Alzheimer’s: Causes of Alzheimer’s Disease

No one knows exactly what triggers the disease process in Alzheimer’s, but most experts would agree that genetics play a role. In fact, approximately 30 percent of all people with AD have a family history of dementia. On the other hand, that leaves 70 percent of people who do not have a family history of dementia, which suggests that other factors are at work as well in the develop¬ment of Alzheimer’s.


The role of genes is most evident when you consider the family history of people who develop early-onset Alzheimer’s, the kind that begins before age 65. People who have early-onset Alzheimer’s tend to have a strong family history for the disease.

The strong family connection prompted scientists to look more closely at genetics as a cause of AD. What they discovered was that people who have early-onset AD have mutations—unexpected changes in a single gene or in sections of chromosomes—in one of three genes, while those with late-onset AD were likely to carry a variant of a gene called apolipoprotein E epsilon-4, or APOE-4.

The APP Gene on Chromosome 21

The APP gene is responsible for making APP, the membrane pro¬tein that gets lodged between the inside and outside of the cell. The mutations associated with Alzheimer’s occur on the part of the APP that’s sticking out of the cell, which causes the formation of excess beta-amyloid plaques.

People who have Down syndrome carry an extra copy of chromosome 21, which automatically means they produce more APP. Not surprisingly then, autopsies done on people with Down syndrome have revealed changes in the brain similar to those seen in people with Alzheimer’s. People with Down syndrome are also generally younger when they develop AD, with symptoms ap¬pearing in their 40s and 50s. Approximately 25 percent of adults with Down syndrome aged 40 and older have Alzheimer’s. By age 60, the percentage rises to 65 percent. But oddly enough, not everyone with Down syndrome will develop Alzheimer’s.

The Presenilin Genes

The presenilin 1 gene on chromosome 14 and die presenilin 2 gene on chromosome 1 are responsible for the clipping of APP into plaque-producing fragments. There are more than thirty dif¬ferent mutations of these proteins, which can trigger early-onset AD. These mutations promote the production of a specific kind of beta amyloid that is stickier and more prone to producing plaques. The presenilin genes have a strong connection to familial forms of AD, in which the disease strikes several members of the same family. A child whose parent had early-onset Alzheimer’s has a 50 percent chance of getting the disease, too.

Apolipoprotein E

Every person has APOE, which helps transport cholesterol in the blood. The APOE gene has three naturally occurring variants, or alleles, epsilon-2, epsilon-3 and epsilon-4. Carrying one or two variants of epsilon-4 increases the chances that you’ll develop late-onset AD. Scientists believe that APOE epsilon-4 is less effective at dissolving beta amyloid from the brain than the other alleles.

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