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 (SNP) 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 pre-symptomatic 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 15O-water PET measurements of rCBF at baseline and up to 8 annual follow-up visits. We also analyzed trajectories of cognitive decline among CLU risk carriers and non-carriers both in individuals who remained cognitively normal (N=599) as well as in those who subsequently converted to mild cognitive impairment (MCI) or AD (N=95). Results Cognitively normal carriers of the CLU risk allele show 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 non-carriers who remained cognitively normal. However, in cognitively normal individuals who eventually convert to MCI or AD, CLU risk carriers show faster rates of decline in memory performance relative to non-carriers in the pre-symptomatic 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 pre-symptomatic 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.

Association of Alzheimer’s related genotypes with cognitive decline in multiple domains: results from the Three-City Dijon study

“…CLU was associated with cognition in three domains in four studies: general cognition (3MS 16 and a composite score 34 ), episodic memory 35 and verbal memory. 36 However, in the study reported by Mengel-From et al, 34 CLU was not associated with MMSE as in our study and the association with verbal memory was observed only in the subset of patients who subsequently developed LOAD or Mild Cognitive Impairment. 36 This latter result was interpreted as reflecting an association between CLU and pre-symptomatic stage of LOAD but not between CLU and normal ageing.…”

“…36 However, in the study reported by Mengel-From et al, 34 CLU was not associated with MMSE as in our study and the association with verbal memory was observed only in the subset of patients who subsequently developed LOAD or Mild Cognitive Impairment. 36 This latter result was interpreted as reflecting an association between CLU and pre-symptomatic stage of LOAD but not between CLU and normal ageing. 36 PICALM was associated with general cognition (3MS) in the study reported by Sweet et al, 16 whereas we did not find any association between PICALM and cognitive function.…”

“…36 This latter result was interpreted as reflecting an association between CLU and pre-symptomatic stage of LOAD but not between CLU and normal ageing. 36 PICALM was associated with general cognition (3MS) in the study reported by Sweet et al, 16 whereas we did not find any association between PICALM and cognitive function. Furthermore, previous studies did not report any positive associations for BIN1, whereas we found an association between BIN1 and general cognition (MMSE).…”

A gene−brain−cognition pathway for the effect of an Alzheimer׳s risk gene on working memory in young adults

“…Another study investigating longitudinal effects of rs11136000 in elderly individuals did not find any difference in memory performance measured by the California Verbal Learning Test in individuals who remained cognitively normal throughout the study. However, that study did find that, for individuals that converted to mild cognitive impairment (MCI) or AD, C allele carriers showed quicker rates of decline than the T allele carriers (Thambisetty et al, 2013). …”

Alzheimer's disease risk variant in CLU is associated with neural inefficiency in healthy individuals

“…The CLU variant may also affect neural activity during attention [22] and resting-state alpha-rhythm activity in older healthy subjects [23]. Related neuroimaging studies also suggest that the CLU variant may affect white matter microstructure [24] and hippocampal blood flow [25].…”