Quantifying Individual Differences in Midlife Structural Brain Integrity Associated with Later AD/ADRD Risk

PROJECT SUMMARY The burden of Alzheimer’s disease and Alzheimer’s disease related dementias (AD/ADRD) is growing as the global population ages. Consistent with a newer model of geroscience, clinically detectable cognitive impairment and AD/ADRD are hypothesized to represent the end of a lifelong aging process in which genetic predisposition, environmental insult, and lifestyle factors interact to drive pathology. In fact, many risk factors for AD/ADRD are measurable in childhood and midlife many decades before clinical detection. This lifespan view of aging, together with the disappointing results of AD/ADRD prevention trials in late life, suggest that there is a promising opportunity to design interventions that target at-risk individuals in midlife to slow the aging process before debilitating brain decline has been cemented. Shifting AD/ADRD prevention research to midlife, however, presents a significant challenge: identifying viable outcomes of intervention. In a typical clinical trial, incidence of AD/ADRD is the intervention target as well as the measured outcome. While methodologically sound, this design will be challenging to export to midlife because it will require trials to last 20 or more years to use AD/ADRD diagnosis, which is uncommon before 65, as the outcome. One alternative strategy is to find midlife surrogate biomarkers that index sub-clinical changes in biology and cognition that are indicative of premorbid AD/ADRD. Such premorbid changes in midlife biology and cognition could further help identify causal disease mechanisms. In this competing renewal application, we propose to quantify individual differences in midlife for one such group of potential surrogate biomarkers: MRI measures of structural brain integrity, which are known to be associated with AD/ADRD later in life. Specifically, we propose to follow up at age 52 a population- representative cohort of 1037 infants born in one city in one year and comprehensively studied ever since: the Dunedin Study. Through our prior award (R01AG049789), we successfully collected high-quality, reliable MRI measures of structural brain integrity at age 45 in 93% of still-alive and participating Study members (N=875). The proposed second wave of MRI data collection at age 52 will allow for the quantification of individual differences in at-risk structural brain changes (e.g., greater increase in WMH, cortical thinning, and hippocampal atrophy) between ages 45 and 52. We will then examine the extent to which these individual differences are predicted by AD/ADRD risk indexes, trajectories of cognitive decline, and the pace of biological aging, which we have tracked across five decades. We will also map individual differences in at-risk midlife structural brain changes onto blood AD/ADRD biomarkers. Importantly, the Dunedin Study design allows for testing of associations in the absence of age and/or cohort effects in a large population representative sample. The very low attrition and absence of attrition bias further afford opportunity to examine associations across the full-range of cognition including low- and high-functioning individuals. These features will help generate novel translational findings of immediate impact for midlife AD/ADRD intervention and prevention research.