Genetic risk of dementia modifies obesity effects on white matter myelin in cognitively healthy adults
Open accessAbstract
APOE-ε4 is a major genetic risk factor for late-onset Alzheimer's disease that interacts with other risk factors, but the nature of such combined effects remains poorly understood. We quantified the impact of APOE-ε4, family history (FH) of dementia, and obesity on white matter (WM) microstructure in 165 asymptomatic adults (38-71 years old) using quantitative magnetization transfer and neurite orientation dispersion and density imaging. Microstructural properties of the fornix, parahippocampal cingulum, and uncinate fasciculus were compared with those in motor and whole-brain WM regions. Widespread interaction effects between APOE, FH, and waist-hip ratio were found in the myelin-sensitive macromolecular proton fraction from quantitative magnetization transfer. Among individuals with the highest genetic risk (FH+ and APOE-ε4), obesity was associated with reduced macromolecular proton fraction in the right parahippocampal cingulum, whereas no effects were present for those without FH. Risk effects on apparent myelin were moderated by hypertension and inflammation-related markers. These findings suggest that genetic risk modifies the impact of obesity on WM myelin consistent with neuroglia models of aging and late-onset Alzheimer's disease.
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White matter and myelin pathology are frequently observed in healthy APOE4 carriers and early Alzheimer's disease subjects.
“White matter (WM) and myelin pathology are frequently observed in healthy APOE4 carriers and early AD subjects, but the underlying cellular mechanism is obscure.”
From Apolipoprotein E ε4 disrupts oligodendrocyte differentiation by interfering with astrocyte‐derived lipid transport (2023) · cites this paper as Mole et al. 2020
Independent clinical studies commonly report that early white matter abnormalities occur in healthy APOE4 carriers in the absence of plaque or cognitive impairments.
“Independent clinical studies reported in common that early WM abnormalities occurs in healthy APOE4 carriers in the absence of plaque or cognitive impairments (Goltermann et al. 2021;Mole et al. 2020;Operto et al. 2018;Bartzokis et al. 2001;Bartzokis et al. 2003;Bartzokis et al. 2007;Bartzokis et al. 2010;Triebswetter et al. 2022).”
From Apolipoprotein E ε4 disrupts oligodendrocyte differentiation by interfering with astrocyte‐derived lipid transport (2023) · cites this paper as Mole et al. 2020
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Obesity-related brain atrophy is independent of Alzheimer's disease protein pathways
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Self-citationBody mass index (BMI) and structural brain connectivity in the human connectome project dataset
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Gallagher, R. L., Koscik, R. L., Moody, J. F., Vogt, N. M., Adluru, N., Kecskemeti, S., Van Hulle, C. A., Chin, N. A., Asthana, S., Kollmorgen, G., et al. (2024) · Figshare · doi:10.6084/m9.figshare.26628052
- Authors
- Mole, J. P., Fasano, F., Evans, J., Sims, R., Hamilton, D. A., Kidd, E., & Metzler-Baddeley, C.
- Affiliations
- Cardiff University (GB)
- University of New Mexico (US)
- Venue
- Neurobiology of Aging
- Publisher
- Elsevier BV
- Published
- 2020-10
- Volume
- 94
- Pages
- 298-310
- ISSN
- 0197-4580 (ISSN-L)
- OpenAlex
- W3038248843
- Cited by
- 20
- References
- 153
- Citations by year
- 2025: 2 · 2024: 3 · 2023: 3 · 2022: 5 · 2021: 6 · 2020: 1
- FWCI
- 2.75
- Type
- journal article
- Language
- en
- Open access
- green
- orca.cardiff.ac.uk
- Licence
- Locations
- Neurobiology of Aging (publishedVersion)
- PubMed (publishedVersion)
- ORCA Online Research @Cardiff (Cardiff University) (acceptedVersion)
- ORCA Online Research @Cardiff (Cardiff University) (submittedVersion, cc-by-nd)
- Funders
- BRACE
- Cardiff University
- Alzheimer's Society
- School of Psychology, Cardiff University
- Topics
- Health Sciences › Medicine › Psychiatry and Mental health › Dementia and Cognitive Impairment Research
- Health Sciences › Medicine › Radiology, Nuclear Medicine and Imaging › Advanced Neuroimaging Techniques and Applications
- Health Sciences › Medicine › Physiology › Alzheimer's disease research and treatments
- Keywords
- APOE ε4, family history of dementia, obesity, white matter microstructure, myelin, quantitative magnetization transfer, macromolecular proton fraction, fornix, uncinate fasciculus, waist-to-hip ratio, hypertension, inflammation, gene-environment interaction, late-onset Alzheimer's disease
- MeSH terms
- Adult, Aged, Alzheimer Disease, Apolipoproteins E, Female, Humans, Hypertension, Inflammation, Male, Middle Aged, Myelin Sheath, Obesity, Risk Factors, Genetic Association Studies, Healthy Volunteers, White Matter
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