Wisconsin Registry for Alzheimer's Prevention

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PROJECT SUMMARY The Wisconsin Registry for Alzheimer’s Prevention (WRAP) is a longitudinal study that follows a risk-enriched cohort from late-midlife into old age and focuses on (1) Defining the preclinical window at the level of the individual including the onset of Alzheimer’s disease (AD) proteinopathy and cognitive decline prior to overt clinical symptoms; (2) gaining a comprehensive picture of the effects of nonmodifiable genetics and modifiable health and lifestyle factors on cognitive and AD biomarker onsets and trajectories; (3) characterizing the presence and impact of other diseases associated with cognitive decline—chiefly vascular disease. WRAP consists of over 1,729 (1386 active) adults who enrolled in midlife (baseline mean age 54 yrs), are followed biannually for an average of 12 years of follow-up so far, and on whom we conduct cognitive, lifestyle, lab, medical and biomarker assessments of AD and related disorders (ADRD). In the prior cycle we: (i) Developed methods for identifying subtle cognitive decline utilizing each participant’s own baseline performance, thereby improving sensitivity to decline while reducing diagnostic bias; (ii) Derived temporal information from amyloid positron emission tomography (PET) and plasma assays showing that amyloid onset age can be estimated and precedes tauopathy, (iii) found that when amyloid and tau proteinopathies are present, cognitive decline accelerates; (iv) showed that lifestyle and health factors affect cognitive decline and likely impact the length of the preclinical window; (v) showed that AD pathology/risk and aspects of vascular changes/risk independently and jointly impact brain health and cognitive decline; (vi) included WRAP data in several multi-cohort collaborations that have advanced the field. With these gains and new supportive preliminary data, WRAP is uniquely positioned to address the following major aims and knowledge gaps in the next cycle: Aim 1 will derive person-level estimates of the preclinical window defined as the interval between onset of AD proteinopathy and the onset of cognitive decline. We will perform 3000 main WRAP study visits from which we will characterize cognitive decline. We will assay 4,400 existing and 2,640 anticipated plasma samples for AD-related biomarkers. Subsets undergo AD (PET and/or CSF) and vascular (MRI and ultrasound) biomarkers. PET—plasma concordances will be established, and analyses using plasma-derived ADRD biomarkers will be conducted on the entire cohort. Aim 2 examines relationships between key genetic and health/lifestyle predictors to cognitive decline in the context of AD biomarkers. Aim 3 examines the inter-relationship between cerebrovascular health spectrum and its associations with cognitive decline relative to AD proteinopathy. Overall, the questions that WRAP is addressing with its longitudinal assessments and advanced temporal modeling are innovative and vital to the field regarding defining preclinical AD with greater precision at the level of the individual, and determining the factors that modify this window.