Spatial Dissection of the Distinct Cellular Responses to Normal Aging and Alzheimer's Disease in Human Prefrontal Cortex at Single-Nucleus Resolution.

Aging significantly elevates the risk for Alzheimer's disease (AD), contributing to the accumulation of AD pathologies, such as amyloid-ß (Aß), inflammation, and oxidative stress. The human prefrontal cortex (PFC) is highly vulnerable to the impacts of both aging and AD. Unveiling and understanding the molecular alterations in PFC associated with normal aging (NA) and AD is essential for elucidating the mechanisms of AD progression and developing novel therapeutics for this devastating disease. In this study, for the first time, we employed a cutting-edge spatial transcriptome platform, STOmics® SpaTial Enhanced Resolution Omics-sequencing (Stereo-seq), to generate the first comprehensive, subcellular resolution spatial transcriptome atlas of the human PFC from six AD cases at various neuropathological stages and six age, sex, and ethnicity matched controls. Our analyses revealed distinct transcriptional alterations across six neocortex layers, highlighted the AD-associated disruptions in laminar architecture, and identified changes in layer-to-layer interactions as AD progresses. Further, throughout the progression from NA to various stages of AD, we discovered specific genes that were significantly upregulated in neurons experiencing high stress and in nearby non-neuronal cells, compared to cells distant from the source of stress. Notably, the cell-cell interactions between the neurons under the high stress and adjacent glial cells that promote Aß clearance and neuroprotection were diminished in AD in response to stressors compared to NA. Through cell-type specific gene co-expression analysis, we identified three modules in excitatory and inhibitory neurons associated with neuronal protection, protein dephosphorylation, and negative regulation of Aß plaque formation. These modules negatively correlated with AD progression, indicating a reduced capacity for toxic substance clearance in AD subject samples. Moreover, we have discovered a novel transcription factor, ZNF460, that regulates all three modules, establishing it as a potential new therapeutic target for AD. Overall, utilizing the latest spatial transcriptome platform, our study developed the first transcriptome-wide atlas with subcellular resolution for assessing the molecular alterations in the human PFC due to AD. This atlas sheds light on the potential mechanisms underlying the progression from NA to AD.

Loss of Adaptive DNA Breaks in Alzheimer's Disease Brains.

Background: DNA breaks accumulate in Alzheimer's disease (AD) brains. While their role as true genomic lesions is recognized, DNA breaks also support cognitive function by facilitating the expression of activity-dependent immediate early genes. This process involves TOP2B, a DNA topoisomerase that catalyzes the formation of DNA double-strand breaks. Objective: To characterize how AD impacts adaptive DNA breaks at nervous system genes. Methods: We leveraged the ability of DNA single- and double-strand breaks to activate poly(ADP-ribose) polymerases (PARPs) that conjugate poly(ADP-ribose) (PAR) to adjacent proteins. To characterize the genomic sites harboring DNA breaks in AD brains, nuclei extracted from 3 AD and 3 non-demented autopsy brains (frontal cortex, all male donors, age 78 to 91 years of age) were analyzed through CUT&RUN in which we targeted PAR with subsequent DNA sequencing. Results: Although the AD brains contained 19.9 times more PAR peaks than the non-demented brains, PAR peaks at nervous system genes were profoundly lost in AD brains, and the expression of these genes was downregulated. This result is consistent with our previous CUT&RUN targeting γH2AX, which marks DNA double-strand breaks. In addition, TOP2B expression was significantly decreased in the AD brains. Conclusions: Although AD brains contain a net increase in DNA breaks, adaptive DNA breaks at nervous system genes are lost in AD brains. This could potentially reflect diminished TOP2B expression and contribute to impaired neuron function and cognition in AD patients.

Extra-Axial Cavernous Angioma: A Case Report and Review of the Literature.

