MAPT Haplotype Variation and Alzheimer's Disease Risk: A Narrative Review with Focus on the Jordanian Population.

Introduction: Genetic variations in the microtubule-associated protein tau (MAPT) gene play a central role in Alzheimer's disease (AD) pathogenesis. Two major MAPT haplotypes, H1 and H2, show differential associations with tau expression and AD risk. However, data from Middle Eastern populations remain limited, restricting our understanding of population-specific disease susceptibility patterns and therapeutic responses.

Methods: We conducted a comprehensive literature review using PubMed, Scopus, and Web of Science databases. Search terms included "MAPT haplotype," "Alzheimer's disease," "H1 H2," "tau pathology," and "pharmacogenetics." We analyzed peer-reviewed articles published between 2000 and 2024, focusing on studies reporting haplotype frequencies, MAPT expression levels, APOE interactions, and clinical outcomes. This review synthesizes published data without generating new experimental results.

Results: The H1 haplotype consistently associates with increased MAPT expression, tau accumulation, and elevated AD risk, particularly in APOE ε4 noncarriers. Conversely, the H2 haplotype appears protective, correlating with reduced tau burden and slower cognitive decline. Notably, recent reports reveal significant overrepresentation of the H2 haplotype in the Jordanian population compared to European and East Asian cohorts, where H2 frequency is substantially lower or absent. This distinct genetic architecture suggests altered regional AD risk profiles.

Discussions: The elevated H2 frequency in Jordan represents a unique population-specific genetic signature that may influence regional AD susceptibility patterns. These findings challenge current risk models predominantly based on European populations and suggest the need for populationtailored approaches in neurodegenerative disease research. The naturally H2-enriched Jordanian cohort provides an exceptional opportunity to investigate protective mechanisms against tau pathology.

Conclusion: MAPT haplotype distributions show significant population variation with important implications for AD risk assessment and therapeutic targeting. The high H2 frequency in Jordan warrants integration into personalized medicine frameworks and population-specific disease models, potentially informing more effective regional prevention and treatment strategies.