Genetic drivers of progression in Alzheimer's disease are distinct from disease risk

Recent trials in Alzheimer's disease (AD) demonstrate encouraging outcomes. These trials target risk mechanisms identified through genetic analysis whilst directly aiming to reduce progression rates. Evidence from other neurodegenerative diseases suggests the genetics of progression is distinct from risk of disease. To expand these initial successes and improve clinical outcomes further we need to understand genetics of progression of disease. These can be deduced through rigorous analysis of meticulously phenotyped longitudinal cohorts. In this study we first looked at known genetic drivers of risk, namely polygenic risk scores for AD and APOE ε4, to assess their role in progression. This was then extended to a genome wide association analysis to identify the role of other genetic variants in progression of AD.

A total of 387 individuals with, genetic data, amyloid positivity and in active decline (ADNI (n=222) and AIBL(n=165)) were used to perform generalised mixed effects linear model genome wide association studies of longitudinal cognitive decline as measured by mini mental state examination. The resulting summary statistics were subjected z, and colocalization analyses.

Established AD risk factors, including APOE ε4 dosage and polygenic risk scores, were not associated with disease progression amyloid positive individuals who are actively declining. A mixed effects GWAS meta-analysis revealed one genome-wide significant locus on chromosome 22 (rs78369883) and 25 nominally significant loci linked with AD progression. Functional annotation, finemapping, and colocalization analyses implicated genes primarily involved in immune response, neurodegeneration (including tau pathology), brain resilience, and neurogenesis. These progression-related genes were significantly enriched in neuronal-interferon-microglial signalling pathways and normal homeostatic processes of neuronal networks, with specific enrichment in dopaminergic and inhibitory neuronal populations.

These findings enhance our understanding of the biological underpinnings of AD progression, opening new avenues for therapeutic intervention.