Dementia: Update for the Practitioner

Early-onset Alzheimer's disease is a rare form of the disease. Fewer than 5 percent of individuals with AD have early-onset Alzheimer's disease. The three known genes, APP, PS1, and PS2, account for a very small number of all Alzheimer's disease cases, under 2 percent. Nevertheless, these genes have helped us understand the pathogenesis leading to the disease. We have seen through cellular and mouse models that with a mutation in the presenilins or the amyloid precursor protein there is an increased production in amyloid-beta 42, which we believe is the primary neurotoxic peptide involved in the pathogenesis of the disease and amyloid plaque production.

A mutation in APP, on chromosome 21, results in autosomal-dominant disease. The presenilin genes also follow an autosomal-dominant pattern of inheritance. If an individual with early-onset disease has a mutation in one of the presenilin genes, PS1 and PS2, his or her children are at a 50 percent risk of inheriting that same mutation and developing the disease.

We believe mutations in presenilin-1 are fully penetrant. The presenilin-1 gene is located on chromosome 14, and this gene accounts for most of the early-onset familial Alzheimer's disease. Onset is usually in the 40s. It is important to note that most families have a unique mutation. If you have a patient with early-onset Alzheimer's disease, who, because of a strong family history, you suspect might have a mutation, genetic testing will sequence the entire gene because there is no panel of common mutations to test for. This is a fairly expensive test.


	The Presenilins
	Presenilin 1 (PS1) Autosomal Dominant Fully Penetrant Chromosome 14 Approximately 30-60% of EOFAD Onset in the 40s Most families with PS1 have unique mutations	Presenilin 2 (PS2) Autosomal Dominant Highly Penetrant, but incomplete Chromosome 1 Explains a very small number of families (mostly Volga Germans) ~1% EOFAD Onset variable (40-80s)

	Characteristics of mutations in the presenilin genes. Courtesy of Jennifer Williamson-Catania, M.S.

Presenilin-2, located on chromosome 1, is also autosomal-dominant and is highly penetrant. There has been some incomplete penetrance, appearing as individuals living to old age and not showing symptoms of the disease. It is a very rare form of the disease. Testing is only clinically available in Spain.

In one family that participated in a Columbia research study, the proband had onset of symptoms in his early 30s and his brother at 27. Both had a very aggressive course of the disease; both died before age 40 and autopsies confirmed that they had AD. Genetic testing revealed that they had a mutation that had not been reported, as we expected, since most families with early-onset AD have unique mutations. The father of these two brothers did have dementia but was not diagnosed with Alzheimer's disease, though because he died in a VA hospital we were able to later confirm with autopsy tissue that he in fact had the same mutation.


	Early-Onset Alzheimer's Disease


	Profile of a family in which the proband and his brother had early-onset Alzheimer's disease. Courtesy of Jennifer Williamson-Catania, M.S.

Just because a family has early-onset familial Alzheimer's disease does not exempt it from late-onset disease. Both grandmothers of the proband had possible Alzheimer's disease and a history of depression.

There was an individual in this family who did not inherit the mutation but, because this was a research study, this person did not find out this result. Although the family was given the opportunity to undergo clinical genetic testing, they chose not to test, so they are unaware that there is a mutation in the family.

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