Increased Risk Of AD Research Articles

Alzheimer's disease risk associated with changes in Epstein-Barr virus nuclear antigen 1-specific epitope targeting antibody levels

BackgroundAlzheimer's disease (AD) is a neurodegenerative disorder influenced by age, sex, genetic factors, immune alterations, and infections. Multiple lines of evidence suggest that changes in antibody response are linked to AD pathology. MethodsTo elucidate the mechanisms underlying AD development, we investigated antibodies that target autoimmune epitopes using high-resolution epitope microarrays. Our study compared two groups: individuals with AD (n = 19) and non-demented (ND) controls (n = 19). To validate the results, we measured antibody levels in plasma samples from AD patients (n = 96), mild cognitive impairment (MCI; n = 91), and ND controls (n = 97). To further explore the invlovement of EBV, we performed epitope masking immunofluorescence microscopy analysis and tests to induce lytic replication using the B95–8 cell line. ResultsIn this study, we analyzed high-resolution epitope-specific serum antibody levels in AD, revealing significant disparities in antibodies targeting multiple epitopes between the AD and control groups. Particularly noteworthy was the significant down-regulation of antibody (anti-DG#29) targeting an epitope of Epstein-Barr virus nuclear antigen 1 (EBNA1). This down-regulation increased AD risk in female patients (odds ratio up to 6.6), but not in male patients. Our investigation further revealed that the down-regulation of the antibody (anti-DG#29) is associated with EBV reactivation in AD, as indicated by the analysis of EBV VCA IgG or IgM levels. Additionally, our data demonstrated that the epitope region on EBNA1 for the antibody is hidden during the EBV lytic reactivation of B95–8 cells. ConclusionOur findings suggest a potential relationship of EBV in the development of AD in female. Moreover, we propose that antibodies targeting the epitope (DG#29) of EBNA1 could serve as valuable indicators of AD risk in female.

Atopic dermatitis-associated genetic variants regulate LOC100294145 expression implicating interleukin-27 production and type 1 interferon signaling

BackgroundAtopic dermatitis (AD) is a complex inflammatory disease with a strong genetic component. A singular approach of genome wide association studies (GWAS) can identify AD-associated genetic variants, but is unable to explain their functional relevance in AD. This study aims to characterize AD-associated genetic variants and elucidate the mechanisms leading to AD through a multi-omics approach. MethodsGWAS identified an association between genetic variants at 6p21.32 locus and AD. Genotypes of 6p21.32 locus variants were evaluated against LOC100294145 expression in peripheral blood mononuclear cells (PBMCs). Their influence on LOC100294145 promoter activity was measured in vitro via a dual-luciferase assay. The function of LOC100294145 was then elucidated through a combination of co-expression analyses and gene enrichment with g:Profiler. Mendelian randomization was further used to assess the causal regulatory effect of LOC100294145 on its co-expressed genes. ResultsMinor alleles of rs116160149 and rs115388857 at 6p21.32 locus were associated with increased AD risk (p = 2.175 × 10−8, OR = 1.552; p = 2.805 × 10−9, OR = 1.55) and higher LOC100294145 expression in PBMCs (adjusted p = 0.0182; 8.267 × 10−12). LOC100294145 expression was also found to be increased in those with AD (adjusted p = 3.653 × 10−2). The genotype effect of 6p21.32 locus on LOC100294145 promoter activity was further validated in vitro. Co-expression analyses predicted LOC100294145 protein's involvement in interleukin-27 and type 1 interferon signaling, which was further substantiated through mendelian randomization. ConclusionGenetic variants at 6p21.32 locus increase AD susceptibility through raising LOC100294145 expression. A multi-omics approach enabled the deduction of its pathogenesis model comprising dysregulation of hub genes involved in type 1 interferon and interleukin 27 signaling.

