Midlife as a window onto the aging brain: surrogate biomarkers, exposures, and biological aging

Abstract

The global population is aging with projections that the number of people over 60 will more than triple by 2050. While many organ systems are impacted by aging, deterioration of the brain is a particularly debilitating form of age-related disease. Alzheimer's disease and related dementias (ADRD) represent neurodegeneration that results in a loss of the ability to perform everyday tasks, maintain independence, and care for oneself. To date, ADRD interventions targeting older adults have largely proven to be ineffective at limiting morbidity and disability, suggesting that interventions may be failing to slow age-related disease because they are implemented too late in the aging process after decline has taken hold. However, to target ADRD interventions to younger adults we will need surrogate biomarkers that track sub-clinical signs of accelerated brain-aging that has yet to be fully cemented. This dissertation consists of 4 original studies that aim to measure and begin to validate magnetic resonance imaging (MRI)-based surrogate biomarkers for accelerated brain-aging in midlife adults. Each of these studies utilizes the Dunedin Study, a population-representative birth cohort of 1,037 adults, who have been followed longitudinally from birth to the most recent wave of data collection, completed when Study members were 45 years old. In Chapter 1, I found that individual differences in WMH volume, an established marker of dementia risk, cognitive decline, and dementia in older adults, were associated with cognitive decline from childhood to age-45. In Chapter 2, I found that individual differences in brainAGE were also associated with cognitive decline from childhood to age-45. In Chapter 3, I found that a known neurotoxicant, lead, was associated with cognitive decline from childhood to age 45, as well as with several MRI measures at age 45 including hippocampal volume, surface area, fractional anisotropy, and brainAGE. In chapter 4, I found that an accelerated Pace of Aging was associated with a thinner cortex, smaller surface area, lower hippocampal volume, higher WMH volume, and older brainAGE. Together, by triangulating evidence from cognitive aging, neurotoxic exposure, and biological aging, these studies help motivate the critical need for researchers to embrace midlife brain aging as a tool for better understanding the aging brain and dementia risk. I conclude with a discussion of the limitations of this research and opportunities for future research to target midlife brain aging itself as a target for clinical translation.