Short telomere length is associated with impaired cognitive performance in European ancestry cohorts

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 (β=0.051 per s.d.-increase of TL; 95% confidence interval (CI): 0.024, 0.077; P=0.0002), and MMSE (β=0.025; 95% CI: 0.002, 0.047; P=0.03), and faster STROOP (β=−0.053; 95% CI: −0.087, −0.018; P=0.003). Effects for DSST were stronger in APOE ɛ4 non-carriers (β=0.081; 95% CI: 0.045, 0.117; P=1.0 × 10−5), whereas carriers performed better in STROOP (β=−0.074; 95% CI: −0.140, −0.009; P=0.03). Causal associations were found for STROOP only (β=−0.598 per s.d.-increase of TL; 95% CI: −1.125, −0.072; P=0.026), with a larger effect in ɛ4-carriers (β=−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 ɛ4-carriers might be at differential risk.

The impact of telomere shortening on human hippocampal neurogenesis: Implications for cognitive function and psychiatric disorder risk

“…The hippocampus is a brain structure important in cognition and mood regulation that is capable of adult neurogenesis due to the retainment of neural progenitors in the dentate gyrus; a specialised niche that allows progenitors to form new, functional neurons (32). Previous studies, including ours, have reported positive associations between peripheral telomere length and hippocampal volume (29,33), and between telomere length and cognitive performance (29,30), and it has been hypothesized that telomere length contributes to this association by moderating the rate of adult neurogenesis (34). This hypothesis is supported by various lines of evidence.…”

“…Genetic and association studies have inferred a causal relationship between telomere length and cognition (73), but no study to-date, has demonstrated a cellular mechanism. Our work supports these findings and demonstrates that telomere shortening affects genes which regulate general cognitive function, in association with reduced hippocampal progenitor cell proliferation.…”

“…In the context of psychiatry, meta-analyses reveal that, in general, psychiatric disorder patients exhibit shorter leukocyte telomere lengths relative to unaffected individuals of equivalent ages, which could contribute to the increased burden of age-related disease (21)(22)(23)(24). In addition to shorter telomere lengths, psychiatric disorder patients frequently exhibit neurological differences such as smaller hippocampi (25)(26)(27), and some studies have suggested a relationship between shortened telomere length and psychiatric disorder neuropathology (28)(29)(30)(31).…”

Differences in cognitive functions between cytomegalovirus-infected and cytomegalovirus-free university students: a case control study

“…Longer telomeres, in turn, were shown to be associated with better cognitive performance in a large meta-analysis 36 .…”

Cognitive performance in survivors of breast cancer and markers of biological aging

“…13,[25][26][27][28] The extant literature supports a role of biological aging and inflammation in cancer-related cognitive difficulties, but substantial gaps remain. Despite some initial investigations of the relationship in aging populations, [29][30][31][32] to our knowledge no study has yet examined whether cellular markers of biological aging correlate with objective and subjective cognitive function in cancer survivors. The goal of the current study was to test the hypothesis that cellular markers of biological aging and inflammation are related to worse subjective cognitive impairment and objective neuropsychological function in survivors of breast cancer.…”