Understanding the protective effect of the PLCG2 P522R variant in human microglia

AbstractBackgroundAlthough recent advances in the field suggest significant involvement of the shared pathway between the proteins ApoE and TREM2 in the pathogenesis of late onset Alzheimer’s disease (LOAD), the direction that disease‐modifying interventions targeting this pathway should take are still under debate.Interestingly, a variant of the Phospholipase C Gamma 2 (PLCG2), a downstream effector of the TREM2 receptor, has been associated with a reduced risk of developing dementia. This variant results in a single amino acid change, which was reported to increment enzyme activity. However, mutations in this same enzyme (S707Y, L848P), which also result in hyperactivity, were found to lead to auto‐inflammatory immune diseases or increased AD risk (M28L), suggesting that there may be specific modulatory effects of the P522R variant. Alternatively, the existence of diverging downstream signaling pathways may explain its protective potential.MethodWe have generated a complete set of human isogenic iPSCs derived from the Bioni037A parental line using Crispr/Cas9 edition to introduce the mutations for the different PLCG2 variants. We obtained homozygous and heterozygous clones with the protective P522R mutation, the immune disease related S707Y or L848P. We also acquired ApoE4 isogenic iPSCs. Microglia differentiation was induced from these iPSCs using a protocol involving embryoid bodies. Our approach includes lipidomics and proteomics analyses, with focus on microglial lipid metabolism.ResultsHere, we show the generation of new human isogenic iPSC lines to study PLCG2 mutations. Preliminary results from the characterization of human iPSC‐derived ApoE4 microglia employing this multi‐omics approach shows a reduced expression of TREM2 pathway components including the tyrosine kinases SYK and BTK. Since BTK and SYK are both PLCG2 kinases that result in enzyme activation, we are expanding this analysis to PLCG2 mutants and base our working hypothesis on the possibility that PLCG2 hyperactive variants show a reverse phenotype compared to ApoE4 microglia.ConclusionWe present new tools and a rationale to explore the protective effect of the PLCG2 P522R variant against LOAD in human microglia.

A novel analytic approach to examine the relationship between APOE4 allele status and CSF complement‐related proteins and signaling pathways

AbstractBackgroundThe mechanisms by which the APOE4 allele contributes to AD risk are unclear. Here, we tested the hypothesis that in cognitively normal adults, APOE4 allele is associated with a decrease in complement‐related proteins and downregulation of complement‐related pathways.MethodUntargeted LC‐MS/MS proteomics was conducted on CSF samples (n = 118) from APOE3/3, APOE3/4 and APOE4/4 individuals over age 60, with groups matched on age and sex. We developed a novel analytic approach (which we term “up/down analysis”) based on the directional consistency of the β‐coefficients from a linear model for the intensities of peptides mapping to a given protein with respect to APOE4 carrier status (APOE4‐/ APOE4+). The analysis involves two steps: 1) The direction of the beta‐coefficient (positive/up or negative/down) for the level of each peptide (the outcome variable) due to APOE4 carrier status was derived from linear regression models adjusting for age, sex, and study. 2) These β‐coefficients were tallied for all peptides from a given protein (i.e. number of positive/up versus negative/down β‐coefficients). We then tested the probability under a binomial distribution that the distribution of up versus down peptides from each protein would be as, or more extreme than what we found, with a = 0.05. Pathway enrichment analysis (using p‐values from binomial tests) was conducted using GAGE and functional annotations based on KEGG. We used Benjamini‐Hochberg for multiple comparison correction.ResultWe found 158 proteins for which the direction of peptide intensity was consistently up (+β‐coefficient) or down (‐β‐coefficient) with respect to APOE4 status beyond what would be expected by chance. Of these 158 proteins, 37 were from the complement pathway. Pathway enrichment analysis further supports the role of the complement system; as the top differentially expressed pathway (FDR <0.05) was related to complement signaling.ConclusionOur results suggest that APOE4 carriers have lower CSF levels of key complement cascade proteins, which has previously been viewed as an indicator of complement activation. These results may provide insights into the mechanisms by which APOE4 and associated complement‐related proteins and signaling pathways ultimately contribute to increased AD risk.

Abstract 12289: A Postpartum Diastolic Murmur

A 44-year-old G3P1011 underwent uncomplicated Caesarian section for obstetric indications with delivery of a healthy girl. Several hours postpartum, she developed hypoxemia requiring transient supplemental oxygen. Cardiology was consulted for further evaluation. Upon initial assessment, she appeared comfortable with an oxygen saturation of 93% on room air. She reports an otherwise uneventful pregnancy. Her past medical history is significant for chronic hypertension on propranolol. She was afebrile with a HR of 91, BP 147/66 (left arm) and 155/68 (right arm). Her JVP was 10-11 cm H20. There was a III/IV low-pitched decrescendo early-mid diastolic murmur, loudest at the left lower sternal border, radiating to the apex, and a systolic ejection murmur. EKG (panel A) showed normal sinus rhythm, with no ischemic abnormalities. Due to the discovery of a new murmur, there was concern for valvular pathology as a cause for her suspected heart failure, particularly aortic regurgitation (AR). An urgent TTE (panel C-E) was requested and showed a dissection flap in the ascending aorta, effacement of the sinotubular junction, and severe AR. CT angiogram confirmed the diagnosis of type A aortic dissection (AD; panel B). Twelve hours after the delivery of her baby, she underwent emergent aortic valve repair and aortic arch replacement. She recovered well and was discharged home post-op day 6. Though no human data exists, animal data suggests increased AD risk in breastfeeding animals with Marfan Syndrome. Due to her near catastrophic presentation, she elected to not breastfeed. Her genetic testing results are pending. AD in pregnancy is rare. There is an increased risk of AD in pregnant compared to non-pregnant women. AD often occurs in the third trimester or postpartum, and most women are unaware of a preexisting arteriopathy. In this case, the detection of a diastolic murmur resulted in rapid diagnosis and treatment, essential in the management of this life-threatening condition.

