref name="pmid20655099">{{cite journal |vauthors=Ittner LM, Ke YD, Delerue F, Bi M, Gladbach A, van Eersel J, Wölfing H, Chieng BC, Christie MJ, Napier IA, Eckert A, Staufenbiel M, Hardeman E, Götz J |title=Dendritic function of tau mediates amyloid-beta toxicity in Alzheimer's disease mouse models |journal=Cell |volume=142 |issue=3 |pages=387–97 |year=2010 |pmid=20655099 |doi=10.1016/j.cell.2010.06.036 |url=}}</ref>
[http://www.cdc.gov/nchs/pressroom/07newsreleases/lifeexpectancy.htm|increase] in the age-adjusted incidence of AD.  Various [[inflammatory processes]] and inflammatory [[cytokines]] may also have a role in the pathology of Alzheimer's disease. However, these are general markers of tissue damage in any disease, and may also be either secondary causes of tissue damage in AD, or else bystander "marker" effects.<ref>{{cite journal |author=Greig NH, Mattson MP, Perry T, Chan SL, Giordano T, Sambamurti K, Rogers JT, Ovadia H, Lahiri DK |title=New therapeutic strategies and drug candidates for neurodegenerative diseases: p53 and TNF-alpha inhibitors, and GLP-1 receptor agonists. |journal=Ann N Y Acad Sci.|volume=1035 |issue=Dec |pages=290–315 |year=2004 |pmid=15681814 |doi=10.1196/annals.1332.018 }}</ref> Other [[cholinergic]] effects have also been proposed&mdash;for example, the initiation of large-scale aggregation of amyloid,<ref name="pmid15236795">{{cite journal
*In response to Aβ, [[Tau protein|tau]] is relocated from [[axons]] and [[dendrites]] into the somatodendritic compartment<ref name="pmid2117840">{{cite journal |vauthors=Delacourte A, Flament S, Dibe EM, Hublau P, Sablonnière B, Hémon B, Shérrer V, Défossez A |title=Pathological proteins Tau 64 and 69 are specifically expressed in the somatodendritic domain of the degenerating cortical neurons during Alzheimer's disease. Demonstration with a panel of antibodies against Tau proteins |journal=Acta Neuropathol. |volume=80 |issue=2 |pages=111–7 |year=1990 |pmid=2117840 |doi= |url=}}</ref>
|author=Shen ZX
*Excess [[Fyn (biochemistry)|fyn]] accompanies the excess [[Tau protein|tau]] in AD [[dendrites]] and upregulates [[NMDA receptor]] activity in those areas, causing an increased [[calcium]] influx. This [[calcium]]-driven [[excitotoxicity]] can damage [[postsynaptic]] sites and cause [[neurodegeneration]]
|title=Brain cholinesterases: II. The molecular and cellular basis of Alzheimer's disease
|journal=Med. Hypotheses
|volume=63
|issue=2
|pages=308–21
|year=2004
|pmid=15236795
|doi=10.1016/j.mehy.2004.02.031
}}</ref> leading to generalized neuroinflammation.<ref name="pmid12934968">{{cite journal
|author=Wenk GL
|title=Neuropathologic changes in Alzheimer's disease
|journal=J Clin Psychiatry
|volume=64 Suppl 9
|pages=7–10
|year=2003
|pmid=12934968
}}</ref>


===Associated Conditions===
==Genetics==
[[Genetic]] origin of Alzheimer's dementia  (AD) demonstrates an [[autosomal dominant]] pattern of [[Inheritance (genetic algorithm)|inheritance]]. Alzheimer's dementia arising from [[genetic]] alterations may lead to early onset (<60 years) of disease. The following mutations are implicated in the development of AD are:<ref name="urlAlzheimer Disease Overview - GeneReviews® - NCBI Bookshelf">{{cite web |url=https://www.ncbi.nlm.nih.gov/books/NBK1161/ |title=Alzheimer Disease Overview - GeneReviews® - NCBI Bookshelf |format= |work= |accessdate=}}</ref><div style="-webkit-user-select: none;">
===Common genes===
<div style="-webkit-user-select: none;">
 
