The causes and consequences of Alzheimer’s disease: phenome-wide evidence from Mendelian randomization

Roxanna Korologou-Linden (), Laxmi Bhatta, Ben M. Brumpton, Laura D. Howe, Louise A. C. Millard, Katarina Kolaric, Yoav Ben-Shlomo, Dylan M. Williams, George Davey Smith, Emma L. Anderson, Evie Stergiakouli and Neil M. Davies
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Roxanna Korologou-Linden: University of Bristol
Laxmi Bhatta: NTNU, Norwegian University of Science and Technology
Ben M. Brumpton: NTNU, Norwegian University of Science and Technology
Laura D. Howe: University of Bristol
Louise A. C. Millard: University of Bristol
Katarina Kolaric: University of Bristol
Yoav Ben-Shlomo: University of Bristol, Barley House, Oakfield Grove
Dylan M. Williams: University College London
George Davey Smith: University of Bristol
Emma L. Anderson: University of Bristol
Evie Stergiakouli: University of Bristol
Neil M. Davies: University of Bristol

Nature Communications, 2022, vol. 13, issue 1, 1-14

Abstract: Abstract Alzheimer’s disease (AD) has no proven causal and modifiable risk factors, or effective interventions. We report a phenome-wide association study (PheWAS) of genetic liability for AD in 334,968 participants of the UK Biobank study, stratified by age. We also examined the effects of AD genetic liability on previously implicated risk factors. We replicated these analyses in the HUNT study. PheWAS hits and previously implicated risk factors were followed up in a Mendelian randomization (MR) framework to identify the causal effect of each risk factor on AD risk. A higher genetic liability for AD was associated with medical history and cognitive, lifestyle, physical and blood-based measures as early as 39 years of age. These effects were largely driven by the APOE gene. The follow-up MR analyses were primarily null, implying that most of these associations are likely to be a consequence of prodromal disease or selection bias, rather than the risk factor causing the disease.

Date: 2022
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DOI: 10.1038/s41467-022-32183-6

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