Rare Mutation Triples Risk of Alzheimer's Disease

Nov. 15, 2012— -- A mutation found in about one in 200 elderly Icelanders raised the risk of developing Alzheimer's disease threefold, a new study found.

The mutation, in an immunoregulatory gene known as TREM2, was more common in Alzheimer's disease patients than in the general 85-and-older population in Iceland, according to Dr. Kari Stefansson of deCode Genetics in Reykjavik, Iceland, and colleagues.

Because of the gene's function within the central nervous system, the mutation "may lead to an increased predisposition to Alzheimer's disease through impaired containment of inflammatory processes," the researchers wrote online in the New England Journal of Medicine.

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Such processes have been implicated in Alzheimer's disease previously, they noted. In fact, the so-called amyloid theory of the disease holds that brain inflammation is the "downstream effect" of the accumulation of beta-amyloid protein plaques, Stefansson and colleagues wrote.

On the other hand, the TREM2 mutation's rarity, and the fact that many carriers in the study remained free of Alzheimer's disease into extreme old age, suggested that it is neither necessary nor sufficient to trigger the disease.

In the study, Stefansson and colleagues first analyzed genome sequences from 2,261 Icelanders to identify variants considered likely to produce gain- or loss-of-function mutations in expressed proteins.

They then compared frequencies of such variants in 3,550 individuals with Alzheimer's disease versus 110,050 individuals from the general Icelandic population. Included in the latter group were 8,888 who had reached the age of 85 without a diagnosis of Alzheimer's disease and 1,236 who were that old and showed no sign of cognitive impairment.

The mutation was present in all three control groups at low frequencies, ranging from 0.62 percent in the general population sample to 0.31 percent in the cognitively intact older controls.

Older control members carrying the mutation -- even those without Alzheimer's disease -- had poorer cognitive performance according to test results obtained periodically in Icelandic nursing home residents.

Mean scores in 3,699 noncarriers trended slowly upward by age, indicating progressively poorer cognitive function, from about 2.2 at age 81 to 2.7 at age 99.

The upward slope was noticeably steeper in 53 mutation carriers, increasing from a mean of about 2.3 at age 81 to 4 at age 97.

Stefansson and colleagues also sought to replicate the frequency comparison in Alzheimer's disease patients versus controls in other cohorts. They were able to test the frequency of the TREM2 mutation in groups of patients and controls assembled in the U.S., Germany, the Netherlands, and Norway -- a total of 2,037 patients and 9,727 controls.