Cavernous angiomas (CAs) are benign vascular malformations predominantly seen in the brain parenchyma and therefore referred to as intra-axial. Extra-axial dural-based cavernous angiomas, on the other hand, are rare vascular lesions found outside of the brain parenchyma. They occur in the middle fossa and may be easily misdiagnosed as meningiomas due to their extra-axial location. In addition, CAs that are located outside the middle fossa, such as in the convexity, have a better prognosis since they are more surgically accessible. Surgical resection is the main treatment of choice in CAs. However, other options, such as embolization and radiotherapy, may also be considered therapeutic choices or additive treatment options. The pathogenesis of CA and the involvement of other factors (genetics or environmental factors) are still unknown and require further investigation. We are presenting a young man who presented for evaluation of seizure-like events without any family history of neurologic conditions. The physical examination was unremarkable except for a slightly antalgic gait. Imaging studies showed an extra-axial left tentorial mass suggestive of a meningioma, hemangiopericytoma, or other extra-axial lesions. The lesion was resected where its vascular nature was mentioned initially, and the histology proved the diagnosis of cavernous angioma. Here we give an overview of the known pathogenesis, causes, clinical features, and diagnostic and therapeutic options in CA. Better knowledge about CA, its causes, clinical features, and treatment options would help clinicians in early diagnosis and patient management.

Enhancing mitosis quantification and detection in meningiomas with computational digital pathology.

Mitosis is a critical criterion for meningioma grading. However, pathologists' assessment of mitoses is subject to significant inter-observer variation due to challenges in locating mitosis hotspots and accurately detecting mitotic figures. To address this issue, we leverage digital pathology and propose a computational strategy to enhance pathologists' mitosis assessment. The strategy has two components: (1) A depth-first search algorithm that quantifies the mathematically maximum mitotic count in 10 consecutive high-power fields, which can enhance the preciseness, especially in cases with borderline mitotic count. (2) Implementing a collaborative sphere to group a set of pathologists to detect mitoses under each high-power field, which can mitigate subjective random errors in mitosis detection originating from individual detection errors. By depth-first search algorithm (1) , we analyzed 19 meningioma slides and discovered that the proposed algorithm upgraded two borderline cases verified at consensus conferences. This improvement is attributed to the algorithm's ability to quantify the mitotic count more comprehensively compared to other conventional methods of counting mitoses. In implementing a collaborative sphere (2) , we evaluated the correctness of mitosis detection from grouped pathologists and/or pathology residents, where each member of the group annotated a set of 48 high-power field images for mitotic figures independently. We report that groups with sizes of three can achieve an average precision of 0.897 and sensitivity of 0.699 in mitosis detection, which is higher than an average pathologist in this study (precision: 0.750, sensitivity: 0.667). The proposed computational strategy can be integrated with artificial intelligence workflow, which envisions the future of achieving a rapid and robust mitosis assessment by interactive assisting algorithms that can ultimately benefit patient management.

Diabetes and diabesity in the view of proteomics, drug, and plant-derived remedies.

Diabetes and obesity are highly prevalent in the world. Proteomics is a promising approach to better understanding enzymes, proteins, and signaling molecules involved in diabetes processes which help recognize the basis of the disease better and find suitable new treatments. This study aimed to summarize the molecular mechanisms from the beginning of insulin secretion in response to stimuli to the pathology of the insulin signaling pathway and, finally, the mechanisms of drugs/chemicals remedies that affect this process. The titles and subtitles of this process were determined, and then for each of them, the articles searched in PubMed and ScienceDirect were used. This review article starts the discussion with the molecular basis of insulin biosynthesis, secretion, insulin's mechanism of action, and molecular aspect of diabetes and diabesity (a new term showing the relation between diabetes and obesity) and ends with the drug and plant-derived intervention for hyperglycemia.

Cell type and sex specific mitochondrial phenotypes in iPSC derived models of Alzheimer's disease.