Peripheral Blood Cell Profile and Monocyte–High-density Lipoprotein Ratio in Alzheimer’s Disease: A Hospital-based Case-control Study

IntroductionAlzheimer’s disease (AD) is a neurodegenerative disorder characterized by a progressive decline in memory and cognitive abilities. The monocyte/HDL-C ratio (MHR) has emerged as a new marker of inflammation in recent years. The purpose of this research was to examine MHR alterations in AD and to assess its feasibility as a straightforward and easily computable biomarker for evaluating the severity of the disease.Material and methodsA retrospective case-control study was conducted with 101 patients with AD and 81 age and sex-matched controls from the hospital records. AD was diagnosed according to the National Institute of Neurological and Communicative Disorders and Stroke/Alzheimer’s Disease and Related Disorders Association (NINCDS-ADRDA) criteria. The hospital’s electronic patient record data between September 2021 and April 2022 were screened.ResultsIndividuals diagnosed as having AD were classified into three subgroups based on the progression of the disease, mild, moderate, and severe. MHR was higher in the moderate and severe dementia subgroups compared with the controls according to subgroup analysis (P=0.013). An increase in MHR was found in patients with AD. The multivariate logistic regression analysis model revealed that a one-unit increase in MHR resulted in a 1.081 times increase in the risk of AD (OR: 1.081, 95% CI: [1.005-1.162]; P= 0.035).ConclusionsHigh MHR values could not be used as a diagnostic test for AD. Instead, because it negatively correlates with MMSE, it could be a good index reflecting the increased AD risk and disease severity.

Mendelian randomization and transcriptomic analysis reveal an inverse causal relationship between Alzheimer’s disease and cancer

BackgroundAlzheimer’s disease (AD) and cancer are common age-related diseases, and epidemiological evidence suggests an inverse relationship between them. However, investigating the potential mechanism underlying their relationship remains insufficient.MethodsBased on genome-wide association summary statistics for 42,034 AD patients and 609,951 cancer patients from the GWAS Catalog using the two-sample Mendelian randomization (MR) method. Moreover, we utilized two-step MR to identify metabolites mediating between AD and cancer. Furthermore, we employed colocalization analysis to identify genes whose upregulation is a risk factor for AD and demonstrated the genes’ upregulation to be a favorable prognostic factor for cancer by analyzing transcriptomic data for 33 TCGA cancer types.ResultsTwo-sample MR analysis revealed a significant causal influence for increased AD risk on reduced cancer risk. Two-step MR analysis identified very low-density lipoprotein (VLDL) as a key mediator of the negative cause-effect relationship between AD and cancer. Colocalization analysis uncovered PVRIG upregulation to be a risk factor for AD. Transcriptomic analysis showed that PVRIG expression had significant negative correlations with stemness scores, and positive correlations with antitumor immune responses and overall survival in pan-cancer and multiple cancer types.ConclusionAD may result in lower cancer risk. VLDL is a significant intermediate variable linking AD with cancer. PVRIG abundance is a risk factor for AD but a protective factor for cancer. This study demonstrates a causal influence for AD on cancer and provides potential molecular connections between both diseases.

The Relationship of Alzheimer’s Disease, Stroke and Ancestry in the Puerto Rican Alzheimer Disease Population.

