Alzheimer's disease pathophysiology: Difference between revisions

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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 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]].


== Pathophysiology ==
==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;">
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;">
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=== Triggers ===
===Triggers===
The following factors lead to the development of Alzheimer's dementia:
The following factors lead to the development of Alzheimer's dementia:
*[[Genetics|Genetic]] factors  
 
*[[Genetics|Genetic]] factors
*Environmental factors
*Environmental factors
*[[Chromosomal]] factors
*[[Chromosomal]] factors
==Pathogenesis==
 
===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>
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 ===
====(i) [[Neuronal]] loss====
 
*[[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
*[[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
*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>
*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>
*[[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>  
*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
*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


=== (ii) Aggregation of [[Extracellular|extra-cellular]] [[Amyloid beta|amyloid β]] (Aβ) ===
====(ii) Aggregation of [[Extracellular|extra-cellular]] [[Amyloid beta|amyloid β]] (Aβ)====
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*[[Amyloid precursor protein]] ([[Amyloid precursor protein|APP]]) is [[Physiological|physiologically]] present in normal [[Brain|brains]]
*[[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>
*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  
*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>
*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>
'''Constitutive (non[[amyloidogenic]]) pathway'''
'''Constitutive (non[[amyloidogenic]]) pathway'''
*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)
*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)
'''[[Amyloidogenic]] pathway'''
'''[[Amyloidogenic]] pathway'''
*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>  
 
*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>
*Abnormal accumulation of Aβ is the result of an imbalance between the levels of Aβ production, aggregation and clearance.
*Abnormal accumulation of Aβ is the result of an imbalance between the levels of Aβ production, aggregation and clearance.
*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>  
*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>
*[[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>
*[[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>
*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>
*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>


=== (iii) [[CDK5]] pathway ===
====(iii) [[CDK5]] pathway====
*[[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  
 
*[[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
*Increased activation of [[CDK5]]/[[P35 (gene)|p35]]/p25 has been linked to the [[pathogenesis]] of [[neurodegenerative diseases]] such as AD
*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>
*[[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>


=== (iv) Formation of intraneuronal [[neurofibrillary tangles]] ([[tau protein]] accumulation) ===
====(iv) Formation of intraneuronal [[neurofibrillary tangles]] ([[tau protein]] accumulation)====
 
*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]]
*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]]
*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>
*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>
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*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]]
*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]]


== Genetics ==
==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;">
[[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 ===
===Common genes===
<div style="-webkit-user-select: none;">
<div style="-webkit-user-select: none;">


==== Early onset (Alzheimer's dementia-AD 1, 3 and 4) ====
====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>
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 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)
*[[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
*[[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)'''
'''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>
*[[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>  
*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===
Less common [[genes]] associated with the development of AD are:  
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]]
*A2M on [[Chromosome 12 (human)|chromosome 12]]
* [[BIN1]], a [[Tumor suppressor gene|tumor suppressor]] [[protein]]
*[[ABCA7]]; when suppressed, results in an elevation of [[amyloid]] production
* 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
*[[AKAP9]], a [[kinase]] anchor [[protein]] 9 (PRKA) that regulates [[NMDA]] channel activity
* [[CD2AP]], an adaptor [[molecule]] involved in dynamic [[actin]] remodeling and membrane trafficking
 
