Genetic Risk for Attention-Deficit/Hyperactivity Disorder Predicts Cognitive Decline and Development Of Alzheimer’s Disease Pathophysiology in Cognitively Unimpaired Older Adults

Attention-deficit/hyperactivity disorder (ADHD) persists in older age and may be a risk factor for cognitive impairment and Alzheimer’s disease. A recent study published in Molecular Psychiatry aimed to determine whether genetic liability for ADHD, as measured by a well-validated ADHD polygenic risk score, is associated with cognitive decline and the development of Alzheimer’s disease pathophysiology in cognitively unimpaired older adults.

A team of investigators including, from Pitt Psychiatry, Douglas Leffa, MD, PhD (PGY1, Psychiatry Research Pathway); Bruna Bellaver, PhD (postdoctoral associate); Pamela Lukasewicz Ferreira, PhD (postdoctoral associate); Dana Tudorascu, PhD, (Associate Professor of Psychiatry and Biostatistics); Victor Villemagne, MD (Professor of Psychiatry); Ann Cohen, PhD (Associate Professor of Psychiatry); William Klunk, MD, PhD (Distinguished Professor Emeritus of Psychiatry); Thomas Karikari, PhD (Assistant Professor of Psychiatry); Brooke Molina, PhD (Professor of Psychiatry, Psychology and Pediatrics); and Tharick Pascoal, MD, PhD (Assistant Professor of Psychiatry and Neurology), used data from the Alzheimer’s Disease Neuroimaging Initiative (ADNI), a longitudinal multicenter study designed to develop clinical, imaging, genetic, and biochemical biomarkers for the early detection and tracking of Alzheimer’s disease. 

The scientists calculated a weighted ADHD polygenic risk score in 212 cognitively unimpaired individuals ages 55 to 90. The study participants had baseline amyloid-β positron emission tomography, longitudinal cerebrospinal fluid phosphorylated tau at threonine 181 (p-tau181), magnetic resonance imaging, and cognitive assessments for up to six years. Linear mixed-effects models were used to test the association of ADHD polygenic risk score with cognition and Alzheimer’s disease biomarkers.

“This study highlights what many in the field are already discussing: The impact of ADHD can be observed throughout the lifespan, and it might be linked to neurodegenerative conditions, such as Alzheimer’s disease,” said Dr. Leffa, the study’s first author.

Findings from the study provided evidence that higher ADHD polygenic risk score was associated with progressive longitudinal cognitive decline, particularly in memory function. Furthermore, cognitive decline was mostly observed in amyloid-β-positive individuals. Finally, in amyloid-β-positive individuals, higher ADHD polygenic risk score was associated with longitudinal increases in cerebrospinal fluid p-tau181 and brain atrophy in frontal and parietal brain regions.

“With new treatments becoming available at earlier stages of Alzheimer’s progression, it is important to determine risk factors to help better identify patients who are likely to progress to severe disease,” said Dr. Pascoal, the study’s corresponding author.

Genetic risk for attention-deficit/hyperactivity disorder predicts cognitive decline and development of Alzheimer’s disease pathophysiology in cognitively unimpaired older adults
Leffa DT, Ferrari-Souza JP, Bellaver B, Tissot C, Ferreira PCL, Brum WS, Caye A, Lord J, Proitsi P, Martins-Silva T, Tovo-Rodrigues L, Tudorascu DL, Villemagne VL, Cohen AD, Lopez OL, Klunk WE, Karikari TK, Rosa-Neto P, Zimmer ER, Molina BSG, Rohde LA, Pascoal TA, for the Alzheimer’s Disease Neuroimaging Initiative
Molecular Psychiatry (2022).