Dataset Information

CLU genetic variants and cognitive decline among elderly and oldest old.

ABSTRACT: The CLU gene is one of the prime genetic candidates associated with Alzheimers disease. In the present study CLU genotypes and haplotypes were associated with baseline cognition and the rate of cognitive decline in two cohorts, the Danish 1905 birth cohort (93 years of age in 1998) and the Longitudinal Study of Aging Danish twins (LSADT) (73-83 year old twins in 1997). Both Mini Mental State Examination (MMSE) and a cognitive composite score was attained up to six times for up to 10 years and analysed using random effects models and vital status. The rs11136000 T allele was associated with better baseline cognitive performance both in the LSADT (effect on intercept: 0.41 95% CI [-0.04; 0.87]) and the 1905 birth cohort (effect on intercept: 0.28 95% CI [0.01; 0.55]), although it did not reach significance in the LSADT cohort. However, the rs11136000 T allele was significantly associated with a steeper decline (effect on slope: -0.06 95% CI [-0.11; -0.01]) in the LSADT cohort, but not in the 1905 birth cohort. Haplotype analyses revealed that carriers of the common rs11136000, rs1532278 and rs9331888 TTC haplotype (36%) in the CLU gene performed cognitively better than non-carriers in the 1905 birth cohort (effect on intercept: 0.50 95% CI [0.12; 0.91]) and carriers of a rare TCC haplotype (1%) performed worse on the cognitive composite score (effect on intercept: -1.51 95% CI [-2.92; -0.06]). The association between the TTC haplotype and better cognitive composite score was higher among those surviving past the age of 98 (p?=?0.014), and among these the TTC haplotype was borderline associated with a steep decline (effect on slope: -0.13 95% CI [-0.27; 0.00]). In summery CLU genetic variants associate with cognition in two cohorts, but the genetic effect of CLU seems to regress toward the mean when aging.

SUBMITTER: Mengel-From J

PROVIDER: S-EPMC3828341 | biostudies-literature | 2013

REPOSITORIES: biostudies-literature

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CLU genetic variants and cognitive decline among elderly and oldest old.

Mengel-From Jonas J Thinggaard Mikael M Lindahl-Jacobsen Rune R McGue Matt M Christensen Kaare K Christiansen Lene L

PloS one 20131114 11

The CLU gene is one of the prime genetic candidates associated with Alzheimers disease. In the present study CLU genotypes and haplotypes were associated with baseline cognition and the rate of cognitive decline in two cohorts, the Danish 1905 birth cohort (93 years of age in 1998) and the Longitudinal Study of Aging Danish twins (LSADT) (73-83 year old twins in 1997). Both Mini Mental State Examination (MMSE) and a cognitive composite score was attained up to six times for up to 10 years and an ...[more]

PMID: 24244428

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Project description:Importance:The prevalence of pathologic conditions of the brain associated with Alzheimer disease increases strongly with age. Little is known about the distribution and clinical significance of preclinical biomarker staging in the oldest old, when most individuals without dementia are likely to have positive biomarkers. Objective:To compare the patterns of long-term cognitive decline in multiple domains by preclinical biomarker status in the oldest old without dementia. Design, Setting, and Participants:A longitudinal observational study with a mean (SD) of 12.2 (2.2) years (range 7.2-15.1 years) of follow-up was conducted in an academic medical center from August 24, 2000, to January 14, 2016, including and extending observations from the Ginkgo Evaluation of Memory study. A total of 197 adults who had completed the Ginkgo Evaluation of Memory study, were free of dementia, and were able to undergo magnetic resonance imaging were eligible for a neuroimaging study in 2009. Of these patients, 175 were included in the present analyses; 140 (80%) were cognitively normal and 35 (20%) had mild cognitive impairment. Main Outcomes and Measures:Biomarker groups included amyloid ? negative (A?-)/neurodegeneration negative (ND-), amyloid ? positive (A?+)/ND-, A?-/neurodegeneration positive (ND+), and A?+/ND+ based on Pittsburgh Compound B retention and hippocampal volume in 2009. Participants completed baseline neuropsychological testing from 2000 to 2002 and annual testing from 2004 to 2016. Domains included memory, executive function, language, visual-spatial reasoning, and attention and psychomotor speed. Slopes of decline were evaluated with linear mixed models adjusted for age, sex, and years of education. Results:Of the 175 participants (71 women and 104 men), at imaging, mean (SD) age was 86.0 (2.9) years (range, 82-95 years). A total of 42 participants (24.0%) were A?-/ND-, 32 (18.3%) were A?+/ND-, 35 (20.0%) were A?-/ND+, and 66 (37.7%) were A?+/ND+. On all cognitive measures, the A?+/ND+ group showed the steepest decline. Compared with the A?-/ND- group, the amyloid deposition alone (A?+/ND-) group showed faster decline on tests of verbal and visual memory (-0.3513; 95% CI, -0.5269 to -0.1756), executive function (0.0158; 95% CI, 0.0013-0.0303), and language (-0.1934; 95% CI, -0.3520 to -0.0348). The A?-/ND+ group showed faster visual memory decline than the A?-/ND- reference group (-0.3007; 95% CI, -0.4736 to -0.1279). Conclusions and Relevance:In the oldest old without dementia, presence of either or both A? and hippocampal atrophy is typical (>75%). Isolated hippocampal volume atrophy is associated only with greater decline in memory. However, isolated A? is associated with decline in memory plus language and executive functions. These findings suggest different underlying pathophysiologic processes in the A?+/ND- and A?-/ND+ groups.

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CLU genetic variants and cognitive decline among elderly and oldest old.

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CLU genetic variants and cognitive decline among elderly and oldest old.

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