Increased Genetic Risk for ADHD Potentiates Cognitive Impairment and Brain Hypometabolism in Alzheimer’s Disease Patients

Abstract

AbstractBackgroundRecent epidemiological studies showed that patients with attention‐deficit/hyperactivity disorder (ADHD) are more likely to be diagnosed with Alzheimer’s Disease (AD). Additionally, increased genetic risk for ADHD, measured with ADHD polygenic risk scores (ADHD‐PRS), was associated with amyloid‐dependent cognitive decline in older adults. However, it is unclear whether higher genetic risk for ADHD is associated with worse cognitive function in patients with AD dementia.MethodWe used data from the Alzheimer’s Disease Neuroimaging Initiative (ADNI) to investigate the association between cognitive function (Preclinical Alzheimer Cognitive Composite [PACC], executive function, and memory) and ADHD‐PRS in subjects with AD dementia. Additionally, we tested whether ADHD‐PRS potentiated brain hypometabolism measured with [18F]FDG‐PET. Analyses were controlled by age, sex, years of study, and number of APOE ε4 alleles.ResultWe evaluated baseline data from 264 AD patients (114 women [43.2%], mean [SD] age of 75 [7.6] years). ADHD‐PRS was associated with decreased cognitive function (p‐value = .04, η2 = .01, Figure 1a), more specifically in executive function (p‐value = .04, η2 = .01, Figure 1c). Higher ADHD‐PRS was associated with brain hypometabolism in frontal, parietal, and temporal regions (Figure 2a,b). Brain hypometabolism correlated with worse cognitive function in the following regions: postcentral gyrus (p‐value = .01, η2 = .03), superior parietal gyrus (p‐value = .001, η2 = .07), precentral gyrus (p‐value = .004, η2 = .05), and fusiform gyrus (p‐value<.0001, η2 = .08, Figure 2c,d,e,f). Finally, decreased metabolism in these four regions mediated the effect of ADHD‐PRS on cognitive function (Figure 3).ConclusionFindings indicate that a higher genetic risk for ADHD is correlated with impaired cognitive function with small effect sizes. Moreover, the effects of the genetic risk of ADHD on cognitive function were mediated by hypometabolism in frontal, parietal, and temporal brain regions, which could point to a decrease resilience to AD pathology in individuals with ADHD. Clinically, our findings suggest that patients with comorbid ADHD and AD dementia have a more severe disease phenotype, with potential implications for prognosis and treatment.