Genetics and pathology of Alzheimer’s disease!
(By dr deeksha)
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Approximately 10% of all cases of Alzheimer’s disease (AD) early-onset familial AD (FAD) -autosomal dominant inheritance.
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Mutations in the Presenilin 1 (PS1) (more common) gene on chromosome 14 and the related gene Presenilin 2 (PS2) on chromosome 1 - causative in approximately 50% of pedigrees with FAD - mostly missense substitutions
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These mutations lead to a gain of function, such that the γ secretase complex generates increased amounts of Aβ, particularly Aβ42.
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Aβ40 and Aβ42 are the predominant soluble Aβ peptides in the brain, and Aβ42 is the most amyloidogenic of the Aβ species that are deposited in senile plaques.
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The genetic locus on chromosome 19 that encodes apolipoprotein E (ApoE) has a strong influence on the risk of developing AD. Three alleles exist (ε2, ε3, and ε4) based on two amino acid polymorphisms.
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The dosage of the ε4 allele increases the risk of AD and lowers the age of onset of the disease
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The number of neurofibrillary tangles correlates better with the degree of dementia than does the number of neuritic plaques
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Biochemical markers that have been correlated with the degree of dementia - loss of choline acetyltransferase, synaptophysin immunoreactivity, and amyloid burden