Exploring the association between attention-deficit/hyperactivity disorder and cognitive decline

Objectives: ADHD persists throughout the lifespan and has been linked with higher risk for MCI and AD dementia based on large epidemiological studies. Recent findings from our group indicated a correlation between higher genetic liability for ADHD and progressive cognitive decline, as well as the development of AD pathophysiology, in cognitively unimpaired older adults with amyloid deposition at baseline. We aim to further explore the association between ADHD and cognitive decline by investigating the role of genetic risk for ADHD in the cognitive profile, as well as amyloid and tau deposition, in individuals diagnosed with AD or MCI. For that, we will calculate the ADHD-PRS, which is a valid biomarker of ADHD pathology, in individuals that are part of the Alzheimer’s Disease Sequencing Project. Study design: This study will analyze cross-sectional and longitudinal data from cohorts included in the Alzheimer’s Disease Sequencing Project. Analysis plan: We will calculate ADHD-PRS based on the latest GWAS. We will use linear and mixed regression models to test the association between ADHD-PRS and cognitive function (executive function, language, memory, and visuospatial) in cognitively unimpaired, MCI, and AD individuals. Analyses will be controlled for age, sex, and ancestry. Linear and mixed effect models will be used to evaluate the association between ADHD-PRS and fluid biomarkers (amyloid and phosphorylated tau), as well as neuropathology markers of amyloid deposition and neurofibrillary degeneration. We will conduct sensitivity analysis to explore the confounding effects of education, vascular risk factors (using clinical data or post-mortem markers of vascular brain injury), and psychiatric comorbidities (by calculating PRS of major depressive disorder, bipolar disorder, autism spectrum disorder, and schizophrenia). We hypothesized that higher ADHD-PRS will be associated with longitudinal decline in memory and executive function, as well as higher markers of tau pathology. Based on prior results from our group, we also hypothesize that these findings will be observed in individuals with amyloid deposition at baseline.

ADHD is a common neurodevelopmental disorder that persists throughout the lifespan. Recent large epidemiological studies have indicated an increased risk for AD and MCI among individuals with ADHD. The underlying mechanisms linking ADHD and cognitive decline remain unclear, but prior data published by our group supports that individuals with ADHD have reduced resilience to amyloid pathology, leading to a decline in cognition at lower pathological levels. The main goal of this project is to further investigate the association between ADHD and cognitive decline, tau, and amyloid deposition in individuals diagnosed with AD or MCI. For that, we plan to utilize GWAS data from the Alzheimer’s Disease Sequencing Project to calculate ADHD polygenic risk scores (ADHD-PRS), which is a validated marker of ADHD pathology. We will evaluate the association between ADHD-PRS and cognitive function, as well as fluid biomarkers of amyloid and tau pathology. As secondary goals, we aim to investigate the confounding role of the genetics risk for other psychiatric disorders in these associations.