Biobank-scale characterization of Alzheimer's disease and related dementias identifies potential disease-causing variants, risk factors, and genetic modifiers across diverse ancestries

Alzheimers disease and related dementias (AD/ADRDs) pose a significant global public health challenge, underscored by the intricate interplay of genetic and environmental factors that differ across ancestries. To effectively implement equitable, personalized therapeutic interventions on a global scale, it is essential to identify disease-causing mutations and genetic risk and resilience factors across diverse ancestral backgrounds. Exploring genetic-phenotypic correlations across the globe enhances the generalizability of research findings, contributing to a more inclusive and universal understanding of disease. This study leveraged biobank-scale data to conduct the largest multi-ancestry whole-genome sequencing characterization of AD/ADRDs. We aimed to build a valuable catalog of potential disease-causing, genetic risk and resilience variants impacting the etiology of these conditions. We thoroughly characterized genetic variants from key genes associated with AD/ADRDs across 11 genetic ancestries, utilizing data from All of Us, UK Biobank, 100,000 Genomes Project, Alzheimers Disease Sequencing Project, and the Accelerating Medicines Partnership in Parkinsons Disease, including a total of 25,001 cases and 93,542 controls. We prioritized 116 variants possibly linked to disease, including 18 known pathogenic and 98 novel variants. We detected previously described disease-causing variants among controls, leading us to question their pathogenicity. Notably, we showed a higher frequency of APOE {varepsilon}4/{varepsilon}4 carriers among individuals of African and African Admixed ancestry compared to other ancestries, confirming ancestry-driven modulation of APOE-associated AD/ADRDs. A thorough assessment of APOE revealed a disease-modifying effect conferred by the TOMM40:rs11556505, APOE:rs449647, 19q13.31:rs10423769, NOCT:rs13116075, CASS4:rs6024870, and LRRC37A:rs2732703 variants among APOE {varepsilon}4 carriers across different ancestries. In summary, we compiled the most extensive catalog of established and novel genetic variants in known genes increasing risk or conferring resistance to AD/ADRDs across diverse ancestries, providing clinical insights into their genetic-phenotypic correlations. The findings from this investigation hold significant implications for potential clinical trials and therapeutic interventions on a global scale. Finally, we present an accessible and user-friendly platform for the AD/ADRDs research community to help inform and support basic, translational, and clinical research on these debilitating conditions (https://niacard.shinyapps.io/MAMBARD_browser/).