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.
Highlights
Sustaining cognitive abilities is a fundamental element for successful aging and a major component of quality of life
The much more abundant form of late onset Alzheimer’s disease (AD) is heritable with genetic contribution of approximately 60% [2] that is caused by complex genetics of which the APOE allele e4 is the primary genetic candidate risk factor [3]
In the 1905 birth cohort, the cognitive composite score was standardised to a mean of 0.0 and a standard deviation (SD) of 1.0 at the baseline assessment at age 93 years and was not significantly different at the later ages i.e. 95, 98 and 100 evaluated from a non-random effect model (Figure 1)
Summary
Sustaining cognitive abilities is a fundamental element for successful aging and a major component of quality of life. The much more abundant form of late onset AD is heritable with genetic contribution of approximately 60% [2] that is caused by complex genetics of which the APOE allele e4 is the primary genetic candidate risk factor [3]. The APOE alleles e4 and e2 have been associated with cognition in the normal range even in the oldest old [4]. Genes and AD have been intensively studied adding up to more than 1200 published genetic association studies [5]. Recent advantages in multistage Genome Wide Association Studies (GWAS) of AD have led to findings of many new genetic risk factors. One of the most appealing findings came from two large independent GWAS studies where association was established with 689 participants provided a blood sample at the assessment in
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