APOE4 and Confluent White Matter Hyperintensities Have a Synergistic Effect on Episodic Memory Impairment in Prodromal Dementia
Abstract
BACKGROUND: White matter hyperintensities (WMH) are a known risk factor for cognitive decline. While the ɛ4 allele of apolipoprotein E gene (APOE4) is another risk factor for cognitive decline, it remains unclear how APOE4 affects the relationship between WMH and cognitive decline, specifically in the prodromal stage of dementia. OBJECTIVE: To determine how APOE4 moderates the relationship between WMH and cognition in prodromal dementia. METHODS: Two-hundred-sixteen participants with prodromal dementia underwent magnetic resonance imaging (MRI), neuropsychological testing (global and domain wise), cardiovascular risk factor assessments, and APOE genotyping. Visual ratings for WMH as well as total and lobar WMH volumes were quantified. Moderation analysis was performed to determine the influence of APOE4 on the relationship between WMH and performance on global and domain-specific cognitive measures. The role of confluent and non-confluent WMH on cognition was additionally studied using logistic regression. RESULTS: APOE4 carriers (n = 49) had poorer memory and higher global WMH (10.01 mL versus 6.23 mL, p = 0.04), temporal WMH (1.17 mL versus 0.58 mL, p = 0.01), and occipital WMH (0.38mL versus 0.22 mL, p = 0.02) compared to APOE4 non-carriers (n = 167). Moderation analysis revealed that APOE4 positivity strengthened the relationship between higher global as well as lobar WMH burden and poorer episodic memory. Furthermore, APOE4 carriers with confluent WMH were 4.81 times more likely to have impaired episodic memory compared to non-confluent WMH and non-APOE carriers. CONCLUSION: The impact of WMH on memory may be strongest among APOE4 carriers. Clinicians targeting WMH would need to consider the APOE4 allele and WMH severity status to strategize cognitive interventions.
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WMHs play an important role as a risk factor for future memory decline even if they may not affect baseline memory performance at the stage of pAD.
“These findings emphasize the important role of WMHs as a risk factor for future memory decline even if they may not affect baseline memory performance at the stage of pAD [11,49].”
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 [10]
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 [10]
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- Authors
- Kumar, D., Yatawara, C., Wang, B., Wong, B., Tan, Y. J., Zailan, F. Z., Ng, K. P., & Kandiah, N.
- Affiliations
- National Neuroscience Institute (SG)
- Duke-NUS Medical School (SG)
- Nanyang Technological University (SG)
- Corresponding author
- Kandiah, Nagaendran
- ORCID
- Venue
- Journal of Alzheimer s Disease
- Publisher
- SAGE Publications
- Published
- 2022-05-31
- Volume
- 87
- Issue
- 3
- Pages
- 1103-1114
- ISSN
- 1387-2877 (ISSN-L)
- 1875-8908
- OpenAlex
- W4223989832
- Cited by
- 12
- References
- 38
- Citations by year
- 2026: 1 · 2025: 3 · 2024: 2 · 2023: 6
- FWCI
- 1.80
- Type
- journal article
- Language
- en
- Open access
- closed
- Locations
- Journal of Alzheimer s Disease (publishedVersion)
- PubMed (publishedVersion)
- DR-NTU (Nanyang Technological University) (submittedVersion)
- 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
- MeSH terms
- Brain, Dementia, Humans, Magnetic Resonance Imaging, Memory Disorders, Neuropsychological Tests, Leukoaraiosis, Apolipoprotein E4, Cognitive Dysfunction, Memory, Episodic, White Matter
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