Background Cognitive decline, including verbal memory and executive function, is among the most feared aspects of growing old, as it frequently heralds onset of dementia spectrum and other adverse health-related outcomes including mortality. Understanding the source of individual differences in withstanding the onslaught of cognitive ageing may highlight how best cognitive abilities may be retained into advanced age.
Methods Using a population representative sample of n=5088 adults aged ≥50 years from the English Longitudinal Study of Ageing, we investigated relationships of polygenic predisposition to general cognition with a rate of change in cognition during a 10-year follow-up period. Polygenic score for general cognition (GC-PGS) was calculated by summing the effect of cognition-associated alleles weighted according to the strength of their effect estimates. Cognition was measured employing tests for verbal memory and semantic fluency. To assess the relationships of PGSs with verbal memory and semantic fluency and to estimate the mean change in each of these cognitive domains over a period of 10 years, we employed linear mixed effect models (LMMs) with maximum likelihood estimation. All analyses were adjusted for age, sex, year of birth, APOE-ε4 and genetic ancestry (as was measured with principal components) to account for any ancestry differences in genetic structures that could bias our results; to capture the non-linear effects of ageing, we further included age2 as a covariate.
Results The average baseline memory score was 11.1 (SD=2.9) and executive function score was 21.5 (SD=5.8). An increase in GC-PGS by one standard deviation (1-SD) was associated with a higher baseline verbal memory by an average 0.27 points (95%CI=0.19 to 0.34, p<0.001). Similarly, 1-SD increase in GC-PGS was associated with a higher semantic fluency score at baseline (β=0.45, 95%CI=0.27 to 0.64, p<0.001). Nonetheless, 1-SD increase in GC-PGS was not associated with decreases in verbal memory nor semantic fluency during the 10-year follow-up period.
Conclusion Drawing on a large, phenotypically well-defined sample of population-representative adults, we demonstrated for the first time that common genetic variants associated with general cognition additively are associated with a stable surplus to cognition in adults. However, our results showed that a polygenic predisposition to general cognition is not associated with age-related cognitive decline during a 10-year follow-up reiterating previous assertations that the rate of cognitive decline in the general population may be primarily driven by environmental factors.
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