NIA-AD Family-Based Study. Since 2003, the NIA late-onset Alzheimer’s disease Family Based Study (NIA- LOAD FBS) has recruited, assessed and followed 1,756 families multiply affected by late-onset Alzheimer’s Disease (AD), with 9,682 family members, and we have assessed and followed 1,096 unrelated, nondemented elderly. Of these 7,925 (82%) have DNA, and 7,014 (88.5%) of those have genome wide SNP array data. 1,340 (76%) of the families have either whole exome or whole genome sequencing. The families are racially/ethnically diverse: 181 (10.3%) are African American, 425 (24.2%) are Latinx, 138 (7.8%) are listed as “other” (mostly Asian) and 1,012 are white non-Hispanic. 67,626 biological samples have been distributed and 830 national and international investigators have used either data or samples in over 122 publications from the NIA-LOAD FBS, including the Alzheimer’s Disease Genetics Consortium and the Alzheimer’s Disease Sequencing Project. Detailed autopsy reports exist for 181 individuals, but we have completed brain autopsy in 655 from which fresh brain tissue in 398 (61%) are undergoing bulk RNA sequencing and DNA methylation from the dorsolateral prefrontal cortex. We have collected peripheral blood mononuclear cells (PBMCs) from 322 individuals during the follow-up visits of family members. We will continue to expand resources to support functional genomics by increasing biospecimen collections including additional DNA, plasma, PBMCs and postmortem brain tissue stored at the National Centralized Repository for Alzheimer’s Disease and Related Disorders for distribution to AD researchers, facilitating molecular profiling instrumental to prediction models that identify drug targets. During the COVID-19 pandemic, we relied on telecommunication methods for follow-up and recruitment and will expand this effort in the renewal. We will also add blood-based biomarkers Ab42, Ab40, total tau (T-tau), neurofilament light chain and phosphorylated tau 217 (P-tau217) to improve the precision of clinical diagnoses. The principal investigators of this U24-Resource Related Cooperative Agreement were asked to extend recruitment to familial early-onset AD (EOAD) and their adult children. EOAD represents the younger boundary of the entire age spectrum of AD and is only partially explained by mutations in the APP, PSEN1 and PSEN2. We have added an investigative team that has already begun recruiting EOAD families and their family members. Our multigenerational approach to the study of AD offers an ideal opportunity to determine the penetrance and heritability of the genetic variants identified in these diverse families. These data will inform and guide international genetic studies. The return of individual genetic and biomarker results in a research study is a challenging task due to the ethical and practical complexity. We will be informed by the recommendations of NIA working groups regarding the return of research results. The goals of this renewal are to provide a rich genetic and biomarker resource for the scientific community. We have renamed the project as NIA-AD FBS to include the entire age spectrum of AD onset.

NARRATIVE The NIA-Alzheimer’s Disease Family Based Study (NIA-AD FBS) has created a resource of 1,756 well- characterized families, 42.4% of whom are from under-represented race/ethnic group and that includes 8,697 consented family members and 1,096 unrelated controls with regular follow up. We have expanded sample acquisition to meet the changing needs of research on Alzheimer’s disease and related disorder, store all biological samples at the National Centralized Repository for Alzheimer's Disease at Indiana University and share all clinical, biomarker and genetic data acquired or generated through the National Institute on Aging Genetics of Alzheimer’s Disease Storage. The central goal of the NIA-AD FBS is to support research by making clinical data, samples and data generated from the samples broadly available to the AD research community.