ArticleAnnals of neurology2015
APOEε2 is associated with milder clinical and pathological Alzheimer disease.
Article in Annals of neurology, 2015. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 119 papers, 1 of them a synthesis that pooled it.
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Who cites it
119 citing papers in PubMed, 1 synthesis or guideline pooled it, 177 citations in OpenAlex.
- Meta-analysis of cognitive ability differences by apolipoprotein e genotype in young humans.Neuroscience and biobehavioral reviews · 2018Pooled it
- Apolipoprotein E ε4-dependent associations between carotenoids and cognitive decline: Findings from the MIND (Mediterranean-DASH Intervention for Neurodegenerative delay) randomized controlled trial.The American journal of clinical nutrition · 2025Trial
- Cholesterol at the Center of Alzheimer's Disease: A Unifying Hypothesis on the Pathogenic Mechanism.Molecules (Basel, Switzerland) · 2026Review
- Reduced CB1 Cannabinoid Receptor Expression in Alzheimer's Disease and Transgenic Mouse Models.Aging medicine (Milton (N.S.W)) · 2026Article
- A critical appraisal of the link between apolipoprotein E and Tau.Current opinion in neurology · 2026Review
- Social network characteristics, self-management behavior, and the mediating role of self-efficacy among diabetes patients: a multicenter cross-sectional study.Frontiers in endocrinology · 2026Article
- Age at natural menopause, reproductive lifespan and Alzheimer's disease in females: is APOE ε4 the missing link?Frontiers in genetics · 2026Article
- Inflammatory mechanisms underlying early Alzheimer's disease pathology: evidence from the aging rhesus macaque brain.Frontiers in cellular neuroscience · 2026Review
- Effects of acute sleep deprivation on individuals across differentFrontiers in neurology · 2026Article
- Sex andInternational journal of molecular sciences · 2025Article
- Aging, Rather than Genotype, Is the Principal Contributor to Differential Gene Expression Within Targeted Replacement APOE2, APOE3, and APOE4 Mouse Brain.Brain sciences · 2025Article
- Apolipoprotein E Alleles and Motor Signs in Older Adults with Alzheimer's Dementia.International journal of molecular sciences · 2025Article
- Psychoactive substances: novel molecular insights and therapeutic potential for Alzheimer's disease.Translational neurodegeneration · 2025Review
- HYPOTHESIS: Lipid-protecting disulfide bridges are the missing molecular link between ApoE4 and sporadic Alzheimer's disease in humans.Prostaglandins, leukotrienes, and essential fatty acids · 2025Article
- The APOE-Microglia Axis in Alzheimer's Disease: Functional Divergence and Therapeutic Perspectives-A Narrative Review.Brain sciences · 2025Review
- Apolipoprotein E in Alzheimer's disease: molecular insights and therapeutic opportunities.Molecular neurodegeneration · 2025Review
- APOE Christchurch enhances a disease-associated microglial response to plaque but suppresses response to tau pathology.Molecular neurodegeneration · 2025Article
- Resilience mechanisms underlying Alzheimer's disease.Metabolic brain disease · 2025Review
- Multi-functional role of apolipoprotein E in neurodegenerative diseases.Frontiers in aging neuroscience · 2025Review
- Stools from a human APOEe2 donor reduces amyloid and tau pathology and increases neuroinflammation in a 3xTg AD mouse model.Frontiers in aging neuroscience · 2025Article
59 more citing papers are in PubMed but not listed here.
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Authors and funding
5 authors at 5 institutions in 1 country.
Funding
Abstract
objectiveThe Alzheimer disease (AD) APOEε4 risk allele associates with an earlier age at onset and increased amyloid-β deposition, whereas the protective APOEε2 allele delays the onset and appears to prevent amyloid-β deposition. Yet the clinical and pathological effects of APOEε2 remain uncertain because of its relative rarity. We investigated the effects of APOEε2 and ε4 alleles on AD pathology and cognition in a large US data set of well-characterized AD patients.
methodsWe studied individuals from the National Alzheimer's Coordinating Center autopsy cohort across the entire clinicopathological continuum of AD. Multivariate models were built to examine the associations between APOE alleles and AD neuropathological changes, using the APOEε3/ε3 group as comparator. Mediation analysis was used to estimate the direct and indirect effects of APOE alleles on AD pathology and cognition (Clinical Dementia Rating Sum of Boxes and Mini-Mental State Examination).
resultsCompared to APOEε3/ε3, APOEε2 is independently associated with lower Braak neurofibrillary tangle (NFT) stages and possibly fewer neuritic plaques, but has no direct effect on cerebral amyloid angiopathy (CAA) severity, whereas APOEε4 is associated with more neuritic plaques and CAA, but has no independent effect on Braak NFT stage. Unadjusted analyses showed marked differences among APOE genotypes with respect to cognitive performance (ε2 > ε3 > ε4). Mediation analysis suggests that this is largely explained through effects on pathology.
interpretationEven when adjusted for age at onset, symptom duration, and other demographic variables, APOEε2 is associated with milder AD pathology and less severe antemortem cognitive impairment compared to APOEε3 and ε4 alleles, suggesting a relative neuroprotective effect of APOEε2 in AD.
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Registered trials
Read under generation 80e0d062 · epoch 390. Bibliography from PubMed, PubMed Central and OpenAlex; grants from NIH RePORTER; trial links from ClinicalTrials.gov; estimates, votes and beliefs from the OpenQuestion graph.