====Early onset (Alzheimer's dementia-AD 1, 3 and 4)====
30-50 percent of early-onset Alzheimer's dementia (AD) is associated with an [[autosomal dominant inheritance]] and consists of mutations in the following [[genes]]:<ref name="pmid10441572">{{cite journal |vauthors=Campion D, Dumanchin C, Hannequin D, Dubois B, Belliard S, Puel M, Thomas-Anterion C, Michon A, Martin C, Charbonnier F, Raux G, Camuzat A, Penet C, Mesnage V, Martinez M, Clerget-Darpoux F, Brice A, Frebourg T |title=Early-onset autosomal dominant Alzheimer disease: prevalence, genetic heterogeneity, and mutation spectrum |journal=Am. J. Hum. Genet. |volume=65 |issue=3 |pages=664–70 |year=1999 |pmid=10441572 |pmc=1377972 |doi=10.1086/302553 |url=}}</ref><ref name="pmid10593304">{{cite journal |vauthors=Tsuang D, Larson EB, Bowen J, McCormick W, Teri L, Nochlin D, Leverenz JB, Peskind ER, Lim A, Raskind MA, Thompson ML, Mirra SS, Gearing M, Schellenberg GD, Kukull W |title=The utility of apolipoprotein E genotyping in the diagnosis of Alzheimer disease in a community-based case series |journal=Arch. Neurol. |volume=56 |issue=12 |pages=1489–95 |year=1999 |pmid=10593304 |doi= |url=}}</ref>
 
*[[Presenilin 1|Presenilin1]] (''[[Presenilin 1|PS1]]'') [[gene]], also called [[PSEN1]] gene on [[Chromosome 14 (human)|chromosome 14]]  (AD3- 20 to 30 percent cases)
*[[Presenilin|Presenilin 2]] (''[[Presenilin|PS2]]'') [[gene]], also called [[PSEN2]] gene on [[Chromosome 1 (human)|chromosome 1]] (AD4- rare)
 
*[[Point mutations]] in [[Amyloid beta|amyloid beta A4]] [[protein]] [[gene]], also called [[amyloid precursor protein]] (APP) [[gene]] on [[Chromosome 21 (human)|chromosome 21]] are associated in some cases of early onset (< 65 yr) [[familial]] AD cases
 
'''Late onset (Alzheimer's dementia -AD2)'''
 
*[[APOE|Apolipoprotein 4]] [[gene]] ([[APOE|APOE4]]) [[mutation]] is associated with late onset (>60 years) Alzheimer's dementia (AD)<ref name="pmid15123497">{{cite journal |vauthors=Khachaturian AS, Corcoran CD, Mayer LS, Zandi PP, Breitner JC |title=Apolipoprotein E epsilon4 count affects age at onset of Alzheimer disease, but not lifetime susceptibility: The Cache County Study |journal=Arch. Gen. Psychiatry |volume=61 |issue=5 |pages=518–24 |year=2004 |pmid=15123497 |doi=10.1001/archpsyc.61.5.518 |url=}}</ref>
*p.Arg47His [[Allele|allelic]] variant in TREM2 [[gene]]<ref name="pmid23150908">{{cite journal |vauthors=Jonsson T, Stefansson H, Steinberg S, Jonsdottir I, Jonsson PV, Snaedal J, Bjornsson S, Huttenlocher J, Levey AI, Lah JJ, Rujescu D, Hampel H, Giegling I, Andreassen OA, Engedal K, Ulstein I, Djurovic S, Ibrahim-Verbaas C, Hofman A, Ikram MA, van Duijn CM, Thorsteinsdottir U, Kong A, Stefansson K |title=Variant of TREM2 associated with the risk of Alzheimer's disease |journal=N. Engl. J. Med. |volume=368 |issue=2 |pages=107–16 |year=2013 |pmid=23150908 |pmc=3677583 |doi=10.1056/NEJMoa1211103 |url=}}</ref>
 
===Less common genes===
Less common [[genes]] associated with the development of AD are:
 
*A2M on [[Chromosome 12 (human)|chromosome 12]]
*[[ABCA7]]; when suppressed, results in an elevation of [[amyloid]] production
*[[AKAP9]], a [[kinase]] anchor [[protein]] 9 (PRKA) that regulates [[NMDA]] channel activity
 
