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 Martinot; Marie 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

doi:10.1136/jnnp-2023-332969

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 journal › Article › peer-review

Abstract

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 language	English
Article number	jnnp-2023-332969
Journal	Journal of Neurology, Neurosurgery and Psychiatry
Early online date	25 Apr 2024
DOIs	https://doi.org/10.1136/jnnp-2023-332969
Publication status	E-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 (https://nda.nih.gov/abcd/request-access).Requests for Generation R data should be directed towards the management team of the Generation R study ([email protected]), which has a protocol of approving data requests. For access to IMAGEN data, researchers may submit a request to the IMAGEN consortium (https://imagen-europe.com/resources/imagen-project-proposal/). ALSPAC details and data descriptions are available on their website (www.bristol.ac.uk/alspac/researchers/access), where applications for individual-level data can be made (managed access). UK Biobank data are available through a procedure described on their website (http://www.ukbiobank.ac.uk/usingthe-resource/). 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 https://github.com/rskl92/AD_BRAIN_BIDIRECTIONAL_MR.Supplemental material This

Funding

Data used in the preparation of this article were obtained from the Adolescent Brain Cognitive Development (ABCD) Study ( https://abcdstudy.org ), held in the NIMH Data Archive (NDA). This is a multisite, longitudinal study designed to recruit >10 000 children aged 9\u201310 years and follow them over 10 years into early adulthood. The ABCD study is supported by the National Institutes of Health (NIH) and additional federal partners under award numbers U01DA041048, U01DA050989, U01DA051016, U01DA041022, U01DA051018, U01DA051037, U01DA050987, U01DA041174, U01DA041106, U01DA041117, U01DA041028, U01DA041134, U01DA050988, U01DA051039, U01DA041156, U01DA041025, U01DA041120, U01DA051038, U01DA041148, U01DA041093, U01DA041089, U24DA041123, U24DA041147. A full list of supporters is available at https://abcdstudy.org/federal-partners.html . A listing of participating sites and a complete listing of the study investigators can be found at https://abcdstudy.org/consortium_members/ . ABCD consortium investigators designed and implemented the study and/or provided data but did not necessarily participate in analysis or writing of this report. The ABCD data repository grows and changes over time. The ABCD data used in this report came from NIMH Data Archive Digital Object Identifier (10.15154/1503209). We are extremely grateful to all the families who took part in this study, the midwives for their help in recruiting them and the whole ALSPAC team, which includes interviewers, computer and laboratory technicians, clerical workers, research scientists, volunteers, managers, receptionists and nurses. The UK Medical Research Council and Wellcome (grant ref: 217065/Z/19/Z) and the University of Bristol provide core support for ALSPAC. This publication is the work of RK-L and ELA and NMD will serve as guarantors for the contents of this paper. A comprehensive list of grants funding is available on the ALSPAC website ( http://www.bristol.ac.uk/alspac/external/documents/grant-acknowledgements.pdf ). The ALSPAC-Testosterone study was funded by the NIH, USA (R01MH085772 to TP). The ALSPAC-PE study was funded by a grant from the UK Medical Research Council (G0901885). ASD was also supported by the NIH Research Biomedical Research Centre at the South London and Maudsley Hospital Foundation NHS Trust and the IoPPN, King\u2019s College London. The ALSPAC SCZ-RbG study was funded by grant MR/K004360/1 from the Medical Research Council (MRC) titled: 'Behavioural and neurophysiological effects of schizophrenia risk genes: a multi-locus, pathway based approach' and by the MRC Centre for Neuropsychiatric Genetics and Genomics (G0800509) and the NIHR Bristol Biomedical Research Centre. IMAGEN is supported by the European Union-funded FP6 Integrated Project IMAGEN (reinforcement-related behaviour in normal brain function and psychopathology) (LSHM-CT- 2007-037286), the Horizon 2020 funded ERC Advanced Grant \u2018STRATIFY\u2019 (brain network-based stratification of reinforcement-related disorders) (695313), Human Brain Project (HBP SGA 2, 785907 and HBP SGA 3, 945539), the Medical Research Council Grant \u2018c-VEDA\u2019 (Consortium on Vulnerability to Externalising Disorders and Addictions) (MR/N000390/1), the National Institute of Health (NIH) (R01DA049238, a decentralised macro and micro gene-by-environment interaction analysis of substance use behaviour and its brain biomarkers), the National Institute for Health Research (NIHR) Biomedical Research Centre at South London and Maudsley NHS Foundation Trust and King\u2019s College London, the Bundesministeriumf\u00FCr Bildung und Forschung (BMBF grants 01GS08152; 01EV0711; Forschungsnetz AERIAL 01EE1406A, 01EE1406B; Forschungsnetz IMAC-Mind 01GL1745B), the Deutsche Forschungsgemeinschaft (DFG grants SM 80/7-2, SFB 940, TRR 265, NE 1383/14-1), the Medical Research Foundation and Medical