While everyone ages chronologically at the same rate, this is not true biologically some individuals experience accelerated age-related biological degeneration. Evaluating interventions to prevent ADRD onset requires the identification of surrogate biomarkers that index subclinical cognitive decline, neurodegeneration, and accelerated aging of the brain by midlife. Alzheimer’s disease and related dementias (ADRD) arise at the end of a chronic pathophysiological process with preclinical stages emerging decades earlier in life. The failure of these interventions may be related to their targeting of individuals too late in the aging process after neurodegeneration has become inexorable. Unfortunately, to date, tested interventions have not slowed age-related cognitive decline. As such there is growing need for interventions to slow the progression of cognitive decline. While old age is associated with higher risk for disease across the entire body, degeneration of the brain and consequent cognitive decline has an outsized influence on disability and loss of independence in older adults. 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. These findings help to validate brainAGE as a potential surrogate biomarker for midlife intervention studies that seek to measure dementia-prevention efforts in midlife. 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. 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. In this cohort, all chronological age 45 years, brainAGE was measured reliably (ICC = 0.81) and ranged from 24 to 72 years. 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). 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. However, these findings are largely based on cross-sectional associations which can confuse age differences with cohort differences. Having an older brainAGE has been linked to Alzheimer’s, dementia, and mortality. BrainAGE has been proposed as a biomarker of age-related deterioration of the brain. An individual’s brainAGE is the difference between chronological age and age predicted from machine-learning models of brain-imaging data.
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