* A [[Single nucleotide polymorphism|SNP]] in [[CD33]]
*There is evidence both for and against [[ADAM10]]
* [[Clusterin]] (CLU, APOJ), a [[molecular]] [[Chaperone|chaperon]] present in [[senile plaques]] that has CR1 and PICALM, implicated in two genome-wide association studies (GWAS)
*[[BIN1]], a [[Tumor suppressor gene|tumor suppressor]] [[protein]]
* [[Dysferlin]] (encoded by DYSF), associated with several limb-girdle muscular dystrophies; accumulates in Alzheimer patients
*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
* [[EPHA1]] (encoding a [[protein]] that belongs to the [[Eph receptor|ephrin receptor]] subfamily); plays part in [[synaptic]] plasticity
*[[CD2AP]], an adaptor [[molecule]] involved in dynamic [[actin]] remodeling and membrane trafficking
* [[GAB2]] on [[Chromosome 11 (human)|chromosome 11]]<nowiki/>q14 interacting with the [[APOE|APOE e4]] [[allele]]
*A [[Single nucleotide polymorphism|SNP]] in [[CD33]]
* GST01 and GST02 on [[Chromosome 10 (human)|chromosome 10]]  
*[[Clusterin]] (CLU, APOJ), a [[molecular]] [[Chaperone|chaperon]] present in [[senile plaques]] that has CR1 and PICALM, implicated in two genome-wide association studies (GWAS)
* PAX1P1, which encodes for a [[nuclear]] [[protein]] that may function in [[DNA]] repair pathways  
*[[Dysferlin]] (encoded by DYSF), associated with several limb-girdle muscular dystrophies; accumulates in Alzheimer patients
* PLD3 on [[Chromosome 19 (human)|chromosome 19]]<nowiki/>q13.2
*[[EPHA1]] (encoding a [[protein]] that belongs to the [[Eph receptor|ephrin receptor]] subfamily); plays part in [[synaptic]] plasticity
* [[SORL1]] on [[Chromosome 11 (human)|chromosome 11]]<nowiki/>q23, a protein involved with [[Amyloid precursor protein|APP]] [[protein]] trafficking
*[[GAB2]] on [[Chromosome 11 (human)|chromosome 11]]<nowiki/>q14 interacting with the [[APOE|APOE e4]] [[allele]]
* 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]]
*GST01 and GST02 on [[Chromosome 10 (human)|chromosome 10]]
* UNC5C is enriched in [[neurons]] of the [[Hippocampus|hippocampal]] [[Pyramidal cell|pyramidal layer]]  
*PAX1P1, which encodes for a [[nuclear]] [[protein]] that may function in [[DNA]] repair pathways
* In a large GWAS meta-analysis, the following genes have been identified as rare causes of Alzheimer's disease:  
*PLD3 on [[Chromosome 19 (human)|chromosome 19]]<nowiki/>q13.2
** [[HLA-DRB5]]/[[HLA-DRB1]]
*[[SORL1]] on [[Chromosome 11 (human)|chromosome 11]]<nowiki/>q23, a protein involved with [[Amyloid precursor protein|APP]] [[protein]] trafficking
** SLC24A4
*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]]
** [[SORL1]]
*UNC5C is enriched in [[neurons]] of the [[Hippocampus|hippocampal]] [[Pyramidal cell|pyramidal layer]]
** PTK2B
*In a large GWAS meta-analysis, the following genes have been identified as rare causes of Alzheimer's disease:  
** ZCWPW1
**[[HLA-DRB5]]/[[HLA-DRB1]]
** CELF1
**SLC24A4
** FERMT2
**[[SORL1]]
** CASS4
**PTK2B
** INPP5D
**ZCWPW1
** [[MEF2C]]
**CELF1
** NME8
**FERMT2
* Several other potential loci under investigation on the following chromosomes:
**CASS4
** [[Chromosome 12 (human)|Chromosome 12]]
**INPP5D
** [[Chromosome 10 (human)|Chromosome 10]]  
**[[MEF2C]]
** [[Chromosome 2 (human)|Chromosome 2]]<nowiki/>q
**NME8
** [[Chromosome 9 (human)|Chromosome 9]]<nowiki/>p
*Several other potential loci under investigation on the following chromosomes:
** [[Chromosome 15 (human)|Chromosome 15]]<nowiki/>q  
**[[Chromosome 12 (human)|Chromosome 12]]
** [[Chromosome 19 (human)|Chromosome 19]]<nowiki/>p13  
**[[Chromosome 10 (human)|Chromosome 10]]
** [[Chromosome 7 (human)|Chromosome 7]]<nowiki/>q36  
**[[Chromosome 2 (human)|Chromosome 2]]<nowiki/>q
** [[Chromosome 9 (human)|Chromosome 9]]<nowiki/>q22 (UBQLN1)  
**[[Chromosome 9 (human)|Chromosome 9]]<nowiki/>p
** [[Chromosome 1 (human)|Chromosome 1]]<nowiki/>q22
**[[Chromosome 15 (human)|Chromosome 15]]<nowiki/>q
** [[Chromosome 3 (human)|Chromosome 3]]<nowiki/>q23
**[[Chromosome 19 (human)|Chromosome 19]]<nowiki/>p13
** [[Chromosome 10 (human)|Chromosome 10]]<nowiki/>q22
**[[Chromosome 7 (human)|Chromosome 7]]<nowiki/>q36
** [[Chromosome 11 (human)|Chromosome 11]]<nowiki/>q25
**[[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==


== Associated Conditions ==
*[[Cerebral amyloid angiopathy]]
*[[Cerebral amyloid angiopathy]]
*[[Down's Syndrome]]
*[[Down's Syndrome]]
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==Gross Pathology==
==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.
*On [[gross pathology]], [[Temporal lobe|temporal]] [[atrophy]] ([[hippocampus]] in particular), dilation of [[lateral ventricles]] and [[third ventricle]] are characteristic findings of Alzheimer's disease.


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==Microscopic Pathology==
==Microscopic Pathology==
*The [[microscopic]] [[histopathological]] features of alzheimer's disease represent [[neurofibrillary tangles]], [[senile plaques]], [[neuronal]] loss, and with or without [[cerebral amyloid angiopathy]]:
*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
**[[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

Latest revision as of 23:28, 24 September 2020

Title
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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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