Effect of APOE genotype on microvascular basement membrane in Alzheimer's disease
Abstract
APOE4 homozygosity has been associated with an increased risk of sporadic Alzheimer's disease through a mechanism, which has yet to be defined. Recent evidence has suggested that microvascular basement membrane injury may be a critical factor in the pathogenesis of AD-related dementia. In previous studies, we have shown that the synaptic organizing protein agrin can be found in neurons, and is a major component of the brain microvascular basement membrane. Here, we compare the basement membrane surface area of cortical microvasculature in AD brains by staining with an anti-agrin antibody. Quantitative morphometric analysis was used to determine the mean basement area (micro(2)) of prefrontal cortical microvessels. An average of 10 capillaries was measured in each of 35 cases of AD genotyped for APOE status. APOE4,4 homozygotes had smaller capillary basement membrane areas (17.4 micro(2))+/-6.2) than APOE3,3 homozygotes (26.9 micro(2)+/-6.5), p<0.001. The capillary basement membrane areas (CBMA) of heterozygotes APOE3,4 did not differ significantly from APOE3,3 or APOE4,4. Braak stage did not contribute significantly to CBMA. However, a preliminary analysis suggests an interaction between APOE4,4 and Braak V-VI producing smaller CBMA, a finding which needs to be confirmed with a larger sample. These data support the hypothesis that APOE4,4 is associated with thinning of the microvascular basement membrane in Alzheimer's disease.
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These blood-derived proteins are often found colocalized with Aβ and are more pronounced in APOE4 carriers compared with noncarriers.
“These blood-derived proteins are often found colocalized with A 𝛃 (267, 509, 527) and are more pronounced in APOE4 carriers compared with noncarriers (230, 267, 516, 691).”
From Blood-Brain Barrier: From Physiology to Disease and Back (2019) · cites this paper as [516]
Human APOE4 carriers compared with non-carriers develop accelerated BBB breakdown and pericyte degeneration, early neurovascular dysfunction, impaired cerebrovascular reactivity, and diminished regional BBB uptake of glucose.
“Human APOE4 carriers compared with non-carriers develop accelerated BBB breakdown and pericyte degeneration (229, 230, 267, 516, 691, 702), early neurovascular dysfunction (494, 531, 584), impaired cerebrovascular reactivity (227, 568), and diminished regional BBB uptake of glucose (457, 486).”
From Blood-Brain Barrier: From Physiology to Disease and Back (2019) · cites this paper as [516]
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- Authors
- Salloway, S., Gur, T., Berzin, T., Zipser, B., Correia, S., Hovanesian, V, Fallon, J., Kuo-Leblanc, V, Glass, D., Hulette, C., Rosenberg, C., Vitek, M., & Stopa, E.
- Affiliations
- Brown University (US)
- Regeneron (United States) (US)
- Duke University (US)
- Corresponding author
- Salloway, S
- Venue
- Journal of the Neurological Sciences
- Publisher
- Elsevier BV
- Published
- 2002-11
- Volume
- 203-204
- Pages
- 183-187
- ISSN
- 0022-510X (ISSN-L)
- OpenAlex
- W2043209737
- Cited by
- 113
- References
- 4
- Citations by year
- 2026: 11 · 2025: 8 · 2024: 10 · 2023: 9 · 2022: 8 · 2021: 10 · 2020: 12 · 2019: 6 · 2018: 3 · 2017: 4 · 2016: 5 · 2015: 3 · 2014: 6 · 2012: 2
- FWCI
- 0.40
- Type
- journal article
- Language
- en
- Open access
- closed
- Locations
- Journal of the Neurological Sciences (publishedVersion)
- PubMed (publishedVersion)
- Funders
- China Building Materials Academy
- National Institutes of Health
- National Institute of Mental Health (K08MH001487, MH01487)
- National Institute of Neurological Disorders and Stroke (P01NS039321)
- National Center for Research Resources (RR-00-003)
- Topics
- Health Sciences › Medicine › Physiology › Alzheimer's disease research and treatments
- Life Sciences › Neuroscience › Neurology › Barrier Structure and Function Studies
- Health Sciences › Medicine › Psychiatry and Mental health › Dementia and Cognitive Impairment Research
- Keywords
- Alzheimer's disease, APOE ε4, APOE genotype, agrin, prefrontal cortex, Braak stages
- MeSH terms
- Aged, Aged, 80 and over, Alzheimer Disease, Apolipoproteins E, Basement Membrane, Capillaries, Female, Genotype, Humans, Image Processing, Computer-Assisted, Immunohistochemistry, Male, Middle Aged, Prefrontal Cortex, Disease Progression
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