Apolipoprotein E–dependent accumulation of Alzheimer disease–related lesions begins in middle age
Abstract
Objective: To study the prevalence and age dependency of senile plaques (SP) and neurofibrillary tangles (NFT), the brain changes characteristic of Alzheimer disease (AD), and their association with apolipoprotein E (APOE) genotypes in a community‐dwelling normal population. Methods: This neuropathological study used both silver staining and Aβ immunohistochemistry in brain tissue microarrays, including SP coverage and NFT counts from frontal cortex and hippocampus, and APOE genotyping, and was performed on a consecutive prospective series of 603 subjects (aged between 0 and 97 years) of an unselected population living outside of institutions. Cases were subjected to autopsy following sudden or unexpected out‐of‐hospital death, covering 22.1% of the mortality of Tampere, Finland and its surroundings. None died of AD, although 22 (3.7%) were demented and 10 (1.7%) had memory problems. Results: Of the series, 30.8% had SP, and 42.1% had NFT; these occurred more commonly among females and showed a strong relationship with age. Both changes had already appeared at around 30 years of age, reaching an occurrence of almost 100% in the oldest. SP were more frequent in APOE ϵ4‐carriers compared with noncarriers in every age group except the oldest (>90 years). The difference was most evident during the ages 50 to 59 years, where 40.7% of ϵ4‐carriers had SP, compared with 8.2% in noncarriers (odds ratio, 8.39; 95% confidence interval, 2.55–27.62). The difference in NFT prevalence between APOE genotypes was not statistically significant in any age group. Interpretation: The brain changes associated with AD may already begin developing early in middle age, especially among APOE ϵ4 carriers. Ann Neurol 2009;65:650–657
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There is strong experimental evidence that the APOE isoforms are major determinants of the amount and quality of amyloid-β peptide (Aβ) and amyloid burden in the brain that develops during aging.
“There is strong experimental evidence that the APOE isoforms are major determinants of the amount and quality of amyloid-β peptide (Aβ) and amyloid burden in the brain that develops during aging.15–17”
From AAVrh.10-Mediated APOE2 Central Nervous System Gene Therapy for APOE4-Associated Alzheimer's Disease (2018) · cites this paper as [17]
APOE's role in promoting β-amyloid plaque pathology in Alzheimer's disease is well established.
“In AD, its specific role in promoting β-amyloid (Aβ) plaque pathology is, however, well established (Fleisher et al, 2013; Kok et al, 2009; Murphy et al, 2013; Schmechel et al, 1993).”
From APOE from astrocytes restores Alzheimer’s Aβ-pathology and DAM-like responses in APOE deficient microglia (2024) · cites this paper as Kok et al, 2009
In AD patients, APOE4 enhances Aβ deposition, with 40.7% of middle-aged APOE ε4 carriers featuring senile plaques compared to 8.2% non-carriers.
“In AD patients, APOE4 enhances Aβ deposition, where 40.7% of middle-aged APOE ε4 carriers featured senile plaques, compared to 8.2% non-carriers identified with senile plaques [459].”
From Molecular and cellular mechanisms underlying the pathogenesis of Alzheimer’s disease (2020) · cites this paper as [459]
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- Authors
- Kok, E., Haikonen, S., Luoto, T., Huhtala, H., Goebeler, S., Haapasalo, H., & Karhunen, P. J.
- Affiliations
- Tampere University (FI)
- Tampere University Hospital (FI)
- Corresponding author
- Kok, Eloise
- Haikonen, Satu
- Luoto, Teemu
- Huhtala, Heini
- Goebeler, Sirkka
- Haapasalo, Hannu
- Karhunen, Pekka J.
- Venue
- Annals of Neurology
- Publisher
- Wiley
- Published
- 2009-06
- Volume
- 65
- Issue
- 6
- Pages
- 650-657
- ISSN
- 0364-5134 (ISSN-L)
- 1531-8249
- OpenAlex
- W2002776021
- Cited by
- 299
- References
- 39
- Citations by year
- 2026: 12 · 2025: 9 · 2024: 9 · 2023: 17 · 2022: 21 · 2021: 20 · 2020: 16 · 2019: 25 · 2018: 15 · 2017: 13 · 2016: 22 · 2015: 13 · 2014: 21 · 2013: 16 · 2012: 22
- FWCI
- 15.24
- Type
- journal article
- Language
- en
- Open access
- closed
- Locations
- Annals of Neurology (publishedVersion)
- PubMed (publishedVersion)
- 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
- Alzheimer's disease, apolipoprotein E, APOE ε4, amyloid plaques, neurofibrillary tangles, middle age (human life stage), age-related prevalence, frontal cortex, hippocampus, sex differences, community-dwelling population, autopsy
- MeSH terms
- Adolescent, Adult, Age Factors, Aged, Aged, 80 and over, Aging, Alzheimer Disease, Apolipoproteins E, Child, Child, Preschool, Female, Genetic Carrier Screening, Humans, Infant, Infant, Newborn, Male, Middle Aged, Prospective Studies, Cohort Studies, Apolipoprotein E4, Young Adult, Plaque, Amyloid
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