PROJECT SUMMARY/ABSTRACT We propose to develop, use and share two important resources for the study of cognitively unimpaired (CU) 50- 90 year-old persons at six levels of genetic risk for Alzheimer's disease (AD) due to their apolipoprotein E (APOE) genotype. The Arizona APOE Cohort will include 300 CU persons with the APOE2/2, 2/3, 3/3, 2/4, 3/4 and 4/4 genotypes who are stratified for genotype and age decile and matched for sex and education. They will provide a comprehensive longitudinal resource of genetic, non-genetic, clinical, cognitive and related data, brain imaging, CSF and emerging blood-based biomarker (BBB) measurements of amyloid-β (Aβ) and tau pathophysiology, neuronal injury and/or neurodegeneration and inflammation (“A,T,N,I”) and CSF, blood and DNA samples. GeneMatch will provide an unusually large resource of potentially interested CU APOE-genotyped persons for enrollment in this project and other studies. It will include persons in the wider 50-90 years age range, characterize the six most common APOE genotypes, identify understudied APOE2 and APOE4 homozygotes (HMs), as well as those with rare and potentially protective APOE variants, and support their enrollment in the longitudinal Arizona APOE Cohort and other studies. We will use these resources to 1) detect and track different A,T,N,I biomarkers; 2) determine the ages at which they rise, plateau and/or decline for each APOE genotype; 3) characterize the differential impact of APOE2 and APOE4 allelic doses, other suggested genetic and non- genetic factors, and their interactions with our preclinical A,T,N,I endophenotypes in 50-75 year-old participants; 4) characterize the differential impact of APOE2 and 4 allelic dose, other genetic and non-genetic factors suggested to be involved in the protection from AD, and their interactions on our preclinical A,T,N,I endophenotypes in 76-90 year-old APOE4 HMs and heterozygotes (HT) who remained CU despite their genetic risk; 5) further inform the design and size of novel 12- and 24-month prevention trials using imaging, CSF, and/or BBB endpoints; and 6) demonstrate the value of promising BBBs (including plasma Aβ42/40, p-tau217, and neurofilament light [NfL]) in these endeavors. We will extensively share 7) annually updated data and biological samples and 8) motivated research participants with common and rare APOE genotypes, including APOE4 HMs at particularly high AD risk, understudied APOE2 HMs at particularly low AD risk, older CU APOE4 HMs and HTs, and those with APOE Christchurch and other potentially protective mutations in APOE's LDLR/HSPG binding domain; 9) complement our other cohorts in important ways; and 10) provide a foundation for a wide range of projects (including a planned “Preclinical APOE Consortium”). This project is designed to investigate the roles of APOE, other genetic and non-genetic factors, and their interactions in the detection, tracking, predisposition to, protection from, and potential treatment and prevention of AD, support a wide range of complementary studies, accelerate the evaluation of prevention and future APOE-modifying therapies, and help our Alzheimer's Prevention Initiative (API) trials find effective AD prevention therapies before 2025.

NARRATIVE We will develop, use, and extensively share two critically important resources of cognitive, biomarker, genetic, and related data from cognitively unimpaired 50-90-year-old persons with each common form of APOE, the major AD susceptibility gene, representing six levels of risk. We will clarify the impact of APOE, other genetic and non-genetic factors, and their interactions on the predisposition to, protection from and potential prevention of AD, inform the design and size of 12 or 24-month prevention trials using biological outcome measurements, and demonstrate the value of extremely promising blood tests in these endeavors. We will provide an extensively shared resource of data, findings, biological samples, and motivated APOE-tested volunteers for the research community, support a wide range of other studies, and increase the chance that our Alzheimer's Prevention Initiative (API) will help find and support the accelerated approval of AD prevention therapies before 2025.