Screening of two mutations at exon 3 of the apolipoprotein E gene (sites 28 and 42) in a sample of patients with sporadic late-onset Alzheimer's disease
Abstract
The search for further variation at the APOE gene in a sample of patients with sporadic late-onset Alzheimer's disease (AD) and related controls revealed two different mutations in the exon 3 of the gene. One, the Leu28-->Pro, always found on an APOE e(*)4 allele, was present in five of the 94 patients and in 1 of the 157 controls. The other, Thr42-->Ala, found on an e(*)3 allele, was observed in only one AD patient, who also carried the Leu28-->Pro, but in none of the controls. In the AD patient group the allele e(*)4(-), corresponding to Leu28-->Pro, showed a frequency of 0.027, compared with only 0.003 in the controls. Compared to E3/3 and E3/2 genotypes, the risk of developing AD associated with the genotypes carrying the e(*)4 allele, the well-established risk allele for AD onset, was observed to be high (OR=3.16; 95% CI=1.62-6.20; P=0.0009), but the risk associated with genotypes carrying the Leu28-->Pro mutation was higher still (OR=10.95; 95% CI=1.25-95.75; P=0.015). The higher risk associated with this mutation was assessed by meta-analysis carried out using the data of three patient groups from a previously published study Kamboh et al. and from our study. The results indicated that, compared with all the other APOE genotypes, those carrying the Leu28-->Pro mutation were at a substantially higher risk of developing AD (OR=4.25; 95% CI=1.21-14.97).
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Carriers of the apoE4[L28P] mutant are at a substantially higher risk of developing LOAD, and this risk remains significant even after adjusting for the known effect of apoE4.
“A rare apoE4 mutant, apoE4[L28P] Pittsburgh, burdens carriers with an added risk for late-onset AD and may be a useful tool for gaining insights into the role of apoE4 in disease pathogenesis.”
From Molecular Basis for Increased Risk for Late-onset Alzheimer Disease Due to the Naturally Occurring L28P Mutation in Apolipoprotein E4 (2014) · cites this paper as [7]
A naturally occurring point mutation in apoE4, L28P (apoE4 Pittsburgh), was found in a heterozygous state in patients with sporadic LOAD and related controls.
“Screening for apoE variants in patients with sporadic LOAD and related controls revealed a naturally occurring point mutation in apoE4, L28P (denoted as apoE4 Pittsburgh), in a heterozygous state (6,7).”
From Molecular Basis for Increased Risk for Late-onset Alzheimer Disease Due to the Naturally Occurring L28P Mutation in Apolipoprotein E4 (2014) · cites this paper as [7]
A rare hereditary mutation in apoE4, L28P, has been associated with an increased risk for late-onset Alzheimer disease in patients.
“A rare hereditary mutation in apoE4, L28P, has been associated with an increased risk for LOAD in patients (6,7).”
From Molecular Basis for Increased Risk for Late-onset Alzheimer Disease Due to the Naturally Occurring L28P Mutation in Apolipoprotein E4 (2014) · cites this paper as [7]
Compared to lipid-free WT ApoE4, lipid-free L28P induced intracellular accumulation of Aβ42 in SK-N-SH human neuroblastoma cells and mouse primary neurons.
“As compared to lipid-free WT ApoE4, lipid-free L28P induced the intracellular accumulation of Aβ42 in SK-N-SH human neuroblastoma cells and mouse primary neurons.”
From Investigation of the independent role of a rare APOE variant (L28P; APOE*4Pittsburgh) in late-onset Alzheimer disease (2023) · cites this paper as [26]
Lipidated L28P significantly reduced the viability of SK-N-SH cells compared to lipidated WT ApoE4, due to greater cellular oxidative stress induced by L28P than WT ApoE4.
“Furthermore, lipidated L28P significantly reduced the viability of SK-N-SH cells when compared to lipidated WT ApoE4, which was due to greater cellular oxidative stress induced by L28P than WT ApoE4 [26].”
From Investigation of the independent role of a rare APOE variant (L28P; APOE*4Pittsburgh) in late-onset Alzheimer disease (2023) · cites this paper as [26]
The L28P mutation is associated with significant structural and conformational changes in wild type ApoE4 that result in intraneuronal Aβ42 accumulation and oxidative stress.
“This genetic observation is further supported by a comprehensive experimental study in which the L28P mutation was associated with significant structural and conformational changes in the wild type (WT) ApoE4 that resulted in intraneuronal Aβ42 accumulation and oxidative stress [26].”
From Investigation of the independent role of a rare APOE variant (L28P; APOE*4Pittsburgh) in late-onset Alzheimer disease (2023) · cites this paper as [26]
WT ApoE4 itself does not induce the intracellular accumulation of Aβ42.
“that itself does not induce the intracellular accumulation of Aβ42.”
From Investigation of the independent role of a rare APOE variant (L28P; APOE*4Pittsburgh) in late-onset Alzheimer disease (2023) · cites this paper as [26]
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- Authors
- Scacchi, R., Gambina, G., Ferrari, G., & Corbo, R. M.
- Affiliations
- National Research Council (IT)
- Azienda Ospedaliera Universitaria Integrata Verona (IT)
- Sapienza University of Rome (IT)
- ORCID
- Venue
- Neurobiology of Aging
- Publisher
- Elsevier BV
- Published
- 2003-03
- Volume
- 24
- Issue
- 2
- Pages
- 339-343
- ISSN
- 0197-4580 (ISSN-L)
- OpenAlex
- W2104722278
- Cited by
- 14
- References
- 15
- Citations by year
- 2025: 1 · 2024: 1 · 2022: 2 · 2021: 1 · 2020: 1 · 2016: 1 · 2014: 3 · 2013: 1
- FWCI
- 0.40
- Type
- journal article
- Language
- en
- Open access
- closed
- Locations
- Neurobiology of Aging (publishedVersion)
- PubMed (publishedVersion)
- IRIS Research product catalog (Sapienza University of Rome) (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 › Biochemistry, Genetics and Molecular Biology › Genetics › Genetic Associations and Epidemiology
- Keywords
- apolipoprotein E, late-onset Alzheimer's disease, sporadic Alzheimer's disease, APOE ε4, genetic risk, APOE genotype
- MeSH terms
- Aged, Alzheimer Disease, Apolipoproteins E, Exons, Gene Frequency, Genetic Testing, Genotype, Humans, Risk Factors, Point Mutation, Age of Onset, Genetic Predisposition to Disease
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