ArticleNature neuroscience2022
Peripheral apoE4 enhances Alzheimer's pathology and impairs cognition by compromising cerebrovascular function.
Article in Nature neuroscience, 2022. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 112 papers, 3 of them syntheses that pooled it.
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Who cites it
112 citing papers in PubMed, 3 syntheses or guidelines pooled it, 156 citations in OpenAlex.
- A meta-analytic approach to identification of clinical biomarkers of hearing loss in cognitive impairment.Neurological sciences : official journal of the Italian Neurological Society and of the Italian Society of Clinical Neurophysiology · 2026Pooled it
- Pooled it
- Quantitative ophthalmic posterior segment optical coherence tomography angiography and neurologic conditions: a review.Frontiers in neurologyPooled it
- PRBS Gas Challenges Reveal Impaired Chemoreflex and Cholinergic Dynamics in MCI.Annals of biomedical engineering · 2026Article
- Article
- Recent advances in Alzheimer's disease: From molecular mechanisms to therapeutic strategies.Cell · 2026Review
- Lipid Metabolism Reprogramming in the Aging Brain: Glial-Mediated Pathogenic Mechanisms and Translational Strategies in Neurodegeneration.International journal of molecular sciences · 2026Review
- Beyond the Amyloid Hypothesis: Systemic Drivers, CNS-PNS Crosstalk, and the Future of Alzheimer's Disease Therapeutics.International journal of molecular sciences · 2026Review
- Alzheimer disease protection from the periphery.Nature reviews. Neurology · 2026Article
- Visceral adipose tissue differentially affects tau and Aβ pathology in 3xTg-AD mice.Cell communication and signaling : CCS · 2026Article
- Liver-nervous system axis: pathways, dysregulation, and translational perspectives.Journal of neuroinflammation · 2026Review
- Single-cell transcriptomic analysis reveals APOE genotype-dependent sex differences in Alzheimer's disease.Alzheimer's & dementia : the journal of the Alzheimer's Association · 2026Article
- Targeting the astrocyte-microglia EFEMP1-GALNT10 axis: a spatially programmable therapeutic strategy for hippocampal vulnerability in Alzheimer's disease.Journal of translational medicine · 2026Article
- Vascular contribution to cognitive impairment and dementia (VCID): proceedings of 2025 workshop of the Jackson Laboratory.Mammalian genome : official journal of the International Mammalian Genome Society · 2026Article
- Association between the atherogenic index of plasma and cognitive impairment.Scientific reports · 2026Article
- Apolipoprotein E4 in Alzheimer's Disease: Role in Pathology, Lipid Metabolism, and Drug Treatment.International journal of molecular sciences · 2026Review
- Cognitive trajectories of older adults before and after the COVID-19 pandemic: socioeconomic and psychological disparities in the Lc65+ cohort.Innovation in aging · 2026Article
- Inhibiting Liver-Derived C3 Protein Rescues Anesthesia/Surgery-Induced Cognitive Impairment, Synaptic Disorders, and Microglial Phagocytosis.Advanced science (Weinheim, Baden-Wurttemberg, Germany) · 2026Article
- APOE Lipoprotein Particles: Pathophysiology, Therapy, and the Crosstalk in Alzheimer's Disease and Cardiovascular Disease.Molecular neurobiology · 2025Review
- Flipping APOE to reverse Alzheimer's disease traits.Nature neuroscience · 2025Article
52 more citing papers are in PubMed but not listed here.
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Authors and funding
40 authors at 6 institutions in 1 country.
Funding
Abstract
The ε4 allele of the apolipoprotein E (APOE) gene, a genetic risk factor for Alzheimer's disease, is abundantly expressed in both the brain and periphery. Here, we present evidence that peripheral apoE isoforms, separated from those in the brain by the blood-brain barrier, differentially impact Alzheimer's disease pathogenesis and cognition. To evaluate the function of peripheral apoE, we developed conditional mouse models expressing human APOE3 or APOE4 in the liver with no detectable apoE in the brain. Liver-expressed apoE4 compromised synaptic plasticity and cognition by impairing cerebrovascular functions. Plasma proteome profiling revealed apoE isoform-dependent functional pathways highlighting cell adhesion, lipoprotein metabolism and complement activation. ApoE3 plasma from young mice improved cognition and reduced vessel-associated gliosis when transfused into aged mice, whereas apoE4 compromised the beneficial effects of young plasma. A human induced pluripotent stem cell-derived endothelial cell model recapitulated the plasma apoE isoform-specific effect on endothelial integrity, further supporting a vascular-related mechanism. Upon breeding with amyloid model mice, liver-expressed apoE4 exacerbated brain amyloid pathology, whereas apoE3 reduced it. Our findings demonstrate pathogenic effects of peripheral apoE4, providing a strong rationale for targeting peripheral apoE to treat Alzheimer's disease.
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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.