Serum apolipoprotein E is associated with long-term risk of Alzheimer’s disease: The Rotterdam Study
Abstract
Background Serum levels of apolipoprotein E (apoE) have been suggested as potential biomarker for dementia, but the long-term association between apoE and risk of dementia is uncertain. Methods Between 1990 and 1993, we measured serum apoE by immunoassay in 1042 non-demented individuals (mean ± SD age 68.4 ± 7.3 years; 59.3% women) from the population-based Rotterdam Study. Follow-up for dementia was complete until 2014. We used Cox models to determine the risk of dementia and Alzheimer's disease in relation to apoE, adjusting for age, sex, educational level, cardiovascular risk factors, and additionally APOE genotype. Results Serum apoE was associated to APOE genotype (p-trend=1.0E-51, r(2)=0.21). In men, apoE tended to be lower with age, whereas in women the opposite was observed (p-trend=0.07 and 0.08, respectively). During a median follow-up of 15.7 years (IQR 9.7-21.7), 220 participants developed dementia, of whom 180 had Alzheimer's disease. Lower serum apoE was associated with an increased risk of dementia (HR, 95%CI, per SD decrease: 1.25, 1.05-1.48) and in particular Alzheimer's disease (1.51, 1.23-1.86), which remained statistically significant for Alzheimer's disease after additionally adjusting for APOE genotype (1.28, 1.01-1.62). When stratifying analyses in 5-year time frames, risk estimates were similar throughout the study period. Serum apoE tended to marginally improve 20-year prediction of Alzheimer's disease (IDI 0.008, 95%CI -0.001-0.026, p=0.086), but not…
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Low plasma levels of apoE are associated with increased risk of dementia.
“Of interest, low levels of plasma apoE per se were recently reported to be associated with increased risk of dementia, 10 , 17”
From <i>APOE</i> and dementia – resequencing and genotyping in 105,597 individuals (2020) · cites this paper as [17]
Low plasma levels of apoE are epidemiologically associated with increased risk of future dementia in the general population, independent of APOE genotype.
“Recently, low plasma levels of apoE was shown to be epidemiologically associated with increased risk of future dementia in the general population, and that this was independent of APOE genotype (Fig. 4), and this has now been shown in different cohorts [23,115].”
From Plasma levels of apolipoprotein E, APOE genotype and risk of dementia and ischemic heart disease: A review (2016) · cites this paper as [115]
Low levels of plasma apoE have been reported to be associated with increased risk of dementia.
“Interestingly, low levels of plasma apoE were recently reported to be associated with increased risk of dementia,17,23,24 whereas high levels were associated with increased risk of ischaemic heart disease.25”
The effect of low apoE levels per se, independent of the ɛ4 allele, was observed to be associated with high risk of dementia in three independent prospective European cohorts.
“Also, recently the effect of low apoE levels per se, independent of the ɛ4 allele, was observed to be associated with high risk of dementia in three independent prospective European cohorts,17,23”
Cites
Apolipoprotein E in Alzheimer’s disease and other neurological disorders
Verghese, P. B., Castellano, J. M., & Holtzman, D. M. (2011) · The Lancet Neurology · doi:10.1016/s1474-4422(10)70325-2 · Cited by 857 · cited 1× · see citing works
“Apolipoprotein E genotype (APOE) is the major genetic risk factor for Alzheimer’s disease (AD), increasing lifetime risk for ε4 carriers 3 to 12-fold.[4] Various cross-sectional studies have shown that plasma levels of apolipoprotein E (apoE) are lower in patients with AD,[5] and a recent Danish”
BackgroundIs dementia incidence declining?: Trends in dementia incidence since 1990 in the Rotterdam Study
Schrijvers, E. M. C., Verhaaren, B. F. J., Koudstaal, P. J., Hofman, A., Ikram, M. A., & Breteler, M. M. B. (2012) · Neurology · doi:10.1212/wnl.0b013e3182553be6 · Cited by 408 · see citing works
Self-citationCerebrovascular Effects of Apolipoprotein E: Implications for Alzheimer Disease
Zlokovic, B. V. (2013) · JAMA Neurology · doi:10.1001/jamaneurol.2013.2152 · Cited by 263 · see citing works
What are lipoproteins doing in the brain?
Wang, H., & Eckel, R. H. (2014) · Trends in Endocrinology & Metabolism · doi:10.1016/j.tem.2013.10.003 · Cited by 234 · see citing works
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Rasmussen, K. L. (2016) · Atherosclerosis · doi:10.1016/j.atherosclerosis.2016.10.037 · Cited by 125 · see citing works
Rasmussen, K. L., Tybjærg-Hansen, A., Nordestgaard, B. G., & Frikke-Schmidt, R. (2019) · European Heart Journal · doi:10.1093/eurheartj/ehz402 · Cited by 86 · see citing works
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<i>APOE</i> and dementia – resequencing and genotyping in 105,597 individuals
Rasmussen, K. L., Tybjærg‐Hansen, A., Nordestgaard, B. G., & Frikke‐Schmidt, R. (2020) · Alzheimer's & Dementia · doi:10.1002/alz.12165 · Cited by 64 · see citing works
Progress and challenges in the diagnosis of dementia: a critical review
Paraskevaidi, M., Martin-Hirsch, P. L., & Martin, F. L. (2018) · ACS Chemical Neuroscience · doi:10.1021/acschemneuro.8b00007 · Cited by 31 · see citing works
- Authors
- Wolters, F. J., Koudstaal, P. J., Hofman, A., Duijn, C. M. V., & Ikram, M. A.
- Affiliations
- Erasmus MC (NL)
- Corresponding author
- Ikram, M.Arfan
- Venue
- Neuroscience Letters
- Publisher
- Elsevier BV
- Published
- 2016-03
- Volume
- 617
- Pages
- 139-142
- ISSN
- 0304-3940 (ISSN-L)
- OpenAlex
- W2268949499
- Cited by
- 31
- References
- 5
- Citations by year
- 2025: 2 · 2024: 3 · 2022: 5 · 2021: 1 · 2020: 6 · 2019: 4 · 2018: 2 · 2017: 4 · 2016: 4
- FWCI
- 4.15
- Type
- journal article
- Language
- en
- Open access
- closed
- Locations
- Neuroscience Letters (publishedVersion)
- PubMed (publishedVersion)
- EUR Research Repository (Erasmus University Rotterdam) (submittedVersion)
- Funders
- Erasmus Medical Centre and Erasmus University Rotterdam
- Netherlands Organization for Scientific Research (NWO
- Netherlands Organization for Health Research and Development
- Research Institute for Diseases in the Elderly
- Netherlands Genomics Initiative
- Ministry of Education, Culture and Science
- Ministry of Health, Welfare and Sports, the European Commission (DG XII
- Municipality of Rotterdam
- Netherlands Cardiovascular Research Initiative (CVON2012-06)
- Topics
- Health Sciences › Medicine › Psychiatry and Mental health › Dementia and Cognitive Impairment Research
- Health Sciences › Medicine › Physiology › Alzheimer's disease research and treatments
- Health Sciences › Medicine › Surgery › Lipoproteins and Cardiovascular Health
- Keywords
- apolipoprotein E, Alzheimer's disease, dementia risk, APOE genotype, biomarkers, risk prediction, sex differences, aging
- MeSH terms
- Aged, Alzheimer Disease, Apolipoproteins E, Female, Genotype, Humans, Male, Middle Aged, Risk Assessment
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