Alzheimer risk variant CLU and brain function during aging

Abstract

Background: We examined the effect of the novel Alzheimer's disease (AD) risk variant rs11136000 single nucleotide polymorphism in the clusterin gene (CLU) on longitudinal changes in resting state regional cerebral blood flow (rCBF) during normal aging and investigated its influence on cognitive decline in presymptomatic stages of disease progression.

Methods: Subjects were participants in the Baltimore Longitudinal Study of Aging. A subset of 88 cognitively normal older individuals had longitudinal (15)O-water positron emission tomography measurements of rCBF at baseline and up to eight annual follow-up visits. We also analyzed trajectories of cognitive decline among CLU risk carriers and noncarriers in individuals who remained cognitively normal (n = 599), as well as in those who subsequently converted to mild cognitive impairment or AD (n = 95).

Results: Cognitively normal carriers of the CLU risk allele showed significant and dose-dependent longitudinal increases in resting state rCBF in brain regions intrinsic to memory processes. There were no differences in trajectories of memory performance between CLU risk carriers and noncarriers who remained cognitively normal. However, in cognitively normal individuals who eventually converted to mild cognitive impairment or AD, CLU risk carriers showed faster rates of decline in memory performance relative to noncarriers in the presymptomatic stages of disease progression.

Conclusions: The AD risk variant CLU influences longitudinal changes in brain function in asymptomatic individuals and is associated with faster cognitive decline in presymptomatic stages of disease progression. These results suggest mechanisms underlying the role of CLU in AD and may be important in monitoring disease progression in at-risk elderly.

Figure-1. Participants in the Baltimore Longitudinal Study of Aging (BLSA) and its neuroimaging substudy

Schematic illustration of the main BLSA and neuroimaging sub-studies showing the selection of participants whose longitudinal ¹⁵O-water PET and cognitive data were analyzed in this study.

Figure-2. Associations between longitudinal changes in resting regional cerebral blood flow (rCBF) and the AD risk variant rs11136000 SNP in the clusterin gene (CLU) in cognitively normal older individuals

Carriers of the C-allele of the rs11136000 SNP were coded additively (CC=2, CT=1 and TT=0) in a voxel-based multiple regression analysis (SPM5). Highlighted regions show significantly greater longitudinal increases in rCBF in carriers of the risk variant C-allele within the right anterior cingulate cortex (left panel) andbilateral hippocampi (right panel) (R and L; right and left cerebral hemispheres respectively).