hide
Free keywords:
Adult
Aged
Apolipoprotein E4/genetics
Cognitive Dysfunction/diagnosis/*genetics
Cohort Studies
European Continental Ancestry Group/*genetics
Female
Genetic Carrier Screening
Genotype
Humans
Male
*Mendelian Randomization Analysis
Middle Aged
Neuropsychological Tests/statistics & numerical data
Psychometrics
Statistics as Topic
Telomere/*genetics
Abstract:
The association between telomere length (TL) dynamics on cognitive performance over the life-course is not well understood. This study meta-analyses observational and causal associations between TL and six cognitive traits, with stratifications on APOE genotype, in a Mendelian Randomization (MR) framework. Twelve European cohorts (N=17 052; mean age=59.2+/-8.8 years) provided results for associations between qPCR-measured TL (T/S-ratio scale) and general cognitive function, mini-mental state exam (MMSE), processing speed by digit symbol substitution test (DSST), visuospatial functioning, memory and executive functioning (STROOP). In addition, a genetic risk score (GRS) for TL including seven known genetic variants for TL was calculated, and used in associations with cognitive traits as outcomes in all cohorts. Observational analyses showed that longer telomeres were associated with better scores on DSST (beta=0.051 per s.d.-increase of TL; 95% confidence interval (CI): 0.024, 0.077; P=0.0002), and MMSE (beta=0.025; 95% CI: 0.002, 0.047; P=0.03), and faster STROOP (beta=-0.053; 95% CI: -0.087, -0.018; P=0.003). Effects for DSST were stronger in APOE varepsilon4 non-carriers (beta=0.081; 95% CI: 0.045, 0.117; P=1.0 x 10(-5)), whereas carriers performed better in STROOP (beta=-0.074; 95% CI: -0.140, -0.009; P=0.03). Causal associations were found for STROOP only (beta=-0.598 per s.d.-increase of TL; 95% CI: -1.125, -0.072; P=0.026), with a larger effect in varepsilon4-carriers (beta=-0.699; 95% CI: -1.330, -0.069; P=0.03). Two-sample replication analyses using CHARGE summary statistics showed causal effects between TL and general cognitive function and DSST, but not with STROOP. In conclusion, we suggest causal effects from longer TL on better cognitive performance, where APOE varepsilon4-carriers might be at differential risk.