AbstractBackgroundThe Puerto Rico Alzheimer and Related Dementias Initiatives (PRADI) patient cohort was developed to investigate AD and the associated genetics factors in the Puerto Rican population. PRADI recruitment was a snowball sampling, with both island‐wide geographic distribution, and extensions of the PR communities in the continental US. A prior analysis suggested that stroke is a contributing factor to AD in the PR population. In this study we further evaluated the association between stroke and AD, while considering also age, gender, and ancestry.MethodWe assessed 1063 elderly PR individuals for dementia and obtained a medical history. Affection status or mild cognitive impairment was established using standard AD clinical criteria (NINCDS‐ADRDA). Medical history was obtained by a self‐report or informant report. The global ancestry was assessed through the ADMIXTURE program. Differences between affected and cognitively unimpaired (CU) individuals were initially evaluated using a chi‐square test (for age, gender, global ancestry, and stroke) and a t‐test for the age at the exam time. Follow‐up analyses on stroke were performed using logistic regression with age‐at‐exam, gender, and global ancestry proportions as covariates in the model. Initially we assess how stroke is associated with AD, while accounting for age, sex, and global ancestry analysis without APOE, results on the first table. The first table is the model without APOE. Then a second tab turns it around and looks at what factors are associated with Stroke, in the context of AD.ResultIn the PRADI population stroke is associated with an increased risk of AD dementia (p=0.012); this association persists even after accounting for APOE dosage (p=0.017). Additionally, age, gender and APOE dosage were all also associated with increased AD risk (p <0.05) (table 1). AD correlated with Stroke (p=0.013). Gender was also associated with stroke, with females having a decreased risk of stroke (p=0.0021). APOE dosage and ancestry proportions measured through ADMIXTURE approach were not associated with stroke (table 2).ConclusionStroke was independently associated to AD after controlling for APOE dosage. In contrast, age and gender were associated with stroke whereas global ancestry and APOE dosage were not.

Association Study and Meta-Analysis of Polymorphisms and Blood mRNA Expression of the ALDH2 Gene in Patients with Alzheimer’s Disease

Background:Late-onset Alzheimer’s disease (LOAD) is a complex disease in which neuroinflammation plays an important pathophysiological role, and exposure to neurotoxic substrates such as aldehydes may contribute. Blood mRNA expression levels of neuroinflammation-related genes appear to be potential biological markers of LOAD. A relationship between ALDH2 and LOAD has been suggested.Objective:Our objective was to examine blood ALDH2 expression in Japanese LOAD patients, conduct a genetic association study, and add new studies to an extended meta-analysis of the Asian population.Methods:A blood expression study (45 AD subjects, 54 controls) in which total RNA was isolated from whole peripheral blood samples and ALDH2 expression measured was conducted. In addition, a genetic association study (271 AD subjects, 492 controls) using genomic DNA from whole peripheral blood samples was conducted. Finally, a meta-analysis examined the relationship between ALDH2*2 frequency and the risk of LOAD.Results:ALDH2 mRNA expression was significantly higher in LOAD than in controls, and also higher in men with LOAD than in women with LOAD (p = 0.043). The genotypes in the two classified groups and the allele frequency were significantly different between AD and control subjects. The meta-analysis showed a significant difference in the ALDH2*2 allele, with an increased AD risk (OR = 1.38; 95% CI = 1.02–1.85; p = 0.0348, I2 = 81.1%).Conclusion:There was a significant increase in blood ALDH2 expression, and a genetic association with ALDH2*2 in LOAD. ALDH2 may have significant roles in the pathogenesis of LOAD in the Asian population.

Causal association evaluation of diabetes with Alzheimer's disease and genetic analysis of antidiabetic drugs against Alzheimer's disease

BackgroundDespite accumulating epidemiological studies support that diabetes increases the risk of Alzheimer’s disease (AD), the causal associations between diabetes and AD remain inconclusive. The present study aimed to explore: i) whether diabetes is causally related to the increased risk of AD; ii) and if so, which diabetes-related physiological parameter is associated with AD; iii) why diabetes drugs can be used as candidates for the treatment of AD. Two-sample Mendelian randomization (2SMR) was employed to perform the analysis.ResultsFirstly, the 2SMR analysis provided a suggestive association between genetically predicted type 1 diabetes (T1D) and a slightly increased AD risk (OR = 1.04, 95% CI = [1.01, 1.06]), and type 2 diabetes (T2D) showed a much stronger association with AD risk (OR = 1.34, 95% CI = [1.05, 1.70]). Secondly, further 2SMR analysis revealed that diabetes-related physiological parameters like fasting blood glucose and total cholesterol levels might have a detrimental role in the development of AD. Thirdly, we obtained 74 antidiabetic drugs and identified SNPs to proxy the targets of antidiabetic drugs. 2SMR analysis indicated the expression of three target genes, ETFDH, GANC, and MGAM, were associated with the increased risk of AD, while CPE could be a protective factor for AD. Besides, further PPI network found that GANC interacted with MGAM, and further interacted with CD33, a strong genetic locus related to AD.ConclusionsIn conclusion, the present study provides evidence of a causal association between diabetes and increased risk of AD, and also useful genetic clues for drug development.