Research Council (grants MR/R00465X/1 and MR/S020306/1), the NIH funded ENIGMA (grants 5U54EB020403-05 and 1R56AG058854-01). Further support was provided by grants from the ANR (ANR-12-SAMA-0004, AAPG2019 \u2014 GeBra), the Eranet Neuron (AF12-NEUR0008-01 \u2014 WM2NA and ANR-18-NEUR00002-01 \u2014 ADORe), the Fondation de France (00081242), the Fondation pour la Recherche M\u00E9dicale (DPA20140629802), the Mission Interminist\u00E9rielle de Lutte-contre-les-Drogues-et-les-Conduites-Addictives (MILDECA), the Assistance-Publique-H\u00F4pitaux-de-Paris and INSERM (interface grant), Paris Sud University IDEX 2012, the Fondation de l\u2019Avenir (grant AP-RM-17-013), the F\u00E9d\u00E9ration pour la Recherche sur le Cerveau; the NIH, Science Foundation Ireland (16/ERCD/3797), USA (Axon, Testosterone and Mental Health during Adolescence; RO1 MH085772-01A1) and by NIH Consortium grant U54 EB020403, supported by a cross-NIH alliance that funds Big Data to Knowledge Centres of Excellence. The UK Biobank data used in this work were obtained from UK Biobank Data Application 48970. We thank UK Biobank for making the data available, and to all UK Biobank study participants, who generously donated their time to make this resource possible. We thank the International Genomics of Alzheimer's Project (IGAP) for providing summary results data for these analyses. The investigators within IGAP contributed to the design and implementation of IGAP and/or provided data but did not participate in analysis or writing of this report. IGAP was made possible by the generous participation of the control subjects, the patients and their families. The i-Select chips was funded by the French National Foundation on Alzheimer's disease and related disorders. EADI was supported by the LABEX (laboratory of excellence programme investment for the future) DISTALZ grant, INSERM, Institut Pasteur de Lille, Universit\u00E9 de Lille 2 and the Lille University Hospital. GERAD/PERADES was supported by the Medical Research Council (grant no. 503480), Alzheimer's Research UK (grant no. 503176), the Wellcome Trust (grant no. 082604/2/07/Z) and German Federal Ministry of Education and Research (BMBF): Competence Network Dementia (CND) grant no. 01GI0102, 01GI0711, 01GI0420. CHARGE was partly supported by the NIH/NIA grant R01 AG033193 and the NIA AG081220 and AGES contract N01-AG-12100, the NHLBI grant R01 HL105756, the Icelandic Heart Association and the Erasmus Medical Center and Erasmus University. ADGC was supported by the NIH/NIA grants U01 AG032984, U24 AG021886, U01 AG016976, and the Alzheimer's Association grant ADGC-10-196728. RK-L 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. YB-S receives grant funding from the following: MRC, Wellcome Trust, NIHER, Templeton Foundation, Parkinson\u2019s UK, HQIP, Versus Arthritis, Dunhill Medical Trust, Gatsby Foundation, Kidney Research UK. LDH is funded by a Career Development Award from the UK Medical Research Council (MR/M020894/1). EW is funded by the European Union\u2019s Horizon 2020 research and innovation programme (grant no. 848158) and by CLOSER, who was funded by the Economic and Social Research Council (ESRC) and the MRC between 2012 and 2017. Its initial 5-year grant has since been extended to March 2021 by the ESRC (grant reference: ES/K000357/1). TW is funded by Netherlands Organization for Health Research and Development (ZonMw) TOP project number 91211021. This research was also supported by contract R01-HL105756-07 from the National Heart, Lung and Blood Institute (NHLBI). EC is supported by grants with the Above and Beyond Charity for research optimising sleep to slow dementia progression and improve quality of life and the Alzheimer\u2019s Research UK on research about the long-term memory testing to predict the presence of Alzheimer\u2019s disease pathology from BRACE charity. CC is supported by the European Union\u2019s Horizon 2020 Research and Innovation Programme under the Marie Sk\u0142odowska-Curie grant agreement no. 707404 and grant agreement no. 848158 (EarlyCause Project). The work of Henning Tiemeier is supported by Netherlands Organization for Health Research and Development (ZonMW: 016.VICI.170.200). GH is supported by the Wellcome Trust and Royal Society (208806/Z/17/Z). AW is supported by Wellcome Trust PhD Grant, BRACE Pilot grant (co-applicant). SD is supported by the MRC. AB has received two grants from the National Children\u2019s Hospital Foundation \u2014 Tallaght (Ireland), a grant from the Health Research Board (Ireland), a grant from the Irish Research Council and a grant from the European Union Horizon 2020 Programme (MSCA-ITN). All funds paid to Trinity College Dublin. HF is supported by the Coviddrug German Research Foundation Perpain German Ministry of Education and Research. TP is supported by the Canadian Institutes of Health research. MS is supported by the Deutsche Forschungsgemeinschaft, grant numbrs 186318919, 178833530 and 402170461. HW is supported by EU Horizon 2020: GA101016127; GA 777084, European Research Commission: GA 695313, BMBF (German Ministery for Health and Education): 01ZX1909C, 01EE1407G, 01ZX1614B, DFG (German Research Foundation): SFB 940; TRR 256/1; GRK 2386; WA 1539/9-1; WA 1539/11-1.

