Accelerated Phenotypical Aging in Midlife is Associated with Long-Term Cognitive Decline in Middle-Aged Adults

Sep 30, 2026

Background: PhenoAge is a multi-system, blood-based aging marker derived from common clinical tests of glucose metabolism, inflammation, and kidney and liver function, distinguishing biological aging from chronological age. Higher PhenoAge predicts disability risk, age-related morbidities, and all-cause mortality, while its relationship with early cognitive change in midlife remains unclear. Objective: assess whether accelerated PhenoAge in midlife relates to 10-year cognitive change in middle-aged to older adults.

LanguageEnglish

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Abstract

Background

Methods

Results

Conclusion

DOI: 10. 1002/alz70856_106183 BIOMARKERS POSTER PRESENTATION BIOMARKERS (NON-NEUROIMAGING) Accelerated Phenotypical Aging in Midlife is Associated with Long-Term Cognitive Decline in Middle-Aged Adults Natascha Merten1 Richard J. Chappell 1 Mary Ryan Baumann 1 Adam J Paulsen 1 Huan Li 1 Yanjun Chen 1 Lindsay R Clark 1 Sterling C Johnson 1 James S Pankow2 Art Walaszek 1 Madeleine G Soss 1 1 University of Wisconsin-Madison, Madison, WI, USA 2 University of Minnesota, Minneapolis, MN, USA Correspondence Natascha Merten, University of Wisconsin-Madison, Madison, WI, USA. Email: [natascha.merten@wisc.edu](natascha.merten@wisc.edu) Abstract Background: PhenoAgeisa multi-system blood-based aging marker that uses common clinical tests of glucose metabolism, inflammation and kidney and liver function. This easily-obtained marker determines whether a person isyounger or older on a biological and physiological level than expected by their chronological age. A higher PhenoAge is associated with increased risk of disability, age-related morbidities and all-cause mortality. Its associations with early cognitive changes in midlife is less understood. The aim of this study was to determine whether accelerated PhenoAge in midlife was associated with 10-year cognitive changes in middle-aged to older adults. Methods: This longitudinal study is based on N = 2,630 (54% women; mean age 50 years;Table1)Beaver Dam Offspring Study(BOSS)participants. We measured baseline blood-based clinical markers of health necessary for calculation of PhenoAge and calculated accelerated PhenoAge (PhenoAgeAccel) as the residual of a linear model with chronological age asthe predictor and PhenoAge asthe outcome. We tested Trailmaking Test B (TMT-B) performance at baseline, 5-year and 10-year follow-up. We used a linear mixed-effects model with PhenoAgeAccel as predictor and TMT-B time as outcome, adjusting for random intercepts, sex and education. We repeated models stratified by sex. Results: We found with every additional year older in PhenoAge compared to chronological age at baseline, participants performed worse on the TMT-B at baseline [complete sample: 0.60 seconds slower, 95% Confidence Interval (0.29,0.91); women: 0. 34 (-0.05,0.72); men: 0. 91 (0.41,1.42), Figure 1]. Moreover, with every additional year older in PhenoAge compared to chronological age at baseline, participants hada faster decline in TMT-B over the 10-year follow-up [main effect + wave interaction: complete sample: 0.94 seconds slower (0.58,1.29); women: 0.51 (0.08,0.95); men: 1.48 (0. 90,2.07);Figure 1]. This is an open access article under the terms of the Creative Commons Attribution License, which permits use, distribution and reproduction in any medium, provided the original work is properly cited. © 2025 The Alzheimer’s Association. Alzheimer’s & Dementia published by Wiley Periodicals LLC on behalf of Alzheimer’s Association. Alzheimer’s Dement. 2025;21(Suppl. 2):e106183. [https://doi.org/10.1002/alz70856_106183](https://doi.org/10.1002/alz70856_106183) wi[leyonlinelibrary.com/journal/alz](leyonlinelibrary.com/journal/alz) 1of3 BIOMARKERS Conclusion: Accelerated PhenoAge in midlife was associated with cognitive decline over 10 years, overall and in men. Longer follow-up will be needed to investigate sex differences further and to determine whether PhenoAge might be predictive of the onset of cognitive impairment later in life. If confirmed, PhenoAge could become a cost-effective marker of cognitive decline and dementia and might help identify atrisk individuals early. This could inform targeted prevention and treatment methods to promote healthy brain aging. BIOMARKERS

FAQs

What is PhenoAgeAccel in this study?

PhenoAgeAccel is calculated as the residual from a linear model where chronological age predicts PhenoAge, and the residual represents accelerated or decelerated biological aging.

How were cognitive outcomes measured across time?

Cognitive performance was assessed using the Trail Making Test B (TMT-B) at baseline, 5-year follow-up, and 10-year follow-up.

What were the main findings regarding accelerated PhenoAge and cognition?

Participants with higher PhenoAge relative to chronological age performed worse on TMT-B at baseline and showed faster TMT-B decline over 10 years. The association was observed overall and in men.

Sep 30, 2026

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