Although the heritability of cognitive function in old age is substantial, genome-wide association studies have had limited success in elucidating its genetic basis, leaving a considerable amount of “missing heritability.” Aside from single nucleotide polymorphisms, genome-wide association studies are unable to assess other large sources of genetic variation, such as tandem repeat polymorphisms. Therefore, here, we studied the association of cytosine-adenine-guanine (CAG) repeat variations in polyglutamine disease-associated genes (PDAGs) with cognitive function in older adults. In a large cohort consisting of 5786 participants, we found that the CAG repeat number in 3 PDAGs (TBP, HTT, and AR) were significantly associated with the decline in cognitive function, which together accounted for 0.49% of the variation. Furthermore, in an magnetic resonance imaging substudy, we found that CAG repeat polymorphisms in 4 PDAGs (ATXN2, CACNA1A, ATXN7, and AR) were associated with different imaging characteristics, including brain stem, putamen, globus pallidus, thalamus, and amygdala volumes. Our findings indicate that tandem repeat polymorphisms are associated with cognitive function in older adults and highlight the importance of PDAGs in elucidating its missing heritability.

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