Funders	Funder number
French National Research Agency
Dunhill Medical Trust
Coviddrug German Research Foundation Perpain German Ministry of Education and Research
LabEx Entreprendre
Economic and Social Research Council
Gatsby Charitable Foundation
CLOSER
Institut National de la Sante et de la Recherche Medicale (INSERM)
NIHR Bristol Biomedical Research Centre
Manchester University NHS Foundation Trust
National Institute for Health and Care Research
Erasmus University Medical Center
NIHER
Fédération pour la Recherche sur le Cerveau
French National Foundation
South London and Maudsley NHS Foundation Trust
Université de Lille
Université Paris-Sud
Parkinson's Disease Society
Healthcare Quality Improvement Partnership
Hjartavernd
Irish Research Council
Health Research Board
MSCA-ITN
Canadian Institute of Health Research
Institute Pasteur Lille
ANR-18-NEUR00002-01
Versus Arthritis
National Heart and Lung Institute
John Templeton Foundation
European Union-funded FP6	LSHM-CT- 2007-037286
Division of Intramural Research, Population Sciences Branch, National Heart, Lung and Blood Institute, Framingham, MA, USA.	R01 HL105756
German Ministery for Health and Education	01ZX1909C, 01EE1407G, 01ZX1614B
University of Cambridge	5U54EB020403-05, MR/R00465X/1, 1R56AG058854-01, MR/S020306/1
The Wellcome Trust	082604/2/07/Z, 217065/Z/19/Z, 215193/Z18/Z
Horizon 2020 Framework Programme	707404, 848158
National Institutes of Health	U54 EB020403, U01DA041106, U01DA041028, U01DA041148, U01DA041048, U01DA041025, R01DA049238, U01DA041089, U01DA041022, U01DA041120, U01DA050987, U01DA050988, U01DA050989, U01DA051039, U01DA051038, U01DA051016, U01DA051018, U01DA051037, U01DA041117, U24DA041147, U24DA041123, U01DA041134, U01DA041156, U01DA041174, U01DA041093
King's College London	MR/K004360/1, G0800509
Centre Hospitalier Régional et Universitaire de Lille	503480
Alzheimer's Research UK	503176
Erasmus University Rotterdam	U24 AG021886, U01 AG016976, U01 AG032984
Deutsche Forschungsgemeinschaft	SM 80/7-2, 178833530, TRR 256/1, GRK 2386, NE 1383/14-1, 186318919, 402170461, SFB 940, TRR 265, WA 1539/9-1
Testosterone and Mental Health	RO1 MH085772-01A1
Science Foundation Ireland	16/ERCD/3797
Medical Research Council	MR/P014437/1, G0901885
Fondation de l'Avenir pour la Recherche Médicale Appliquée	AP-RM-17-013
Fondation Hôpital Saint Joseph	00081242
Horizon 2020	GA 777084, GA101016127
Fondation pour la Recherche Médicale	DPA20140629802
Royal Society	208806/Z/17/Z
University of Bristol	R01MH085772
European Commission	GA 695313
Kidney Research UK	MR/M020894/1
Australasian Gynaecological Endoscopy and Surgery Society	N01-AG-12100
ERA-Net NEURON	AF12-NEUR0008-01 — WM2NA
Norges Forskningsråd	295989
European Research Council	695313, 785907, 945539, MR/N000390/1
ANR-12-SAMA-0004	AAPG2019 — GeBra
Bundesministerium für Bildung und Forschung	01GL1745B, 01GS08152, 01EV0711, AERIAL 01EE1406A, 01GI0711, 01GI0420, 01GI0102, 01EE1406B
ZonMw	R01-HL105756-07, 91211021
Alzheimer's Association	ADGC-10-196728
NHS Innovation Accelerator	R01 AG033193, AG081220

