ArticleJournal of Alzheimer's disease : JAD2015
Human ApoE Isoforms Differentially Modulate Glucose and Amyloid Metabolic Pathways in Female Brain: Evidence of the Mechanism of Neuroprotection by ApoE2 and Implications for Alzheimer's Disease Prevention and Early Intervention.
Article in Journal of Alzheimer's disease : JAD, 2015. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 59 papers, 1 of them a synthesis that pooled it.
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Who cites it
59 citing papers in PubMed, 1 synthesis or guideline pooled it, 97 citations in OpenAlex.
- APOE4 is associated with cognitive and pathological heterogeneity in patients with Alzheimer's disease: a systematic review.Alzheimer's research & therapy · 2020Pooled it
- Review
- Connecting the Dots: Neurobiological Interplay Between Type 2 Diabetes and Alzheimer's Disease.International journal of molecular sciences · 2026Review
- Role of apolipoprotein E4 in alzheimer's disease pathogenesis and emerging therapeutic strategies.Metabolic brain disease · 2025Review
- Neuronal APOE4 alone is sufficient to drive tau pathology, neurodegeneration, and neuroinflammation in an Alzheimer's disease mouse model.bioRxiv : the preprint server for biology · 2025Article
- WNKs regulate mouse behavior and alter central nervous system glucose uptake and insulin signaling.bioRxiv : the preprint server for biology · 2025Article
- The multifaceted roles of apolipoprotein E4 in Alzheimer's disease pathology and potential therapeutic strategies.Cell death discovery · 2025Review
- Apolipoprotein E in Alzheimer's disease: molecular insights and therapeutic opportunities.Molecular neurodegeneration · 2025Review
- ApoE2 affects insulin signaling in the hippocampus and spatial cognition of aged mice in a sex-dependent manner.Cell communication and signaling : CCS · 2025Article
- Energy metabolism in health and diseases.Signal transduction and targeted therapy · 2025Review
- The role ofFrontiers in neuroscience · 2025Review
- Diverse signaling mechanisms and heterogeneity of astrocyte reactivity in Alzheimer's disease.Journal of neurochemistry · 2024Review
- Advancements in APOE and dementia research: Highlights from the 2023 AAIC Advancements: APOE conference.Alzheimer's & dementia : the journal of the Alzheimer's Association · 2024Review
- APOE2 protects against Aβ pathology by improving neuronal mitochondrial function through ERRα signaling.Cellular & molecular biology letters · 2024Article
- The Role of Impaired Receptor Trafficking in Mediating the Pathological Effects of APOE4 in Alzheimer's Disease.Journal of Alzheimer's disease : JAD · 2024Article
- Advances in Blood Biomarkers for Alzheimer's Disease: Ultra-Sensitive Detection Technologies and Impact on Clinical Diagnosis.Degenerative neurological and neuromuscular disease · 2024Review
- The Role of Insulin-like Growth Factor I in Mechanisms of Resilience and Vulnerability to Sporadic Alzheimer's Disease.International journal of molecular sciences · 2023Review
- Apolipoprotein ε in Brain and Retinal Neurodegenerative Diseases.Aging and disease · 2023Review
- Integrated genomic, proteomic and cognitive assessment in Duchenne Muscular Dystrophy suggest astrocyte centric pathology.Heliyon · 2023Article
- Role of neuroinflammation in neurodegeneration development.Signal transduction and targeted therapy · 2023Review
Corrections and comments
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Authors and funding
3 authors at 1 institution in 1 country.
Funding
Abstract
Three major genetic isoforms of apolipoprotein E (ApoE), ApoE2, ApoE3, and ApoE4, exist in humans and lead to differences in susceptibility to Alzheimer's disease (AD). This study investigated the impact of human ApoE isoforms on brain metabolic pathways involved in glucose utilization and amyloid-β (Aβ) degradation, two major areas that are significantly perturbed in preclinical AD. Hippocampal RNA samples from middle-aged female mice with targeted human ApoE2, ApoE3, and ApoE4 gene replacement were comparatively analyzed with a qRT-PCR custom array for the expression of 85 genes involved in insulin/insulin-like growth factor (Igf) signaling. Consistent with its protective role against AD, ApoE2 brain exhibited the most metabolically robust profile among the three ApoE genotypes. When compared to ApoE2 brain, both ApoE3 and ApoE4 brains exhibited markedly reduced levels of Igf1, insulin receptor substrates (Irs), and facilitated glucose transporter 4 (Glut4), indicating reduced glucose uptake. Additionally, ApoE4 brain exhibited significantly decreased Pparg and insulin-degrading enzyme (Ide), indicating further compromised glucose metabolism and Aβ dysregulation associated with ApoE4. Protein analysis showed significantly decreased Igf1, Irs, and Glut4 in ApoE3 brain, and Igf1, Irs, Glut4, Pparg, and Ide in ApoE4 brain compared to ApoE2 brain. These data provide the first documented evidence that human ApoE isoforms differentially affect brain insulin/Igf signaling and downstream glucose and amyloid metabolic pathways, illustrating a potential mechanism for their differential risk in AD. A therapeutic strategy that enhances brain insulin/Igf1 signaling activity to a more robust ApoE2-like phenotype favoring both energy production and amyloid homeostasis holds promise for AD prevention and early intervention.
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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.