The bidirectional causal effects of brain morphology across the life course and risk of Alzheimer’s disease: A cross-cohort comparison and Mendelian randomization meta-analysis

Neuropathological changes associated with Alzheimer’s disease (AD) can occur decades before clinical symptoms. We investigated whether neurodevelopment and/or neurodegeneration affects the risk of AD, through reducing structural brain reserve and/or accelerating brain atrophy, respectively. We used bidirectional two-sample Mendelian randomization to estimate the effects of genetic liability to AD on global and regional cortical thickness, total intracranial volume, volume of subcortical structures and cerebral white matter in 36,842 participants aged eight to 81 years across five independent cohorts, and the effects of global and regional cortical thickness and subcortical volumes on AD risk in 94,337 participants. 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. We also found little evidence to suggest brain morphology alters AD risk. Thus, genetic liability to AD is likely to alter mechanisms and/or rates of neurodegeneration, rather than reduce structural brain reserve. ### Competing Interest Statement Dr Banaschewski served in an advisory or consultancy role for Lundbeck, Medice, Neurim Pharmaceuticals, Oberberg GmbH, Shire. He received conference support or speaker fee by Lilly, Medice, Novartis and Shire. He has been involved in clinical trials conducted by Shire & Viforpharma. He received royalties from Hogrefe, Kohlhammer, CIP Medien, Oxford University Press. The present work is unrelated to the above grants and relationships. Dr Poustka served in an advisory or consultancy role for Roche and Viforpharm and received speaker fee by Shire. She received royalties from Hogrefe, Kohlhammer and Schattauer. The present work is unrelated to the above grants and relationships. ### Funding Statement RKL was supported by a Wellcome Trust PhD studentship (Grant ref: 215193/Z18/Z). ELA is supported by a fellowship from the UK Medical Research Council (MR/P014437/1). The Medical Research Council (MRC) and the University of Bristol support the MRC Integrative Epidemiology Unit [MC\_UU\_00011/1]. NMD is supported by a Norwegian Research Council Grant number 295989. LDH is funded by a Career Development Award from the UK Medical Research Council (MR/M020894/1). EW is funded by the European Union Horizon 2020 research and innovation programme (grant number 848158) and by CLOSER, who was funded by the Economic and Social Research Council (ESRC) and the Medical Research Council (MRC) between 2012 and 2017. Its initial five year grant has since been extended to March 2021 by the ESRC (grant reference: ES/K000357/1). This research was supported by contract R01-HL105756-07 from the National Heart, Lung, and Blood Institute (NHLBI). ### Author Declarations I confirm all relevant ethical guidelines have been followed, and any necessary IRB and/or ethics committee approvals have been obtained. Yes The details of the IRB/oversight body that provided approval or exemption for the research described are given below: Ethical 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. In Generation R, all study protocols and measurements assessed in each wave of data collection were approved by the Medical Ethical Committee (MEC 198.782/2001/31) 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 Energies Alternatives, and University Medical Center at the University of Hamburg in accordance with the Declaration of Helsinki. The UCSD IRB approved all data collection protocols for ABCD. IRB number: 160091. All analyses in this study used de-identified data, therefore no additional IRB approval was required. All necessary patient/participant consent has been obtained and the appropriate institutional forms have been archived. All necessary patient/participant consent has been obtained and the appropriate institutional forms have been archived. Yes I understand that all clinical trials and any other prospective interventional studies must be registered with an ICMJE-approved registry, such as [ClinicalTrials.gov][1]. I confirm that any such study reported in the manuscript has been registered and the trial registration ID is provided (note: if posting a prospective study registered retrospectively, please provide a statement in the trial ID field explaining why the study was not registered in advance). Yes I have followed all appropriate research reporting guidelines and uploaded the relevant EQUATOR Network research reporting checklist(s) and other pertinent material as supplementary files, if applicable. Yes Summary statistics for Alzheimers disease were obtained from the NIAGADS platform. ENIGMA MRI summary measures from genetic association analyses of estimated total intracranial volume, subcortical structures, as well as cortical thickness were requested online at . The ABCD Study data are openly available to qualified researchers for free. Access can be requested at . Requests for Generation R data should be directed toward the management team of the Generation R Study (secretariaat.genr{at}erasmusmc.nl), 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 at [www.bristol.ac.uk/alspac/researchers/access][2] where applications for individual-level data can be made (managed access). UK Biobank data are available through a procedure described at . [1]: http://ClinicalTrials.gov [2]: http://www.bristol.ac.uk/alspac/researchers/access