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Cited by 17Dementia and Cognitive Impairment ResearchCerebrovascular and genetic disordersNeurological Disease Mechanisms and Treatments

APOE4 carrier status determines association between white matter disease and grey matter atrophy in early-stage dementia

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Vipin, Ashwati, Kumar, Dilip, Soo, See Ann, Zailan, Fatin Zahra, Leow, Yi Jin, Koh, Chen Ling, Ng, Adeline Su Lyn, Ng, Kok Pin +1 more·2023·Alzheimer's Research & Therapy
DOI 10.1186/s13195-023-01251-4PMC PMC10239168
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Abstract

Background: White matter hyperintensities, a neuroimaging marker of small-vessel cerebrovascular disease and apolipoprotein ε4 (APOE4) allele, are important dementia risk factors. However, APOE4 as a key effect modifier in the relationship between white matter hyperintensities and grey matter volume needs further exploration. Methods: One hundred ninety-two early-stage dementia (including mild cognitive impairment and mild dementia) and 259 cognitively unimpaired participants from a neurocognitive research cohort with neuroimaging data, APOE genotyping, and neuropsychological assessments were studied. We investigated independent and interactive effects of white matter hyperintensities and APOE4 on whole-brain voxel-wise grey matter volume using voxel-based morphometry (uncorrected p < 0.001; minimum cluster size = 100 voxels). We further assessed interactive effects between APOE4 and white matter hyperintensities on global cognition, memory, and executive function in early-stage dementia and cognitively unimpaired participants. Results: Independent of APOE4 status, higher white matter hyperintensity load was associated with greater grey matter atrophy across frontal, parietal, temporal, and occipital lobes in cognitively unimpaired and early-stage dementia subjects. However, interaction analyses and independent sample analyses revealed that APOE4 non-carriers demonstrated greater white matter hyperintensity-associated grey matter atrophy compared to APOE4 carriers in both cognitively unimpaired and early-stage dementia groups. Additional confirmatory analyses among APOE4 non-carriers demonstrated that white matter hyperintensities resulted in widespread grey matter loss. Analyses of cognitive function demonstrated that higher white matter hyperintensity load was associated with worse global (Mini-Mental State Examination, Montreal Cognitive Assessment) and executive function (Color Trails 2) in APOE4 non-carriers compared to APOE4 carriers in early-stage dementia but not cognitively unimpaired participants. Conclusions: The association between white matter hyperintensities and grey matter loss is more pronounced in APOE4 non-carriers than APOE4 carriers in the cognitively unimpaired and early-stage dementia stages. Furthermore, white matter hyperintensity presence results in poorer executive function in APOE4 non-carriers compared to APOE4 carriers. This finding may have significant impact on the design of clinical trials with disease modifying therapies.

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  • APOE4 compromises the integrity of white matter, further disrupting brain connectivity and function.

    “Beyond its effects on gray matter, APOE4 also compromises the integrity of white matter, further disrupting brain connectivity and function. 10 , 11 , 12”

    From Apolipoprotein ε4 exacerbates white matter impairment in a mouse model of Aβ amyloidosis by decreasing actively myelinating oligodendrocytes (2025) · cites this paper as [11]

    The Discussion (page unavailable) suggests that APOE4-related blood–brain barrier disruption may contribute to white matter hyperintensities, but does not establish that APOE4 compromises white matter integrity. The Results (page unavailable) link greater white matter hyperintensity load to poorer cognition primarily in APOE4 non-carriers, and the paper does not show that APOE4 disrupts brain connectivity. (LLM, conf=0.84)

    Experimental — accuracy not yet measured

  • Multiple MRI studies have reported that the APOE4 isoform is associated with white matter degeneration in patients with dementia.

    “Multiple MRI studies have reported that APOE4 isoform is associated with white matter degeneration in patients with dementia. 10 , 11 , 22 , 23”

    From Apolipoprotein ε4 exacerbates white matter impairment in a mouse model of Aβ amyloidosis by decreasing actively myelinating oligodendrocytes (2025) · cites this paper as [11]

    The Introduction reports prior associations between APOE4 and white matter hyperintensity burden, an MRI marker of white matter disease, but says findings on APOE4’s influence on that burden are mixed. It does not establish that multiple MRI studies found white matter degeneration specifically in patients with dementia; the Discussion also reports no difference in hyperintensity load between carriers and non-carriers in this study. (LLM, conf=0.84)

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Cited by

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Authors
Vipin, A., Kumar, D., Soo, S. A., Zailan, F. Z., Leow, Y. J., Koh, C. L., Ng, A. S. L., Ng, K. P., & Kandiah, N.
Affiliations
  • Nanyang Technological University (SG)
  • National Neuroscience Institute (SG)
  • Duke-NUS Medical School (SG)
Corresponding author
Kandiah, Nagaendran
ORCID
Venue
Alzheimer's Research & Therapy
Publisher
Springer Science and Business Media LLC
Published
2023-06-03
Volume
15
Issue
1
Pages
103-103
ISSN
1758-9193 (ISSN-L)
DOI
10.1186/s13195-023-01251-4
PMC
PMC10239168
OpenAlex
W4379259455
Cited by
17
References
5
Citations by year
2026: 2 · 2025: 8 · 2024: 6 · 2023: 1
FWCI
3.46
Type
journal article
Language
en
Open access
Licence
Locations
  • Alzheimer s Research & Therapy (publishedVersion, cc-by)
  • PubMed Central (publishedVersion, cc-by)
  • PubMed (publishedVersion)
  • DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion, cc-by-sa)
  • DR-NTU (Nanyang Technological University) (submittedVersion, cc-by)
Funders
  • Ministry of Education - Singapore (MOE AcRF Tier 3 Award MOE2017-T3-1-002)
  • National Medical Research Council (NMRC/CIRG/1415/2015, NMRC/CSA/063/2014, MOH-CSAINV18nov-0007, NMRC/CIRG/14MAY025)
  • National Neuroscience Institute-Health Research Endowment Fund (NNI-HREF), Singapore (Reference Number: 991016)
Topics
  • Health Sciences › Medicine › Psychiatry and Mental health › Dementia and Cognitive Impairment Research
  • Health Sciences › Medicine › Neurology › Cerebrovascular and genetic disorders
  • Life Sciences › Neuroscience › Neurology › Neurological Disease Mechanisms and Treatments
Keywords
APOE ε4, white matter hyperintensities, gray matter atrophy, early-stage dementia, mild cognitive impairment, cerebral small vessel disease, gene-environment interaction, executive function, cognitive decline, gray matter volume
MeSH terms
Alzheimer Disease, Apolipoproteins, Atrophy, Brain, Dementia, Humans, Magnetic Resonance Imaging, Apolipoprotein E4, Leukoencephalopathies, White Matter, Gray Matter

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