Alzheimer’s Signs Hidden in Midlife Brains, Study Shows

Alzheimer’s disease pathology was detected in midlife and was tied to minor changes in cognitive performance in people without dementia, data from a prospective cohort study showed.

This pathology, measured by amyloid and tau blood biomarkers, was uncommon in middle age, and was associated with a higher likelihood of cognitive decline over 5 years, reported Kristine Yaffe, MD, of the University of California San Francisco, and co-authors in The Lancet.

In a cohort of 1,350 middle-age adults, 6% tested positive for Alzheimer’s pathology based on the ratio of plasma phosphorylated tau 217 (p-tau217) to amyloid-beta 42. At baseline, people with positive biomarkers scored lower in processing speed and executive function than those without pathology, but no differences were seen in global cognition or memory.

Five years later, people with baseline Alzheimer’s pathology had more than twice the risk of rapid decline in verbal memory (OR 2.44, 95% CI 1.16-5.13) and a nearly fourfold increased risk of rapid decline in processing speed (OR 3.98, 95% CI 1.71-9.3), suggesting a higher likelihood of developing Alzheimer’s disease.

The study provides novel insights about the presence of Alzheimer’s pathology in midlife adults, Yaffe and colleagues said. “Although not consistent, some effect modification was observed, with stronger associations among women and Black participants and individuals with APOE4,” they noted.

In Alzheimer’s disease, amyloid and tau pathology accumulate years before cognitive decline emerges. “This preclinical phase provides an opportunity for earlier disease detection and interventions to prevent or delay dementia,” observed Tiia Ngandu, MD, PhD, and Anna Rosenberg, PhD, both of the Finnish Institute for Health and Welfare in Helsinki, in an accompanying editorial.

“Emerging blood-based biomarkers provide a minimally invasive approach to assess Alzheimer’s disease-related pathology and show promising diagnostic and prognostic value in symptomatic individuals,” Ngandu and Rosenberg wrote.

However, in “populations with a low pre‑test probability of amyloid-beta positivity, such as younger or cognitively unimpaired adults, the positive predictive value of blood biomarkers decreases, increasing the number of false‑positive results,” the editorialists pointed out.

“In these settings, a positive biomarker result should not be used as a stand-alone indicator without other biological or clinical information,” Ngandu and Rosenberg emphasized. “Therefore, these blood biomarkers are not suitable for large‑scale, untargeted screening for Alzheimer’s disease pathology in cognitively unimpaired populations or in the community.”

Yaffe and co-authors assessed blood levels of Alzheimer’s biomarkers in 1,350 dementia-free participants in the Coronary Artery Risk Development in Young Adults (CARDIA) cohort, a longitudinal U.S. project that started in 1983. Blood was sampled at the year 35 visit, from 2020 to 2022.

Cognition was measured with five standardized tests that evaluated different domains at years 30 and 35. Accelerated cognitive decline in each domain was defined as a 5-year drop that was at least 1.5 standard deviations greater than the cohort mean change.

Plasma p-tau217, amyloid-beta 42, and amyloid-beta 40 levels were assessed with the FDA-approved Fujirebio Lumipulse assay and were used to calculate the ratio of p-tau217 to amyloid-beta 42 and the ratio of amyloid-beta 42 to amyloid-beta 40.

Mean participant age was 61 years and 58% of participants were women; 45% were Black and 55% were white. Alzheimer’s pathology positivity was present in 86 participants (6%) based on the ratio of p-tau217 to amyloid-beta 42, in 196 participants (15%) based on the ratio of amyloid-beta 42 to amyloid-beta 40, and in 48 participants (4%) based on p-tau217.

Midlife adults who were positive and negative for Alzheimer’s pathology differed in key characteristics, including demographics, cardiovascular risk factor profile, and APOE4 status.

The study has several limitations, the researchers said. Longitudinal analysis of biomarker changes or prospective cognitive trajectories was not possible, they acknowledged. Analyses were restricted to CARDIA participants who survived and attended the year 35 examination, which may have influenced the results.

Alzheimer’s blood tests are promoted through direct-to-consumer advertising but should be used with caution, Yaffe noted. “The tests are supposed to be for those with symptoms but many people are getting these tests without symptoms off-label,” she said. “There’s a possibility of false positives and they can only be used for Alzheimer’s, not other dementias, meaning about 60% to 70% of all dementia cases.”