The Offspring Study: Understanding Biologic and Social Pathways of ADRD

Cohort studies are an important resource for studying many diseases, including Alzheimer’s disease (AD). Numerous cohorts exist across the country, but they often have common weaknesses. Often, these cohorts tend to be racially, ethnically, and socioeconomically homogenous, with affluent, white patients typically being represented at much higher levels than patients of other socioeconomic statuses, races, and ethnicities. This can lead to misleading findings and blind spots in understanding how disease risk and prevention manifest in individuals from different backgrounds and communities. Another issue in the context of AD is that these cohorts often focus on a single generation. We know genetics play a significant role in AD, but most cohorts do not also follow the children of the patients at risk of or battling AD. Studying the children of patients who have been followed in a cohort for years could provide critical information about how disease risk is affected from one generation to the next.

Drs. Manly and Brickman have committed substantial effort to building, characterizing, and maintaining a cohort that addresses these two weaknesses. The Offspring Study is a community-based, ethnically diverse, intergenerational cohort that enables the study of midlife phenotypes (i.e., the offspring) tied to AD in parallel with the parental AD status and progression. The cohort now consists of over 2,200 participants of diverse races, ethnicities, and socioeconomic backgrounds, positioning it as an incredible resource for identifying approaches to managing and treating AD across the entire population. Through this project, Drs. Manly and Brickman aim to deploy next-generation proteomics to capture the protein changes happening in blood associated with a wide range of disease-related changes, including vascular and metabolic dysregulation and immune dysfunction.

This ambitious effort consists of two primary aims. Both will leverage data generated via NULISA, an ultra-sensitive, next-generation assay that enables detection of several hundred proteins at a time. This panel of proteins includes common AD biomarkers, like ptau-217 and NfL, as well as proteins related to inflammation, metabolic pathways, and vascular function. The first aim will focus on identifying the changes in these proteins and their associated mechanisms that interact most strongly with parental AD status, cognitive trajectories, and AD risk. The second aim will do the inverse and seek to identify the changes associated with resilience against AD and cognitive decline.

Overall, this study aims to identify the molecular mechanisms that underpin the risk of AD conferred from one generation to the next. This will enable a more comprehensive understanding of potential biomarkers for offspring of AD patients, and identify mechanisms that might have therapeutic potential.