Alzheimer's disease (AD) is associated with impaired lipid metabolism in the brain. To identify the specific regions where pathological change to cell functionality occurs, a spatial investigation of regional lipid dysregulation is needed. We measured untargeted spatial lipidomics using Desorption Electrospray Ionization (DESI) mass spectrometry in the brains of mice from two genotypes, wild type (WT) and APPsw, an AD mouse model overexpression amyloid precursor protein (APP). We generated a longitudinal profile of these mice at ages 6 months, 12 months, and 22 months. We computationally segmented brain regions defined by the Allen Mouse Brain Atlas to discover region-specific differential lipid biomarkers across age and genotype. We developed “Spatial Lipidomics Analysis Tool” (SLAT), a computational framework which identifies statistically differential ions between age and genotype in a region-specific manner, and applied this to our data. Independently of SLAT, we applied K-means clustering to lipidomics as an unbiased approach to find regions in whole brains that may drive the development of disease. We applied K-means clustering to log2 fold changes (log2FC) to find groups of significant ions reported by SLAT characterized by similar changes in abundance in APPsw mice over time compared to 6 months WT mice. We identified the globus pallidus (GP) as having multiple significantly differential lipids between WT and APPsw samples. However, whole brain analysis was unable to identify significant differential ions between genotypes, demonstrating the advantage of region-specific-analysis. Additionally, the GP was found to drive clustering for specific ages and genotypes. Longitudinal analysis of significant GP ions revealed multiple groups of ions with coordinated changes in ion intensity over time. The group of ions with the greatest temporal changes had a 0.50 log2FC increase from 6 to 12 months, followed by a 0.63 log2FC decrease from 12 to 22 months, on average. Our results illustrate lipid biomarkers specific to the GP which may have potential use for the diagnosis and prognosis of AD. The development of SLAT as a partially automated pipeline to analyze longitudinal data with different phenotypes can be utilized as a tool for discovery of disease-specific mechanisms from spatial lipidomics and metabolomics data.

At least one-third of the identified risk alleles from Genome Wide Association Studies of Alzheimer’s disease (AD) are involved in lipid metabolism, lipid transport, or direct lipid binding. BIN1 which is also known as Amphiphysin 2; and PICALM which are involved in phosphoinositide metabolism and binding rank just below the highest risk gene variant of Apolipoprotein E (ApoEε4), a cholesterol and phospholipid transporter. In addition to genetic variants, lipidomic studies have reported severe metabolic dysregulation in human autopsy brain tissue, CSF, blood and multiple mouse models of AD. We aimed to identify an overarching metabolic pathway in lipid metabolism by integrating analyses of transcriptomics and lipidomics in the Religious Order Study-Memory Aging Project (ROS-MAP) as well as models of disease. Lipidomic data in ROS-MAP was generated using the Biocrates AbsoluteIDQ p180 platform, a multiplexed targeted metabolomic assay covering lipids and metabolites including acylcarnitines, glycerophospholipids and sphingolipids. We confirmed global lipid dysregulation of acyl chain remodeling using pharmacological inhibitors of lipid modifying enzymes in cell models overexpressing amyloid precursor protein (APP) and identified similarly dysregulated lipids in an animal model of AD overexpressing APP harboring the Swedish mutation in a targeted lipidomic panel of over 600 lipid species. Our analysis of transcriptomic data from ROS-MAP lead to identification of multiple genes in the pathway for acyl chain remolding, Lands Cycle, which were associated with cognitive decline independently of amyloid and tau pathologies. Coordinate changes in lipids were found to be dysregulated in association with both mild cognitive impairment (MCI) and the ApoEe4 genotype which showed a correlated lipid profile shift. WGCNA analysis identified dysregulated lipids within a single module which are substrates and products in the Lands Cycle for acyl chain remodeling. Our studies highlight the critical dysregulation of acyl chain remodeling in ApoEe4 carriers and MCI in human brain which could be modeled in mouse and cell models of disease. A coordinated lipid profile shift in both ApoEe4 carriers and MCI suggest pathological changes in lipid metabolism underly early disease and highlight lipid dyshomeostasis as a tractable target for early disease modifying intervention.

