Project Summary Alzheimer’s disease and related dementias (ADRD) affect 47 million individuals world-wide. The etiology of ADRD is complex and not well understood, and there are few treatment options. ADRD has a long preclinical stage ranging from years to decades. There is thus potential for early preventive and treatment interventions by targeting risk factors and biological mechanisms in midlife. Shortened leukocyte telomere length (LTL) and reduced mitochondrial DNA copy number (MTCN), important aging biomarkers, have recently been implicated in the pathogenesis of ADRD. However, the underlying mechanisms mediating their associations with ADRD are not understood. It is important to establish whether LTL and peripheral MTCN measured in midlife predict the risk of ADRD in prospective studies, and to evaluate the downstream pathways by which shortened LTL and reduced MTCN may lead to the development of ADRD. Finding from such work could provide etiologic insights that may inform targeted pathways for prevention and early intervention. This R21 study will utilize existing data from the Atherosclerosis Risk in Communities Neurocognitive Study (ARIC-NCS), the NHLBI Trans-Omics for Precision Medicine (TOPMed), and NHGRI Centers for Common Disease Genomics (CCDG) programs. ARIC-NCS (baseline n: 15,792; age: 45-64y) has identified 2,719 incident dementia cases over 30 years of follow-up. We have obtained estimates for LTL and leukocyte MTCN (l-MTCN) for 3,353 ARIC participants based on visits 2 or 3 whole genome sequencing (WGS) data from TOPMed. Our preliminary analysis of this sample suggests that 1) midlife LTL and l-MTCN are associated with future risk of dementia and 2) an unbiased proteomics analysis (i.e. 4,931 proteins from the aptamer-based SOMAscan v.4 plasma proteomics panel) can identify functionally relevant proteins for LTL and l-MTCN. Our objectives are to: (1) Complete the estimates for LTL and l-MTCN for the remaining ARIC participants (n=10,193) using ARIC WGS data available through CCDG. (2) Assess the prospective association of LTL and l-MTCN measured in middle age with dementia incidence in whole ARIC cohort. (3) Leverage the SOMAScan proteomics data, available for the entire ARIC cohort from visits 2 and 3, to conduct a proteomics analysis of LTL and l-MTCN. We will also conduct a proteomics analysis of genetic polygenic risk scores (PRS) for LTL, that we will derive using a published LTL GWAS and categorize into different gene-based pathways. (4) Conduct a mediation analysis to evaluate which of the proteins identified in (3) above may mediate the associations of LTL and l-MTCN with incident dementia. This study will use ARIC’s multi-omics resources to evaluate the associations of midlife LTL and l-MTCN with ADRD, and to identify proteomics signatures of these aging biomarkers that are relevant to the etiology of ADRD, with the broad objective of improving the prevention and treatment of ADRD.