The DOI matches its Crossref record; 39 of the 39 references it cites were found in a registry or an index.
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
Overview
Integrity signals
Registry
Cites
Statistics
Verification
Claims the paper makes
Claims other papers make about this one
Each is checked against this paper’s own text: does it say what the citing paper says it does?
In the citing paper
“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]
In the citing paper
“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 the citing paper
“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]
Citations
Cites
Mirra, S. S., Heyman, A., McKeel, D., Sumi, S. M., Crain, B. J., Brownlee, L. M., Vogel, F. S., Hughes, J. P., Belle, G. V., Berg, L., et al. (1991) · Neurology · doi:10.1212/wnl.41.4.479 · Cited by 4,961
Tissue microarrays for high-throughput molecular profiling of tumor specimens
Kononen, J., Bubendorf, L., Kallionimeni, A., Barlund, M. T., Schraml, P., Leighton, S. B., Torhorst, J. K. H., Mihatsch, M. J., Sauter, G., & Kallionimeni, O.-P. (1998) · Nature Medicine · doi:10.1038/nm0798-844 · Cited by 4,101
Restriction isotyping of human apolipoprotein E by gene amplification and cleavage with HhaI.
Hixson, J., & Vernier, D. (1990) · Journal of Lipid Research · doi:10.1016/s0022-2275(20)43176-1 · Cited by 2,933
Consortium to Establish a Registry for Alzheimer's Disease (CERAD)
Fillenbaum, G., & Heyman, A. (2002) · doi:10.1002/0470846410.ch42(iii · Cited by 2,859
Protective effect of apolipoprotein E type 2 allele for late onset Alzheimer disease
Corder, E. H., Saunders, A. M., Risch, N. J., Strittmatter, W. J., Schmechel, D. E., Gaskell, P. C., Rimmler, J. B., Locke, P. A., Conneally, P. M., Schmader, K. E., et al. (1994) · Nature Genetics · doi:10.1038/ng0694-180 · Cited by 1,920
Apolipoprotein E: Far More Than a Lipid Transport Protein
Mahley, R. W., & Rall, S. C. (2000) · Annual Review of Genomics and Human Genetics · doi:10.1146/annurev.genom.1.1.507 · Cited by 1,836
Frequency of Stages of Alzheimer-Related Lesions in Different Age Categories
Braak, H., & Braak, E. (1997) · Neurobiology of Aging · doi:10.1016/s0197-4580(97)00056-0 · Cited by 1,656
(2001) · The Lancet · doi:10.1016/s0140-6736(00)03589-3 · Cited by 1,338
Obesity and Vascular Risk Factors at Midlife and the Risk of Dementia and Alzheimer Disease
Kivipelto, M., Ngandu, T., Fratiglioni, L., Viitanen, M., Kåreholt, I., Winblad, B., Helkala, E.-L., Tuomilehto, J., Soininen, H., & Nissinen, A. (2005) · Archives of Neurology · doi:10.1001/archneur.62.10.1556 · Cited by 1,291
Braak, F., Braak, H., & Mandelkow, E. (1994) · Acta Neuropathologica · doi:10.1007/bf00293315 · Cited by 769
Research works printed but not linked: 1
- O'Brien J, 2000, Dementia
Cited by
Sorted by citations
Apolipoprotein E and Alzheimer disease: risk, mechanisms and therapy
Liu, C.-C., Kanekiyo, T., Xu, H., & Bu, G. (2013) · Nature Reviews Neurology · doi:10.1038/nrneurol.2012.263 · Cited by 3,459
Microglia in Alzheimer’s disease
Hansen, D. V., Hanson, J. E., & Sheng, M. (2018) · Journal of Cell Biology · doi:10.1083/jcb.201709069 · Cited by 1,935
The Amyloid-β Pathway in Alzheimer’s Disease
Hampel, H., Hardy, J., Blennow, K., Chen, C., Perry, G., Kim, S. H., Villemagne, V. L., Aisen, P., Vendruscolo, M., Iwatsubo, T., et al. (2021) · Molecular Psychiatry · doi:10.1038/s41380-021-01249-0 · Cited by 1,952
Apolipoprotein E and Alzheimer disease: pathobiology and targeting strategies
Yamazaki, Y., Zhao, N., Caulfield, T. R., Liu, C.-C., & Bu, G. (2019) · Nature Reviews Neurology · doi:10.1038/s41582-019-0228-7 · Cited by 1,425
Molecular and cellular mechanisms underlying the pathogenesis of Alzheimer’s disease
Guo, T., Zhang, D., Zeng, Y., Huang, T. Y., Xu, H., & Zhao, Y. (2020) · Molecular Neurodegeneration · doi:10.1186/s13024-020-00391-7 · Cited by 994
Metadata
- 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
- Life Sciences › Neuroscience › Cellular and Molecular Neuroscience › 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
About these checks
Registry, retraction, Cites and statistics results are computed, not judged, with one exception: a printed reference that no index lists is read once by a model before it counts as a citation error. Claims are extracted by a model and kept only when their quote appears verbatim in the text; each cited source is then checked, with a model’s help, for whether it says what the claim relies on. Those verdicts can be wrong — read the claim’s quote and the cited source before relying on one.
Statistics and arithmetic are recomputed, not judged.
Confidence bands are shown only for fields calibrated on our annotated test set. None is calibrated yet, so no band is shown.
What counts as a claim ›How we measure confidence ›How we check this ›
Are you an author, or do you see a problem with this page? Request a review