*There is evidence both for and against [[ADAM10]]
*[[BIN1]], a [[Tumor suppressor gene|tumor suppressor]] [[protein]]
*CALHM1 on [[Chromosome 10 (human)|chromosome 10]]<nowiki/>q24; CALHM1 influences [[calcium]] homeostchaperon has a [[single nucleotide polymorphism]] ([[Single nucleotide polymorphism|SNP]]) associated with late-onset AD
*[[CD2AP]], an adaptor [[molecule]] involved in dynamic [[actin]] remodeling and membrane trafficking
*A [[Single nucleotide polymorphism|SNP]] in [[CD33]]
*[[Clusterin]] (CLU, APOJ), a [[molecular]] [[Chaperone|chaperon]] present in [[senile plaques]] that has CR1 and PICALM, implicated in two genome-wide association studies (GWAS)
*[[Dysferlin]] (encoded by DYSF), associated with several limb-girdle muscular dystrophies; accumulates in Alzheimer patients
*[[EPHA1]] (encoding a [[protein]] that belongs to the [[Eph receptor|ephrin receptor]] subfamily); plays part in [[synaptic]] plasticity
*[[GAB2]] on [[Chromosome 11 (human)|chromosome 11]]<nowiki/>q14 interacting with the [[APOE|APOE e4]] [[allele]]
*GST01 and GST02 on [[Chromosome 10 (human)|chromosome 10]]
*PAX1P1, which encodes for a [[nuclear]] [[protein]] that may function in [[DNA]] repair pathways
*PLD3 on [[Chromosome 19 (human)|chromosome 19]]<nowiki/>q13.2
*[[SORL1]] on [[Chromosome 11 (human)|chromosome 11]]<nowiki/>q23, a protein involved with [[Amyloid precursor protein|APP]] [[protein]] trafficking
*TOMM40, located on [[Chromosome 19 (human)|chromosome 19]]<nowiki/>q very close to the [[APOE]] locus,TOMM40 has been implicated in late-onset AD both by [[linkage analysis]] and by the presence of a variable length poly-T repeat within the [[gene]]
*UNC5C is enriched in [[neurons]] of the [[Hippocampus|hippocampal]] [[Pyramidal cell|pyramidal layer]]
*In a large GWAS meta-analysis, the following genes have been identified as rare causes of Alzheimer's disease:
**[[HLA-DRB5]]/[[HLA-DRB1]]
**SLC24A4
**[[SORL1]]
**PTK2B
**ZCWPW1
**CELF1
**FERMT2
**CASS4
**INPP5D
**[[MEF2C]]
**NME8
*Several other potential loci under investigation on the following chromosomes:
**[[Chromosome 12 (human)|Chromosome 12]]
**[[Chromosome 10 (human)|Chromosome 10]]
**[[Chromosome 2 (human)|Chromosome 2]]<nowiki/>q
**[[Chromosome 9 (human)|Chromosome 9]]<nowiki/>p
**[[Chromosome 15 (human)|Chromosome 15]]<nowiki/>q
**[[Chromosome 19 (human)|Chromosome 19]]<nowiki/>p13
**[[Chromosome 7 (human)|Chromosome 7]]<nowiki/>q36
**[[Chromosome 9 (human)|Chromosome 9]]<nowiki/>q22 (UBQLN1)
**[[Chromosome 1 (human)|Chromosome 1]]<nowiki/>q22
**[[Chromosome 3 (human)|Chromosome 3]]<nowiki/>q23
**[[Chromosome 10 (human)|Chromosome 10]]<nowiki/>q22
**[[Chromosome 11 (human)|Chromosome 11]]<nowiki/>q25
 
