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Background: The greatest risk factors for Alzheimer's disease (AD) are age, APOɛ4 allele and female sex. The estimated lifetime risk for AD is 19.5% for women compared to 10.3% in men. Accumulating evidence points to life‐time estrogen exposure as a protective factor against cognitive decline and AD in women, and to the menopause transition as a trigger for an existing AD predisposition. Estrogen replacement therapy (ERT) is effective for sustaining neurological health, but fear of breast cancer is the principal reason menopausal women reject it. Instead, women utilize over the counter products labeled as natural and considered to be safer. Thus, to attain brain protection and address breast protection we developed a rationally designed combination of select ERβ‐selective phytoestrogens that promote brain health to reduce AD risk without increasing breast cell proliferation. Method: A total of 100 participants, 50 per treatment arm, will be enrolled. Eligible participants are woman, 45‐60 years, peri or post‐menopausal (last menstrual period completed ≥ 60 days and ≤ 4 years), MoCA≥22, and experiencing ≥7 hot flashes per day. Participants will be randomized to 50 mg of PhytoSERM or placebo (orally, once‐per‐day) for a 24‐week period. FDG‐PET scans will be conducted at baseline and 24 weeks. Cognitive measures and clinical ratings will be assessed. Hot flashes will be measured both subjectively with a diary and objectively with a digital wristband measuring electrodermal activity. Result: Primary endpoint is change from baseline to 24 weeks in regional brain glucose metabolism standardized uptake value ratio (SUVR). Secondary outcome measures include cognitive test battery scores, hot flash score and clinical ratings scores. Exploratory measures will include MRI brain volumes, fractional anisotropy, quantitative anisotropy, functional connectivity, and cerebral blood perfusion. Conclusion: Herein we present a phase 2 proof‐of‐concept framework to assess the efficacy of PhytoSERM as a potential non‐pharmacologic therapeutic to improve cognitive health and reduce menopausal symptoms. Results from this study will validate previous findings that indicate that PhytoSERM is a safe alternative to hormone therapy and has the potential to sustain neurological health during the menopausal transition. [ABSTRACT FROM AUTHOR]

Background: Women develop Alzheimer's disease (AD) at a 2:1 rate compared to men. Changes associated with menopause exacerbate a midlife bioenergetic crisis that, when unsuccessfully resolved, leads to white matter degradation and ultimately brain atrophy. Understanding how white matter structural properties differ between sexes and evolve over midlife transitions may provide insight into the exacerbated AD risk for women. Here, we report differences in white matter bundle properties comparing pre‐ (n = 40, 44.1±3.34y), peri‐ (n = 60, 49.6±3.90y), and post‐menopausal women (n = 70, 56.0±4.12y) to age‐matched males. Method: Diffusion weighted MRI was acquired for each participant. Data were preprocessed with QSIPrep and analyzed using a fixel‐based approach implemented in MRtrix (v. 3.0.3). Fiber density (FD), cross‐section (FC), and a combined density/cross‐section metric (FDC) were compared between sexes after controlling for age, education, APOE ε4 carrier status, and total brain volume (FC and FDC only). Continuous covariates were standardized to 2 standard deviations. Analyses were conducted using connectivity‐enhanced fixel‐based permutation analyses and thresholded at family‐wise error corrected p<0.05. Result: Pre‐, peri‐, and post‐ menopausal women exhibited greater FD and FDC in the corpus callosum, inferior occipto‐frontal fasciculus, cortico‐spinal, and cingulum bundles. By contrast, males had greater fiber cross section in the splenium of the corpus callosum (compared to pre‐), (compared to peri‐), and in fibers near the left uncinate fasciculus and inferior longitudinal fasciculus (compared to both peri‐ and post‐menopausal women). After controlling for age, education, total brain volume, and APOE ε4 carrier status, a smaller cluster of fibers in the left splenium survived