ADHD Genetic Risk Probed as Biomarker for Alzheimer

The study covered in this summary was published in medrxiv.org as a preprint and has not yet been peer-reviewed.

Key Takeaways

• Elderly patients with a high attention deficit hyperactivity disorder polygenic risk score but no clinical ADHD diagnosis are at elevated risk for progressive longitudinal cognitive deterioration.

• Cognitive decline was most common in people with amyloid-β (Aβ) pathology confirmed on PET, suggesting that those with a genetic liability for ADHD and those who are Aβ-positive have cognitive susceptibility.

• Longitudinal increases in cerebrospinal fluid (CSF) p-tau₁₈₁ and brain atrophy in the frontal and parietal regions were associated in Aβ-positive individuals with high ADHD-PRS scores, suggesting an elevated susceptibility to tau pathology in patients with ADHD.

Why This Matters

• Although cognitive deficits across various neurocognitive domains have been described extensively in ADHD, no study has yet linked ADHD with a decline in cognitive performance in adults or with progression of Alzheimer’s disease dementia.

• This study used a well-validated ADHD polygenic risk score (ADHD-PRS) to support epidemiologic associations between ADHD and cognitive decline and the development of Alzheimer’s disease in adults with no cognitive impairment.

• The study results indicate that ADHD-PRS can inform the risk of developing cognitive decline in the cognitively unimpaired elderly population in the absence of biomarkers for Alzheimer’s disease.

Study Design

• The researchers used data from the Alzheimer’s Disease Neuroimaging Initiative to develop clinical, imaging, genetic, and biochemical markers for the early detection and tracking of Alzheimer’s disease.

• They used whole-genome information to calculate a weighted ADHD-PRS in 212 cognitively unimpaired people 55 to 90 years of age who had no clinical diagnosis of ADHD.

• Baseline Aβ PET and baseline medical data were available for all study participants, and all had undergone at least two clinical neuropsychologic assessments.

• Patients who experienced major depression or bipolar disorder in the year prior to enrollment were excluded from the study, as were people with a history of schizophrenia and people with a geriatric depression score above 6.

Key Results

• At baseline, all 212 participants had a clinical dementia rating of 0, 196 had longitudinal CSF p-tau₁₈₁ data available, and 193 had MRI data available. Average age of the study participants was 73.1 years, and 54.7% were women.

• A high ADHD-PRS was more likely to be associated with cognitive decline over the 6-year study period, and was also associated with elevated CSF p- tau₁₈₁ and frontoparietal atrophy in Aβ-positive individuals.

• The combined effect of high ADHD-PRS and brain Aβ deposition on cognitive deterioration was greater than either factor alone.

Limitations

• No detail on the clinical assessment of ADHD diagnosis in study participants was reported.

• Patients with neuropsychiatric conditions — such as depression, bipolar disorder, and schizophrenia — were excluded from the study, which limits the external validity of results.

• In ADHD populations treated at clinical centers, psychiatric comorbidities are common, but in this study cohort, there would have been fewer comorbidities, affecting the generalizability of the findings.

• Most of the study participants were White.

Disclosures

• The study received no commercial funding.

• Of the authors, Luis Augusto Rohde, MD, PhD, has received research grants and served as a consultant to Ache, Bial, Medice, Norvartis, Pfizer, and Shire; received authorship royalties from ArtMed; and has acted as a consultant for Knight Therapeutics.

This is a summary of a preprint research study, Genetic Risk for Attention-Deficit/Hyperactivity Disorder Predicts Cognitive Decline and Development of Alzheimer’s Disease Pathophysiology in Cognitively Unimpaired Older Adults, written by researchers from the Department of Psychiatry at the University of Pittsburgh, the Department of Neuroscience at King’s College London, and the Alzheimer’s Disease Neuroimaging Initiative, published on medRxiv and provided to you by Medscape. The study has not yet been peer-reviewed. The full text of the study can be found on medrxiv.org. 

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