Keywords

Alzheimer's disease
brain mapping
epidemiology
genetics
neuroanatomy

ASJC Scopus subject areas

Surgery
Clinical Neurology
Psychiatry and Mental health

UN SDGs

This output contributes to the following UN Sustainable Development Goals (SDGs)

Access to Document

10.1136/jnnp-2023-332969Licence: CC BY

Cite this

Korologou-Linden, R., Xu, B., Coulthard, E., Walton, E., Wearn, A., Hemani, G., White, T., Cecil, C., Sharp, T., Tiemeier, H., Banaschewski, T., Bokde, A., Desrivières, S., Flor, H., Grigis, A., Garavan, H., Gowland, P., Heinz, A., Brühl, R., ... Anderson, E. L. (2024). Genetics impact risk of Alzheimer's disease through mechanisms modulating structural brain morphology in late life. Journal of Neurology, Neurosurgery and Psychiatry, Article jnnp-2023-332969. Advance online publication. https://doi.org/10.1136/jnnp-2023-332969

Korologou-Linden, R, Xu, B, Coulthard, E, Walton, E, Wearn, A, Hemani, G, White, T, Cecil, C, Sharp, T, Tiemeier, H, Banaschewski, T, Bokde, A, Desrivières, S, Flor, H, Grigis, A, Garavan, H, Gowland, P, Heinz, A, Brühl, R, Martinot, JL, Paillère Martinot, ML, Artiges, E, Nees, F, Orfanos, DP, Paus, T, Poustka, L, Millenet, S, Fröhner, JH, Smolka, M, Walter, H, Winterer, J, Whelan, R, Schumann, G, Howe, LD, Ben-Shlomo, Y, Davies, NM & Anderson, EL 2024, 'Genetics impact risk of Alzheimer's disease through mechanisms modulating structural brain morphology in late life', Journal of Neurology, Neurosurgery and Psychiatry. https://doi.org/10.1136/jnnp-2023-332969

