Wisconsin longitudinal study: Initial lifetime's impact on Alzheimer's disease and related disorders (WLS-ILIAD)

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Abstract The overarching scientific premise of this application is to evaluate how the accumulation of social advantage and adversity over the full life course impacts risk and resilience against Alzheimer’s Disease (AD) and Related Dementias (ADRD). While there is considerable enthusiasm across the social and biological sciences regarding the sociobiological underpinnings of multifaceted diseases, including a growing research base on the social exposome and social determinants of health, evidence clearly linking *lifetime* social exposures to AD/ADRD remains limited. Existing work has been hampered by the paucity of data that covers the full life course, and relative inattention to how sex and, especially gender, may shape these processes. We address these gaps with the competing renewal application of an NIA-funded R01 (AG06073), entitled the “Wisconsin Longitudinal Study-Initial Lifetime’s Impact on ADRD (WLS-ILIAD)”, which began tracking AD and related dementia onset in 2019 among a cohort of older adults with prospectively collected data extending to their birth year. Having achieved an ~80% response rate during the current grant cycle (2018-2023), the renewed project would continue to assess for dementia as participants surpass age 85. We propose to continue the WLS-ILIAD project to build an invaluable and uniquely comprehensive dataset, which will allow us-and our broader user base-to characterize the AD biomarkers, cognitive, social, behavioral, and medical profile of participants at risk or resilient to dementia. The specific aims for this proposal include: Aim 1: We will continue to track dementia in the WLS cohort using rigorous AD biomarkers, when participants will be ~age 85-90. As before, data will be released for broad public use. Aim 2: We will add plasma AD biomarkers to the full sample (n=~5000) to examine whether core AD biomarkers predict and moderate cognitive function, AD risk, or resilience. Amyloid and tau PET brain scans, and cerebrospinal fluid (CSF) collection will be performed on 200 participants with 100 follow up visits to validate the blood-based biomarkers and identify cut points for specific blood AD biomarkers. Aim 3. Examine how accumulated social advantage and adversity influence risk and resilience against dementia onset, with attention to sex/gender differences. This aim focuses on two forms of resilience. The first is resilience to dementia. Regardless of underlying pathology, the costs attributable to dementia are high, with global health care spending on dementia projected to reach $1.6 trillion by 2050, so attention to its determinants are critical. The second type is the absence of clinical symptoms or dementia in the presence of AD pathology as established through antemortem disease biomarkers. Aim 4: Drawing on AD biomarkers collected in Aim 2, we will fold a large sample (n=468) of African American and Indigenous participants enrolled in the Wisconsin ADRC to analyze how early life advantage and adversity impact resilience in cognitive function in the presence of AD pathology. This extends the aims of the prior grant period’s attention to early life influences on dementia risk and resilience.