Alzheimer's disease pathophysiology
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Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]
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Overview
Pathogenesis
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.
- The pathogenesis of Alzheimer's dementia (AD) can be explained by three pathological processes. The processes inloved in the developement of AD and their molecular basis is as follows:
(i.) Neuronal loss
(ii.) Aggregation of amyloid β (Aβ)
(iii.) Formation of intraneuronal neurofibrillary tangles
Triggers
The following factors lead to the development of Alzheimer's dementia:
- Genetic factors
- Environmental factors
- Chromosomal factors
Genetic Factors
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:
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:
- Presenilin1 (PS1) gene, also called PSEN1 gene on chromosome 14 (AD3- 20 to 30 percent cases)
- Presenilin 2 (PS2) gene, also called PSEN2 gene on chromosome 1 (AD4- rare)
- Point mutations in amyloid beta A4 protein gene, also called amyloid precursor protein (APP) gene on chromosome 21 are associated in some cases of early onset (< 65 yr) familial AD cases
Late onset (Alzheimer's dementia -AD2)
- Apolipoprotein 4 gene (APOE4) mutation is associated with late onset (>60 years) Alzheimer's dementia (AD)
- p.Arg47His allelic variant in TREM2 gene
Hypotheses for Alzheimer's dementia
Two major hypothses for the development of Alzheimer's dementia (AD) have been proposed:
Amyloid cascade hypothesis