BACKGROUND:Blood-brain barrier (BBB) dysfunction is emerging as an important pathophysiologic factor in Alzheimer disease (AD). Cerebrospinal fluid (CSF) platelet-derived growth factor receptor-β (PDGFRβ) is a biomarker of BBB pericyte injury and has been implicated in cognitive impairment and AD. METHODS:We aimed to study CSF PDGFRβ protein levels, along with CSF biomarkers of brain amyloidosis and tau pathology in a well-characterized population of cognitively unimpaired individuals and correlated CSF findings with amyloid-PET positivity. We performed an institutional review board (IRB)-approved cross-sectional analysis of a prospectively enrolled cohort of 36 cognitively normal volunteers with available CSF, Pittsburgh compound B PET/CT, Mini-Mental State Exam score, Global Deterioration Scale, and known apolipoprotein E ( APOE ) ε4 status. RESULTS:Thirty-six subjects were included. Mean age was 63.3 years; 31 of 36 were female, 6 of 36 were amyloid-PET-positive and 12 of 36 were APOE ε4 carriers. We found a moderate positive correlation between CSF PDGFRβ and both total Tau (r=0.45, P =0.006) and phosphorylated Tau 181 (r=0.51, P =0.002). CSF PDGFRβ levels were not associated with either the CSF Aβ42 or the amyloid-PET. CONCLUSIONS:We demonstrated a moderate positive correlation between PDGFRβ and both total Tau and phosphorylated Tau 181 in cognitively normal individuals. Our data support the hypothesis that BBB dysfunction represents an important early pathophysiologic step in AD, warranting larger prospective studies. TRIAL REGISTRATION:ClinicalTrials.gov Identifier: NCT00094939.

INTRODUCTION:While the role of apolipoprotein E (APOE) ε4 in Alzheimer's disease (AD) susceptibility has been studied extensively, much less is known about the differences in disease presentation in APOE ε4 carriers versus non-carriers. METHODS:To help elucidate these differences, we performed a broad analysis comparing the regional levels of six different neuroimaging biomarkers in the brains of APOE ε4 carriers versus non-carriers who participated in the Alzheimer's Disease Neuroimaging Initiative (ADNI). RESULTS:We observed significant APOE ε4-associated heterogeneity in regional amyloid beta deposition, tau accumulation, glucose uptake, brain volume, cerebral blood flow, and white matter hyperintensities within each AD diagnostic group. We also observed important APOE ε4-associated differences in cognitively unimpaired individuals who converted to mild cognitive impairment/AD versus those who did not convert. DISCUSSION:This observed heterogeneity in neuroimaging biomarkers between APOE ε4 carriers versus non-carriers may have important implications regarding the prevention, diagnosis, and treatment of AD in different subpopulations. HIGHLIGHTS:An extensive study was performed on the apolipoprotein E (APOE) ε4-associated heterogeneity in neuroimaging biomarkers from the Alzheimer's Disease Neuroimaging Initiative. Robust APOE ε4-associated increases in amyloid beta (Aβ) deposition throughout the brain, in every diagnostic group, were observed. APOE ε4-associated increases in tau pathology, decreases in glucose uptake, and increases in brain atrophy, which expand in regional scope and magnitude with disease progression, were observed. Significant sex- and age-related differences in APOE ε4-associated neuroimaging biomarker heterogeneity, with overall increases in pathological presentation in female APOE ε4 carriers, were observed. Regional differences in Aβ deposition, tau accumulation, glucose uptake, ventricle size, and white matter hyperintensities were observed in cognitively normal participants who converted to mild cognitive impairment/Alzheimer's disease, which may hold potential predictive value.

Tools for acute manipulation of protein localization enable elucidation of spatiotemporally defined functions, but their reliance on exogenous triggers can interfere with cell physiology. This limitation is particularly apparent for studying mitosis, whose highly choreographed events are sensitive to perturbations. Here we exploit the serendipitous discovery of a phosphorylation-controlled, cell cycle-dependent localization change of the adaptor protein PLEKHA5 to develop a system for mitosis-specific protein recruitment to the plasma membrane that requires no exogenous stimulus. Mitosis-enabled anchor-away/recruiter system comprises an engineered, 15 kDa module derived from PLEKHA5 capable of recruiting functional protein cargoes to the plasma membrane during mitosis, either through direct fusion or via GFP-GFP nanobody interaction. Applications of the mitosis-enabled anchor-away/recruiter system include both knock sideways to rapidly extract proteins from their native localizations during mitosis and conditional recruitment of lipid-metabolizing enzymes for mitosis-selective editing of plasma membrane lipid content, without the need for exogenous triggers or perturbative synchronization methods. Cao et al. describe the development and application of an engineered protein system (MARS) derived from PLEKHA5 that allows mitosis-specific recruitment of proteins to the plasma membrane to study protein function in cell division.