Introduction: Mitochondrial dysfunction is observed in Alzheimer's disease (AD). Altered mitochondrial respiration, cytochrome oxidase (COX) Vmax, and mitophagy are observed in human subjects and animal models of AD. Models derived from induced pluripotent stem cells (iPSCs) may not recapitulate these phenotypes after reprogramming from differentiated adult cells. Methods: We examined mitochondrial function across iPSC derived models including cerebral organoids, forebrain neurons, and astrocytes. iPSCs were reprogrammed from fibroblasts either from the University of Kansas Alzheimer's Disease Research Center (KU ADRC) cohort or purchased from WiCell. A total of four non-demented and four sporadic AD iPSC lines were examined. Models were subjected to mitochondrial respiration analysis using Seahorse XF technology, spectrophotometric cytochrome oxidase (COX) Vmax assays, fluorescent assays to determine mitochondrial mass, mitochondrial membrane potential, calcium, mitochondrial dynamics, and mitophagy levels. AD pathological hallmarks were also measured. Results: iPSC derived neurons and cerebral organoids showed reduced COX Vmax in AD subjects with more profound defects in the female cohort. These results were not observed in astrocytes. iPSC derived neurons and astrocytes from AD subjects had reduced mitochondrial respiration parameters with increased glycolytic flux. iPSC derived neurons and astrocytes from AD subjects showed sex dependent effects on mitochondrial membrane potential, mitochondrial superoxide production, and mitochondrial calcium. iPSC derived neurons from AD subjects had reduced mitochondrial localization in lysosomes with sex dependent effects on mitochondrial mass, while iPSC derived astrocytes from female AD subjects had increased mitochondrial localization to lysosomes. Both iPSC derived neurons and astrocytes from AD subjects showed altered mitochondrial dynamics. iPSC derived neurons had increased secreted Aß, and sex dependent effects on total APP protein expression. iPSC derived astrocytes showed sex dependent changes in GFAP expression in AD derived cells. Conclusion: Overall, iPSC derived models from AD subjects show mitochondrial phenotypes and AD pathological hallmarks in a cell type and sex dependent manner. These results highlight the importance of sex as a biological variable in cell culture studies.

Illustrated Neuropathologic Diagnosis of Alzheimer's Disease.

As of 2022, the prevalence of Alzheimer's disease (AD) among individuals aged 65 and older is estimated to be 6.2 million in the United States. This figure is predicted to grow to 13.8 million by 2060. An accurate assessment of neuropathologic changes represents a critical step in understanding the underlying mechanisms in AD. The current method for assessing postmortem Alzheimer's disease neuropathologic change follows version 11 of the National Alzheimer's Coordinating Center (NACC) coding guidebook. Ambiguity regarding steps in the ABC scoring method can lead to increased time or inaccuracy in staging AD. We present a concise overview of how this postmortem diagnosis is made and relate it to the evolving understanding of antemortem AD biomarkers.

Landscape of Double-Stranded DNA Breaks in Postmortem Brains from Alzheimer's Disease and Non-Demented Individuals.

BACKGROUND: Alzheimer's disease (AD) brains accumulate DNA double-strand breaks (DSBs), which could contribute to neurodegeneration and dysfunction. The genomic distribution of AD brain DSBs is unclear. OBJECTIVE: To map genome-wide DSB distributions in AD and age-matched control brains. METHODS: We obtained autopsy brain tissue from 3 AD and 3 age-matched control individuals. The donors were men between the ages of 78 to 91. Nuclei extracted from frontal cortex tissue were subjected to Cleavage Under Targets & Release Using Nuclease (CUT&RUN) assay with an antibody against γH2AX, a marker of DSB formation. γH2AX-enriched chromatins were purified and analyzed via high-throughput genomic sequencing. RESULTS: The AD brains contained 18 times more DSBs than the control brains and the pattern of AD DSBs differed from the control brain pattern. In conjunction with published genome, epigenome, and transcriptome analyses, our data revealed aberrant DSB formation correlates with AD-associated single-nucleotide polymorphisms, increased chromatin accessibility, and upregulated gene expression. CONCLUSION: Our data suggest in AD, an accumulation of DSBs at ectopic genomic loci could contribute to an aberrant upregulation of gene expression.

Lipid Keratopathy: Histopathology, Major Differential Diagnoses and The Importance of Clinical Correlation.

Lipid keratopathy (LK) is a rare ophthalmological condition characterized by a progressive reduction in visual acuity caused by corneal opacification due to central lipid accumulation. LK is characterized by lipid deposits, cholesterol clefts, and neovascularization (NV) leading to disruption in corneal optical quality. LK classification includes a primary and secondary form which depend on pre-existing corneal or systemic disorders and the evidence of NV. Secondary LK is typically associated with a prior occurrence of herpetic infection, such as herpes zoster keratitis. Patients with LK usually present with progressive vision loss and dense cream-colored corneal opacification. Treatment modalities include conservative and surgical approaches focused on corneal NV elimination. When evaluating corneal lipidosis, it is crucial to consider a range of differential diagnoses, including corneal arcus, Schnyder corneal dystrophy, and other corneal deposit conditions. We report a case of a 62-year-old male with herpes zoster keratitis complicated with LK. He presented with painless progressive vision loss and corneal scarring, which raised suspicion about LK diagnosis. This paper emphasizes the importance of correlating clinical and histological findings for accurate LK diagnosis.