 
==Associated Conditions==


*[[Cerebral amyloid angiopathy]]
*[[Cerebral amyloid angiopathy]]
*[[Down's Syndrome]]
*Reccurent respiratory infections ([[pneumonia]])<div style="-webkit-user-select: none;">
<div style="-webkit-user-select: none;">
<div style="-webkit-user-select: none;">
<div style="-webkit-user-select: none;"><div style="-webkit-user-select: none;">
<div style="-webkit-user-select: none;"><div style="-webkit-user-select: none;"><div style="-webkit-user-select: none;">
==Gross Pathology==
*On [[gross pathology]], [[Temporal lobe|temporal]] [[atrophy]] ([[hippocampus]] in particular), dilation of [[lateral ventricles]] and [[third ventricle]] are characteristic findings of Alzheimer's disease.
[[image:Alzheimer's_disease_brain_comparison.jpg|thumb|500px|center|Comparison of alzheimer's disease brain, By derivative work: Garrondo,"Alzheimer's Disease Education and Referral Center, a service of the National Institute on Aging.", via Wikimedia Commons]]
==Microscopic Pathology==
*The [[microscopic]] [[histopathological]] features of alzheimer's disease represent [[neurofibrillary tangles]], [[senile plaques]], [[neuronal]] loss, and with or without [[cerebral amyloid angiopathy]]:
**[[Neurofibrillary tangles]]: Consists of [[Tau protein|tau]], location in the [[hippocampus]], [[cerebral cortex]], [[hypothalamus]]. Dementia severity correlates better with [[neurofibrillary tangles]] number rather than [[Senile plaques|senile plaque]] number
**[[Senile plaques]] or the neuritic plaques consists of two components which are [[Beta amyloid|A-beta amyloid]] which radiate from the center and the neurites with swollen [[axons]]. [[Senile plaques]] are considered to be more specific for alzheimer's than [[neurofibrillary tangles]]
**Loss of [[neurons]]
**With or without [[cerebral amyloid angiopathy]]
[[image:Neurofibrillary_tangles_in_the_Hippocampus_HE_3.JPG|thumb|350px|left| Neurofibrillary tangles in the Hippocampus of an old person with Alzheimer's,  https://creativecommons.org/licenses/by-sa/3.0/deed.en]]
[[image:Neuritic_plaque_HE_stain.jpg|thumb|350px|right| Biopsy specimen displaying a neuritic plaque in a case of Alzheimers Disease,  https://creativecommons.org/licenses/by-sa/3.0/deed.en]]
[[image:NF_tangles_in_the_Hippocampus_Alzheimer_tau_protein.JPG|thumb|350px|center| Neurofibrillary tangles in the Hippocampus of elderly with Alzheimer,  https://creativecommons.org/licenses/by-sa/3.0/deed.en]]


==References==
==References==
{{Reflist|2}}
{{Reflist|2}}
{{WH}}
{{WS}}


[[Category:Psychiatry]]
[[Category:Psychiatry]]
[[Category:Neurology]]
[[Category:Neurology]]
{{WH}}
{{WS}}

Latest revision as of 23:28, 24 September 2020

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Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]; Associate Editor(s)-in-Chief: Syed Hassan A. Kazmi BSc, MD [2], Aravind Reddy Kothagadi M.B.B.S[3]

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Overview

Alzheimer disease (AD), is a progressive neurodegenerative disorder. The dysfunction of amyloid precursor protien (APP) metabolism and the resulting build up of of Aβ peptides and their aggregation in the form of senile plaques in the brain parenchyma of individuals have been considered pivotal for neurodegeneration in the disease. Cognitive impairment in patients with AD is closely associated with synaptic loss in the neocortex and limbic system. In familial forms of AD, mutations result in an increased Aβ production or aggregation, in sporadic AD, failure of the clearance mechanisms might play a key role. Loss of mature neurons and alterations in neural progenitor cells (NPCs) in areas such as the dentate gyrus (DG) of the hippocampus have been found to be responsible for manifestations of AD. On gross pathology, temporal atrophy (hippocampus in particular), dilation of lateral ventricles and third ventricle are characteristic findings of Alzheimer's disease. The microscopic histopathological features of alzheimer's disease consist neurofibrillary tangles, senile plaques, neuronal loss, and with or without cerebral amyloid angiopathy.

Pathophysiology

Alzheimer disease (AD), is a progressive neurodegenerative disorder. The dysfunction of amyloid precursor protien (APP) metabolism and the resulting build up of of Aβ peptides and their aggregation in the form of senile plaques in the brain parenchyma of individuals have been considered pivotal for neurodegeneration in the disease. There is also an accumulation of intracellular neurofibrillary tangles that consist of hyperphosphorylated tau protein and a profound loss of basal forebrain cholinergic neurons that innervate the hippocampus, and the neocortex.

Triggers

The following factors lead to the development of Alzheimer's dementia:

Pathogenesis

The pathogenesis of Alzheimer's dementia (AD) can be explained by four pathological processes. The processes involved in the development of AD and their molecular basis is as follows:[1][2]

(i) Neuronal loss

(ii) Aggregation of extra-cellular amyloid β (Aβ)

Constitutive (nonamyloidogenic) pathway

  • In the constitutive pathway, proteolysis of APP by α- and γ-secretases results in nonpathogenic fragments (sAPPα and α-C-terminal fragment)

Amyloidogenic pathway

(iii) CDK5 pathway

(iv) Formation of intraneuronal neurofibrillary tangles (tau protein accumulation)

Genetics

Genetic origin of Alzheimer's dementia (AD) demonstrates an autosomal dominant pattern of inheritance. Alzheimer's dementia arising from genetic alterations may lead to early onset (<60 years) of disease. The following mutations are implicated in the development of AD are:[20]

Common genes

Early onset (Alzheimer's dementia-AD 1, 3 and 4)

