Three Genotypes Confirmed as Alzheimer's Disease Risk Loci

CR1, CLU, and PICALM confer risk for AD; plasma β-amyloid associated with faster cognitive decline

12 aug 2010-- Three specific genotypes at CLU, PICALM, and CR1 confer risk for Alzheimer's disease (AD), and an apolipoprotein E genotype, APOE ε4, interacts synergistically in those who also have the PICALM variant, according to a study published online Aug. 9 in the Archives of Neurology. A related study in the same issue clarifies the association between plasma β-amyloid (Aβ) and various aspects of cognition.

Gyungah Jun, Ph.D., of Boston University, and colleagues conducted a meta-analysis of studies on AD and the CLU, PICALM, CR1, and APOE genotypes. They included studies with 8,169 elderly cognitively normal controls and 7,070 cases with AD from four ethnic groups (whites, African-Americans, Israeli-Arabs, and Caribbean Hispanics). CLU, PICALM, and CR1 were associated with AD in whites, but not in other ethnicities. The Arab cohort and all except one small white cohort had significant associations between AD and APOE ε4. After adjustments for the presence of APOE ε4, age, and sex, there was reduced evidence for association of AD with PICALM but not CR1 or CLU.

In another study, Stephanie A. Cosentino, Ph.D., of the Columbia University Medical Center in New York City, and colleagues studied 888 ethnically diverse individuals who had two Aβ samples and were free of dementia at the first sample. The study subjects had three visits over about four and a half years; 481 stayed cognitively healthy, 329 were cognitively or functionally impaired but never demented, and 70 developed AD. The researchers found that high baseline plasma Aβ42 and Aβ40 were related to faster cognitive decline in several domains, as was decreasing or relatively stable Aβ42. In cognitively healthy subjects, high baseline plasma Aβ42 and relatively stable or decreasing Aβ42 were also related to faster decline, especially in memory.

"The association between plasma Aβ and multiple aspects of cognition more clearly specifies the previously documented downward trajectory of plasma Aβ with AD onset. The predominant association with memory seen only in healthy elderly individuals also suggests that plasma Aβ is linked with even earlier neurologic changes that may or may not culminate in dementia," Cosentino and colleagues write.

Authors of the first study disclosed financial ties to pharmaceutical and medical device companies.

Abstract - Jun
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Abstract - Cosentino
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