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==Pathogenesis==
==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.  
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:
* The pathogenesis of Alzheimer's dementia (AD) can be explained by three pathological processes. The processes inloved in the development of AD and their molecular basis is as follows:
=== (i) Neuronal loss ===


=== (ii) Aggregation of amyloid β (Aβ) ===
* Amyloid precurosr protein (APP) is physiologically present in normal brains
* It is proteolytically processed by α-, β-, and γ-secretases following two pathways:
'''Constitutive (nonamyloidogenic) pathway'''


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


=== (ii.) Aggregation of amyloid β (Aβ) ===
'''Amyloidogenic pathway'''


=== (iii.) Formation of intraneuronal neurofibrillary tangles ===
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 brains of AD patients.
 
=== (iii) Formation of intraneuronal neurofibrillary tangles ===
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Revision as of 17:56, 17 September 2017

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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 development of AD and their molecular basis is as follows:

(i) Neuronal loss

(ii) Aggregation of amyloid β (Aβ)

  • Amyloid precurosr protein (APP) is physiologically present in normal brains
  • It is proteolytically processed by α-, β-, and γ-secretases following two pathways:

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

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 brains of AD patients.

(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


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