Impact of the polygenic risk scores for attention‐deficit/hyperactivity disorder in Alzheimer's disease

Abstract INTRODUCTION Epidemiological studies indicate a link between attention‐deficit/hyperactivity disorder (ADHD) and elevated risk of dementia. However, the impact of ADHD on cognition and Alzheimer's disease (AD) biomarkers in individuals with cognitive impairment remains unclear. METHODS We computed weighted ADHD polygenic risk scores (ADHD‐PRS) in 938 cognitively impaired participants (674 mild cognitive impairment [MCI] and 264 dementia; mean age 73.5 years). A subset underwent cerebrospinal fluid (CSF) analysis for amyloid beta (Aβ) and phosphorylated tau, as well as fluorodeoxyglucose positron emission tomography ([ 18 F]FDG‐PET). RESULTS We observed lower executive function in individuals with high ADHD‐PRS for both MCI and dementia participants. Higher levels of CSF phosphorylated tau, but not Aβ, were observed in dementia participants with higher ADHD‐PRS. Increased ADHD‐PRS was associated with glucose hypometabolism in the frontal and parietal cortices. DISCUSSION ADHD‐PRS is associated with a more severe disease presentation in individuals with cognitive impairment due to dementia, characterized by impaired executive function, elevated tau pathology, and hypometabolism in the frontal and parietal cortices. Highlights We calculated the genetic liability for attention‐deficit/hyperactivity disorder (ADHD) using polygenic risk scores (ADHD‐PRS). Elevated ADHD‐PRS was associated with executive function deficits in individuals with mild cognitive impairment (MCI) or Alzheimer's disease (AD) dementia. Higher levels of cerebrospinal fluid (CSF) phosphorylated tau, but not amyloid beta (Aβ), were observed in dementia participants with higher ADHD‐PRS. Higher ADHD‐PRS was associated with brain hypometabolism in individuals with AD dementia. Hypometabolism in the parietal cortex mediated the effects of ADHD‐PRS on executive function.