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

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....

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Main Authors: Korologou-Linden, Roxanna (Author) , Xu, Bing (Author) , Coulthard, Elizabeth (Author) , Walton, Esther (Author) , Wearn, Alfie (Author) , Hemani, Gibran (Author) , White, Tonya (Author) , Cecil, Charlotte (Author) , Sharp, Tamsin (Author) , Tiemeier, Henning (Author) , Banaschewski, Tobias (Author) , Bokde, Arun (Author) , Desrivières, Sylvane (Author) , Flor, Herta (Author) , Grigis, Antoine (Author) , Garavan, Hugh (Author) , Gowland, Penny (Author) , Heinz, Andreas (Author) , Brühl, Rüdiger (Author) , Martinot, Jean-Luc (Author) , Martinot, Marie-Laure Paillère (Author) , Artiges, Eric (Author) , Nees, Frauke (Author) , Orfanos, Dimitri Papadopoulos (Author) , Paus, Tomáš (Author) , Poustka, Luise (Author) , Millenet, Sabina (Author) , Fröhner, Juliane (Author) , Smolka, Michael (Author) , Walter, Henrik (Author) , Winterer, Jeanne (Author) , Whelan, Robert (Author) , Schumann, Gunter (Author) , Howe, Laura D. (Author) , Ben-Shlomo, Yoav (Author) , Davies, Neil M. (Author) , Anderson, Emma Louise (Author)
Format: Article (Journal)
Language:English
Published: 2024
In: Journal of neurology, neurosurgery, and psychiatry
Year: 2025, Volume: 96, Issue: 4, Pages: 350-360
ISSN:1468-330X
DOI:10.1136/jnnp-2023-332969
Online Access:Verlag, kostenfrei, Volltext: https://doi.org/10.1136/jnnp-2023-332969
Verlag, kostenfrei, Volltext: http://jnnp.bmj.com/content/early/2024/04/25/jnnp-2023-332969
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Author Notes: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
Description
Summary: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.
Item Description:Erstmals online veröffentlicht: 25. April 2024
Gesehen am 29.10.2024
Physical Description:Online Resource
ISSN:1468-330X
DOI:10.1136/jnnp-2023-332969

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