APOE4, Blood Neurodegenerative Biomarkers, and Cognitive Decline in Community-Dwelling Older Adults - PubMed (original) (raw)

APOE4, Blood Neurodegenerative Biomarkers, and Cognitive Decline in Community-Dwelling Older Adults

Ted K S Ng et al. JAMA Netw Open. 2025.

Erratum in

Abstract

Importance: Scarce population-based data exist on whether APOE4 modifies associations of blood-based neurodegenerative biomarkers with cognitive decline, particularly in a diverse, biracial population of community-dwelling older adults without dementia.

Objective: To assess whether APOE4 carrier status is associated with an accelerated rate of cognitive decline in older adults without dementia and with elevated neurodegenerative burden.

Design, setting, and participants: This 20-year prospective cohort study started in 1993 and was conducted through 2012 on the South Side of Chicago among community-dwelling older adults without dementia from the longitudinal biracial Chicago Health and Aging Project. The interaction of APOE4 carrier status with prospective associations of serum neurodegenerative biomarkers with global cognitive decline was examined using a mixed-effects regression model, adjusting for demographics and chronic health conditions. Statistical analyses were conducted from June 2024 to January 2025.

Exposure: APOE4 carrier status and serum biomarker levels for total tau (t-tau), neurofilament light (NfL) chain, and glial fibrillary acidic protein (GFAP) measured with a Quanterix Neuroplex kit at baseline.

Main outcomes and measures: Cognitive decline calculated from composite global cognition scores across study waves.

Results: Among 1038 community-dwelling older adults (mean [SD] age, 77.1 [5.9] years; 615 Black [59.2%] and 423 White [40.8%]; 651 female [62.7%]), there was a mean (SD) of 12.8 (3.4) years of education and 343 individuals (33.0%) were APOE4 carriers. Higher levels of blood-based neurodegenerative biomarkers (ie, t-tau, NfL, and GFAP) were associated with a faster rate of cognitive decline among APOE4 carriers than noncarriers. Specifically, compared with noncarriers, APOE4 carriers had annual rates of cognitive decline per 1-log10 unit higher levels in t-tau and GFAP that were accelerated by a β (SD) of -0.03 (0.02) (P = .046) and -0.07 (0.03) (P = .02), respectively. Similarly, compared with noncarriers and participants in the lower NfL tertile, APOE4 carriers with middle and upper tertiles of NfL levels experienced accelerated cognitive decline, with a β (SD) of -0.04 (0.02) (P = .006) and -0.03 (0.02) (P = .07), respectively, although the difference was not significant for upper tertiles.

Conclusions and relevance: This study found that higher levels of neurodegeneration (t-tau), axonal injury (NfL), and reactive astrocytes and neuroinflammation (GFAP) biomarkers were associated with accelerated cognitive decline in genetically susceptible APOE4 carriers. These findings highlight the association of APOE4 with exacerbation of neurodegenerative processes, with not only significant implications for understanding and tracking the progression of neurodegenerative diseases, but also a call for inclusivity of APOE4 status in scientific investigations and clinical trials.

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Conflict of interest statement

Conflict of Interest Disclosures: Dr Dhana reported receiving grants from the Alzheimer's Association and National Institute on Aging paid to Rush University Medical Center outside the submitted work. Dr Desai reported receiving grants from the National Institute on Aging during the conduct of the study. No other disclosures were reported.

Figures

Figure 1.

Figure 1.. Estimated Baseline Levels of Cognitive Function and Annual Rate of Cognitive Decline

Estimated measures are given with 95% CIs by serum neurodegenerative biomarker tertile among APOE4 carriers vs noncarriers. Compared with noncarriers, APOE4 carriers had lower baseline levels of cognitive function and accelerated annual rates of cognitive decline, especially those with upper tertiles of biomarkers. Estimates are derived from the interaction of biomarkers with time since baseline in linear mixed-effects regression models adjusting for demographic and chronic health conditions. Whiskers indicate 95% CIs.

Figure 2.

Figure 2.. Longitudinal Cognitive Decline in Lower and Upper Tertiles of Biomarkers

Models were adjusted for demographic and chronic health conditions to examine the interaction between APOE4 carrier status and the combined associations of biomarkers with global cognitive function.

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