Blood test can identify signs of accumulation of highly accurate Alzheimer’s Disease (AD)–associated biomarkers in the brains of middle-aged adults, a large community-based cohort study has shown.
“AD neuropathology, characterized by amyloid ß [Aß] and p-tau protein accumulation, has primarily been assessed with biomarkers in clinical samples of older adults,” wrote the researchers. “Less is known about plasma biomarkers of AD neuropathology and their associations with cognitive outcomes in midlife in diverse community-based samples.” [Lancet 2026;407:2208-2216]
To address these gaps, the researchers identified 2,248 participants from the CARDIIA study who attended the year 35 clinical visit. Among them, 1,500 participants were randomly selected for plasma biomarker measurement, but 150 were excluded due to lack of cognitive measures, poor assay quality, and probable dementia, resulting in a final cohort of 1,350 dementia-free adults (mean age, 61 years; female, 42 percent).
“This study is among the first to examine early AD neuropathology biomarkers and their associations with cognition in midlife,” noted the researchers.
AD neuropathology present in midlife
AD neuropathology positivity was characterized by plasma p-tau217-to-Aβ42 ratio (p-tau217/Aβ42), Aβ42-to-Aβ40 ratio (Aβ42/40), and p-tau217.
AD neuropathology positivity was present in 86 participants (6 percent) based on p-tau217/Aβ42, 196 (15 percent) based on Aβ42/40, and 48 (4 percent) based on p-tau217.
“Compared with individuals who were negative for AD neuropathology, participants who tested positive were more likely to be APOE ε4 carriers [p<0.0001],” pointed out the researchers.
Worse cognitive performance, accelerated cognitive decline
“As early as at the mean age of 61 years, individuals without dementia who tested positive for AD neuropathology showed worse cognitive performance and higher odds of accelerated decline compared with individuals who tested negative for AD neuropathology,” highlighted the researchers.
AD neuropathology positivity was associated with worse performance in both processing speed (Aß42/40: standardised cognitive difference [β], -0.25; p-tau217: β, -0.54; p-tau217/Aß42: β, -0.34; p<0.05 for all) and executive function (Aβ42/40: β, -0.19; p-tau217: β, -0.42; p-tau217/Aβ42: β, -0.27; p<0.05 for all) vs AD neuropathology negativity.
AD neuropathology positivity was also associated with higher odds of 5-year accelerated decline in both verbal memory (Aß42/40: odds ratio [OR], 4.31; 95 percent confidence interval [CI], 1.71–10.9; p-tau217/Aß42: OR, 2.44; 95 percent CI, 1.16–5.13) and processing speed (p-tau217: OR, 3.98; 95 percent CI, 1.71–9.3; p-tau217/Aß42: OR, 3.35; 95 percent CI, 1.77–6.35) vs AD neuropathology negativity. However, there was no association for global cognition or fluency.
“Our results extend previous work on AD biomarkers in older adults by showing that evidence of AD neuropathology is present in midlife, which, although infrequent, is already linked to measurable cognitive differences,” commented the researchers.
Clinical implications
These findings show the potential of detecting AD neuropathology among middle-aged adults with the use of highly accurate plasma biomarkers.
This could enable timely intervention targeting modifiable risk factors and pharmacological therapies for AD neuropathology in midlife, to potentially delay the onset of clinical symptoms and the development of clinical AD.