ArticleAnnals of neurology2016
APOE2 eases cognitive decline during Aging: Clinical and preclinical evaluations.
Article in Annals of neurology, 2016. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 77 papers, 1 of them a synthesis that pooled it.
What it found
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The trial behind it
Trials whose registry record cites this paper, or whose number appears in the abstract. A trial that started after this paper was published is citing it as background, not reporting it.
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Who cites it
77 citing papers in PubMed, 1 synthesis or guideline pooled it, 112 citations in OpenAlex.
- Meta-analysis of cognitive ability differences by apolipoprotein e genotype in young humans.Neuroscience and biobehavioral reviews · 2018Pooled it
- Parent-of-origin effects in Alzheimer's liability dissociate neurocognitive and cardiovascular traits in at-risk individuals.Cell reports. Medicine · 2026Article
- Cholesterol at the Center of Alzheimer's Disease: A Unifying Hypothesis on the Pathogenic Mechanism.Molecules (Basel, Switzerland) · 2026Review
- Longevity and cognitive resilience in a Colombian family carrying theJournal of Alzheimer's disease : JAD · 2026Article
- Emerging New Pathways in Malignant Neoplasms and Neurodegenerative Disorders: Perspectives for Therapeutics.Cells · 2026Review
- APOE is a presynaptic protein that accumulates with age and modulates neurotransmitter release.bioRxiv : the preprint server for biology · 2026Article
- The apolipoprotein gene: a modulating role on brain volume and cognitive function in carriers of the fragile X premutation.Neurobiology of disease · 2026Article
- APOE, Aβ42, and tau differentially impact cognitive decline in Sporadic, GBA1 and LRRK2 Parkinson's disease.NPJ Parkinson's disease · 2026Article
- Evaluating the association of apolipoprotein E genotype and cognitive resilience in SuperAgers.Alzheimer's & dementia : the journal of the Alzheimer's Association · 2026Article
- Interplay Between 3D Chromatin Architecture and Gene Regulation at theInternational journal of molecular sciences · 2025Article
- APOE genotype determines cell-type-specific pathological landscape of Alzheimer's disease.Neuron · 2025Article
- Article
- Genome-wide association analysis identifies APOE as a mitophagy modifier in Lewy body disease.Alzheimer's & dementia : the journal of the Alzheimer's Association · 2025Article
- Neuronal ABCA7 deficiency aggravates mitochondrial dysfunction and neurodegeneration in Alzheimer's disease.Alzheimer's & dementia : the journal of the Alzheimer's Association · 2025Article
- 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
- Age-related behavioural abnormalities in C57BL/6.KOR-Translational neuroscience · 2025Article
- Unraveling APOE4's Role in Alzheimer's Disease: Pathologies and Therapeutic Strategies.Current protein & peptide science · 2025Review
- Inflammation and DNA methylation in Alzheimer's disease: mechanisms of epigenetic remodelling by immune cell oxidants in the ageing brain.Redox report : communications in free radical research · 2024Review
- Brain-targeting liposome-basedHeliyon · 2024Article
- Multifaceted roles of APOE in Alzheimer disease.Nature reviews. Neurology · 2024Review
17 more citing papers are in PubMed but not listed here.
Corrections and comments
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Authors and funding
11 authors at 4 institutions in 1 country.
Funding
Abstract
objectiveApolipoprotein E (apoE), a major cholesterol carrier in the brain, is associated with a strong risk for Alzheimer disease. Compared to the risky APOE4 gene allele, the effects of the protective APOE2 gene allele are vastly understudied, and thus need to be further clarified.
methodsWe reviewed National Alzheimer's Coordinating Center clinical records and performed preclinical experiments using human apoE-targeted replacement (apoE-TR) mice, which do not show amyloid pathology.
resultsClinically, the APOE2 allele was associated with less cognitive decline during aging. This effect was also seen in subjects with little amyloid pathology, or after adjusting for Alzheimer disease-related pathologies. In animal studies, aged apoE2-TR mice also exhibited preserved memory function in water maze tests. Regardless, apoE2-TR mice showed similar or greater age-related changes in synaptic loss, neuroinflammation, and oxidative stress compared to apoE3-TR or apoE4-TR mice. Interestingly, apoE concentrations in the cortex, hippocampus, plasma, and cerebrospinal fluid (CSF) were positively correlated with memory performance across apoE isoforms, where apoE2-TR mice had higher apoE levels. Moreover, apoE2-TR mice exhibited the lowest levels of cholesterol in the cortex, despite higher levels in CSF and plasma. These cholesterol levels were associated with apoE levels and memory performance across apoE isoforms.
interpretationAPOE2 is associated with less cognitive decline during aging. This can occur independently of age-related synaptic/neuroinflammatory changes and amyloid accumulation. Higher levels of apoE and associated cholesterol metabolism in APOE2 carriers might contribute to this protective effect. Ann Neurol 2016;79:758-774.
Identifiers
What OpenQuestion holds
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.