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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.

SUBMITTER: Thambisetty M

PROVIDER: S-EPMC3488132 | biostudies-literature | 2013 Mar

REPOSITORIES: biostudies-literature

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Alzheimer risk variant CLU and brain function during aging.

Thambisetty Madhav M Beason-Held Lori L LL An Yang Y Kraut Michael M Nalls Michael M Hernandez Dena G DG Singleton Andrew B AB Zonderman Alan B AB Ferrucci Luigi L Lovestone Simon S Resnick Susan M SM

Biological psychiatry 20120715 5

<h4>Background</h4>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.<h4>Methods</h4>Subjects were participants in the Baltimore Longitudinal Study of Aging. A subset of 88 cognitively normal older individuals ...[more]

PMID: 22795969

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Project description:Background"Brain-predicted age" estimates biological age from complex, nonlinear features in neuroimaging scans. The brain age gap (BAG) between predicted and chronological age is elevated in sporadic Alzheimer disease (AD), but is underexplored in autosomal dominant AD (ADAD), in which AD progression is highly predictable with minimal confounding age-related co-pathology.MethodsWe modeled BAG in 257 deeply-phenotyped ADAD mutation-carriers and 179 non-carriers from the Dominantly Inherited Alzheimer Network using minimally-processed structural MRI scans. We then tested whether BAG differed as a function of mutation and cognitive status, or estimated years until symptom onset, and whether it was associated with established markers of amyloid (PiB PET, CSF amyloid-β-42/40), phosphorylated tau (CSF and plasma pTau-181), neurodegeneration (CSF and plasma neurofilament-light-chain [NfL]), and cognition (global neuropsychological composite and CDR-sum of boxes). We compared BAG to other MRI measures, and examined heterogeneity in BAG as a function of ADAD mutation variants, APOE ε4 carrier status, sex, and education.ResultsAdvanced brain aging was observed in mutation-carriers approximately 7 years before expected symptom onset, in line with other established structural indicators of atrophy. BAG was moderately associated with amyloid PET and strongly associated with pTau-181, NfL, and cognition in mutation-carriers. Mutation variants, sex, and years of education contributed to variability in BAG.ConclusionsWe extend prior work using BAG from sporadic AD to ADAD, noting consistent results. BAG associates well with markers of pTau, neurodegeneration, and cognition, but to a lesser extent, amyloid, in ADAD. BAG may capture similar signal to established MRI measures. However, BAG offers unique benefits in simplicity of data processing and interpretation. Thus, results in this unique ADAD cohort with few age-related confounds suggest that brain aging attributable to AD neuropathology can be accurately quantified from minimally-processed MRI.

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Alzheimer risk variant CLU and brain function during aging.

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Alzheimer risk variant CLU and brain function during aging.

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