A novel mutation in the apolipoprotein E gene (APOE*4 Pittsburgh) is associated with the risk of late-onset Alzheimer's disease
Abstract
Using a combination of polymerase chain reaction (PCR), single-strand conformation polymorphism (SSCP) and DNA sequencing techniques, we identified a unique missense mutation (T-->C) in exon 3 of the APOE gene which resulted in the substitution of pro-28 for leu-28. We screened 1118 White cases of late-onset (>60 years) Alzheimer's disease (AD) from three independent centers (Pittsburgh = 489, Indiana = 319, Mayo Clinic Rochester = 310) and 1123 controls (607 clinically assessed and 516 individuals randomly ascertained from the general population). Two of the 1123 control subjects had the pro-28 mutation (0.18%). However, this mutation was observed in heterozygous state in 2.66, 2.51 and 1.94% of the AD cases from Pittsburgh, Indiana and Mayo Clinic Rochester, respectively, with an overall frequency of 2.42%. All individuals with this mutation were carriers of the APOE*4 allele and hence the mutation was denoted as APOE*4 Pittsburgh (APOE*4P). Compared with the non-E*4P carriers, the E*4P carriers were associated with an increased risk of AD (odds ratio (OR) 13.2) and this risk remained significant even after adjusting for the known effect of APOE*4 (OR 5.4). The risk associated with the E*4P/E*4 combination was about five times (OR 29.1) the risk attributed to APOE*4 carriers alone (OR 5.7). Our data indicates that the new mutation most likely exists in cis-orientation with APOE*4 and is associated with increased risk of developing AD.
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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 [6]
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 [6]
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 [6]
APOE4 Freiburg/Pittsburgh (Leu28Pro, Cys112Arg) was found in the same year in a screening focused on hyperlipidemia and in a screening for AD.
“APOE4 Freiburg/Pittsburgh (Leu28Pro, Cys112Arg) was found in the same year in a screening focused on hyperlipidemia and in a screening for AD108, 109).”
From Impact of Apolipoprotein E Variants: A Review of Naturally Occurring Variants and Clinical Features (2025) · cites this paper as [109]
Specific APOE rare missense variants (p.L46P, p.R154S, p.R163C, p.V254E, p.R269G) have been reported in Western populations and suggest potential resistance to amyloid-β accumulation, phosphorylated tau pathology, or the effects of the APOE ε4 allele.
“For example, RMVs such as p.L46P (p.L28P; rs769452 [Pittsburgh]), 17 p.R154S (p.R136S; rs121918393 [Christchurch]), 18 p.R163C (p.R145C; rs769455), 19 p.V254E (p.V236E; rs199768005 [Jacksonville]), 20 and p.R269G (p.R251G; rs267606661) 21 have been reported in Western populations, suggesting potential resistance to amyloid-β (Aβ) accumulation, phosphorylated tau pathology, or the effects of the AP”
From Association of rare <i>APOE</i> missense variants with Alzheimer's disease in the Japanese population (2025) · cites this paper as [17]
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Alzheimer’s disease: rare variants with large effect sizes
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- Authors
- Kamboh, M. I., Aston, C. E., Perez-Tur, J., Kokmen, E., Ferrell, R. E., Hardy, J., & DeKosky, S. T.
- Affiliations
- University of Pittsburgh (US)
- Mayo Clinic (US)
- Corresponding author
- Kamboh, M.Ilyas
- Venue
- Neuroscience Letters
- Publisher
- Elsevier BV
- Published
- 1999-03
- Volume
- 263
- Issue
- 2-3
- Pages
- 129-132
- ISSN
- 0304-3940 (ISSN-L)
- OpenAlex
- W2001642685
- Cited by
- 40
- References
- 8
- Citations by year
- 2025: 3 · 2024: 2 · 2022: 2 · 2021: 3 · 2020: 3 · 2018: 1 · 2016: 3 · 2015: 2 · 2014: 4 · 2012: 2
- FWCI
- 1.70
- Type
- journal article
- Language
- en
- Open access
- closed
- Locations
- Neuroscience Letters (publishedVersion)
- PubMed (publishedVersion)
- UCL Discovery (University College London) (submittedVersion)
- Funders
- National Institute on Aging (P30AG010133, AG 05-133, P50AG005133, AG13672, R01AG013672, P30 AG-10133, U24AG021886)
- 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, APOE ε4, late-onset Alzheimer's disease, missense mutations, genetic risk, exon 3, allele frequency
- MeSH terms
- Adult, Aged, Aged, 80 and over, Alzheimer Disease, Apolipoproteins E, Exons, Female, Humans, Leucine, Male, Middle Aged, Proline, Reference Values, Registries, Risk Factors, United States, Age of Onset, Polymorphism, Single-Stranded Conformational, Amino Acid Substitution, Mutation, Missense, Apolipoprotein E4
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