IntroductionAt least one-third of the identified risk alleles from Genome-Wide Association Studies (GWAS) of Alzheimer’s disease (AD) are involved in lipid metabolism, lipid transport, or direct lipid binding. In fact, a common genetic variant (ε4) in a cholesterol and phospholipid transporter, Apolipoprotein E (APOEε4), is the primary genetic risk factor for late-onset AD. In addition to genetic variants, lipidomic studies have reported severe metabolic dysregulation in human autopsy brain tissue, cerebrospinal fluid, blood, and multiple mouse models of AD.MethodsWe aimed to identify an overarching metabolic pathway in lipid metabolism by integrating analyses of lipidomics and transcriptomics from the Religious Order Study and Rush Memory Aging Project (ROSMAP) using differential analysis and network correlation analysis.ResultsCoordinated differences in lipids were found to be dysregulated in association with both mild cognitive impairment (MCI) and APOEε4 carriers. Interestingly, these correlations were weakened when adjusting for education. Indeed, the cognitively non-impaired APOEε4 carriers have higher education levels in the ROSMAP cohort, suggesting that this lipid signature may be associated with a resilience phenotype. Network correlation analysis identified multiple differential lipids within a single module that are substrates and products in the Lands Cycle for acyl chain remodeling. In addition, our analyses identified multiple genes in the Lands Cycle acyl chain remodeling pathway, which were associated with cognitive decline independent of amyloid-β (Aβ) load and tau tangle pathologies.DiscussionOur studies highlight the critical differences in acyl chain remodeling in brain tissue from APOEε4 carriers and individual non-carriers with MCI. A coordinated lipid profile shift in dorsolateral prefrontal cortex from both APOEε4 carriers and MCI suggests differences in lipid metabolism occur early in disease stage and highlights lipid homeostasis as a tractable target for early disease modifying intervention.

With the advent of therapeutics with potential to slow Alzheimer’s disease progression the necessity of understanding the diagnostic value of plasma biomarkers is critical, not only for understanding the etiology and progression of Alzheimer’s disease, but also for access and response to potentially disease modifying therapeutic agents. Multiple studies are currently assessing the sensitivity and specificity of plasma biomarkers in large cohorts such as the Alzheimer’s Disease Neuroimaging Initiative. This study uses machine learning to predict the progression from mild cognitive impairment using plasma biomarkers in conjunction with well-established cerebrospinal fluid and imaging biomarkers of disease progression.

Our review summarizes the diagnostic accuracy of plasma and cerebrospinal fluid (CSF) phosphorylated tau 217 (p-tau217) in detecting amyloid and tau pathology on positron emission tomography (PET). We systematically reviewed studies that reported the diagnostic accuracy of plasma and CSF p-tau217, searching MEDLINE/PubMed, Scopus, and Web of Science through August 2024. The accuracy of p-tau217 in predicting amyloid and tau pathology on PET was evaluated in 30 studies. Both plasma and CSF p-tau217 effectively detect amyloid and tau PET deposition. Plasma p-tau217 showed 82% sensitivity for detecting amyloid and 83% for tau, with 86% and 83% specificity, respectively. CSF p-tau217 had 79% sensitivity for amyloid and 91% for tau, with 91% and 84% specificity. p-tau217 effectively identifies Alzheimer's disease (AD) pathology. Plasma p-tau217 was comparable to CSF p-tau217 in detecting amyloid deposition on PET. Despite being less sensitive for detecting tau deposition on PET, plasma p-tau217 can be an efficient screening tool for underlying AD pathology. HIGHLIGHTS: Plasma phosphorylated tau 217 (p-tau217) serves as a viable biomarker alternative to cerebrospinal fluid p-tau217 due to the strong concordance between their results. Plasma p-tau217 accurately identifies amyloid and tau positron emission tomography (PET) positivity, exhibiting a low rate of false negatives and positives, thereby establishing it as a reliable diagnostic tool for Alzheimer's disease (AD). Plasma p-tau217 demonstrates slightly higher accuracy in predicting amyloid PET positivity compared to tau PET positivity. Plasma p-tau217 demonstrates higher predictive accuracy in detecting AD pathology among cognitively impaired individuals, compared to cognitively unimpaired individuals, suggesting its enhanced utility as a diagnostic biomarker in clinical settings.

