ADHD Linked to Late-Life Dementia

People with attention deficit-hyperactivity disorder (ADHD) had a higher risk of late-life dementia or mild cognitive impairment, a retrospective U.S. study suggested.

In a study of more than 187,000 participants, people with ADHD had more than four times the risk of developing mild cognitive impairment or dementia over time versus those without ADHD after accounting for age, sex, and health conditions (HR 4.60, 95% CI 3.99-5.29, P<0.001), reported Tharick Pascoal, MD, PhD, of the University of Pittsburgh, and co-authors.

Adjusting for comorbidities, educational attainment, and healthcare use weakened but did not eliminate the association. Elevated risk persisted in analyses restricted to dementia outcomes only (HR 3.07, 95% CI 2.12-4.44, P<0.001).

Those with the highest genetic risk for ADHD were 35% more likely to develop incident cognitive impairment (HR 1.35, 95% CI 1.25-1.46, P<0.001 for the highest vs lowest quintile), the researchers wrote in JAMA Psychiatry. Among people with cognitive impairment, ADHD was linked to poorer health outcomes and higher healthcare use, they added.

The findings do not prove a causal link, “but seeing the same pattern show up independently in medical records and in people’s genes gives us greater confidence that the association is not simply an artifact of how ADHD gets diagnosed,” Pascoal said in a statement. “Two different kinds of evidence are pointing in the same direction.”

The study builds on other work from Pascoal and colleagues, including a 2022 study that tied ADHD genetic risk to cognitive decline and Alzheimer’s disease pathophysiology in cognitively normal older adults. The current study is the largest and most comprehensive to date to combine clinical diagnoses and genetic risk scores in the same population, the researchers noted.

Pascoal and co-authors used data from the All of Us Research Program, following 187,341 participants ages 50 and older for an average of 10.26 years. All had available electronic health record (EHR) and genomic data.

ADHD and cognitive impairment (defined as mild cognitive impairment or dementia) were determined by EHR algorithms that required multiple diagnoses or medication records. ADHD polygenic risk scores were calculated using data from a large recent genome-wide association study. Covariates included sex at birth, self-identified race and ethnicity, calendar year of cohort entry, and APOE4 status.

The cohort had a mean age of 56 years and 57.3% were female. Most participants (61.6%) were white, 17.3% were Black, and 13.6% were Hispanic.

Overall, 1.6% of participants had ADHD. Among those with ADHD, 6.7% developed cognitive impairment compared with 3.4% of people without ADHD.

Of people who developed cognitive impairment, a comorbid ADHD diagnosis was associated with higher odds of suboptimal mental health (OR 1.69, P=0.01), quality of life (OR 1.66, P=0.02), and social satisfaction (OR 2.39, P<0.001), and higher healthcare use (incidence rate ratio 1.20, P=0.003), suggesting a greater care burden beyond dementia risk.

A key unanswered question is whether treating ADHD modifies cognitive impairment risk, the researchers pointed out. A recent study in Israel suggested that adults with a late-life ADHD diagnosis who were treated with stimulants did not have an elevated dementia risk, but confounding could not be excluded, they said.

Residual confounding may also be a factor in the current study, Pascoal and colleagues noted. Given the long prodromal phase of dementia, reverse causation is a concern. Selection bias that occurs in volunteer research cohorts like All of Us may limit generalizability, they added.

“We’re replicating a pattern that’s been observed in other countries, now in a large U.S. sample, and adding genetic evidence on top of it,” said co-author Douglas Teixeira Leffa, MD, PhD, also of the University of Pittsburgh. “That combination gives us more confidence that ADHD deserves a closer look as a potential factor in cognitive aging.”