The trajectory of cognitive decline in patients with late-onset Alzheimer’s disease varies widely. Genetic variations in CLU (clusterin), PICALM (phosphatidylinositol binding clathrin assembly protein), and CR1 (complement component (3b/4b) receptor 1) are associated with Alzheimer’s disease, but it is unknown whether they exert their effects by altering the trajectory of cognitive decline in elderly subjects at risk for the disease.

In this study, the authors developed a Bayesian model to fit trajectories of cognitive decline and tested for genetic effects. They validated the model by examining previously established effects of APOE ε4 alleles on age at cognitive decline and of psychosis on the rate of cognitive decline.  This involved 802 subjects from the Cardiovascular Health Cognition Study who did not have dementia at study entry and developed incident dementia during follow-up. The authors then evaluated the effects of CLU, PICALM, and CR1 on age and rate of decline in 1,831 subjects who did not have dementia at study entry and then did or did not develop dementia by study’s end.

CLU and CR1 were associated with more rapid cognitive decline. PICALM was associated with an earlier age at midpoint of cognitive decline in these test subjects. Associations remained after accounting for the effects of APOE and demographic factors.

Sweet RA, Seltman H, Emanuel JE, Lopez OL, Becker JT, Bis JC, Weamer EA, Demichele-Sweet MA, Kuller LH: Effect of Alzheimer’s disease risk genes on trajectories of cognitive function in the cardiovascular health study. Am. J. Psychiatry 169(9):954-962 (2012).

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