Genetics impact risk of Alzheimer's disease through mechanisms modulating structural brain morphology in late life

Roxanna Korologou-Linden, Bing Xu, Elizabeth Coulthard, Esther Walton, Alfie Wearn, Gibran Hemani, Tonya White, Charlotte Cecil, Tamsin Sharp, Henning Tiemeier, Tobias Banaschewski, Arun Bokde, Sylvane Desrivières, Herta Flor, Antoine Grigis, Hugh Garavan, Penny Gowland, Andreas Heinz, Rüdiger Brühl, Jean Luc MartinotMarie Laure Paillère Martinot, Eric Artiges, Frauke Nees, Dimitri Papadopoulos Orfanos, Tomáš Paus, Luise Poustka, Sabina Millenet, Juliane H. Fröhner, Michael Smolka, Henrik Walter, Jeanne Winterer, Robert Whelan, Gunter Schumann, Laura D. Howe, Yoav Ben-Shlomo, Neil M. Davies, Emma Louise Anderson

Research output: Contribution to journalArticlepeer-review


Background: Alzheimer's disease (AD)-related neuropathological changes can occur decades before clinical symptoms. We aimed to investigate whether neurodevelopment and/or neurodegeneration affects the risk of AD, through reducing structural brain reserve and/or increasing brain atrophy, respectively. Methods: We used bidirectional two-sample Mendelian randomisation to estimate the effects between genetic liability to AD and global and regional cortical thickness, estimated total intracranial volume, volume of subcortical structures and total white matter in 37 680 participants aged 8-81 years across 5 independent cohorts (Adolescent Brain Cognitive Development, Generation R, IMAGEN, Avon Longitudinal Study of Parents and Children and UK Biobank). We also examined the effects of global and regional cortical thickness and subcortical volumes from the Enhancing NeuroImaging Genetics through Meta-Analysis (ENIGMA) Consortium on AD risk in up to 37 741 participants. Results: Our findings show that AD risk alleles have an age-dependent effect on a range of cortical and subcortical brain measures that starts in mid-life, in non-clinical populations. Evidence for such effects across childhood and young adulthood is weak. Some of the identified structures are not typically implicated in AD, such as those in the striatum (eg, thalamus), with consistent effects from childhood to late adulthood. There was little evidence to suggest brain morphology alters AD risk. Conclusions: Genetic liability to AD is likely to affect risk of AD primarily through mechanisms affecting indicators of brain morphology in later life, rather than structural brain reserve. Future studies with repeated measures are required for a better understanding and certainty of the mechanisms at play.

Original languageEnglish
Article numberjnnp-2023-332969
JournalJournal of Neurology, Neurosurgery and Psychiatry
Early online date25 Apr 2024
Publication statusE-pub ahead of print - 25 Apr 2024

Data Availability Statement

Data may be obtained from a third party and are not publicly available. The ENIGMA consortium MRI summary measures from genetic association analyses of estimated total intracranial volume, subcortical structures as well as cortical thickness were requested online. The ABCD study data are openly available to qualified researchers for free ( for Generation R data should be directed towards the management team of the Generation R study (, which has a protocol of approving data requests. For access to IMAGEN data, researchers may submit a request to the IMAGEN consortium ( ALSPAC details and data descriptions are available on their website (, where applications for individual-level data can be made (managed access). UK Biobank data are available through a procedure described on their website ( The UCSD IRB approved all data collection protocols for ABCD. IRBnumber: 160091. In Generation R, all study protocols and measurements assessed ineach wave of data collection were approved by the Medical Ethical Committee (MEC198.782/2001/31) of the Erasmus MC, University Medical Center Rotterdam. The IMAGEN study was approved by the institutional ethics committee of Kings College London, University of Nottingham, Trinity College Dublin, University of Heidelberg, Technische Universität Dresden, Commissariat á l Energie Atomique et aux nergies Alternatives, and University Medical Center at the University of Hamburg in accordance with the Declaration of Helsinki. Ethics approval for the study was obtained from the ALSPAC Ethics and Law Committee and the Local Research Ethics Committees and informed consent for the use of data collected via questionnaires and clinics was obtained from participants. UK Biobank is approved by the National Health Service National Research Ethics Service (ref 11/NW/0382; UK Biobank application number 48970). All analyses in this study used de-identified data, therefore no additional IRB approval was required. All necessary patient/participant consent has been obtained. Code is available at material This


  • Alzheimer's disease
  • brain mapping
  • epidemiology
  • genetics
  • neuroanatomy

ASJC Scopus subject areas

  • Surgery
  • Clinical Neurology
  • Psychiatry and Mental health

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