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. 2025 Sep;107(1):92-103.
doi: 10.1177/13872877251359680. Epub 2025 Jul 27.

Obesity-related brain atrophy is independent of Alzheimer's disease protein pathways

Filip Morys  1   2 , Lang Liu  1   2   3 , Konstantin Senkevich  1   2   3   4 , Ziv Gan-Or  1   2   3 , Alain Dagher  1   2
Affiliations

Obesity-related brain atrophy is independent of Alzheimer's disease protein pathways

Filip Morys et al. J Alzheimers Dis. 2025 Sep.

Abstract

BackgroundObesity increases the risk for Alzheimer's disease (AD) and other dementias. Obesity causes structural brain injury, and it has been suggested that this may contribute to the development of AD pathology. Neurodegeneration in AD results from the aggregation of misfolded and dysfunctional tau and amyloid-β. However, it remains unknown whether adiposity-related brain injury acts through tau and amyloid deposition or as an independent cause of neurodegeneration.ObjectiveHere, we tested whether obesity, cerebrovascular disease, and obesity-related metabolic risk score were associated with structural brain and cognitive changes via the same mechanisms as AD or independent of them.MethodsWe used the UK Biobank sample of over 33,000 individuals aged 64 years on average. We tested the influence of the microtubule-associated protein tau (MAPT) and apolipoprotein E (APOE) risk alleles involved in tau and amyloid-β synthesis, folding, and clearance, as well as AD polygenic risk score (PRS) to define genetic risk of AD. Specifically, we investigated whether these genetic risk factors moderated the relationship between obesity and brain structure and cognition.ResultsWe found that MAPT and APOE status and AD PRS did not moderate the relationship between obesity and brain atrophy. We also found limited evidence for the moderation of MAPT and APOE of the cerebrovascular disease-brain structure relationship as well as the metabolic risk score-brain structure relationship.ConclusionsWe conclude that the mechanisms linking obesity with brain atrophy are most likely independent of the ones governing AD-related protein deposition.

Keywords: APOE; Alzheimer's disease; MAPT; brain structure; obesity.

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Conflict of interest statement

Declaration of conflicting interestsZ.G.O received consultancy fees from Lysosomal Therapeutics Inc. (LTI), Idorsia, Prevail Therapeutics, Ono Therapeutics, Denali, Handl Therapeutics, Neuron23, Bial Biotech, Bial, UCB, Capsida, Vanqua bio, Congruence Therapeutics, Takeda, Jazz Guidepoint, Lighthouse and Deerfield. Remaining authors declare no conflicting interest with respect to the research, authorship, and/or publication of this article. Data availability statementData used in this study are available upon request from the UK Biobank. Code used to analyze the dataset is deposited at https://github.com/FilipMorys/MAPT_ApoE.

Figures

Figure 1.
Figure 1.
Associations between genotypes and grey matter phenotypes; (a, b) APOE ε4 carriers versus non-carriers; (c, d) MAPT H1 versus H2 haplotype.
Figure 2.
Figure 2.
Associations between genotypes and grey matter phenotypes; (a) fractional anisotropy in APOE ε4 carriers versus non-carriers; (b) mean diffusivity in APOE ε4 carriers versus non-carriers; (c) fractional anisotropy in MAPT H1 versus H2 haplotype; (d) mean diffusivity in MAPT H1 versus H2 haplotype.
Figure 3.
Figure 3.
Associations between body mass index (BMI) and grey matter phenotypes; (a) Relationship between BMI and cortical thickness (CT) and surface area (SA); (b) relationship between BMI and subcortical volumes; (c-f) effects of genotypes on cortical thickness and surface area in regions significantly related to BMI.
Figure 4.
Figure 4.
Associations between body mass index (BMI) and white matter microstructure; (a) Relationship between BMI and fractional anisotropy (FA); (b) relationship between BMI and mean diffusivity (MD); (c-f) effects of genotypes on fractional anisotropy and mean diffusivity in regions significantly related to BMI.
See this image and copyright information in PMC

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