Abstract
Background: 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. Methods: 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 (MMSE). The resulting summary statistics were subjected to functional annotation, and colocalisation analyses. Results: Established AD risk factors, including APOE‑ε4 dosage and polygenic risk scores, were not associated with disease progression in amyloid positive individuals who are actively declining. A mixed effects GWAS meta-analysis revealed one genome-wide significant locus on chromosome 22 (rs78369883) and several nominally significant loci linked with AD progression. Functional annotation, finemapping, and colocalisation 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. Conclusion: These findings enhance our understanding of the biological underpinnings of AD progression, opening new avenues for therapeutic intervention.
Keywords
Alzheimer’s disease, APOE‑ε4, genome-wide association studies, polygenic risk score, progression
Document Type
Journal Article
Date of Publication
12-1-2026
Article Number
142
Volume
18
Issue
1
PubMed ID
42035106
Publication Title
Alzheimer's Research & Therapy
Publisher
Springer
School
Centre for Precision Health / School of Medical and Health Sciences
RAS ID
99965
Funding Information
MS and JH received funding from Fidelity Bermuda Foundation, and Dolby Family Ventures for the work carried out in this manuscript. JH, DS, and UY are supported by the UK Dementia Research Institute [UKDRI-1210] through UK DRI Ltd, principally funded by the Medical Research Council (MRC). Funding for this research was also supported through NHMRC grants (GNT1161706, GNT1191535) awarded to SML. A.N. is supported by the UK Dementia Research Institute through UK DRI Ltd, principally funded by the Medical Research Council [UKDRI-5208], and by the Vivensa Foundation [AISRPG2305\26] and the Alzheimer’s Association [ADSF-24–1,345,198-C]. A.A. is supported by the Imperial College London President’s PhD Scholarships award.
Funding received from the National Health and Medical Research Council (NHMRC)
GNT1161706, GNT1191535
Creative Commons License
This work is licensed under a Creative Commons Attribution-Noncommercial-No Derivative Works 4.0 License.
Recommended Citation
Cohen, C. E., Fernandez, S., Yaman, U., Ehyaei, A. R., Kodosaki, E., Askarova, A., Porter, T., O’Brien, E., Study, A. I. B. a. L., Initiative, A. D. N., Maruff, P., Nott, A., Hardy, J. A., Laws, S. M., Salih, D. A., & Shoai, M. (2026). Genetic drivers of progression in Alzheimer’s disease are distinct from disease risk. Alzheimer’s Research & Therapy, 18, Article 142. https://doi.org/10.1186/s13195-026-02036-1