Involvement of CNS luteinizing hormone receptor in Alzheimer's disease pathogenesis.

CNS Luteinizing hormone and its receptor have been shown to modulate neuronal plasticity and cognition. Importantly, levels of brain LH are inversely related to levels in the periphery, thus low upon menopause-related upregulation of peripheral LH. Previously we have shown that downregulation of peripheral LH improves function and plasticity in AD mouse models, improvements that are positively correlated with brain LH. However, whether these improvements are driven directly through the activation of central LHR signaling is not known. Therefore, the current study addresses whether central LHR activation was able to rescue cognitive and neuronal plasticity changes previously observed by peripheral LH downregulation. Female APP/PS1 transgenic and wild-type mice underwent ovariectomy or sham surgery and received ICV hCG or aCSF treatment for 8 weeks. Upon completion cognitive testing, tissue was collected to determine changes in structural plasticity and Abeta pathology. Preliminary data demonstrates the ability of hCG treatment to differentially modulate cognition, pathology, and plasticity markers. This work supports the involvement of LHR in CNS function and begets its further study as a contributor linking menopause and increased AD risk.

Association between acid‐suppressive drug use and atopic dermatitis in patients with upper gastrointestinal diseases: A population‐based retrospective cohort study

Proton-pump inhibitors (PPIs) and histamine-2-receptor antagonists (H2RAs) are two of the most widely used acid-suppressive drugs (ASDs). Some studies have reported that prenatal ASD exposure may increase the risk of asthma and other allergic diseases. This study investigated the effects of ASDs on the risk of atopic dermatitis in patients with upper gastrointestinal diseases. This population-based retrospective cohort study used data of 289,850 patients with at least two diagnoses of upper gastrointestinal diseases (UGIDs) between 1 January 2001 and 31 December 2005, from Taiwan's National Health Insurance Research Database. The AD risks among ASD users and nonusers were compared. Differences in sociodemographic characteristics and potential covariates were examined. AD hazard ratios were estimated, and groups were compared using Cox proportional hazards regression analysis after adjustment for age, sex and other covariates. In total, 109,980 patients were included. The adjusted hazard ratio (HR) of AD risk in ASD users relative to that in nonusers was 1.52 (95% confidence interval [CI]: 1.40-1.64, p<0.001). For a dose-effect sub-analysis, patients were divided into four groups based on their defined daily dose. ASDs dose-dependently affected the AD risk (p for trend <0.01). Furthermore, the adjusted HR of the AD risk among ASD nonusers was 2.30 (95% CI: 2.06-2.57) relative to that in the comparison group (ASD nonusers without UGIDs). Among patients with UGIDs, ASD users had a higher AD risk than ASD nonusers. A subgroup analysis revealed only H2RA use was associated with an increased AD risk (adjusted HR 1.70, 95% CI: 1.53-1.89, p<0.001). These results indicate that the use of H2RAs was associated with an increased risk of AD among patients with UGIDs, and the increase in risk appeared to be dose-dependent. ASDs should be used only in situations where clear clinical benefits can be obtained.

ApoE4 Impairs Neuron-Astrocyte Coupling of Fatty Acid Metabolism

SUMMARYAlzheimer’s disease (AD) risk gene ApoE4 perturbs brain lipid homeostasis and energy transduction. However, the cell-type-specific mechanism of ApoE4 in modulating brain lipid metabolism is unclear. Here, we describe a detrimental role of ApoE4 in regulating fatty acid (FA) metabolism across neuron and astrocyte in tandem with their distinctive mitochondrial phenotypes. ApoE4 disrupts neuronal function by decreasing FA sequestering in lipid droplets (LDs). FAs in neuronal LDs are exported and internalized by astrocytes, with ApoE4 diminishing the transport efficiency. Further, ApoE4 lowers FA oxidation and leads to lipid accumulation in both astrocyte and the hippocampus. Importantly, diminished capacity of ApoE4 astrocytes in eliminating neuronal lipids and degrading FAs accounts for their compromised metabolic and synaptic support to neurons. Collectively, our findings reveal a mechanism of ApoE4 disruption to brain FA and bioenergetic homeostasis that could underlie the accelerated lipid dysregulation and energy deficits and increased AD risk for ApoE4 carriers.

