Age, APOE and sex: triad of risk of Alzheimer’s disease.

Riedel, Brandalyn C.; Thompson, Paul M.; Brinton, Roberta Diaz

doi:10.1016/j.jsbmb.2016.03.012

Cited by 627Dementia and Cognitive Impairment ResearchAlzheimer's disease research and treatmentsMenopause: Health Impacts and Treatments

Age, APOE and sex: triad of risk of Alzheimer’s disease.

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Riedel, Brandalyn C., Thompson, Paul M., Brinton, Roberta Diaz·2016·The Journal of Steroid Biochemistry and Molecular Biology

DOI 10.1016/j.jsbmb.2016.03.012PMC PMC4905558

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Abstract

Age, apolipoprotein E ε4 (APOE) and chromosomal sex are well-established risk factors for late-onset Alzheimer's disease (LOAD; AD). Over 60% of persons with AD harbor at least one APOE-ε4 allele. The sex-based prevalence of AD is well documented with over 60% of persons with AD being female. Evidence indicates that the APOE-ε4 risk for AD is greater in women than men, which is particularly evident in heterozygous women carrying one APOE-ε4 allele. Paradoxically, men homozygous for APOE-ε4 are reported to be at greater risk for mild cognitive impairment and AD. Herein, we discuss the complex interplay between the three greatest risk factors for Alzheimer's disease, age, APOE-ε4 genotype and chromosomal sex. We propose that the convergence of these three risk factors, and specifically the bioenergetic aging perimenopause to menopause transition unique to the female, creates a risk profile for AD unique to the female. Further, we discuss the specific risk of the APOE-ε4 positive male which appears to emerge early in the aging process. Evidence for impact of the triad of AD risk factors is most evident in the temporal trajectory of AD progression and burden of pathology in relation to APOE genotype, age and sex. Collectively, the data indicate complex interactions between age, APOE genotype and gender that belies a one size fits all approach and argues for a precision medicine approach that integrates across the three main risk factors for Alzheimer's disease.

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Non-modifiable determinants including age, sex, and parental history of dementia are consistently recognized contributors to dementia.
“Finally, non-modifiable determinants, including age, sex, and parental history of dementia, are consistently recognized contributors [13,14].”
From Sociodemographic differences in dementia prevention knowledge in Germany: Implications for targeted health communication (2026) · cites this paper as [13]
The Introduction identifies age and female sex as major risk factors for Alzheimer’s disease. Our copy does not identify parental history of dementia as a risk factor, and its discussion is principally about Alzheimer’s disease rather than dementia generally. (LLM, conf=0.88)
Experimental — accuracy not yet measured
Age, chromosomal sex, family history, and apoE genotype remain the primary risk factors for the development of AD.
“While age, chromosomal sex, family history, and apoE genotype remain the primary risk factors for the development of AD [154,155]”
From Mitochondrial Oxidative and Nitrosative Stress and Alzheimer Disease (2020) · cites this paper as [154]
The Introduction identifies age, the APOE4 allele, and female sex as the three greatest risk factors for Alzheimer’s disease. It does not identify family history as a primary risk factor; a search for “family history” found no passage supporting that addition. The paper’s Abstract frames these factors chiefly in relation to late-onset Alzheimer’s disease. (LLM, conf=0.88)
Experimental — accuracy not yet measured
Alzheimer's disease prevalence and symptom progression are disproportionately higher in women.
“AD disease prevalence and symptom progression are disproportionately higher in women [97,98,99].”
From Alzheimer's Disease: Treatment Strategies and Their Limitations. (2022) · cites this paper as [99]
Section 3.1 reports that postmenopausal women make up more than 60% of the affected Alzheimer population. It also reports faster cognitive decline in women with mild cognitive impairment, particularly APOE-ε4 carriers; that does not establish faster symptom progression among women diagnosed with Alzheimer’s disease generally. No page numbers are available in our copy. (LLM, conf=0.85)
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[140]Reiman EM Chen K Alexander GE Caselli RJ Bandy D Osborne D Saunders AM Hardy J 2005 Correlations between apolipoprotein E epsilon4 gene dose and brain-imaging measurements of regional hypometabolism Proc Natl Acad Sci U S A 102 8299 8302 15932949 PMC1149416
[157]Yao J Hamilton RT Cadenas E Brinton RD 2010 Decline in mitochondrial bioenergetics and shift to ketogenic profile in brain during reproductive senescence Biochimica et Biophysica Acta (BBA)-General Subjects 1800 1121 1126 20538040 PMC3200365
[158]Yao J Irwin R Chen S Hamilton R Cadenas E Brinton RD 2012 Ovarian hormone loss induces bioenergetic deficits and mitochondrial β-amyloid Neurobiology of aging 33 1507 1521 21514693 PMC3181273

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Authors: Riedel, B. C., Thompson, P. M., & Brinton, R. D.
Affiliations: University of Southern California (US)
ORCID: Riedel, Brandalyn C.
Thompson, Paul M.
Venue: The Journal of Steroid Biochemistry and Molecular Biology
Publisher: Elsevier BV
Published: 2016-06
Volume: 160
Pages: 134-147
ISSN: 0960-0760 (ISSN-L)
DOI: 10.1016/j.jsbmb.2016.03.012
PMC: PMC4905558
OpenAlex: W2327790265
Cited by: 627
References: 180
Citations by year: 2026: 51 · 2025: 89 · 2024: 61 · 2023: 75 · 2022: 84 · 2021: 92 · 2020: 70 · 2019: 40 · 2018: 28 · 2017: 16 · 2016: 20 · 2012: 1
FWCI: 4.95
Type: journal article
Language: en
Open access: green
europepmc.org
Licence: www.elsevier.com/tdm/userlicense/1.0/ (tdm)
www.elsevier.com/legal/tdmrep-license (tdm)
Locations: The Journal of Steroid Biochemistry and Molecular Biology (publishedVersion)
PubMed (publishedVersion)
Europe PMC (PubMed Central) (acceptedVersion)
PubMed Central (acceptedVersion)
Funders: National Institute on Aging (R01AG040060, RF1AG041915, P01AG026572)
National Institute of Biomedical Imaging and Bioengineering (U54EB020403)
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 › Endocrinology, Diabetes and Metabolism › Menopause: Health Impacts and Treatments
Keywords: Alzheimer's disease, late-onset Alzheimer's disease, APOE ε4, sex differences, age, chromosomal sex, perimenopause, menopause, mild cognitive impairment, disease progression, precision medicine
MeSH terms: Aging, Alleles, Alzheimer Disease, Animals, Cholesterol, Female, Genotype, Homozygote, Humans, Male, Menopause, Models, Molecular, Risk Factors, Sex Factors, Apolipoprotein E4

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Age, APOE and sex: triad of risk of Alzheimer’s disease.

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