Hyaline protoplasmic astrocytopathy in epilepsy.

Hyaline protoplasmic astrocytopathy (HPA) describes a rare histologic finding of eosinophilic, hyaline cytoplasmic inclusions in astrocytes, predominantly in the cerebral cortex. It has mainly been observed in children and adults with a history of developmental delay and epilepsy, frequently with focal cortical dysplasia (FCD), but the nature and significance of these inclusions are unclear. In this study, we review the clinical and pathologic features of HPA and characterize the inclusions and brain tissue in which they are seen in surgical resection specimens from five patients with intractable epilepsy and HPA compared to five patients with intractable epilepsy without HPA using immunohistochemistry for filamin A, previously shown to label these inclusions, and a variety of astrocytic markers including aldehyde dehydrogenase 1 family member L1 (ALDH1L1), SRY-Box Transcription Factor 9 (SOX9), and glutamate transporter 1/excitatory amino acid transporter 2 (GLT-1/EAAT2) proteins. The inclusions were positive for ALDH1L1 with increased ALDH1L1 expression in areas of gliosis. SOX9 was also positive in the inclusions, although to a lesser intensity than the astrocyte nuclei. Filamin A labeled the inclusions but also labeled reactive astrocytes in a subset of patients. The immunoreactivity of the inclusions for various astrocytic markers and filamin A as well as the positivity of filamin A in reactive astrocytes raise the possibility that these astrocytic inclusions may be the result of an uncommon reactive or degenerative phenomenon.

Implementation of a method for a clinical biochemistry lesson plan based on the flowchart.

Biochemistry is believed to be a difficult subject to understand for most life science and medical students. This article explains an experience with a flowchart-based teaching approach that is applicable to different kinds of biochemistry courses (basic, medical, and clinical) for undergraduate and postgraduate students. After preparing the flowcharts, they were given to the students at the beginning of the semester, and the flowchart-based teaching was performed for a whole semester. At the end of the semester, they were asked about the effectiveness and facilitation of learning using flowchart-based teaching. This survey was performed for several semesters. Approximately, 95% stated that it facilitates learning and understanding.

Loss of Adaptive DNA Breaks in Alzheimer's Disease Brains.

Background: DNA breaks accumulate in Alzheimer's disease (AD) brains. While their role as true genomic lesions is recognized, DNA breaks also support cognitive function by facilitating the expression of activity-dependent immediate early genes (IEGs). This process involves TOP2B, a DNA topoisomerase that catalyzes the formation of DNA double-strand breaks (DSBs). Objective: To characterize how AD impacts adaptive DNA breaks at nervous system genes. Methods: We leveraged the ability of DNA single- and double-strand breaks to activate poly(ADP-ribose) polymerases (PARPs) that conjugate poly(ADP-ribose) (PAR) to adjacent proteins. To characterize the genomic sites harboring DNA breaks in AD brains, nuclei extracted from 3 AD and 3 non-demented (ND) autopsy brains (frontal cortex, all male donors, age 78 to 91 years of age) were analyzed through CUT&RUN in which we targeted PAR with subsequent DNA sequencing. Results: Although the AD brains contained 19.9 times more PAR peaks than the ND brains, PAR peaks at nervous system genes were profoundly lost in AD brains, and the expression of these genes was downregulated. This result is consistent with our previous CUT&RUN targeting γH2AX, which marks DNA double-strand breaks (DSBs). In addition, TOP2B expression was significantly decreased in the AD brains. Conclusion: Although AD brains contain a net increase in DNA breaks, adaptive DNA breaks at nervous system genes are lost in AD brains. This could potentially reflect diminished TOP2B expression and contribute to impaired neuron function and cognition in AD patients.

Antibacterial Effect of Some Eukaryotic Sterol Biosynthesis Inhibitors.

