Alzheimer's disease pathophysiology

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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]

(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:[19]

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:[20][21]

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

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