multiple comparisons correction demonstrating greater fiber cross‐section in post‐menopausal women compared to peri‐menopausal women. Conclusion: Women across menopausal transition states exhibited greater fiber density than their age‐matched male counterparts in commissural and association tracts, which agrees with previous work demonstrating stronger inter‐hemispheric connections in women. However, peri‐ and post‐menopausal females exhibited 4‐8% decrease in fiber cross section in uncinate fasciculus fibers, which have been implicated in Alzheimer's related cognitive decline. These findings suggest that reductions in white matter cross‐section, particularly in regions associated with Alzheimer's disease, may begin for women in menopause and be an early indicator of neurodegenerative risk. [ABSTRACT FROM AUTHOR]

Background: Age, female sex and APOEε4 allele are among the top risk factors for developing late‐onset Alzheimer's disease (LOAD). To enable Precision medicine for AD drug development, it is crucial targeting specific biological pathways driving AD pathology. While individual effects of sex or APOE have been studied, genes and biological pathways commonly or uniquely altered by these two factors are less understood. Method: ROSMAP RNA‐Seq data were obtained from AMP‐AD including 369 frontal cortex samples from APOEε3/ε3 and APOEε3/ε4 individuals. Of these, 209 had an AD diagnosis and 160 were controls. Differentially expressed genes (DEGs, pvalue<.05) between LOAD and cognitively normal individuals were identified using a generalized linear regression model. Gene Set Enrichment Analysis (GSEA) was performed using Gene Ontology Biological Processes (GOBP). Redundant GOBP enriched terms were removed computing semantic similarity measures (adjusted pvalue<.05). Comparison analyses were conducted to identify common and unique DEGs and enriched GOBPs across sex‐genotype conditions. Result: APOEε3/ε3 female brains exhibited the greatest DEG number (n = 11,851) while APOEε3/ε3 males exhibited the least (n = 714). Nine DEGs were shared across all comparisons, which were involved in metabolic processes, synaptic function, myelination, and GPCR signaling. GSEA revealed comparable numbers of LOAD‐enriched pathways in all female groups and male APOEε3/ε4s (n = 144‐155 GOBP terms), whereas APOEε3/ε3 males exhibited the fewest enriched terms (n = 13). Identified GOBP terms included pathways related to metabolism, cellular responses and regulation, and immune response regulation. However, there were no common GOBP terms across all sex‐genotype conditions. Conclusion: Our analyses provide evidence of sex‐ and APOE‐ specific transcriptomic signatures and biological processes altered in LOAD brains. The findings suggest significantly greater transcriptomic dysregulation in female APOEε3/ε3 brains despite the similar extent of affected biological pathways as other sex‐APOE conditions. In contrast, a significantly smaller number of affected biological processes were identified in male APOEε3/ε3s despite having comparable transcriptomic dysregulation as the male APOε4 carriers but less than the female groups. These analyses provide rationale to develop risk factor‐specific therapeutics for the prevention and treatment of LOAD by considering the interaction between biological sex and APOE genotype. [ABSTRACT FROM AUTHOR]

Background: Apolipoprotein E (APOE) ε4 is the strongest genetic risk factor for the development of late‐onset Alzheimer's disease (LOAD). Additionally, females have a 2x greater risk of developing LOAD than males. LOAD patients show brain glucose hypometabolism and severe reduction in hippocampal volume. Hippocampal atrophy has also been linked with plasma ceramide and phosphotidylcholine (PC) levels in these patients. This study explores the effects of sex and genotype on the plasma metabolome and potential correlations to brain imaging metrics in an aged humanized APOE (hAPOE) mouse model. Method: Plasma samples from 23–25‐month‐old hAPOE mice (37M/32F) expressing ε3/3, ε3/4 or ε4/4 genotypes were analyzed via mass spectrometry using the Biocrates MxP® Quant 500 platform. In a subset of these animals (24M/20F), in‐vivo FDG‐PET and