Chronic dysregulation of peripheral lipids has been found to be associated with depression and cognition, but their interaction has not been investigated. Growing evidence has highlighted the association between peripheral lipoprotein levels with depression and cognition with inconsistent results. We assessed the association between peripheral lipids, depression, and cognition while evaluating their potential interactions using robust clinically relevant predictors such as lipoprotein levels and chronic medical disorders that dysregulate lipoproteins. We report an association between peripheral lipids, depression, and cognition, suggesting a common underlying biological mechanism driven by lipid dysregulation in two independent studies. Analysis of a longitudinal study of a cohort at high or low familial risk for major depressive disorder (MDD) ( n = 526) found metabolic diseases, including diabetes, hypertension, and other cardiovascular diseases, were associated with MDD and cognitive outcomes. Investigating a cross-sectional population survey of adults in the National Health and Nutrition Examination Survey 2011–2014 (NHANES) ( n = 2377), depression was found to be associated with high density lipoprotein (HDL) and cognitive assessments. In the familial risk study, medical conditions were found to be associated with chronic lipid dysregulation and were significantly associated with MDD using the structural equation model. A positive association between chronic lipid dysregulation and cognitive scores was found in an exploratory analysis of the familial risk study. In a complementary study, analysis of NHANES revealed a positive association of HDL levels with cognition. Further analysis of the NHANES cohort indicated that depression status mediated the interaction between HDL levels and cognitive tests. Importantly, the protective effect of HDL on cognition was absent in those with depressive symptoms, which may ultimately result in worse outcomes leading to cognitive decline. These findings highlight the potential for the early predictive value of medical conditions with chronic lipid dyshomeostasis for the risk of depression and cognitive decline.

Neuroinflammation is believed to be a key process in Alzheimer’s disease (AD) pathogenesis. Recently, the neutrophil-to-lymphocyte (NLR) and lymphocyte-to-monocyte ratios (LMR) have been proposed to be useful peripheral markers of inflammation. However, it is unclear how these inflammatory ratios relate to AD pathology, such as β-amyloid (Aβ) plaques and tau tangles. Using 18 F-florbetapir and 18 F-flortaucipir positron emission tomography (PET), we sought to determine how the NLR and LMR are associated with AD pathology both cross-sectionally and longitudinally. We further evaluated associations between the NLR and LMR and longitudinal cognitive decline. Using data from the Alzheimer’s Disease Neuroimaging Initiative, we analyzed blood, PET, and cognitive data from 1544 subjects—405 cognitively normal, 838 with mild cognitive impairment (MCI), and 301 with AD. Associations between the NLR and LMR and Aβ and tau on PET were assessed using ordinary least-squares and mixed-effects regression models, while adjusting for age, sex, years of education, and apolipoprotein E ε2 or ε4 carrier status. Associations between the NLR and LMR and cognitive function, as measured by the AD Assessment Scale-Cognitive Subscale, 13-item version, were also assessed. MCI and AD subjects had higher NLR ( p = 0.017, p < 0.001, respectively) and lower LMR ( p = 0.013, p = 0.023). The NLR, but not the LMR, was significantly associated with Aβ ( p = 0.028), suggesting that higher NLR was associated with greater Aβ deposition in the brain. Neither the NLR nor the LMR was associated with tau deposition ( p > 0.05). A higher NLR was associated with greater longitudinal cognitive decline ( p < 0.001). A higher ratio of peripheral neutrophils to lymphocytes, possibly reflecting an imbalance in innate versus adaptive immunity, is related to greater Aβ deposition and longitudinal cognitive decline. As the field moves toward blood-based biomarkers of AD, the altered balance of innate versus adaptive immunity could be a useful biomarker of underlying pathology and may also serve as a potential therapeutic target.

Fasting triggers diverse physiological adaptations including increases in circulating fatty acids and mitochondrial respiration to facilitate organismal survival. The mechanisms driving mitochondrial adaptations and respiratory sufficiency during fasting remain incompletely understood. Here we show that fasting or lipid availability stimulates mTORC2 activity. Activation of mTORC2 and phosphorylation of its downstream target NDRG1 at serine 336 sustains mitochondrial fission and respiratory sufficiency. Time-lapse imaging shows that NDRG1, but not the phosphorylation-deficient NDRG1 Ser336Ala mutant, engages with mitochondria to facilitate fission in control cells, as well as in those lacking DRP1. Using proteomics, a small interfering RNA screen, and epistasis experiments, we show that mTORC2-phosphorylated NDRG1 cooperates with small GTPase CDC42 and effectors and regulators of CDC42 to orchestrate fission. Accordingly, Rictor KO , NDRG1 Ser336Ala mutants and Cdc42 -deficient cells each display mitochondrial phenotypes reminiscent of fission failure. During nutrient surplus, mTOR complexes perform anabolic functions; however, paradoxical reactivation of mTORC2 during fasting unexpectedly drives mitochondrial fission and respiration.

