Your Brain Doesn't Look a Day Past 70! Cross-Sectional Associations with Brain-Predicted Age in the Cognitively-Intact Oldest-Old

Britton, M. K.; Hoogerwoerd, H.; Juhasz, J.; Johnson, K. J.; Stewart, P. D.; Merritt, S. S.; Jessup, C. J.; Wright, C. B.; Raichlen, D. A.; Hishaw, G. A.; Del Bene, V. A.; Wadley, V. G.; Trouard, T. P.; Alperin, N.; Levin, B. E.; Rundek, T.; Visscher, K. M.; Alexander, G. E.; Cohen, R. A.; Porges, E. C.; Gullett, J. M.

doi:10.1101/2025.05.26.655855

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bioRxiv · 10.1101/2025.05.26.655855

Your Brain Doesn't Look a Day Past 70! Cross-Sectional Associations with Brain-Predicted Age in the Cognitively-Intact Oldest-Old

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Abstract

The cognitively-intact oldest-old (85+) may be the most-resilient members of their birth cohort; due to survivorship effects (e.g., depletion of susceptibles), risk factors associated with brain aging biomarkers in younger samples may not generalize to the oldest-old. We evaluated associations between established aging-related risk factors and brain-predicted age difference (brainPAD) in a cross-sectional cognitively-intact oldest-old sample. Additionally, we evaluated brainPAD-cognition associations to characterize brain maintenance vs. cognitive reserve in our sample. Oldest-old adults (N = 206; 85-99 years; MoCA > 22 or neurologist evaluation) underwent T1-weighted MRI; brainPAD was generated with brainageR, such that more-positive brainPAD reflected relatively advanced brain aging. Sex, educational attainment, alcohol and smoking history, exercise history, BMI, cardiovascular and metabolic disease history, and anticholinergic medication burden were self-reported. Global cognitive z-score and coefficient of variation were derived from the NACC UDS 3.0 cognitive battery; crystallized-fluid discrepancy was derived from the NIH Toolbox Cognitive Battery. Mean brainPAD was -7.99 (SD: 5.37; range: -24.50, 6.03). Women showed more-delayed brain aging than men (B = -2.35, 95% CI = - 4.28, -0.41, p = 0.018). No other exposures were associated with brainPAD. BrainPAD was not associated with any cognitive variable. These findings suggest that cognitively-intact oldest-old adults may be atypically-resistant to risk factors associated with aging in younger samples, consistent with survivorship effects in aging. Furthermore, brainPAD may have limited explanatory value for cognitive performance in cognitively-intact oldest-old adults, potentially due to high cognitive reserve. Overall, our findings highlight the impact of survivorship effects on brain aging research. HighlightsO_LIBrain-predicted age difference was assessed in cognitively-intact oldest-old ([≥]85) C_LIO_LIMean brain-predicted age corresponded to an 8-year delay in brain aging C_LIO_LIBrain age in oldest-old was not associated with self-reported health history C_LIO_LIBrain age was not associated with cognitive performance C_LI

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Britton, M. K., Hoogerwoerd, H., Juhasz, J., Johnson, K. J., Stewart, P. D., Merritt, S. S., Jessup, C. J., Wright, C. B., Raichlen, D. A., Hishaw, G. A., Del Bene, V. A., Wadley, V. G., Trouard, T. P., Alperin, N., Levin, B. E., Rundek, T., Visscher, K. M., Alexander, G. E., Cohen, R. A., Porges, E. C., Gullett, J. M.. 2025-05-30. Your Brain Doesn't Look a Day Past 70! Cross-Sectional Associations with Brain-Predicted Age in the Cognitively-Intact Oldest-Old. https://doi.org/10.1101/2025.05.26.655855

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