Alzheimer's genetic risk factor FERMT2 (kindlin‐2) controls axonal growth and synaptic plasticity in an APP‐dependent manner

AbstractBackgroundAlthough APP metabolism is being intensively investigated, a large fraction of its modulators are yet to be characterized. In this context, we combined two genome‐wide high‐content screenings to assess the functional impact of miRNAs and genes on APP metabolism and the signaling pathways involved.MethodWe combined genome‐wide high‐content screenings to identify miRNAs (n = 2,555) and target genes (n = 18,107) involved in the APP metabolism. To predict the function(s) of miRNAs that target these genes, pathway enrichment analysis was performed using DIANA Tools mirPath (v3.0). CRISPR/Cas9 technology has been used to generate HEK293 cell lines carrying rs7143400 variant located in the FERMT2 3’UTR and its impact on miRNA binding. Involvement of FERMT2 in axonal growth and synaptic connectivity was assessed using primary neurons cultured in microfluidic devices that fluidically isolate axons from their cell bodies. The functional impact of FERMT2 on CA1 basal synaptic transmission and long‐term potentiation (LTP) has been recorded in ex vivo mouse hippocampal slices, after stereotactic lentivirus injection allowing expression of shNT, shFERMT2 or shAPP.ResultOur systematic approaches led us to characterize 180 genes targeted by 41 miRNAs as modulators of APP metabolism. Among these genes, we focused on FERMT2, a known genetic risk factor of sporadic AD. We found that FERMT2 directly interacts with APP to modulate its metabolism and that FERMT2 under‐expression impacts axonal growth, synaptic connectivity and long‐term potentiation in an APP‐dependent manner.Lastly, the rs7143400‐T allele, which is associated with an increased AD risk and localized within the 3’UTR of FERMT2, induced a down‐regulation of FERMT2 expression through binding of miR‐4504. This miRNA is mainly expressed in neurons and significantly overexpressed in AD brains compared to controls.ConclusionAltogether, our data provide strong evidence for a detrimental effect of FERMT2 under‐expression in neurons and insight on how this may influence AD pathogenesis.

Measurement bias in depression assessment according to brain amyloid burden, cognitive function, and sex in the A4 study

AbstractBackgroundWe sought to identify measurement bias (differential item functioning, DIF) in the Geriatric Depression Scale (15 item version) attributable to cerebral amyloid level (Aβ) among cognitively normal older adults. Specifically, we were interested in determining if endorsement of self‐reported memory problems on the GDS‐15 differed by Aβ level. We hypothesized that persons with high Aβ would have a greater probability of endorsing memory problems than those with low Aβ, consistent with the literature showing that subjective cognitive decline in older adults is associated with increased AD risk. We also examined DIF attributable to level of cognitive functioning and sex as positive controls that may account for differences in self‐reported depression.MethodAnalyses were conducted using the pre‐randomization database of the Anti‐Amyloid Treatment in Asymptomatic Alzheimer's Disease (A4)/Longitudinal Evaluation of Amyloid Risk and Neurodegeneration (LEARN) Study (N=3,961). We used the MIMIC (multiple indicators, multiple causes) approach to detect DIF. The MIMIC approach is consistent with item response theory, and allows for the detection of uniform DIF for predictors that are either discretely observed (sex) or continuously observed (Aβ level, cognitive function).ResultWe found DIF with respect to Aβ level, sex, and cognitive functioning. Most DIF detected was of a trivial effect size with some showing small‐to‐moderate effect sizes. Mild DIF, attributable to Aβ level, was shown for the GDS memory item in the hypothesized direction: after adjustment for depressive symptom severity (overall GDS symptoms), persons with high Aβ had a greater probability of endorsing memory problems than those with low Aβ (effect size = 0.22, p &lt;.001). Interestingly, DIF for 2 items assessing hopelessness were also observed according to high Aβ versus low Aβ. Despite these findings we determined that there was negligible impact of DIF attributable to Aβ level on overall depressive symptom level.ConclusionParticipant responses on items of the GDS‐15 are sensitive to Aβ burden, sex, and level of cognitive functioning over and above what would be expected given the effect of those factors on depressive symptom severity overall. However, these direct effects are of small magnitude and do not appreciably impact the validity of inferences based on the GDS‐15.