high‐resolution ex‐vivo MRI were obtained. Cerebral FDG‐PET standardized uptake values were normalized to cerebellum (SUVr). Cerebral SUVr and regional volumes were correlated with detected metabolites and metabolic indicators using Pearson correlations. Two‐way ANOVAs were used to identify sex and genotype effects with post‐hoc t‐tests to determine statistical significance. Result: hAPOE ε3/3 mice had significantly greater cholesteryl ester (54%; p < 0.026) and lysophosphotidylcholine (lysoPC; 27%; p < 0.031) levels compared to ε4/4 mice. Females had lower levels of PCs (93%; p < 0.007), lysoPCs (82%; p < 0.018), triglycerides (62%; p < 0.045), and 1‐Met‐His (p = 5.84E‐25) than males. Significant positive correlations were observed between cerebral SUVr and PCs (45%; p < 0.049) as well as lysoPCs (82%; p <0.017). Total brain volume was negatively correlated with plasma 3‐Met‐His:creatinine ratio, indicative of muscle protein degradation (r = ‐0.44; p = 0.003) and positively correlated with (LysoPC+ arachidonic acid): PC ratio, indicative of phospholipase A2 activity (r = 0.42; p = 0.004). Right hippocampal volume percentage was significantly positively correlated with PCs (64%; p < 0.045) and 1‐Met‐His (p = 0.00067). Conclusion: At a comparable human age of ∼ 70 years, within the humanized APOE mouse, sex was the major contributing factor to metabolic differences in peripheral blood plasma. Levels of peripheral metabolites correlated with brain volumetrics and glucose metabolism, highlighting potential therapeutic targets for interventions designed to preserve neuronal health in AD. [ABSTRACT FROM AUTHOR]

Background: Apolipoprotein E (APOE) plays a critical metabolic role by facilitating the binding of lipid complexes to cell surface receptors, providing tissues with energy substrates. The APOE‐ε4 (APOE4) polymorphism is the predominant genetic risk factor for late‐onset Alzheimer's Disease (LOAD), while APOE3 is considered risk‐neutral. Female biological sex also nearly doubles LOAD risk. This study utilizes the JAX humanized APOE knock‐in mouse model to investigate the contributions of chromosomal sex and APOE genotype to plasma metabolic profiles, along with potential correlates to cognitive performance in a novel objection recognition (NOR) task. Method: Male and female mice aged 23‐25 months old (37M/32F) with humanized APOE3/3, APOE3/4, and APOE4/4 genotypes underwent blood plasma extraction and subsequent metabolic profiling via mass spectrometry using the Biocrates MxP® Quant 500 platform. A subset of animals (34M/28F) additionally performed an NOR paradigm prior to metabolic profiling. Two‐way ANOVA and post‐hoc t‐tests were utilized to determine data significance. Result: Metabolomic analyses indicated that male mice exhibited relatively higher levels of glucogenic amino acids, including glycine, asparagine, and histidine. In contrast, female mice had higher levels of TMAO and ADMA along with lower levels of phosphatidylcholines, cholesteryl esters (CE), and triglycerides. In males, APOE3/4 and APOE4/4 genotypes were associated with lowered CE levels. APOE3/4 female mice had the lowest CE plasma concentrations. Female APOE4/4 mice had increased concentrations of several diglyceride and triglyceride species, relative to APOE3/3 and APOE3/4 female mice. Behavioral correlates indicated that triglyceride levels negatively correlated with locomotion throughout the NOR paradigm. Memory performance, as determined by the discrimination index, positively correlated with plasma concentrations of glycine and negatively correlated with hydroxy acylcarnitine levels. Conclusion: In mice aged to resemble a ∼70‐year‐old human population, these results suggest that biological sex affects peripheral metabolic profiles greater than APOE genotype. Male metabolism was characterized by elevated glucogenic amino acid levels; female metabolic profiles demonstrated increased TMAO and lower phosphatidylcholines and triglycerides, suggesting differences in lipid metabolism. APOE3/4 genotype was associated with lowered CE in both sexes while APOE4/4 females had higher triglycerides, indicating potential sex‐genotype interactions upon metabolism that may confer elevated LOAD risk and influence behavior. [ABSTRACT FROM AUTHOR]