Amyloid precursor protein (APP) is a transmembrane protein expressed at the synapse throughout life. In absence of APP, extracellular Aß- and tau-oligomers no longer impair memory and its synaptic surrogate, long-term potentiation (LTP). Synapses include pre- and post-synaptic compartments. However, the relative role of pre- vs. post-synaptic APP at the CA3-CA1 hippocampal synapse in the Aß- and tau-oligomer-induced damage of memory and LTP is not know. We used a combination of gene editing, electrophysiological, behavioral and biochemical techniques to investigate the contribution of the pre- and post-synaptic APP in oligomer induced impairment of memory and LTP. Specific ablation of APP expression in the post-synaptic neuron did not alter the negative effects of Aß and tau oligomers on LTP and memory. In contrast, APP-KO in the presynaptic neuron mimicked and occluded the negative effects of Aß and tau oligomers on LTP and memory, suggesting that presynaptic APP mediates the synapto-toxic effect of Aß and tau. Further investigation demonstrated that pre-synaptic APP deletion (but not post-synaptic) mimicked and occluded the Aß and tau oligomer induced reduction of neurotransmitter vesicle availability during tetanic stimulation and increase of refilling rate after depletion of the readily-releasable pool. Moreover, the increase in refilling rate after deletion of presynaptic APP was dependent upon intracellular calcium. Indeed, intracellular calcium homeostasis was affected both in basal conditions and after activity in full APP-KO mice, likely due to decrease in the levels of inositol 1,4,5-trisphosphate receptor, ryanodine receptor and the calcium pump, SERCA3. These data support the view that Aß and tau oligomers affect synaptic function and memory through pre-synaptic APP.

Radiation therapy (RT) is essential for the management of glioblastoma (GBM). However, GBM frequently relapses within the irradiated margins, thus suggesting that RT might stimulate mechanisms of resistance that limits its efficacy. GBM is recognized for its metabolic plasticity, but whether RT-induced resistance relies on metabolic adaptation remains unclear. Here, we show in vitro and in vivo that irradiated GBM tumors switch their metabolic program to accumulate lipids, especially unsaturated fatty acids. This resulted in an increased formation of lipid droplets to prevent endoplasmic reticulum (ER) stress. The reduction of lipid accumulation with genetic suppression and pharmacological inhibition of the fatty acid synthase (FASN), one of the main lipogenic enzymes, leads to mitochondrial dysfunction and increased apoptosis of irradiated GBM cells. Combination of FASN inhibition with focal RT improved the median survival of GBM-bearing mice. Supporting the translational value of these findings, retrospective analysis of the GLASS consortium dataset of matched GBM patients revealed an enrichment in lipid metabolism signature in recurrent GBM compared to primary. Overall, these results demonstrate that RT drives GBM resistance by generating a lipogenic environment permissive to GBM survival. Targeting lipid metabolism might be required to develop more effective anti-GBM strategies.

Apolipoprotein ε allele 4 (APOE4) influences the metabolism of polyunsaturated fatty acids (PUFAs) such as docosahexaenoic acid (DHA). The entorhinal cortex (EC) in the brain is affected early in Alzheimer's disease and is rich in DHA. The purpose of this study is to identify the effect of APOE4 and DHA lipid species on the EC. Plasma and cerebrospinal fluid (CSF) lipidomic measurements were obtained from the DHA Brain Delivery Pilot, a randomized clinical trial of DHA supplementation (n = 10) versus placebo (n = 12) for six months in nondemented older adults stratified by APOE4 status. Wild-type C57B6/J mice were fed a high or low DHA diet for 6 months followed by plasma and brain lipidomic analysis. Levels of phosphatidylcholine DHA (PC 38:6) and cholesterol ester DHA (CE 22:6) had the largest increases in CSF following supplementation (P < 0.001). DHA within triglyceride (TG) lipids in CSF strongly correlated with corresponding plasma TG lipids, and differed by APOE4, with carriers having a lower increase than noncarriers. Changes in plasma PC DHA had the strongest association with changes in EC thickness in millimeters, independent of APOE4 status (P = 0.007). In mice, a high DHA diet increased PUFAs within brain lipids. Our findings demonstrate an exchange of DHA at the CSF-blood barrier and into the brain within all lipid species with APOE having the strongest effect on DHA-containing TGs. The correlation of PC DHA with EC suggests a functional consequence of DHA accretion in high density lipoprotein for the brain.

