Biological brain age and resilience in cognitively unimpaired 70-year-old individuals

Abstract

Introduction: This study investigated the associations of brain age gap (BAG)-a biological marker of brain resilience-with life exposures, neuroimaging measures, biological processes, and cognitive function.

Methods: We derived BAG by subtracting predicted brain age from chronological age in 739 septuagenarians without dementia or neurological disorders. Robust linear regression models assessed BAG associations with life exposures, plasma inflammatory and metabolic biomarkers, magnetic resonance imaging, and cerebrospinal fluid biomarkers of neurodegeneration and vascular brain injury, and cognitive performance.

Results: Greater BAG (older-looking brains) was associated with physical inactivity, diabetes, and stroke, while prediabetes was related to lower BAG, that is, younger-looking brains. Physical activity mitigated the link between obesity and BAG. Greater BAG was associated with greater small vessel disease burden, white-matter alterations, inflammation, high glucose, poorer vascular-related cognitive domains. Sex-specific associations were identified.

Discussion: Vascular-related lifestyles and health shape brain appearance. Inflammation and insulin-related processes may be keys to understanding vascular cognitive disorders.

Highlights: BAG, reflecting deviations from CA, can indicate resilience. Diabetes, stroke, and low physical activity link to "older" brains (greater BAG). Physical activity yielded to "younger" brains in septuagenarians with obesity. High cerebrovascular burden, inflammation, and glucose associate with "older" brains. Sex differences were detected in all BAG-associated factors.

Keywords: Alzheimer's disease; brain age; fluid biomarkers; glucose; inflammation; resilience; sex differences; small vessel disease; vascular cognitive impairment.

FIGURE 1

Brain age gap as potential biological markers of brain resilience. Panel A (left) presents a conceptual framework illustrating two complimentary resilience mechanisms (brain maintenance and cognitive reserve) based on the differences between an individual's PBA and CA, knows as the BAG. These differences can serve as personalized biomarkers of brain and/or cognitive health. Hypothetically, younger‐appearing brains (negative differences, PBA < CA) suggest preserved brain structure, indicative of brain maintenance. Conversely, older‐appearing brains (positive differences, PBA > CA), especially in the presence of no/minimal cognitive decline, suggest coping abilities linked to cognitive reserve. Panel B (right) shows the T1‐weighted and FLAIR brain MRIs from three participants in the Gothenburg H70 Birth Cohort Studies–Birth cohort 1944. The images illustrate cases where there are no differences between PBA and CA (BAG = 0 years), a negative difference indicative of a younger‐appearing brain (BAG = −3.7 years), and a positive difference indicative of an older‐appearing brain (BAG = +3.7 years). BAG, brain age gap; CA, chronological age; FLAIR, fluid attenuated inversion recovery; MRI, magnetic resonance imaging; PBA, predicted brain age.

FIGURE 2

Sex‐specific associations of brain age gap with life exposures, biological processes, brain injury, and cognitive outcomes. The figure displays robust linear regression models’ β‐coefficients and 95% CIs for the associations of brain age gap with cardiometabolic conditions (panel A); plasma inflammatory, glucose, and lipids biomarkers (panel B), neuroimaging markers of neurodegenerative and vascular brain injury (panel C), and cognitive outcomes (panel D) in males (blue circle) and females (red square). All models displayed in Tables 2, 3, 4, 5, 6 were repeated in stratified analysis by biological sex at birth (i.e., among males and females) to identify sex‐specific factors related to the brain age gap. In panels A–C: Brain age gap was used as dependent variable (outcome). In panel D, cognitive composite scores were used as dependent variables in separate education‐adjusted robust linear regression models, whereas the brain age gap was entered as independent variable. BMI, body mass index; CI, confidence interval; CRP, C‐reactive protein.