Abstract
BACKGROUND: Cumulative deficit frailty (CDF) is a syndrome characterized by the accumulation of negative physical, functional and psychosocial insults. Accumulation of CDF and changes in brain structure both occur during the transition to older age and are associated with the development of Alzheimer's disease (AD) and related dementias. However, how these phenomena are temporally related to each other during the aging process is not well understood. METHODS: We examined bidirectional relationships between CDF and brain structure using structural MRI-based brain-predicted age difference and an AD brain signature. Longitudinal MRI and questionnaire-based data were collected from men in the Vietnam Era Twin Study of Aging at three study waves (average ages 56, 62, and 68). RESULTS: Best-fitting longitudinal random intercepts cross-lagged panel models support the strong overall association between CDF and brain structural integrity with significant covariance between random intercepts for CDF and brain-predicted age difference (r = 0.36, p < .001) and between CDF and AD brain signature (r = -0.16, p = .005) after controlling for chronological age, smoking, race/ethnicity, and education. Significant bidirectional negative cross-lagged associations suggested attenuation over time of the association between CDF and nonspecific brain aging (βs = -0.33 to -0.23, p ≤ .012) but not between CDF and AD brain signature. CONCLUSIONS: CDF was associated with age-related brain structure via strong time-invariant common variance as well as weaker across-time factors. By contrast, the association between CDF and AD-related brain structure was via moderate common variance and was not temporally dynamic. Together, this suggests that CDF is differentially associated with age-related and AD-related brain changes and may be a clinically relevant risk factor for pathological brain aging.