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

^*Corresponding author for this work

Research output: Contribution to journal › Article (Academic Journal) › 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
Number of pages	11
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

Bibliographical note

Publisher Copyright:
© Author(s) (or their employer(s)) 2024. Re-use permitted under CC BY. Published by BMJ.

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10.1136/jnnp-2023-332969Licence: CC BY

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Life course aetiology of dementia and cognitive decline: improving causal inference
Anderson, E. L. (Principal Investigator)
1/06/17 → 31/01/22
Project: Research
Laura Howe Population Health Scientist Fellowship
Howe, L. D. (Principal Investigator)
1/09/15 → 31/12/22
Project: Research

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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. Advance online publication. https://doi.org/10.1136/jnnp-2023-332969

@article{3986a8e28ead4688a6f42e9084669fa8,

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

abstract = "Background Alzheimer{\textquoteright}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.",

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 Jean-Luc Martinot 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}",

note = "Publisher Copyright: {\textcopyright} Author(s) (or their employer(s)) 2024. Re-use permitted under CC BY. Published by BMJ.",

year = "2024",

month = apr,

day = "25",

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

language = "English",

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

issn = "0022-3050",

publisher = "BMJ Publishing Group",

}

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, J-L, Paillère Martinot, M-L, 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

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.

U2 - 10.1136/jnnp-2023-332969

DO - 10.1136/jnnp-2023-332969

M3 - Article (Academic Journal)

C2 - 38663994

SN - 0022-3050

JO - Journal of Neurology, Neurosurgery, and Psychiatry

JF - Journal of Neurology, Neurosurgery, and Psychiatry

ER -

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

Abstract

Bibliographical note

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Projects

Life course aetiology of dementia and cognitive decline: improving causal inference

Laura Howe Population Health Scientist Fellowship

Cite this