Background: Astrocytes provide key neuronal support, and their phenotypic transformation is strongly implicated in neurodegenerative disorders including Alzheimer's disease (AD). Metabolically, astrocytes possess modest mitochondrial oxidative phosphorylation (OxPhos) activity, yet the pathological role of astrocytic OxPhos in neurodegeneration remains to be defined. Method: We generated the TfamAKO mice, in which the transcription factor A mitochondrial (Tfam) is deleted selectively in astrocytes. Behavioral, electrophysiological, immunostaining, transcriptomics, metabolomics, and magnetic resonance imaging analyses were employed to characterize AD‐relevant phenotypes of TfamAKO mice, which were further compared to an AD mouse model (5xFAD). Primary cell cultures and co‐cultures were used to determine the cell autonomous and non‐autonomous mechanisms by which disrupted astrocytic OxPhos induces astrocyte reactivity, neuroinflammation and neurodegeneration. Result: Here we show that the brain critically depends on astrocytic OxPhos to degrade fatty acids (FAs) and maintain lipid homeostasis. Aberrant astrocytic OxPhos induces lipid droplet (LD) accumulation followed by neurodegeneration that recapitulates key features of AD including reactive astrogliosis, synaptic loss, microgliosis, demyelination, and cognitive impairment. Mechanistically, when FA load overwhelms astrocytic OxPhos capacity, elevated acetyl‐CoA levels induce astrocyte reactivity by enhancing STAT3 acetylation and activation. Intercellularly, lipid‐laden reactive astrocytes stimulate neuronal FA oxidation and oxidative stress, activate microglia via IL‐3 signaling, and inhibit the biosynthesis of FAs and phospholipids required for myelin replenishment. Moreover, the metabolic and transcriptional signatures of the hippocampus of TfamAKO mice highly overlap with that of 5xFAD mice. Conclusion: We reveal a lipid‐centric, AD‐resembling mechanism by which astrocytic mitochondrial dysfunction progressively induces neuroinflammation and neurodegeneration. [ABSTRACT FROM AUTHOR]

Background and Purpose: Previous research has reported that younger adults make fewer cognitive errors on an auditory vigilance task while in chest-deep water compared with on land. The purpose of this study was to extend this previous work to include older adults and to examine the effect of environment (water vs land) on linear and nonlinear measures of postural control under single- and dual-task conditions. Methods: Twenty-one older adult participants (age = 71.6 ± 8.34 years) performed a cognitive (auditory vigilance) and motor (standing balance) task separately and simultaneously on land and in chest-deep water. Listening errors (n = count) from the auditory vigilance test and sample entropy (SampEn), center of pressure area, and velocity for the balance test served as dependent measures. Environment (land vs water) and task (single vs dual) comparisons were made with a Wilcoxon matched-pair test. Results: Listening errors were 111% greater during land than during water environments (single-task = 4.0 ± 3.5 vs 1.9 ± 1.7; P = .03). Conversely, SampEn values were 100% greater during water than during land environments (single-task = 0.04 ± 0.01 vs 0.02 ± 0.01; P < .001). Center of pressure area and velocity followed a similar trend to SampEn with respect to environment differences, and none of the measures were different between single- and dual-task conditions (P > .05). Conclusions: The findings of this study expand current support for the potential use of partial aquatic immersion as a viable method for challenging both cognitive and motor abilities in older adults. [ABSTRACT FROM AUTHOR]

