White matter microstructure in late middle-age: Effects of apolipoprotein E4 and parental family history of Alzheimer's disease
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INTRODUCTION: Little is still known about the effects of risk factors for Alzheimer's disease (AD) on white matter microstructure in cognitively healthy adults. The purpose of this cross-sectional study was to assess the effect of two well-known risk factors for AD, parental family history and APOE4 genotype. METHODS: This study included 343 participants from the Wisconsin Registry for Alzheimer's Prevention, who underwent diffusion tensor imaging (DTI). A region of interest analysis was performed on fractional anisotropy maps, in addition to mean, radial, and axial diffusivity maps, aligned to a common template space using a diffeomorphic, tensor-based registration method. The analysis focused on brain regions known to be affected in AD including the corpus callosum, superior longitudinal fasciculus, fornix, cingulum, and uncinate fasciculus. Analyses assessed the impact of APOE4, parental family history of AD, age, and sex on white matter microstructure in late middle-aged participants (aged 47-76 years). RESULTS: Both APOE4 and parental family history were associated with microstructural white matter differences. Participants with parental family history of AD had higher FA in the genu of the corpus callosum and the superior longitudinal fasciculus. We observed an interaction between family history and APOE4, where participants who were family history positive but APOE4 negative had lower axial diffusivity in the uncinate fasciculus, and participants who were both family history positive and APOE4 positive had higher axial diffusivity in this region. We also observed an interaction between APOE4 and age, whereby older participants (=65 years of age) who were APOE4 carriers, had higher MD in the superior longitudinal fasciculus and in the portion of the cingulum bundle running adjacent to the cingulate cortex, compared to non-carriers. Older participants who were APOE4 carriers also showed higher radial diffusivity in the genu compared to non-carriers. Across all participants, age had an effect on FA, MD, and axial and radial diffusivities. Sex differences were observed in FA and radial diffusivity. CONCLUSION: APOE4 genotype, parental family history of AD, age, and sex are all associated with microstructural white matter differences in late middle-aged adults. In participants at risk for AD, alterations in diffusion characteristics-both expected and unexpected-may represent cellular changes occurring at the earliest disease stages, but further work is needed. Higher mean, radial, and axial diffusivities were observed in participants who are more likely to be experiencing later stage preclinical pathology, including participants who were both older and carried APOE4, or who were positive for both APOE4 and parental family history of AD.
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Prior diffusion MRI studies have identified microstructural white matter abnormalities in cognitively normal older APOE4 carriers, including increased mean diffusivity and reduced fractional anisotropy or restricted diffusion.
“Diffusion MRI studies have identified microstructural white matter (WM) abnormalities in cognitively normal older APOE4 carriers, including increased mean diffusivity and reduced fractional anisotropy or restricted diffusion [3–5]”
From Effects of APOE2 and APOE4 on brain microstructure in older adults: modification by age, sex, and cognitive status (2024) · cites this paper as [3]
The Abstract Results and Discussion Summary report higher mean diffusivity in cognitively healthy older APOE4 carriers than in non-carriers. They do not report reduced fractional anisotropy or restricted diffusion in those carriers; lower axial diffusivity was observed in participants with parental family history who did not carry APOE4. Page numbers are unavailable in our copy. (LLM, conf=0.86)
Experimental — accuracy not yet measuredSome studies have reported stronger effects of APOE4 on WM microstructure with age, whereas others observed no such interaction.
“some studies have reported stronger effects of APOE4 on WM microstructure with age [3, 15, 18], whereas others observed no such interaction [8].”
From Effects of APOE2 and APOE4 on brain microstructure in older adults: modification by age, sex, and cognitive status (2024) · cites this paper as [3]
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- Authors
- Adluru, N., Destiche, D. J., Lu, S. Y.-F., Doran, S. T., Birdsill, A. C., Melah, K. E., Okonkwo, O. C., Alexander, A. L., Dowling, N. M., Johnson, S. C., Sager, M. A., & Bendlin, B. B.
- Affiliations
- University of Wisconsin–Madison (US)
- Corresponding author
- Bendlin, Barbara B.
- ORCID
- Venue
- NeuroImage: Clinical
- Publisher
- Elsevier BV
- Published
- 2014
- Volume
- 4
- Pages
- 730-742
- ISSN
- 2213-1582 (ISSN-L)
- PMC
- PMC4053649
- OpenAlex
- W1983801775
- Cited by
- 85
- References
- 166
- Citations by year
- 2026: 4 · 2025: 7 · 2024: 6 · 2023: 10 · 2022: 5 · 2021: 5 · 2020: 7 · 2019: 10 · 2018: 9 · 2017: 9 · 2016: 6 · 2015: 6 · 2014: 1
- FWCI
- 5.74
- Type
- journal article
- Language
- en
- Open access
- gold
- doi.org
- Licence
- Locations
- NeuroImage Clinical (publishedVersion, cc-by)
- Europe PMC (PubMed Central) (publishedVersion, cc-by)
- PubMed Central (publishedVersion, cc-by)
- PubMed (publishedVersion)
- DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion, cc-by-sa)
- Funders
- the Alzheimer's Association (NIRG-09-132626)
- National Institute on Aging (R01 AG037639, R01 AG027161, ADRC P50 AG033514, R01 AG021155)
- National Center for Research Resources/National Institutes of Health Clinical and Translational Science Award (1UL1RR025011)
- Veteran's Administration (I01CX000165)
- Waisman Center Core (P30 HD003352-45)
- William S. Middleton Memorial Veterans Hospital, Madison, WI (GRECC MS # 2013-08)
- Topics
- Health Sciences › Medicine › Radiology, Nuclear Medicine and Imaging › Advanced Neuroimaging Techniques and Applications
- Health Sciences › Medicine › Psychiatry and Mental health › Dementia and Cognitive Impairment Research
- Health Sciences › Medicine › Physiology › Alzheimer's disease research and treatments
- Keywords
- white matter microstructure, Alzheimer's disease risk factors, APOE ε4, late middle age, corpus callosum, superior longitudinal fasciculus, uncinate fasciculus, fornix, cingulum, fractional anisotropy, axial diffusivity, radial diffusivity, mean diffusivity, sex differences, age effects
- MeSH terms
- Age Factors, Aged, Alzheimer Disease, Family Health, Female, Genotype, Humans, Image Processing, Computer-Assisted, Male, Middle Aged, Parents, Multivariate Analysis, Apolipoprotein E4, Diffusion Tensor Imaging, White Matter
About these checks
Registry, retraction, Cites and statistics results are computed, not judged, with one exception: a printed reference that no index lists is read once by a model before it counts as a citation error. Claims are extracted by a model and kept only when their quote appears verbatim in the text; each cited source is then checked, with a model’s help, for whether it says what the claim relies on. Those verdicts can be wrong — read the claim’s quote and the cited source before relying on one.
Statistics and arithmetic are recomputed, not judged.
Confidence bands are shown only for fields calibrated on our annotated test set. None is calibrated yet, so no band is shown.
What counts as a claim ›How we measure confidence ›How we check this ›
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