Cognitive Age Delta as a Marker of Healthy and Pathological Cognitive Aging: The Role of Lifestyle, Cognitive Reserve, and Vascular Risk.

Background

Chronological age is an imprecise proxy for cognitive aging. The Cognitive Age Delta (CAD)-the difference between predicted cognitive age and chronological age-offers a scalable, individualized marker of functional brain aging. We examined determinants of CAD in cognitively unimpaired (CU) adults stratified by Alzheimer's disease (AD) and vascular biomarkers.

Methods

We analyzed 177 CU participants from the Gipuzkoa Alzheimer Project (Basque Country, Northern Spain) classified as amyloid-negative/vascular-negative (CUA-V-, n = 140), amyloid-positive (CUA+, n = 23), or vascular-positive (CUV+, n = 14) using CSF and MRI criteria; vascular burden was defined as Fazekas ≥ 2 on T2-FLAIR or ≥4 microbleeds on SWI, excluding non-traumatic superficial siderosis and established ischemic lesions. MRI was used solely for vascular classification. Associations with demographic, genetic, lifestyle, and reserve measures were tested with General Linear Models.

Results

CAD did not differ across biomarker groups (Kruskal-Wallis H(2) = 0.17, p = 0.91). Median (IQR) CAD values were 0.28 (-4.13, 4.69) for CUA-V-, -0.14 (-3.15, 2.87) for CUA+, and 0.77 (-2.22, 3.76) for CUV+, indicating comparable distributions. Higher vocabulary scores (proxy of cognitive reserve) related to a younger cognitive age in CUA-V- (β = -1.39, p < 0.001) and CUA+ (β = -2.08, p = 0.054). In CUA+, greater sedentary time-particularly computer-based sitting-was also associated with lower CAD (daily sitting β = -2.13, p = 0.009; workday computer sitting β = -2.32, p = 0.015). CAD showed no associations with CSF Aβ42, p-tau or t-tau, APOE ε4 load, or vascular risk factors (all p > 0.05).

Conclusions

CAD captures interindividual resilience-related variability beyond classical AD biomarkers. Vocabulary, a marker of lifelong enrichment, emerged as a robust determinant of a younger cognitive age, while amyloid and vascular pathology exerted limited influence at preclinical stages. These findings support CAD as a sensitive, scalable endpoint for identifying protective factors and guiding personalized prevention in early Aging.