Background: Isoprenoids and their derivatives are building blocks for the synthesis of biomolecules with important biological functions such as cholesterol in eukaryotes and lipid carrier undecaprenol, which is involved in cell wall biosynthesis in bacteria. With the global threat of multidrug-resistant bacteria, there is a need for finding new metabolic targets for killing bacteria. In the present study, we examined the impact of eukaryotic sterol biosynthesis inhibitors on the growth of four pathogenic bacteria. Materials and Methods: Antibacterial effect of HMG CoA reductase inhibitor (simvastatin), farnesyl pyrophosphate synthase inhibitor (alendronate), squalene epoxidase inhibitor (terbinafine), and lanosterol demethylase inhibitor (ketoconazole) were studied against four pathogenic bacteria: two gram-positive bacteria, Staphylococcus aureus and Enterococcus faecalis and two gram-negative bacteria, Escherichia coli and Pseudomonas aeruginosa. Broth microdilution method was used for assessing the antibacterial susceptibility of the components using 96 well plats. MIC and MBC were determined visibly. Results: MIC of Ketoconazole for Staphylococcus aureus and Enterococcus faecalis were 0.166 and 1 mg/mL, respectively. Terbinafine had a weak inhibitory effect on Staphylococcus aureus (MIC: 8 mg/mL). Ketoconazole and terbinafine had no inhibitory effect on gram-negative bacteria. MBC of Simvastatin for both Staphylococcus aureus and Enterococcus faecalis was 0.5 mg/mL and of Alendronate for Pseudomonas aeruginosa was 6.6 mg/mL. Conclusion: Our results show that farnesyl pyrophosphate synthase and class II HMG-CoA reductases inhibitors (ketoconazole and simvastatin) have reasonable antibacterial activity against gram-positive bacteria. These two enzymes provide suitable targets for designing new antibiotics based on modifying the chemical structure of currently used drugs to obtain maximum activity.

The Effect of Long-Term Iron Chelator Therapy on Serum Levels of Hepcidin and Ferritin in Patients with Thalassemia Major and Intermediate.

Serum hepcidin is a good predictor of iron overload compared with serum ferritin. However, serum hepcidin levels may change under different conditions. The current study aims to determine the role of long-term iron chelator therapy on serum levels of hepcidin and ferritin in patients with thalassemia major (TM) and intermediate (TI). In this cross-sectional study 91 patients with thalassemia TM and TI, who referred to the thalassemia center were chosen. The serum levels of hepcidin and ferritin were measured after two years of iron chelator therapy by ELISA and ECL methods, respectively. The patients' demographic information was extracted from their records. After treatment with iron chelator, ferritin levels decreased in 44 patients (48.4%), and increased in 47 patients (%51.6). Median serum levels of hepcidin decreased in all patients (%100). Also, there was a significant association between serum levels of hepcidin and ferritin (p value = 0.034). Furthermore, while a significant difference was observed between ferritin changes (p = 0.01), no difference was found between changes in hepcidin based on the type of iron chelator (p value = 0.94). Increased levels of hepcidin and ferritin in ß-thalassemia patients are significantly ameliorated by iron chelator.

Magnesium supplementation and insulin resistance in patients with rheumatoid arthritis.

Rheumatoid arthritis (RA) is a multifactorial disease affecting the immune system and many tissues in the body. This study aimed to evaluate the effect of magnesium supplementation on insulin resistance and fasting blood sugar (FBS) of patients with RA. In this prospective uncontrolled before-after study, RA patients referring to Rheumatology clinics of Qom City from January 2020 to January 2021 were evaluated. First, the patients received the routine rheumatoid arthritis treatment including 5 mg Prednisolone and 200mg Hydroxychloroquine daily for 6 months and FBS and insulin levels were measured after. Then, they received the routine arthritis rheumatoid treatment in addition to 300 mg/day oral Magnesium sulfate for 6 months and then, FBS and insulin levels were measured. The Homeostasis Model Assessment of insulin resistance (HOMA-IR) was used for determining insulin resistance. Thirty five patients with RA and the mean age of 49.83±2.58 years were enrolled. Twenty eight cases (80%) were female and 7 cases (20%) were male. The mean HOMA-IR before and after consumption of oral magnesium were 3.04±0.29 and 2.43±0.19, respectively. Statistically significant differences were found between FBS, insulin and HOMA-IR before and after consumption of oral magnesium (p<0.05). Our data suggested that magnesium supplementation reduces FBS, insulin and HOMA-IR in patients with rheumatoid arthritis. Thus, magnesium supplements may be an alternative method for prevention of type 2 diabetes in RA patients.

Mitochondrial function and Aß in Alzheimer's disease postmortem brain.