30-50 percent of early-onset Alzheimer's dementia (AD) is associated with an autosomal dominant inheritance and consists of mutations in the following genes:[21][22]

Late onset (Alzheimer's dementia -AD2)

Less common genes

Less common genes associated with the development of AD are:


Associated Conditions

Gross Pathology

Comparison of alzheimer's disease brain, By derivative work: Garrondo,"Alzheimer's Disease Education and Referral Center, a service of the National Institute on Aging.", via Wikimedia Commons

Microscopic Pathology

Neurofibrillary tangles in the Hippocampus of an old person with Alzheimer's, https://creativecommons.org/licenses/by-sa/3.0/deed.en
Biopsy specimen displaying a neuritic plaque in a case of Alzheimers Disease, https://creativecommons.org/licenses/by-sa/3.0/deed.en
Neurofibrillary tangles in the Hippocampus of elderly with Alzheimer, https://creativecommons.org/licenses/by-sa/3.0/deed.en

References

  1. ↑ Crews L, Masliah E (2010). "Molecular mechanisms of neurodegeneration in Alzheimer's disease". Hum. Mol. Genet. 19 (R1): R12–20. doi:10.1093/hmg/ddq160. PMC 2875049. PMID 20413653.
  2. ↑ Weller J, Budson A (2018). "Current understanding of Alzheimer's disease diagnosis and treatment". F1000Res. 7. doi:10.12688/f1000research.14506.1. PMC 6073093. PMID 30135715.
  3. ↑ 3.0 3.1 Beach TG, Walker R, McGeer EG (1989). "Patterns of gliosis in Alzheimer's disease and aging cerebrum". Glia. 2 (6): 420–36. doi:10.1002/glia.440020605. PMID 2531723.
  4. ↑ DeKosky ST, Scheff SW (1990). "Synapse loss in frontal cortex biopsies in Alzheimer's disease: correlation with cognitive severity". Ann. Neurol. 27 (5): 457–64. doi:10.1002/ana.410270502. PMID 2360787.
  5. ↑ Terry RD, Masliah E, Salmon DP, Butters N, DeTeresa R, Hill R, Hansen LA, Katzman R (1991). "Physical basis of cognitive alterations in Alzheimer's disease: synapse loss is the major correlate of cognitive impairment". Ann. Neurol. 30 (4): 572–80. doi:10.1002/ana.410300410. PMID 1789684.
  6. ↑ Boekhoorn K, Joels M, Lucassen PJ (2006). "Increased proliferation reflects glial and vascular-associated changes, but not neurogenesis in the presenile Alzheimer hippocampus". Neurobiol. Dis. 24 (1): 1–14. doi:10.1016/j.nbd.2006.04.017. PMID 16814555.
  7. ↑ Selkoe DJ (1989). "Amyloid beta protein precursor and the pathogenesis of Alzheimer's disease". Cell. 58 (4): 611–2. PMID 2504495.
  8. ↑ Tanzi RE, Gusella JF, Watkins PC, Bruns GA, St George-Hyslop P, Van Keuren ML, Patterson D, Pagan S, Kurnit DM, Neve RL (1987). "Amyloid beta protein gene: cDNA, mRNA distribution, and genetic linkage near the Alzheimer locus". Science. 235 (4791): 880–4. PMID 2949367.
  9. ↑ 9.0 9.1 Walsh DM, Selkoe DJ (2004). "Oligomers on the brain: the emerging role of soluble protein aggregates in neurodegeneration". Protein Pept. Lett. 11 (3): 213–28. PMID 15182223.
  10. ↑ Van Cauwenberghe C, Van Broeckhoven C, Sleegers K (2016). "The genetic landscape of Alzheimer disease: clinical implications and perspectives". Genet. Med. 18 (5): 421–30. doi:10.1038/gim.2015.117. PMC 4857183. PMID 26312828.
  11. ↑ Bendiske J, Bahr BA (2003). "Lysosomal activation is a compensatory response against protein accumulation and associated synaptopathogenesis--an approach for slowing Alzheimer disease?". J. Neuropathol. Exp. Neurol. 62 (5): 451–63. PMID 12769185.
  12. ↑ Volles MJ, Lansbury PT (2002). "Vesicle permeabilization by protofibrillar alpha-synuclein is sensitive to Parkinson's disease-linked mutations and occurs by a pore-like mechanism". Biochemistry. 41 (14): 4595–602. PMID 11926821.