Major disappointments in late-stage clinical trials have made it clear that additional therapeutic targets beyond amyloid β-peptide (Aβ) and tau are urgently required for Alzheimer’s disease (AD). Phosphatidylinositol 4,5-biphosphate [PI(4,5)P 2 ] has previously been established as an important signaling lipid at the synapse and in a mouse model of Alzheimer’s disease. We hypothesize that the level of PI(4,5)P 2 in the plasma membrane may be an early and critical determinant of AD associated molecular and behavioral deficits in cellular and mouse models of the disease. We tested the ability of a light-inducible dimerization system to modify phosphoinositide content in vitro using a PC12 cell line overexpressing cryptochrome-interacting basic-helix-loop-helix (CIBN) fusion to a membrane targeted CAAX domain (CIBN-CAAX), and blue-light mediated binding of cryptochrome 2 (CRY2) fused with the catalytic domain of phosphatidylinositol 4-phosphate 5-kinase (CRY2-PIP5K2A-CD). We detected PI(4,5)P 2 using the PI(4,5)P 2 sensor plextrin homology domain of phospholipase C δ (PH-PLCδ). Using virally mediated transduction of these constructs in mouse brain, we manipulated PI(4,5)P 2 levels in hippocampus of a mouse model of AD, harboring the Amyloid Precursor Protein transgene (APP-Tg). Behavioral deficits were assessed using novel object recognition (NOR). Brains were analyzed for detection of phosphoinositide using Imaging Mass Spectrometry. In PC12 cells, initial results indicate that after optogenetic stimulation, cytosolic labeling by PH-PLCδ was largely lost, and plasma membrane labeling was observed. In a mouse model of AD (APP-Tg) after stimulation with blue light or control yellow light, behavioral paradigms including NOR were completed. NOR discrimination index was significantly reduced for Tg+/control compared to other groups (WT/control, WT/Opto) as expected. However, Tg+/Opto was not significantly different than WT/control or WT/Opto indicating amelioration of behavioral deficits in Tg+/Opto through optogenetic stimulation of PI(4,5)P 2 production. Experimental groups did not show significant changes in motor function in the open field task. Our data indicate that optogenetic stimulation of PI(4,5)P 2 accumulation in brain is able to rescue behavioral AD associated behavioral deficits. Using sophisticated and specific optogenetic manipulation we have demonstrated that stimulation of PI(4,5)P 2 synthesis rescued behavioral deficits in a mouse model supporting the critical role of PI(4,5)P 2 levels in AD.

Apolipoprotein E ε4 ( APOE4 ) is the primary genetic risk factor for the late-onset form of Alzheimer’s disease (AD). Although the reason for this association is not completely understood, researchers have uncovered numerous effects of APOE4 expression on AD-relevant brain processes, including amyloid beta (Aβ) accumulation, lipid metabolism, endosomal-lysosomal trafficking, and bioenergetics. In this study, we aimed to determine the effect of APOE4 allelic dosage on regional brain lipid composition in aged mice, as well as in cultured neurons. We performed a targeted lipidomic analysis on an AD-vulnerable brain region (entorhinal cortex; EC) and an AD-resistant brain region (primary visual cortex; PVC) from 14–15 month-old APOE3/3 , APOE3/4 , and APOE4/4 targeted replacement mice, as well as on neurons cultured with conditioned media from APOE3/3 or APOE4/4 astrocytes. Our results reveal that the EC possesses increased susceptibility to APOE4 -associated lipid alterations compared to the PVC. In the EC, APOE4 expression showed a dominant effect in decreasing diacylglycerol (DAG) levels, and a semi-dominant, additive effect in the upregulation of multiple ceramide, glycosylated sphingolipid, and bis(monoacylglycerol)phosphate (BMP) species, lipids known to accumulate as a result of endosomal-lysosomal dysfunction. Neurons treated with conditioned media from APOE4/4 vs. APOE3/3 astrocytes showed similar alterations of DAG and BMP species to those observed in the mouse EC. Our results suggest that APOE4 expression differentially modulates regional neuronal lipid signatures, which may underlie the increased susceptibility of EC-localized neurons to AD pathology.