Background: Repetitive sub‐concussive head impacts (RSHIs) are common in American football, result in changes to white matter microstructural integrity, and are suggested as a potential risk factor for neurodegenerative diseases, including Alzheimer's disease. RSHI‐induced white matter degradation may accelerate neurodegenerative processes, necessitating effective preventative and therapeutic approaches in this population. Prior studies indicate potential neuroprotective and remyelinating effects of docosahexaenoic acid (DHA). Here, we conducted a double‐blind, randomized, placebo‐controlled trial to assess the effects DHA supplementation during a National Collegiate Athletic Association football season on neuroimaging measures of white matter integrity. Method: Thirty‐eight participants were randomized to treatment (6g DHA/EPA) or placebo (6g oleic/linoleic acid) group for seven months of five‐times‐per‐week supplementation. 27 participants completed the trial and had complete neuroimaging datasets (n = 16 placebo; n = 11 treatment). White matter integrity changes from preseason to immediately post‐season were quantified using voxel‐wise fractional anisotropy and diffusivity (mean, axial, radial) as well as deterministic tractography using quantitative anisotropy (QA). Gray matter volume as well as intra‐regional, edge‐wise, and network level functional connectivity were obtained as secondary measures along with serum neurofilament light (NfL) as a peripheral biomarker of axonal damage. Result: There were no voxel‐wise, between‐group differences in voxel‐wise DTI analyses. Compared to placebo, the treatment group had increased QA in ascending corticostriatal fibers and decreased QA in long association and commissural fibers. Increased mean (ρ = 0.47), axial (ρ = 0.44), and radial (ρ = 0.51) diffusivity and decreased QA (ρ = ‐0.52) in the corpus callosum and bilateral corona radiata were correlated with increasing NfL levels during the season irrespective of treatment group. Default mode/frontoparietal network connectivity (g = 0.96, p = 0.024) was greater in the treatment group. Conclusion: In‐season DHA supplementation was insufficient to prevent or protect against axonal damage as it occurred during the season. However, there may be neuroprotective effects on functional connectivity despite structural damage. If RSHIs are a risk factor for future neurodegeneration, then alternative therapeutic merit further investigation. These present outcomes do not support the use of in‐season DHA supplementation as a preventive strategy to reduce brain injury resulting from collegiate football. Acknowledgement: Study funded by the Center for Innovation in Brain Science, University of Arizona. DHA provided by Pharmavite [ABSTRACT FROM AUTHOR]

Background: Inflammation is a well‐documented feature of Alzheimer's disease (AD) in human brain. Previous findings from our group demonstrated upregulated immune transcripts in the AD brain as well as sex differences in immune transcript levels during pre‐clinical midlife aging. Using our humanized APOE mouse model, we identified elevated immune transcripts in the female brain including interferon signaling genes, CD3, CD4, and MHCII. We hypothesized that activation via increased interferon gamma (IFN‐γ) during endocrine aging may disrupt the immune‐metabolic balance in the brain and therefore advance changes in grey and white matter. With this study, we test the hypothesis that increased levels of peripheral IFN‐γ induces genotype dependent immuno‐metabolic changes in the JAX humanized APOE (hAPOE) mouse model. Method: To determine the role of IFN‐γ in female midlife aging and AD risk, pre‐menopausal and peri‐menopausal hAPOE mice were intraperitoneally treated with recombinant IFN‐γ for 9 days. Immunophenotyping using multi‐color flow cytometry was conducted microglial reactivity, phagocytosis, neutral lipid content, oxidative stress, and the presence of lymphocytes were determined. Structural and diffusion weighted analysis using MRI was conducted to evaluate grey and white matter structural integrity in the brain. ELISA assays were conducted to assess the presence of beta amyloid 40 and 42 and levels of pro‐inflammatory cytokines. Result: IFN‐γ treated animals exhibited upregulation of markers that perpetuate neuroinflammation and white matter catabolism including MHCII, CD8, pHrodo, and BODIPY. Peripheral immune effects were genotype dependent while immune signaling in brain largely exhibited treatment‐dependent effects. Fasting blood glucose levels were significantly increased by IFN‐γ consistent with an accelerated aging profile. Diffusion metrics including mean and radial kurtosis in addition to mean, axial, and radial diffusivity were greater in IFN‐treated animals. Conclusion: Peripheral increase of interferon gamma signaling during female endocrine aging in hAPOE mice induced 1) dysfunction of metabolic systems and neuroinflammatory response and 2) decreases in white and grey matter microstructural integrity throughout the brain. These outcomes support the investigation of therapeutic strategies targeting interferon signaling pathways at the earliest stages of midlife aging to reduce risk of AD or delay AD onset. [ABSTRACT FROM AUTHOR]

