How are genes associated with Alzheimer disease?

How are genes associated with Alzheimer disease?

Alzheimer disease (AD) is responsible for 50% to 80% of cases of progressive cognitive impairment (dementia) among older adults.

It affects approximately 1 in 10 individuals older than 65 years of age and 1 in 3 individuals older than 85 years of age.

Due to the aging of the population, the number of Americans with AD is predicted to increase substantially during the coming decade.

AD is characterized by progressive dementia and memory loss and by the formation of amyloid plaques and neurofibrillary tangles in the brain, particularly in the cerebral cortex and hippocampus.

The plaques and tangles lead to progressive neuronal loss, and death usually occurs within 7 to 10 years after the first appearance of symptoms.

The risk of developing AD doubles in individuals who have an affected first-degree relative.

Although most cases do not appear to be caused by single loci, approximately 10% follow an autosomal dominant mode of transmission.

Approximately 5% of AD cases occur before age 65 and are considered early onset; these are likely to be an autosomal dominant inheritance.

AD is a genetically heterogeneous disorder.

Approximately half of early-onset cases can be attributed to mutations in any of three genes, all of which affect amyloid-β deposition.

Two of the genes, presenilin 1 
(PSEN1)
 and presenilin 2 
(PSEN2),
 are very similar to one another, and their protein products are involved in cleavage of the amyloid-β precursor protein (APP).

When APP is not cleaved normally, a long form of it accumulates excessively and is deposited in the brain. This is thought to be a primary cause of AD.

Mutations in 
PSEN1
 typically result in early-onset AD, with the first occurrence of symptoms in the fifth decade of life.

A small number of cases of early-onset AD are caused by mutations of the gene that encodes APP itself, which is located on chromosome 21.

These mutations disrupt normal cleavage sites in APP, again leading to the accumulation of the longer protein product.

This gene is present in three copies in trisomy 21 individuals, in which the extra gene copy leads to amyloid deposition and the occurrence of AD in those with Down syndrome.

High-throughput DNA sequencing (techniques allowing the sequencing of massive amounts of DNA at once) studies have revealed an allele in APP that is protective against AD and may help to prevent cognitive decline.

An important risk factor for the more common late-onset form of AD is allelic variation in the apolipoprotein E (APOE) locus, which has three major alleles
: ε2, ε3
, and 
ε4
.

Studies conducted in diverse populations shows that persons who have one copy of the 
ε4
 allele are at least 2 to 5 times more likely to develop AD, whereas those with two copies of this allele are at least 5 to 10 times more likely to develop AD.

The risk varies somewhat by population, with higher 
ε4
-associated risks in Europeans and Japanese and relatively lower risks in Hispanics and Blacks.

Despite the strong association between 
ε4
 and AD, approximately half of individuals who develop late-onset AD do not have a copy of the 
ε4
 allele, and many who are homozygous for 
ε4
 remain free of AD even at advanced age.

The APOE protein product is not involved in cleavage of APP but instead appears to be associated with clearance of amyloid from the brain.

Recent studies reveal, at least 20 additional genes are associated with AD. How are genes associated with Alzheimer disease?