Associations and interactions between premorbid cognitive health, apolipoprotein e4 genotype, and incident Alzheimer’s disease in UK Biobank (N = 252,340)
Abstract It is unclear to what extent genetic risk offsets the protective effects of better premorbid cognitive health on the risk of Alzheimer’s disease (AD). We tested for associations between measures of premorbid cognitive health, apolipoprotein ( APOE ) e4 ‘risk’ genotype, and their interaction, with risk of incident AD and age of diagnosis, in UK Biobank participants aged ≥55 years at baseline, adjusted for potential confounders. During follow-up, 3,505/252,340 (1.39%) participants received an incident diagnosis of AD. There were significant associations between better performance on each cognitive test with lower risk of incident AD, and later age at diagnosis. However, the benefit of better baseline cognitive scores on AD risk was significantly attenuated in APOE e4 carriers. These data demonstrate that the association between premorbid cognitive health and subsequent risk of AD is influenced by APOE e4 genotype. This has implications for risk stratification and targeted intervention.
Authors
- Rachana Tank (ORCID: https://orcid.org/0000-0002-4771-6685)
- Emma Russell (ORCID: https://orcid.org/0000-0002-5320-5910)
- Mohammad A. Jareebi (ORCID: https://orcid.org/0000-0002-4525-1191)
- Joey Ward (ORCID: https://orcid.org/0000-0003-0951-8511)
- William Stewart (ORCID: https://orcid.org/0000-0003-2199-2582)
- Lachlan Gilchrist (ORCID: https://orcid.org/0009-0005-6484-2105)
- Jana Anderson (ORCID: https://orcid.org/0000-0001-7290-6635)
- Josie Fullerton (ORCID: https://orcid.org/0000-0002-1967-9522)
- Angelina Kancheva (ORCID: https://orcid.org/0000-0002-0077-3543)
- Ian J. Deary (ORCID: https://orcid.org/0000-0002-1733-263X)
- Terence J. Quinn (ORCID: https://orcid.org/0000-0003-1401-0181)
- Laura M. Lyall (ORCID: https://orcid.org/0000-0001-7216-1434)
- Donald M. Lyall (ORCID: https://orcid.org/0000-0003-3850-1487)
- Simon R. Cox (ORCID: https://orcid.org/0000-0003-4036-3642)
- Rona J. Strawbridge (ORCID: https://orcid.org/0000-0001-8506-3585)
Institutions
- King's College London (GB)
- Karolinska Institutet (SE)
- University of Oxford (GB)
- Public Health Agency (GB)
- Health Data Research UK (GB)
- Perron Institute for Neurological and Translational Science (AU)
- Queen Elizabeth University Hospital (GB)
- University of Glasgow (GB)
- Jazan University (SA)
- University of Edinburgh (GB)
Publication Details
- Journal
- npj Dementia
- Published
- 2025-06-18
- DOI
- https://doi.org/10.1038/s44400-025-00013-3
- Primary Topic
- Dementia and Cognitive Impairment Research
- Type
- article
- Field-Weighted Citation Impact
- 0.00
Funders
- Wellcome Trust
- UK Research and Innovation
- British Heart Foundation
- King's College London
- University of Glasgow
- Northwest Regional Development Agency
- Medical Research Council