SUMMARY The roots of Alzheimer’s Disease (AD) and AD-Related Dementias (ADRD) extend backward in development to the earliest stages of life. Perinatal insults and intra-uterine growth restriction are linked to increased risk for several AD/ADRD risk factors, including obesity, type 2 diabetes mellitus, and cardio-metabolic disease, and therefore represent a crucial feature of the AD/ADRD exposome. The mechanisms mediating these perinatal- insult effects are hypothesized to operate through epigenetic changes involving DNA methylation. However, isolating the causal effects of in-utero exposures from correlated risk factors, such as poverty, is challenging in human studies. Natural experiments, including famine studies, provide a model to study causal effects of perinatal insults on human aging and are an ideal setting in which to develop research infrastructure to study the AD/ADRD exposome. The Dutch Hunger Winter Families Study (DHWFS) uses a sudden, war-induced famine as a natural experiment. The famine was caused by a Nazi blockade during WWII in 1944-45. Because the impact of famine was immediate, transient, and population-wide, DHWFS comparison of infants born during the famine with those born before or after the famine will identify potential long-term effects of perinatal- insults. In the parent grant to this supplement application, stored DHWFS biospecimens are being genotyped to examine if famine effects on fertility and fetal survival could induce significant selection bias in the natural experiment. Biospecimens are available of N=956 individuals, 37% of whom were exposed to famine in-utero and the remainder of whom are siblings of the famine-exposed individuals and "time controls" born immediately before or after the famine. Under this supplement application we propose new assays of stored biospecimens to generate a new DNA methylation database for the DHWFS. We will use Illumina EPIC array technology to assay ~850,000 CpG sites across the genome; apply published algorithms to compute a library of exposome variables; link these data with detailed in-utero exposure and neuropsychological test data to build an AD/ADRD exposome DNA methylation database; and develop platforms for electronic sharing of the data with outside research teams. The proposed project will build unique infrastructure for studies of the AD/ADRD exposome that will enable causal identification of impacts of in-utero exposure on the life-course development of AD/ADRD risk via epigenetic mechanisms.