Background: Given that hippocampal volume is a well‐established imaging biomarker predictive of cognitive decline although not itself a measure of cognition, we propose its use as a surrogate endpoint to test the efficacy of allopregnanolone as a regenerative therapeutic for mild AD. Method: Phase 2 multi‐center, double‐blind, parallel‐group, randomized‐controlled clinical trial. A total of 20 sites will recruit 200 participants with mild AD, 100 participants per treatment arm. Eligible participants are male or female, age 55 to 80 years old, diagnosed with probable AD, with a MMSE between 20‐26 and APOE ε4 genotype (3/4 and 4/4). Participants will be randomized to 4 mg Allo (administered intravenously over 30 minutes, once per week) or matching placebo, 1:1 allocation, for a 12‐month period. After 12 months, all participants in the placebo group will be crossed‐over to receive Allo for the remainder of the study (6 month open‐label phase). Brain imaging to evaluate the primary endpoint will be conducted at baseline, 6 and 12 months. A critical component of this trial is that all imaging sites participating in the trial are capable of performing both basic and advanced MRI sequences required in the protocol. Result: Primary Endpoint is Mean rate of change in hippocampal volume at 12 months. Secondary Endpoints include mean rate of change in cognitive outcomes (CANTAB‐PAL, ADAS‐Cog11), functional outcomes (ADCS‐iADL) and safety outcomes at 12 months. Exploratory endpoints include other imaging outcomes (regional brain volumes, white matter fiber tract diffusion measures as determined by DTI, average intrinsic connectivity as determined by resting state fMRI, and cerebral region cerebral blood flow); blood‐based biomarkers of target engagement; other cognitive and functional outcomes (CDR‐SB score, ADAS‐Cog14 score, MMSE score, NPI‐Q score, EuroQol 5‐Dimension / 5‐Level (EQ‐5D‐5L) health‐related quality of life scale scores, QoL‐AD score, Zarit Burden Interview Questionnaire score at 12 and 18 months. Additionally, change from baseline to 6, 12 and 18 months in open‐label treatment participants switching from placebo to Allo at 12 months in the above endpoints. Conclusion: Results from this study will validate previous findings indicating that allopregnanolone may exert both regenerative and neuroprotective effects on structure and connectivity in the Alzheimer's brain. [ABSTRACT FROM AUTHOR]

Background: Apolipoprotein (APOE) is the strongest genetic risk factor for the development of late‐onset Alzheimer's disease (LOAD). Clinically, LOAD exhibits strong sex effects with females being twice at the risk of developing AD than males. Models exhibiting strong AD etiology are used in preclinical settings, however lack of translatability necessitates model development with a reverse translational approach. This study explores metabolic hallmarks of LOAD assessing the clinical translatability of the JAX humanized APOE (hAPOE) mouse model. Method: hAPOE mice (M/F, n = 65, mean age = 23.35 +/‐ 0.90 months) with e3/3, e3/4 or e4/4 genotype underwent a metabolic and body composition screening assay including fasting blood glucose (FBG) and ketone (FKB) measurement, EchoMRI, and 18F‐FDG‐PET brain imaging, prior to being sacrificed. Blood plasma was analyzed for triglyceride levels. Cerebral FDG‐PET standardized uptake values were normalized to cerebellum. All data were analyzed with genotype x sex analysis of variance. P ≤ 0.05 was considered statistically significant and post‐hoc pairwise analyses were conducted for interaction effects with p ≤ 0.1 (FKB, adipose index) for future