  13. ↑ Selkoe DJ (1999). "Translating cell biology into therapeutic advances in Alzheimer's disease". Nature. 399 (6738 Suppl): A23–31. PMID 10392577.
  14. ↑ Lin H, Bhatia R, Lal R (2001). "Amyloid beta protein forms ion channels: implications for Alzheimer's disease pathophysiology". FASEB J. 15 (13): 2433–44. doi:10.1096/fj.01-0377com. PMID 11689468.
  15. ↑ Nakamura T, Lipton SA (2010). "Redox regulation of mitochondrial fission, protein misfolding, synaptic damage, and neuronal cell death: potential implications for Alzheimer's and Parkinson's diseases". Apoptosis. 15 (11): 1354–63. doi:10.1007/s10495-010-0476-x. PMC 2978885. PMID 20177970.
  16. ↑ Nixon RA, Cataldo AM (2006). "Lysosomal system pathways: genes to neurodegeneration in Alzheimer's disease". J. Alzheimers Dis. 9 (3 Suppl): 277–89. PMID 16914867.
  17. ↑ Matsubara M, Kusubata M, Ishiguro K, Uchida T, Titani K, Taniguchi H (1996). "Site-specific phosphorylation of synapsin I by mitogen-activated protein kinase and Cdk5 and its effects on physiological functions". J. Biol. Chem. 271 (35): 21108–13. PMID 8702879.
  18. ↑ Ittner LM, Ke YD, Delerue F, Bi M, Gladbach A, van Eersel J, Wölfing H, Chieng BC, Christie MJ, Napier IA, Eckert A, Staufenbiel M, Hardeman E, Götz J (2010). "Dendritic function of tau mediates amyloid-beta toxicity in Alzheimer's disease mouse models". Cell. 142 (3): 387–97. doi:10.1016/j.cell.2010.06.036. PMID 20655099.
  19. ↑ Delacourte A, Flament S, Dibe EM, Hublau P, Sablonnière B, Hémon B, Shérrer V, Défossez A (1990). "Pathological proteins Tau 64 and 69 are specifically expressed in the somatodendritic domain of the degenerating cortical neurons during Alzheimer's disease. Demonstration with a panel of antibodies against Tau proteins". Acta Neuropathol. 80 (2): 111–7. PMID 2117840.
  20. ↑ "Alzheimer Disease Overview - GeneReviews® - NCBI Bookshelf".
  21. ↑ Campion D, Dumanchin C, Hannequin D, Dubois B, Belliard S, Puel M, Thomas-Anterion C, Michon A, Martin C, Charbonnier F, Raux G, Camuzat A, Penet C, Mesnage V, Martinez M, Clerget-Darpoux F, Brice A, Frebourg T (1999). "Early-onset autosomal dominant Alzheimer disease: prevalence, genetic heterogeneity, and mutation spectrum". Am. J. Hum. Genet. 65 (3): 664–70. doi:10.1086/302553. PMC 1377972. PMID 10441572.
  22. ↑ Tsuang D, Larson EB, Bowen J, McCormick W, Teri L, Nochlin D, Leverenz JB, Peskind ER, Lim A, Raskind MA, Thompson ML, Mirra SS, Gearing M, Schellenberg GD, Kukull W (1999). "The utility of apolipoprotein E genotyping in the diagnosis of Alzheimer disease in a community-based case series". Arch. Neurol. 56 (12): 1489–95. PMID 10593304.
  23. ↑ Khachaturian AS, Corcoran CD, Mayer LS, Zandi PP, Breitner JC (2004). "Apolipoprotein E epsilon4 count affects age at onset of Alzheimer disease, but not lifetime susceptibility: The Cache County Study". Arch. Gen. Psychiatry. 61 (5): 518–24. doi:10.1001/archpsyc.61.5.518. PMID 15123497.
  24. ↑ Jonsson T, Stefansson H, Steinberg S, Jonsdottir I, Jonsson PV, Snaedal J, Bjornsson S, Huttenlocher J, Levey AI, Lah JJ, Rujescu D, Hampel H, Giegling I, Andreassen OA, Engedal K, Ulstein I, Djurovic S, Ibrahim-Verbaas C, Hofman A, Ikram MA, van Duijn CM, Thorsteinsdottir U, Kong A, Stefansson K (2013). "Variant of TREM2 associated with the risk of Alzheimer's disease". N. Engl. J. Med. 368 (2): 107–16. doi:10.1056/NEJMoa1211103. PMC 3677583. PMID 23150908.

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