APOE4 impairs neuron‐astrocyte coupling of fatty acid metabolism

AbstractBackgroundAs the strongest genetic risk factor for late‐onset Alzheimer’s disease, the ε4 variant of apolipoprotein E (APOE4) is known to perturb both lipid homeostasis and energy metabolism in brain. However, the mechanistic role of APOE4 in modulating the bioenergetic aspects of lipid species, and its connection with cell‐type‐specific mitochondrial phenotypes are not well understood.MethodHere, in individual‐ and co‐culture models of primary neurons and astrocytes from humanized APOE3 or APOE4 knockin mice, we describe a loss‐of‐function role of APOE4 in regulating key mechanisms controlling neuron‐astrocyte coupling of lipid metabolism, from neuronal storage of fatty acids (FAs) in lipid droplets (LDs), to the mobilization of neuronal LDs and transport of FAs to astrocytes, and eventually to the energetic degradation of FAs in astrocytes.ResultCompared to APOE3, APOE4 decreases the sequestering of free fatty acids (FAs) in neuronal lipid droplets (LDs), elevates FA levels and leads to mitochondrial‐ and neuronal dysfunction. These neuronal LDs are eliminated upon astrocyte exposure and FAs are transported to astrocytes together with APOE, with APOE4 in either neurons or astrocytes diminishing the transport efficiency. In APOE4 astrocytes, increased mitochondrial fragmentation underlies a metabolic shift towards enhanced glucose metabolism and reduced FA β‐oxidation, which further elicits astrocytic LD accumulation. Moreover, the lesser capacity in eliminating neuronal lipids and performing β‐oxidation results in compromised ability of APOE4 astrocytes in providing metabolic‐ and synaptic support to neurons.ConclusionThese data support the coupling of neuron lipid homeostasis, astrocytic FA degradation with cell‐specific mitochondrial function, which is essential to protect neurons from bioenergetic deficits and lipotoxicity. Further, our findings reveal the mechanistic basis of APOE4 in disrupting inter‐cellular FA metabolism in brain that may underlie the exaggerated lipid dyshomeostasis and bioenergetic decline, and increased AD risk for APOE4 carriers.

Alzheimer\u2019s genetic risk factor FERMT2 (Kindlin-2) controls axonal growth and synaptic plasticity in an APP-dependent manner

Although APP metabolism is being intensively investigated, a large fraction of its modulators is yet to be characterized. In this context, we combined two genome-wide high-content screenings to assess the functional impact of miRNAs and genes on APP metabolism and the signaling pathways involved. This approach highlighted the involvement of FERMT2 (or Kindlin-2), a genetic risk factor of Alzheimer’s disease (AD), as a potential key modulator of axon guidance, a neuronal process that depends on the regulation of APP metabolism. We found that FERMT2 directly interacts with APP to modulate its metabolism, and that FERMT2 underexpression impacts axonal growth, synaptic connectivity, and long-term potentiation in an APP-dependent manner. Last, the rs7143400-T allele, which is associated with an increased AD risk and localized within the 3′UTR of FERMT2, induced a downregulation of FERMT2 expression through binding of miR-4504 among others. This miRNA is mainly expressed in neurons and significantly overexpressed in AD brains compared to controls. Altogether, our data provide strong evidence for a detrimental effect of FERMT2 underexpression in neurons and insight into how this may influence AD pathogenesis.

Systemic and CNS Inflammation Crosstalk: Implications for Alzheimer's Disease.

After years of failed therapeutic attempts targeting beta-amyloid (Aβ) in AD, there is now increasing evidence suggesting that inflammation holds a pivotal role in AD pathogenesis and immune pathways can possibly comprise primary therapeutic targets. Inflammation is a key characteristic of numerous diseases including neurodegenerative disorders and thus not surprisingly suppression of inflammation frequently constitutes a major therapeutic strategy for a wide spectrum of disorders. Several brain-resident and peripherally-derived immune populations and inflammatory mediators are involved in AD pathophysiology, with microglia comprising central cellular player in the disease process. Systemic inflammation, mostly in the form of infections, has long been observed to induce behavioral alterations and cognitive dysfunction, suggesting for a close interaction of the peripheral immune system with the brain. Systemic inflammation can result in neuroinflammation, mainly exhibited as microglial activation, production of inflammatory molecules, as well as recruitment of peripheral immune cells in the brain, thus shaping a cerebral inflammatory milieu that may seriously impact neuronal function. Increasing clinical and experimental studies have provided significant evidence that acute (e.g. infections) or chronic (e.g. autoimmune diseases like rheumatoid arthritis) systemic inflammatory conditions may be associated with increased AD risk and accelerate AD progression. Here we review the current literature that links systemic with CNS inflammation and the implications of this interaction for AD in the context of acute and chronic systemic pathologies as acute infection and rheumatoid arthritis. Elucidating the mechanisms that govern the crosstalk between the peripheral and the local brain immune system may provide the ground for new therapeutic approaches that target the immune-brain interface and shed light on the understanding of AD.

