— Research offers insight into the possibility of predicting Alzheimer's risk decades ahead

PHILADELPHIA — Specific blood biomarkers associated with Alzheimer’s disease — particularly amyloid-beta 42/40 ratios and measures of phosphorylated tau 181 (p-tau181) — were found to be linked to later-life dementia, a retrospective study has revealed.

These midlife biomarkers demonstrated a long-lasting association with amyloid positivity and eventual dementia, according to findings shared by Priya Palta, PhD, MHS, of the UNC School of Medicine in Chapel Hill, during a presentation at the Alzheimer’s Association International Conference.

An increased dementia risk was observed with every standard deviation (SD) change in midlife plasma amyloid-beta 42/40 ratio (HR 1.11, 95% CI 1.02-1.21) and midlife plasma p-tau181 levels (HR 1.15, 95% CI 1.06-1.25), Palta and colleagues reported in their study published in JAMA.

The study also highlighted the significance of late-life levels of amyloid, tau, neurofilament light chain (NfL), and glial fibrillary acidic protein (GFAP), which appeared to be markers of dementia as well. NfL is linked to neuronal damage, while GFAP signifies astrogliosis.

“This is a robust dataset that tracked individuals for decades, including a substantial portion of African American participants,” noted Stephen Salloway, MD, MS, of Brown University in Providence, Rhode Island, who authored a corresponding editorial in JAMA.

The results, Salloway noted, suggest that “as we improve early detection and refine prevention strategies, we may, in the future, be able to pinpoint individuals at risk for Alzheimer’s disease many years — even decades — before symptoms first appear. This would allow for risk reduction interventions or treatments aimed at slowing or stopping the disease,” he shared during a JAMA podcast.

“We’re not yet at the stage where we can implement wide-scale screenings for midlife adults based on these findings,” Salloway cautioned.

However, the research “points toward the possibility of future advancements in precision testing. As our methods and sensitivity improve, one day we might be able to identify those on the path to Alzheimer’s long before cognitive decline occurs,” he added, calling the concept “exciting, though futuristic.”

The research team led by Palta utilized data from the Atherosclerosis Risk in Communities Neurocognitive Study (ARIC-NCS), a diverse cohort of middle-aged adult participants recruited in the late 1980s.

The study analyzed data from 1,525 participants retrospectively, collecting blood biomarkers during midlife (average age 58) and later life (average age 76). Relationships between these biomarkers and the incidence of all-cause dementia were examined in a subgroup of 1,339 individuals who were dementia-free by 2011-2013 and had biomarker data recorded in both 1993-1995 and 2011-2013.

Of the total participants, 59.9% were women and 25.8% were Black. Dementia diagnoses were made based on neuropsychological testing, contact with participants or their informants, and medical record reviews. In total, 252 individuals (16.5%) developed dementia in later life.

Amyloid-beta 42/40 ratios decreased while p-tau181, NfL, and GFAP levels increased from midlife to late life, pointing to a rising Alzheimer’s disease pathology. These biomarker changes accelerated in carriers of the APOE4 allele.

Midlife hypertension was associated with a 0.15-SD faster rise in NfL and a 0.08-SD faster rise in GFAP per decade. Midlife diabetes led to a 0.11-SD and 0.15-SD faster increase in NfL and GFAP, respectively.

It was primarily midlife amyloid and tau biomarkers that exhibited long-term relationships with future dementia, while all late-life biomarkers showed statistically significant links to dementia risk. Plasma NfL had the strongest association with late-life dementia (HR 1.92, 95% CI 1.72-2.14).

“There is a lack of research studying how blood biomarkers change across mid- to late-life, particularly within diverse, community-based cohorts, and how midlife cardiometabolic conditions affect these changes,” Palta explained.

“Understanding these interactions could provide new insights on maintaining brain health in people at risk, tracking disease progression, and identifying candidates for potential treatment,” Palta added.

However, the study had limitations, including that plasma biomarkers were measured only at three time points. Moreover, only modest relationships between p-tau181 and dementia were recorded; alternative assays like p-tau217 might show stronger correlations.

Disclosures

The Atherosclerosis Risk in Communities (ARIC) study is funded through NIH grants, with biomarker data collection partially supported by the National Institute on Aging (NIA).

Palta received partial support from NIA grants.

Salloway disclosed multiple connections with industry sponsors.

Primary Source

JAMA

Reference: Lu Y, et al. “Blood biomarkers of Alzheimer’s and incident all-cause dementia.” JAMA 2024; DOI: 10.1001/jama.2024.6619.

Secondary Source

JAMA

Reference: Salloway S, et al. “Are blood tests for Alzheimer’s ready for broad use?” JAMA 2024; DOI: 10.1001/jama.2024.12814.