ReviewThe European journal of neuroscience2022
A multi-hit hypothesis for an APOE4-dependent pathophysiological state.
Review in The European journal of neuroscience, 2022. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 22 papers.
What it found
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The abstract states no effect estimate the extractor could read, or names no intervention and outcome on the map, so this paper lights no cell and moves no belief. It is still indexed, cited and linked below.
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Who cites it
22 citing papers in PubMed, 36 citations in OpenAlex.
- Apolipoprotein E ε4 and type 2 diabetes cooperatively accelerate amyloid beta and tau neurodegeneration.European journal of nuclear medicine and molecular imaging · 2026Article
- Progressive behavioral and cognitive decline inbioRxiv : the preprint server for biology · 2026Article
- Neuronal Injury and Regeneration-Linked Gene Expression Dynamics in the Hypothalamic-Pituitary-Adrenal Axis Following Experimental Traumatic Brain Injury.International journal of molecular sciences · 2026Article
- Case Report of Dual Variants inClinical case reports · 2026Article
- Integrated imaging and molecular profiling reveals APOE4-associated neurovascular and glial disruptions in young adult mice.Journal of neuroinflammation · 2026Article
- Ginkgolide as a Promising Multi-Target Therapeutic for Alzheimer's Disease: Targeting ApoE4 and Beyond.Current pharmaceutical design · 2026Article
- Genetic factors and comorbid pathologies interact to drive regional mitophagy alterations in Lewy body dementia.Acta neuropathologica · 2025Article
- Intervention Role of APOE in CNS Diseases: APOE Actions and APOE Neurogenesis Capability.Molecular neurobiology · 2025Review
- Pluripotent Cells Expressing APOE4 Exhibit a Pronounced Pro-Apoptotic Phenotype Accompanied by Markers of Hyperinflammation and a Blunted NF-κB Response.International journal of molecular sciences · 2025Article
- Relationship between cytomegalovirus antibody levels and cognitive performance is dependent on age and genetic risk.BMC neurology · 2025Article
- Perceptual discrimination of complex objects: Apolipoprotein E e4 gene-dose effects in mid-life.Alzheimer's & dementia : the journal of the Alzheimer's Association · 2025Article
- APOE4 and sedentary lifestyle synergistically impair neurovascular function in the visual cortex of awake mice.Communications biology · 2025Article
- Traffic-related air pollution significantly aggravates the detrimental effect of infections on the risk of Alzheimer's disease and other dementias, especially in non-carriers ofFrontiers in dementia · 2025Article
- Inhibiting the Cholesterol Storage Enzyme ACAT1/SOAT1 in Aging Apolipoprotein E4 Mice Alters Their Brains' Inflammatory Profiles.International journal of molecular sciences · 2024Article
- APOE ε4 carrier status moderates the effect of lifestyle factors on cognitive reserve.Alzheimer's & dementia : the journal of the Alzheimer's Association · 2024Article
- Multifaceted roles of APOE in Alzheimer disease.Nature reviews. Neurology · 2024Review
- Risk factors for severe COVID-19 disease increase SARS-CoV-2 infectivity of endothelial cells and pericytes.Open biology · 2024Article
- Repetitive head trauma and apoE4 induce chronic cerebrovascular alterations that impair tau elimination from the brain.Experimental neurology · 2024Article
- APOE Peripheral and Brain Impact: APOE4 Carriers Accelerate Their Alzheimer Continuum and Have a High Risk of Suicide in PMBiomolecules · 2023Review
- Neuropathology-Independent Association BetweenNeurology. Genetics · 2023Article
Corrections and comments
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Authors and funding
11 authors at 1 institution in 1 country.
Funding
Abstract
The APOE gene encoding the Apolipoprotein E protein is the single most significant genetic risk factor for late-onset Alzheimer's disease. The APOE4 genotype confers a significantly increased risk relative to the other two common genotypes APOE3 and APOE2. Intriguingly, APOE4 has been associated with neuropathological and cognitive deficits in the absence of Alzheimer's disease-related amyloid or tau pathology. Here, we review the extensive literature surrounding the impact of APOE genotype on central nervous system dysfunction, focussing on preclinical model systems and comparison of APOE3 and APOE4, given the low global prevalence of APOE2. A multi-hit hypothesis is proposed to explain how APOE4 shifts cerebral physiology towards pathophysiology through interconnected hits. These hits include the following: neurodegeneration, neurovascular dysfunction, neuroinflammation, oxidative stress, endosomal trafficking impairments, lipid and cellular metabolism disruption, impaired calcium homeostasis and altered transcriptional regulation. The hits, individually and in combination, leave the APOE4 brain in a vulnerable state where further cumulative insults will exacerbate degeneration and lead to cognitive deficits in the absence of Alzheimer's disease pathology and also a state in which such pathology may more easily take hold. We conclude that current evidence supports an APOE4 multi-hit hypothesis, which contributes to an APOE4 pathophysiological state. We highlight key areas where further study is required to elucidate the complex interplay between these individual mechanisms and downstream consequences, helping to frame the current landscape of existing APOE-centric literature.
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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.