study planning. Result: Females had significantly lower lean mass (p < 0.0001) and FBG (p=0.05), with a trend toward lower glucose uptake on FDG‐PET compared to males (p=0.072). Post‐hoc interaction analyses of FKB (interaction p=0.105) demonstrated lower ketone body levels in male e4/4s compared to female e4/4s (uncorrected p=0.0685) and male e3/4s (p=0.034). Post‐hoc interaction analyses of adipose index (interaction p=0.093) demonstrated greater adiposity in female e4/4s compared to male e4/4s (uncorrected p=0.005) and female e3/3s (uncorrected p=0.035). No effects of APOE genotype were observed. Conclusion: In a mouse cohort at a comparable human age of ∼ 70 years, lower lean mass, fasting blood glucose, and glucose uptake in the brain for female mice indicates ongoing bioenergetic deficits and is corroborated by observations within clinical populations. Greater adiposity in female e4/4s suggests that brain bioenergetic demand is not being met through fat reserves. However, the overall lack of genotypic effects suggests this bioenergetic crisis is not driven by hAPOE in this animal model, limiting clinical translatability. NIA R01AG057931; University of Arizona TBIR (NIH S10 OD025016). [ABSTRACT FROM AUTHOR]

Background: Whole brain and hippocampal atrophy are the most prominent structural features of late‐onset Alzheimer's disease (LOAD) and are accepted endpoints in many clinical trials. The APOE ε4 allele is the strongest genetic risk factor for LOAD, with the ε4/ε4 genotype associated with the greatest atrophy rates. To date, there is limited hippocampal volume reporting in preclinical APOE models. To assess the translational potential of a humanized APOE (hAPOE) mouse model, we report age, sex, and genotype effects on total brain and hippocampal volume. Method: High resolution ex‐vivo MRIs were obtained from two separate cohorts of male and female hAPOE mice (Cohort 1: n=53, 18.47±0.99 months; Cohort 2: n=33, 24.24±0.58 months). A validated mouse brain atlas was used for volumetric analysis. Cohorts were analyzed separately with genotype by sex analyses of variance for total brain volume (sum of all regions in atlas) as well as left and right hippocampal volume as percent of total brain volume. Result: In Cohort 1, hAPOEε4/ε4 mice had significantly larger brains than hAPOEε3/ε3s or hAPOEε3/ε4s, with female hAPOEε4/ε4s having the largest brains (p<0.001). Regardless of genotype, females had smaller left (p=0.006) and right (p<0.001) hippocampi relative to males. In Cohort 2, there were no genotype or sex differences in total brain volume. However, left (p=0.044) and right (p=0.034) hippocampal volumes were smaller for hAPOEε4/ε4 mice compared to hAPOEε3/ε4 mice without sex effects. Conclusion: Our findings capitalize on a large dataset (n=88) of high‐resolution MRIs. At 18‐20 months old (∼60 human years), hAPOEε4/ε4 mice had greater total brain volume than comparably aged hAPOEε3/ε3 or hAPOEε3/ε4 mice without hippocampal atrophy. However, hippocampal atrophy was evident when mice were aged to 24‐25 months (∼70 human years). These findings of larger brain volume and greater hippocampal atrophy in hAPOEε4/ε4 carriers are consistent with large‐scale AD imaging datasets. The timing of evident hippocampal atrophy in these mice also coincides with the global average age of clinical diagnosis. Based on these findings, the translational potential of this model requires utilizing very old mice, limiting the window for therapeutic testing. Acknowledgements: NIA R01AG057931, RF1AG059093; University of Arizona TBIR (NIH S10 OD025016) [ABSTRACT FROM AUTHOR]