@article{0c4e68d1da214f1ea61a3905d93652cc,

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

abstract = "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.",

keywords = "Alzheimer's disease, brain mapping, epidemiology, genetics, neuroanatomy",

author = "Roxanna Korologou-Linden and Bing Xu and Elizabeth Coulthard and Esther Walton and Alfie Wearn and Gibran Hemani and Tonya White and Charlotte Cecil and Tamsin Sharp and Henning Tiemeier and Tobias Banaschewski and Arun Bokde and Sylvane Desrivi{\`e}res and Herta Flor and Antoine Grigis and Hugh Garavan and Penny Gowland and Andreas Heinz and R{\"u}diger Br{\"u}hl and Martinot, {Jean Luc} and {Paill{\`e}re Martinot}, {Marie Laure} and Eric Artiges and Frauke Nees and Orfanos, {Dimitri Papadopoulos} and Tom{\'a}{\v s} Paus and Luise Poustka and Sabina Millenet and Fr{\"o}hner, {Juliane H.} and Michael Smolka and Henrik Walter and Jeanne Winterer and Robert Whelan and Gunter Schumann and Howe, {Laura D.} and Yoav Ben-Shlomo and Davies, {Neil M.} and Anderson, {Emma Louise}",

year = "2024",

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doi = "10.1136/jnnp-2023-332969",

language = "English",

journal = "Journal of Neurology, Neurosurgery and Psychiatry",

issn = "0022-3050",

publisher = "BMJ Publishing Group",

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TY - JOUR

T1 - Genetics impact risk of Alzheimer's disease through mechanisms modulating structural brain morphology in late life

AU - Korologou-Linden, Roxanna

AU - Xu, Bing

AU - Coulthard, Elizabeth

AU - Walton, Esther

AU - Wearn, Alfie

AU - Hemani, Gibran

AU - White, Tonya

AU - Cecil, Charlotte

AU - Sharp, Tamsin

AU - Tiemeier, Henning

AU - Banaschewski, Tobias

AU - Bokde, Arun

AU - Desrivières, Sylvane

AU - Flor, Herta

AU - Grigis, Antoine

AU - Garavan, Hugh

AU - Gowland, Penny

AU - Heinz, Andreas

AU - Brühl, Rüdiger

AU - Martinot, Jean Luc

AU - Paillère Martinot, Marie Laure

AU - Artiges, Eric

AU - Nees, Frauke

AU - Orfanos, Dimitri Papadopoulos

AU - Paus, Tomáš

AU - Poustka, Luise

AU - Millenet, Sabina

AU - Fröhner, Juliane H.

AU - Smolka, Michael

AU - Walter, Henrik

AU - Winterer, Jeanne

AU - Whelan, Robert

AU - Schumann, Gunter

AU - Howe, Laura D.

AU - Ben-Shlomo, Yoav

AU - Davies, Neil M.

AU - Anderson, Emma Louise

PY - 2024/4/25

Y1 - 2024/4/25

N2 - 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.

AB - 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.

KW - Alzheimer's disease

KW - brain mapping

KW - epidemiology

KW - genetics

KW - neuroanatomy

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U2 - 10.1136/jnnp-2023-332969

DO - 10.1136/jnnp-2023-332969

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AN - SCOPUS:85191604430

SN - 0022-3050

JO - Journal of Neurology, Neurosurgery and Psychiatry

JF - Journal of Neurology, Neurosurgery and Psychiatry

M1 - jnnp-2023-332969

ER -

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

Abstract

Data Availability Statement

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Keywords

ASJC Scopus subject areas

UN SDGs

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EarlyCause

Cite this

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

Abstract

Data Availability Statement

Funding

Keywords

ASJC Scopus subject areas

UN SDGs

Access to Document

Other files and links

Fingerprint

Projects

EarlyCause

Cite this