Evidence map›Paper›PMID 42035106›Full record

ArticleAlzheimer's research & therapy2026

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

Celeste E Cohen, Shane Fernandez, Umran Yaman, Ahmad R Ehyaei, Eleftheria Kodosaki, Aydan Askarova, Tenielle Porter, Eleanor O'Brien, Australian Imaging Biomarkers and Lifestyle Study, Alzheimer’s Disease Neuroimaging Initiative and 6 more

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Article in Alzheimer's research & therapy, 2026. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Not yet cited in PubMed.

0numbers the graph read from it
0cells of the map it votes in
0citing papers in PubMed
–field-weighted citation impact
1 · What the graph read from it

What it found

Each row is one number read from the abstract, on the scale the paper reported it, with its interval. Left of the dashed line favours the treatment, right favours the comparator. Under each row is the sentence it came from. New to these charts? A ten-minute tutorial.

The abstract states no effect estimate the extractor could read, or names no intervention and outcome on the map, so this paper lights no cell and moves no belief. It is still indexed, cited and linked below.

2 · The registry

The trial behind it

Trials whose registry record cites this paper, or whose number appears in the abstract. A trial that started after this paper was published is citing it as background, not reporting it.

Neither the registry nor the abstract names a trial number. If this is a trial report, that itself is worth knowing.

3 · Its place in the literature

Who cites it

0 citing papers in PubMed.

No citing paper in PubMed yet.

4 · The record

Corrections and comments

5 · Who and what money

Authors and funding

16 authors.

Celeste E Cohen *Department of Neurodegenerative Disease, UCL Queen Square Institute of Neurology, London, UK.
Shane Fernandez *Centre for Precision Health, Edith Cowan University, Joondalup, WA, Australia.
Umran YamanDepartment of Neurodegenerative Disease, UCL Queen Square Institute of Neurology, London, UK.
Ahmad R EhyaeiMax-Planck-Institute for Intelligent Systems, Tubingen, Germany.
Eleftheria KodosakiDepartment of Neurodegenerative Disease, UCL Queen Square Institute of Neurology, London, UK.
Aydan AskarovaUK Dementia Research Institute, Imperial College London, London, UK.
Tenielle PorterCentre for Precision Health, Edith Cowan University, Joondalup, WA, Australia.
Eleanor O'BrienCentre for Precision Health, Edith Cowan University, Joondalup, WA, Australia.
Australian Imaging Biomarkers and Lifestyle Study
Alzheimer’s Disease Neuroimaging Initiative
Paul MaruffFlorey Department of Neuroscience and Mental Health, University of Melbourne, Melbourne, Australia.
Alexi NottUK Dementia Research Institute, Imperial College London, London, UK.
John A HardyDepartment of Neurodegenerative Disease, UCL Queen Square Institute of Neurology, London, UK.
Simon M LawsCentre for Precision Health, Edith Cowan University, Joondalup, WA, Australia.
Dervis A SalihDepartment of Neurodegenerative Disease, UCL Queen Square Institute of Neurology, London, UK.
Maryam ShoaiDepartment of Neurodegenerative Disease, UCL Queen Square Institute of Neurology, London, UK. m.shoai@ucl.ac.uk.

Funding

Alzheimer's Association ADSF-24-1345198-CImperial College London President's PhD Scholarships awardNational Health and Medical Research Council GNT1161706, GNT1191535UK Dementia Research Institute through UK DRI Ltd UKDRI-5208Vivensa Foundation AISRPG2305\26
6 · The paper itself

Abstract

backgroundRecent 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.

methodsA 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.

resultsEstablished 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.

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

Indexed as

Alzheimer DiseaseDisease ProgressionGenetic Predisposition to DiseaseAgedAged, 80 and overApolipoprotein E4FemaleGenetic Risk ScoreGenome-Wide Association StudyHumansLongitudinal StudiesMalePolymorphism, Single NucleotideRisk FactorsApolipoprotein E4Alzheimer’s diseaseAPOE‑ε4Genome-wide association studiesPolygenic risk scoreProgression

Identifiers

PMID42035106

What Socratic holds

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Registered trials

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Read under generation 80e0d062 · epoch 390. Bibliography from PubMed, PubMed Central and OpenAlex; grants from NIH RePORTER; trial links from ClinicalTrials.gov; estimates, votes and beliefs from the Socratic graph.