Preferential deposition of amyloid β protein (Aβ) in the form Aβ40 in Alzheimer's disease is associated with a gene dosage effect of the apolipoprotein E E4 allele
Abstract
The effect of apolipoprotein E (ApoE) genotype on the deposition of amyloid beta protein (Abeta) was examined in 54 patients with Alzheimer's disease. No difference in the amount of Abeta deposited as Abeta42(43) was seen between genotype groups with no, one or two E4 alleles. However, the amount of Abeta40 deposited increased according to the copy number of E4 alleles with patients possessing one E4 allele containing more than twice, and those with two E4 alleles, four times, the amount of Abeta40 in their brains compared to patients without an E4 allele. The increase in total Abeta deposited within the tissue (i.e. Abeta40 plus Abeta42(43) loads) in the presence of an E4 allele is therefore due entirely to an enhanced deposition of Abeta40. These data are consistent with the suggestion that the presence of E4 within pre-existing Abeta42(43) containing plaques may lower the threshold to fibrilization of Abeta40 thereby promoting its subsequent deposition. Thus, although the total amount of Abeta initially deposited in the brain as Abeta42(43) is not affected by the binding of any one particular ApoE isoform this does influence the subsequent maturation of plaques with a greater proportion transforming into Abeta40 containing cored plaques when the E4 isoform is present.
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Several reports suggest that Aβ40 preferentially aggregates in an apoE4 gene dose-dependent manner in AD subjects.
“Interestingly, there have been several reports suggesting that Aβ40 preferentially aggregates in an apoE4 gene dose-dependent manner in AD subjects (Gearing et al., 1996; Ishii et al., 1997; Mann et al., 1997).”
From The role of apolipoprotein E in Alzheimer's disease (2009) · cites this paper as Mann et al., 1997
Increased CAA in ε4-positive subjects does not entirely account for the preferential Aβ40 deposition.
“Although the apparent differential effects on Aβ40 and Aβ42 aggregation by apoE4 might be simply attributed to the increased CAA in apoε4 subjects, careful immunohistochemical analyses of plaques using Aβ40 or Aβ42 specific antibodies suggest that increased CAA in ε4-positive subjects does not entirely account for the preferential Aβ40 deposition (Gearing et al., 1996; Mann et al., 1997).”
From The role of apolipoprotein E in Alzheimer's disease (2009) · cites this paper as Mann et al., 1997
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The role of apolipoprotein E in Alzheimer's disease
Kim, J., Basak, J. M., & Holtzman, D. M. (2009) · Neuron · doi:10.1016/j.neuron.2009.06.026 · Cited by 1,661 · see citing works
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- Authors
- Mann, D. M. A., Iwatsubo, T., Pickering-Brown, S. M., Owen, F., Saido, T. C., & Perry, R. H.
- Affiliations
- University of Manchester (GB)
- The University of Tokyo (JP)
- Tokyo Metropolitan Institute of Medical Science (JP)
- Newcastle upon Tyne Hospital (GB)
- Corresponding author
- Mann, D.M.A
- Venue
- Neuroscience Letters
- Publisher
- Elsevier BV
- Published
- 1997-01
- Volume
- 221
- Issue
- 2-3
- Pages
- 81-84
- ISSN
- 0304-3940 (ISSN-L)
- OpenAlex
- W2026163540
- Cited by
- 91
- References
- 3
- Citations by year
- 2025: 2 · 2022: 1 · 2021: 2 · 2020: 1 · 2019: 1 · 2018: 1 · 2015: 1 · 2014: 3 · 2013: 3 · 2012: 1
- FWCI
- 4.91
- Type
- journal article
- Language
- en
- Open access
- closed
- Locations
- Neuroscience Letters (publishedVersion)
- PubMed (publishedVersion)
- Research Explorer (The University of Manchester) (submittedVersion)
- Topics
- Health Sciences › Medicine › Physiology › Alzheimer's disease research and treatments
- Health Sciences › Medicine › Psychiatry and Mental health › Dementia and Cognitive Impairment Research
- Life Sciences › Neuroscience › Neurology › Neuroinflammation and Neurodegeneration Mechanisms
- Keywords
- amyloid-beta, Aβ40, amyloid-beta 42, apolipoprotein E, E4 allele, gene dosage, Alzheimer's disease, amyloid plaques, plaque maturation, APOE genotype
- MeSH terms
- Aged, Aged, 80 and over, Alleles, Alzheimer Disease, Apolipoproteins E, Brain Chemistry, Female, Frontal Lobe, Humans, Immunohistochemistry, Male, Middle Aged, Peptide Fragments, Amyloid beta-Peptides, Age of Onset, Apolipoprotein E4
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