Attention-deficit/hyperactivity disorder polygenic risk score and incidence of cognitive impairment in older adults: A prospective multicohort study.

INTRODUCTION

Preliminary evidence suggests a link between attention-deficit/hyperactivity disorder (ADHD) and later-life cognitive impairment. Whether genetic risk for ADHD, estimated using an ADHD polygenic risk score (ADHD-PRS), is associated with incident cognitive impairment (mild cognitive impairment or Alzheimer's disease dementia) remains unknown.

METHODS

We analyzed 7761 cognitively unimpaired (CU) older adults with whole-genome sequencing from eight cohorts participating in the Alzheimer's Disease Sequencing Project (ADSP).

RESULTS

During follow-up, 1347 participants developed cognitive impairment. Ten-year cumulative incidence was 33.8% in the highest ADHD-PRS tertile versus 23.4% in the lowest. In Cox models, higher ADHD-PRS remained associated with greater risk of cognitive impairment after adjustment for education, apolipoprotein E (APOE) ε4 status, or vascular risk. PRSs for other major psychiatric disorders were not associated with cognitive impairment in the same analytic framework. In a subsample with biomarker data, the association was not modified by baseline amyloid-β status.

DISCUSSION: These findings support ADHD-PRS as a novel correlate of cognitive impairment and vulnerability in aging.