Abstract
An individual’s brainAGE is the difference between chronological age and age predicted from machine-learning models of brain-imaging data. BrainAGE has been proposed as a biomarker of age-related deterioration of the brain. Having an older brainAGE has been linked to Alzheimer’s, dementia, and mortality. However, these findings are largely based on cross-sectional associations which can confuse age differences with cohort differences. To illuminate the validity of brainAGE as a biomarker of accelerated brain aging, a study is needed of a large cohort all born in the same year who nevertheless vary on brainAGE. In the Dunedin Study, a population-representative 1972–73 birth cohort, we measured brainAGE at age 45 years, as well as the pace of biological aging and cognitive decline in longitudinal data from childhood to midlife (N = 869). In this cohort, all chronological age 45 years, brainAGE was measured reliably (ICC = 0.81) and ranged from 24 to 72 years. Those with older midlife brainAGEs tended to have poorer cognitive function in both adulthood and childhood, as well as impaired brain health at age 3. Furthermore, those with older brainAGEs had an accelerated pace of biological aging, older facial appearance, and early signs of cognitive decline from childhood to midlife. These findings help to validate brainAGE as a potential surrogate biomarker for midlife intervention studies that seek to measure dementia-prevention efforts in midlife. However, the findings also caution against the assumption that brainAGE scores represent only age-related deterioration of the brain as they may also index central nervous system variation present since childhood.
Highlights
While old age is associated with higher risk for disease across the entire body, degeneration of the brain and Supplementary information The online version of this article contains supplementary material, which is available to authorized users.the end of a chronic pathophysiological process with preclinical stages emerging decades earlier in life [3]
The premise and analysis plan for this project were preregistered on https://sites.google. com/site/dunedineriskconceptpapers/elliott
Using data from a population-representative longitudinal birth cohort followed over four decades, we compared two perspectives of aging that provide disparate explanations for cross-sectional associations between older brainAGE and age-related health outcomes (e.g., ADRD and mortality)
Summary
The resulting measures of accelerated biological aging have been associated with health span, cognitive decline, cancer risk, and all-cause mortality [5, 6, 8] Such aging biomarkers have not directly quantified aging in the organ most directly linked to ADRD, namely the brain. The first perspective is that older brainAGE could be an indicator of accelerated brain aging that has accumulated over an individual’s lifetime and increases susceptibility to ADRD and age-related cognitive decline. Instead of reflecting accelerated brain aging and the brain’s accumulated biological degeneration, an older brainAGE at midlife reflects compromised system integrity that has been present since childhood and stable for decades These two perspectives are not mutually exclusive and both may help explain the phenomenon of accelerated brain aging.
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