APOE genotype and sex affect microglial interactions with plaques in Alzheimer\u2019s disease mice

Microglia affect Alzheimer’s disease (AD) pathogenesis in opposing manners, by protecting against amyloid accumulation in early phases of the disease and promoting neuropathology in advanced stages. Recent research has identified specific microglial interactions with amyloid plaques that exert important protective functions including attenuation of early pathology. It is unknown how these protective microglial interactions with plaques are affected by apolipoprotein E (APOE) genotype and sex, two well-established AD risk factors that modulate microglial function. We investigated this question using quantitative confocal microscopy to compare microglial interactions with amyloid plaques in male and female EFAD mice across APOE3 and APOE4 genotypes at 6 months of age. We observed that microglial coverage of plaques is highest in male APOE3 mice with significant reductions in coverage observed with both APOE4 genotype and female sex. Plaque compaction, a beneficial consequence of microglial interactions with plaques, showed a similar pattern in which APOE4 genotype and female sex were associated with significantly lower values. Within the plaque environment, microglial expression of triggering receptor expressed on myeloid cells 2 (TREM2), a known regulator of microglial plaque coverage, was highest in male APOE3 mice and reduced by APOE4 genotype and female sex. These differences in plaque interactions were unrelated to the number of microglial processes in the plaque environment across groups. Interestingly, the pattern of amyloid burden across groups was opposite to that of microglial plaque coverage, with APOE4 genotype and female sex showing the highest amyloid levels. These findings suggest a possible mechanism by which microglia may contribute to the increased AD risk associated with APOE4 genotype and female sex.

IMPACT OF APOE GENOTYPE ON THE SEX-DIFFERENTIATED BIOENERGETIC TRAJECTORIES AND AD RISKS IN AGING MOUSE BRAINS

Age, APOE4 genotype, and female sex are top risk factors for AD. Our previous studies demonstrated that the bioenergetic shifts occurring in the perimenopausal female brain could contribute to an increased AD risk in women. We also observed substantial sex disparities in brain bioenergetic trajectories in normal aging mice. The goal of this study is to determine the sex differences in the impact of APOE genotype on AD at-risk phenotypes during brain aging. Female and male, APOE3- and APOE4 targeted replacement (TR) mice were assessed for: (a) bioenergetic-, inflammatory-, and AD pathology-related gene expression in hippocampus followed by bioinformatic analysis, and (b) key metabolic parameters in the periphery. Functional assessments are undergoing, including: (a) FDG-microPET for cerebral glucose metabolism, (b) brain mitochondrial function, and (c) glucose tolerance test for peripheral metabolism. Gene expression analyses revealed that female APOE4 mice at pre-menopause age (6-month old) exhibited a significantly different bioenergetic profile relative to APOE3 controls: APOE4 mice showed a higher expression of genes involved in mitochondrial oxidative phosphorylation, mitochondrial membrane transport, and mitochondrial fusion. These changes in female APOE4 brains could represent an adaptive response to deficits in brain glucose availability and a shift in energy fuels from glucose to ketone bodies and glucose. This hypothesis is further supported by: (a) APOE4 mice had lower levels of plasma glucose in both sexes while the higher levels of ketone bodies and triglycerides were only seen in the females; (b) both APOE3 and APOE4 females had lower peripheral glucose levels and higher ketone body levels than their genotype-matched male counterparts, indicating a potential earlier shift in bioenergetic fuel usage in females. These findings suggest that APOE4 genotype interacts with the age-related decline in glucose metabolism and the bioenergetic shift to alternative fuels, particularly in females. Outcomes of this study will provide mechanistic details of the APOE4 genetic burden on the sex-differentiated bioenergetic fluctuation during aging and its contribution to higher AD risks in women. This work was supported by NIA 5P01AG026572 to RDB and Alzheimer's Association SAGA-17–419459 to RDB.