Genetic risk for attention‐deficit/hyperactivity disorder is associated with amyloid‐dependent cognitive decline in older adults

Background Recent epidemiological studies using population‐based registers showed that patients with Attention‐Deficit/Hyperactivity Disorder (ADHD) are more likely to be diagnosed with mild cognitive impairment (MCI) and Alzheimer’s disease (AD), suggesting a higher risk for cognitive impairment in older age. Here, we aimed to assess whether genetic liability for ADHD, as measured by a validated polygenic risk score (ADHD‐PRS), is associated with cognitive decline in cognitively unimpaired (CU) subjects and whether these effects vary according to baseline amyloid‐β (Aβ) burden. Method We studied 212 CU participants (116 women [54.7%], mean [SD] age of 73.1 [5.9]) from the Alzheimer’s Disease Neuroimaging Initiative (ADNI) cohort. Subjects had available baseline Aβ burden (measured by [18F]Florbetapir Aβ‐PET) and genetic information, as well as a minimum of 2 cognitive assessments (Preclinical Alzheimer Cognitive Composite [PACC] and MMSE) in a 6‐year period. Aβ positivity was defined using a previously published cutoff of global [18F]Florbetapir PET SUVR > 1.11. We calculated ADHD‐PRS using data from the latest genome‐wide association study on ADHD, with a p‐value threshold of 1. Statistical analyses were performed using linear mixed‐effects models adjusted for age, sex, APOE ε4 status, and the first seven principal components to adjust for population stratification. Result ADHD‐PRS was normally distributed and was not associated with age, sex, or APOE ε4 status (Figure 1). We observed a significant ADHD‐PRS by time interaction (β=‐.03, 95% CI ‐.05 to ‐.01, p‐value=.001 for PACC, β=‐.04, 95% CI ‐.07 to ‐.009, p‐value=.01 for MMSE) on cognitive performance, indicating that higher ADHD‐PRS is associated with decreased cognitive function over time (Figure 2). Additionally, we observed a significant interaction between ADHD‐PRS, time, and baseline Aβ burden (β=‐.05, 95% CI ‐.10 to ‐.008, p‐value=.02 for PACC, β=‐.08, 95% CI ‐.15 to ‐.01, p‐value=.02 for MMSE), suggesting that higher ADHD‐PRS is associated with longitudinal cognitive decline only in Aβ‐positive individuals (Figure 3). Conclusion Our findings indicate that higher genetic liability for ADHD is associated with cognitive decline in Aβ‐positive older adults without cognitive impairment. These findings support the hypothesis that higher rates of MCI and AD in patients with ADHD may result from decreased resilience to Aβ pathology.