Genetic variations associated with Alzheimer's disease, but do not help predict risk

"One of every 5 persons aged 65 years is predicted to de­velop AD in their lifetime, and genetic variants may play an important part in the development of the disease. The apparent substantial heritability of late-onset AD is inadequately ex­plained by genetic variation within the well-replicated genes," the authors write.

Monique M. B. Breteler, M.D., Ph.D., of University Medical Center Rotterdam, the Netherlands and colleagues conducted a study to identify and strengthen associations of additional loci (the position of a gene on a chromosome) with AD and confirm these in an independent sample. The researchers also examined the contribution of recently identified genes to AD risk prediction in a 3-stage analysis of new and previously pub­lished genome-wide association studies (GWAS) on more than 35,000 persons (8,371 AD cases).

After conducting various analyses from different AD patient and population groups, in the gene discovery phase, the researchers found genome-wide sig­nificance for 2 loci related to AD, one on chromosome 2 and a second locus on chromosome 19, that had not pre­viously been found to achieve genome-wide significance and that appear to be independent of the gene well established to be associated with AD, apolipoprotein E (APOE).

"These findings were replicated in an independent popu­lation. Two recently reported associations were also confirmed. [In analyses including age, sex and APOE genotype], These loci did not im­prove AD risk prediction," the authors write. "The value of these associa­tions may lie in the insights they could provide for research into the pathophysiological mechanisms of AD."

Editorial: Reaching the Limits of Genome-wide Significance in Alzheimer Disease

In an accompanying editorial, Nancy L. Pedersen, Ph.D., of the Karolinska Institutet, Stockholm, Sweden, writes that the findings of this study are a reminder that family history is very important, even for late-onset AD, that was once thought to be sporadic.

"But the world is facing an escalation in AD prevalence now that life expectancy is well past 75 years in most developed countries. Greater portions of the adult population will recognize signs of failing memory and cognitive impairment among their parents who are now among the oldest old. Lessons from increasing num­bers of epidemiological studies with prospective informa­tion indicate that changes in midlife behavior, particularly those that are also conducive to cardiovascular health, can reduce risk of dementia or at least postpone onset. Find­ings such as those reported [in this study] reinforce the futility of using individual genetic risk profiling for AD beyond collecting information on age, sex, family history, and APOE status. The challenge for the clinician today is to ensure that individuals in midlife engage in the well-established, personally advantageous preventive behaviors already associated with benefit."