Background: Alzheimer's Disease (AD) drives the global rising incidence of neurodegenerative dementia. Disease progression includes cerebral aggregation of amyloid‐beta plaques and immune activation. Many AD animal models carry mutations that cause an early onset of these phenotypes, but the mutations are rare in human populations; most cases are idiopathic and late‐onset AD (LOAD). Another approach utilizing a transgenic APOE animal model may better model clinical populations. APOE4 is the predominant genetic risk factor for LOAD and confers increasing risk for LOAD in allelic fashion, relative to normative APOE3. This study investigates the JAX humanized APOE knock‐in mouse model of LOAD's translational potential for peripheral biomarkers of pathology in aged, male and female mice. Method: Aged mice of both sexes (23‐25 months old; 39M/37F) with APOE3/3,APOE3/4, andAPOE4/4 genotypes underwent blood plasma amyloid‐beta (Aß) measurement. A subset of these animals (30M/28F) additionally received peripheral immunophenotyping of whole blood via flow cytometry. Two‐way ANOVA and post‐hoc t‐tests were conducted to determine data significance. Results: Female mice had lower Aß42 plasma levels as well as a decreased Aß42/40 ratio, suggesting higher levels of the aggregate‐prone Aß42 protein in the brain, but there were no observed APOE genotype effects. Blood plasma Aß40 levels did not differ by genotype or sex. Whole blood flow cytometry showed an elevation in CD8+ memory T cells in APOE4/4 mice relative to APOE3/3 andAPOE3/4 mice. Aged female mice had a peripheral immune cell profile consistent with a more reactive and dysfunctional immune system than genotype‐matched aged males: higher levels of CD11b+ B cells, CD4+ helper T cells, and CD8+ cytotoxic T cells along with a lower percentage of naïve CD4+ and CD8+ T cells. Conclusion: In mice aged to resemble a ∼70‐year‐old human population, these results suggest increased brain levels of the aggregate‐prone Aß42 isoform and a reactive peripheral immune system in female APOE mice. This sex difference is consistent with the increased prevalence of LOAD in women. However, the specificity of APOE4 genotype effects may define the translational potential of this humanized APOE mouse model of late‐onset Alzheimer's Disease. Research supported by T32AG061897, R01AG057931, and RF1AG059093 to RDB. [ABSTRACT FROM AUTHOR]

Background: Genome‐wide association studies have identified Apolipoprotein (APOE) as one of the strongest risk factors associated with Late‐Onset Alzheimer's disease (LOAD) with females exhibiting a two‐fold higher incidence as compared to males. MRI studies of patients with LOAD link APOE‐e4 gene load with increased hippocampal volume loss as well as reduction in white matter integrity (WMI) in the limbic and medial temporal regions (Bagepally, 2012). However, there are few translational LOAD mouse model studies utilizing imaging. We hypothesized that hippocampal volume and WMI would be reduced in females and APOE e4 carriers in our humanized APOE (hAPOE) LOAD mouse model. Method: Six cohorts of APOE e3 and e4 genotype (M/F; N=53; mean age = 17.95 month) skull‐extracted ex‐vivo mouse brains were imaged (7T Bruker Biospec MRI scanner). Imaging included structural and diffusion weighted imaging. Bilateral hippocampal volumes, as well as total brain volume (TBV), were extracted using a well‐validated mouse brain atlas (Dorr, 2008). Fractional anisotropy (FA) was used to quantify WMI and between‐group comparisons were made using a groupwise connectometry approach (Yeh, 2013; Yeh, 2016). Result: MRI image analysis indicated genotypic differences in white matter FA where APOE‐e4 carriers exhibited lower FA values (mean tractography FA = 0.263 ± 0.043) compared to APOE‐e3/3 (mean tractography FA = 0.311 ± 0.067) in a total of 10657 tracts (FDR corrected p < 0.003; Figure 1). No statistically significant differences were identified across genotypes for left or right hippocampal volumes. However, right hippocampal volume was significantly greater in males as compared to females (p = 0.007) whereas no effect was observed between sexes for left hippocampus. Conclusion: Outcomes of MRI analyses indicate a significant reduction in FA values and reduced white matter integrity across the brain in APOE e4 carriers, irrespective of sex. Contrary to human literature, no significant volumetric differences between genotypes were found in this mouse sample. Consistent with sex‐dependent literature, males exhibited greater total brain volume and additionally greater right hippocampal volume compared to females, irrespective of genotype. These findings may provide evidence of deficits in cholesterol or lipid transport manifest in decreased white matter integrity in this hAPOE mouse model. [ABSTRACT FROM AUTHOR]