INTRODUCTION: Mitochondrial dysfunction is observed in Alzheimer's disease (AD). However, the relationship between functional mitochondrial deficits and AD pathologies is not well established in human subjects. METHODS: Post-mortem human brain tissue from 11 non-demented (ND) and 12 AD subjects was used to examine mitochondrial electron transport chain (ETC) function. Data were analyzed by neuropathology diagnosis and Apolipoprotein E (APOE) genotype. Relationships between AD pathology and mitochondrial function were determined. RESULTS: AD subjects had reductions in brain cytochrome oxidase (COX) function and complex II Vmax. APOE ε4 carriers had COX, complex II and III deficits. AD subjects had reduced expression of Complex I-III ETC proteins, no changes were observed in APOE ε4 carriers. No correlation between p-Tau Thr 181 and mitochondrial outcomes was observed, although brains from non-demented subjects demonstrated positive correlations between Aß concentration and COX Vmax. DISCUSSION: These data support a dysregulated relationship between brain mitochondrial function and Aß pathology in AD.

The key to an effective AI-powered digital pathology: Establishing a symbiotic workflow between pathologists and machine.

Pathology is a fundamental element of modern medicine that determines the final diagnosis of medical conditions, leads medical decisions, and portrays the prognosis. Due to continuous improvements in AI capabilities (e.g., object recognition and image processing), intelligent systems are bound to play a key role in augmenting pathology research and clinical practices. Despite the pervasive deployment of computational approaches in similar fields such as radiology, there has been less success in integrating AI in clinical practices and histopathological diagnosis. This is partly due to the opacity of end-to-end AI systems, which raises issues of interoperability and accountability of medical practices. In this article, we draw on interactive machine learning to take advantage of AI in digital pathology to open the black box of AI and generate a more effective partnership between pathologists and AI systems based on the metaphors of parameterization and implicitization.

Charcot-Bouchard aneurysms revisited: clinicopathologic correlations.

Intracerebral hemorrhage (ICH) is a significant cause of morbidity and mortality worldwide. Hypertension and cerebral amyloid angiopathy (CAA) are the most common causes of primary ICH, but the mechanism of hemorrhage in both conditions is unclear. Although fibrinoid necrosis and Charcot-Bouchard aneurysms (CBAs) have been postulated to underlie vessel rupture in ICH, the role and significance of CBAs in ICH has been controversial. First described as the source of bleeding in hypertensive hemorrhage, they are also one of the CAA-associated microangiopathies along with fibrinoid necrosis, fibrosis and "lumen within a lumen appearance." We describe clinicopathologic findings of CBAs found in 12 patients out of over 2700 routine autopsies at a tertiary academic medical center. CBAs were rare and predominantly seen in elderly individuals, many of whom had multiple systemic and cerebrovascular comorbidities including hypertension, myocardial and cerebral infarcts, and CAA. Only one of the 12 subjects with CBAs had a large ICH, and the etiology underlying the hemorrhage was likely multifactorial. Two CBAs in the basal ganglia demonstrated associated microhemorrhages, while three demonstrated infarcts in the vicinity. CBAs may not be a significant cause of ICH but are a manifestation of severe cerebral small vessel disease including both hypertensive arteriopathy and CAA.

Bioenergetic and inflammatory systemic phenotypes in Alzheimer's disease APOE ε4-carriers.

We examined the impact of an APOE ε4 genotype on Alzheimer's disease (AD) subject platelet and lymphocyte metabolism. Mean platelet mitochondrial cytochrome oxidase Vmax activity was lower in APOE ε4 carriers and lymphocyte Annexin V, a marker of apoptosis, was significantly higher. Proteins that mediate mitophagy and energy sensing were higher in APOE ε4 lymphocytes which could represent compensatory changes and recapitulate phenomena observed in post-mortem AD brains. Analysis of the lipid synthesis pathway found higher AceCSI, ATP CL, and phosphorylated ACC levels in APOE ε4 lymphocytes. Lymphocyte ACC changes were also observed in post-mortem brain tissue. Lymphocyte RNAseq showed lower APOE ε4 carrier sphingolipid Transporter 3 (SPNS3) and integrin Subunit Alpha 1 (ITGA1) expression. RNAseq pathway analysis revealed APOE ε4 alleles activated inflammatory pathways and modulated bioenergetic signaling. These findings support a relationship between APOE genotype and bioenergetic pathways and indicate platelets and lymphocytes from APOE ε4 carriers exist in a state of bioenergetic stress. Neither medication use nor brain-localized AD histopathology can account for these findings, which define an APOE ε4-determined molecular and systemic phenotype that informs AD etiology.