Leveraging Consanguinity in Pakistan to Uncover the Genomic Architecture of Alzheimer's Disease: Feasibility Study with ENIGMA-PAK

PROJECT SUMMARY/ABSTRACT Currently, there are almost 55 million people living with dementia worldwide, and this number is estimated to double every 20-years, reaching about 131.5 million in 2050. Most of the patients suffering from dementia (58%) live in low- and middle-income countries (LMIC), with the fastest growth in the elderly population taking place in

China, Pakistan, and their South Asian and Western Pacific neighbors. Pakistan is the fifth most populous country in the world and currently has an estimated 150,000–200,000 patients with dementia. Importantly, more than 63% of all marital unions in Pakistan are consanguineous posing a greater impact on genetically transmitted

diseases like AD. Consanguinity, although prevalent in densely populated LMICs (e.g., Middle Eastern and North African countries), is gravely underrepresented in current international AD research initiatives. Thus, including the Pakistani population, provides a unique opportunity to further diversify genomic studies of AD and related

dementia. Therefore, the ENIGMA-PAK team along with Aga Khan University (AKU) in Karachi, Pakistan, and NIA-funded ADSP investigators have joined hands to conduct a pilot study to establish feasibility and collect preliminary genetic data from a consanguineous cohort (n=200) from an urban and a peri-urban site in Pakistan.

Additionally, MRI data from 10 individuals will also be collected on ADNI-3 protocol to show feasibility. The study will leverage existing NIA-funded resources, including (1) Urdu-translated consent forms and instruments as well as data protocol from the Longitudinal Aging Study in India - Diagnostic Assessment of Dementia (LASI-DAD)

study, which is based in India; (2) NIA-funded National Cell Repository for AD (NCRAD) and NIA Genetics of Alzheimer's Disease Data Storage (NIAGADS) which will process and store genetic data; and (3) the Phenotype Harmonization Center (PHC) to harmonize the phenotypic data. The main aims of this feasibility study are to

harmonize data acquisition with the protocol used in the LASI-DAD study (Aim 1), collect blood and MRI data from small cohorts and to harmonize both genetic and phenotypic data with NIA-funded ADSP cores (Aim 2). Eventually, the goal is to acquire feasibility data from Pakistan that is verified and harmonized by the ADSP cores

to allow us to pursue subsequent NIA funding under the “ADSP Follow-Up Study (FUS) 2.0: The Diverse Population Initiative''.