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Microglia signatures refer to distinct gene expression profiles or patterns of gene activity that are characteristic of microglia. Advances in gene expression profiling techniques, such as single-cell RNA sequencing, have allowed us to study microglia at a more detailed level and identify unique gene expression patterns that are associated, but not always, with different functional states of these cells. Microglial signatures depend on the developmental stage, brain region, and specific pathological conditions. By studying these signatures, it has been possible to gain insights into the underlying mechanisms of microglial activation and begin to develop targeted therapies to modulate microglia-mediated immune responses in the CNS. Historically, the first two signatures coincide with M1 pro-inflammatory and M2 anti-inflammatory phenotypes. The first one includes upregulation of genes such as CD86, TNF-α, IL-1β, and iNOS, while the second one may involve genes like CD206, Arg1, Chil3, and TGF-β. However, it has long been known that many and more specific phenotypes exist between M1 and M2, likely with corresponding signatures. Here, we discuss specific microglial signatures and their association, if any, with neurodegenerative pathologies and other brain disorders. [ABSTRACT FROM AUTHOR]

Objective: This meta-analysis with a systematic review was undertaken to assess the association between APOE allelic genotypes and the risk of Alzheimer's disease (AD) in the Italian population. Methods: The Web of Science, PubMed, and Scopus databases were searched until 15 November 2023. The odds ratio (OR) with a 95% confidence interval (CI) was calculated using fixed and random effect models, depending on the I2 statistic value. The systematic review and meta-analysis were conducted in agreement with the PRISMA guideline and registered with PROSPERO (CRD42023492580). Results: Our meta-analysis based on 15 studies revealed a higher risk of AD among Italian individuals carrying the APOE ε4 allele (OR = 3.60, 95% CI [2.90–4.47], p < 0.0001). The association of AD genotype APOE ε2ε4 (OR = 1.36, 95% CI [0.76–2.41], p = 0.29) was not statistically significant, while APOE ε3ε4 (OR = 3.43, 95% CI [2.95–3.99], p < 0.0001) has a high risk of AD development; the risk is more notably in the APOE ε4ε4 genotype (OR = 7.08, 95% CI [4.22–11.86], p < 0.0001). The APOE ε2 allele has a protective effect (APOE ε2 (OR = 0.47, 95% CI [0.29–0.74], p = 0.0013)), and similar results were achieved by APOE ε3 (OR  =  0.49, 95% CI [0.37–0.65], p < 0.0001). Subgroup analysis of three areas of Italy (southern, northern, and center) revealed that that APOE ε4 allele was a risk factor with a higher OR in northern Italy (OR 4.22; 95% CI [3.46–5.16], p < 0.0001) compared to southern and center Italy (OR 3.02; 95% CI [2.28–4.01], p < 0.0001 and OR 3.97; 95% CI [1.37–11.56], p < 0.0001, respectively). As well, APOE ε4ε4 genotype carriers had a significantly higher OR in northern Italy (OR 9.69; 95% CI [4.94–18.99], p < 0.0001) compared to in southern and center Italy (OR 4.38; 95% CI [1.54–12.47], p < 0.0001 and OR 3.59; 95% CI [0.87–14.86], p < 0.0001, respectively). Conclusions: This systematic review with a meta-analysis of the Italian population on APOE alleles, genotyping, and AD incidence, highlights that individuals harboring APOE ε4 have a higher risk of developing AD compared to those with other alleles. It also supports the protective effect of the APOE ε2 allele against the progress of AD. The qualitative analysis on the complex genetic interactions influencing Alzheimer risk emphasizes the need for further research on genetic and environmental factors for effective prevention strategies. [ABSTRACT FROM AUTHOR]

Given the high growth rates of cognitive decline among the elderly population and the lack of effective etiological treatments, early diagnosis of cognitive impairment progression is an imperative task for modern science and medicine. It is of particular interest to identify predictors of an unfavorable subsequent course of cognitive disorders, specifically, rapid progression. Our study assessed the informative role of various risk factors on the dynamics of cognitive impairment among mild cognitive impairment (MCI) patients. The study included patients with MCI (N = 338) who underwent neuropsychological assessment, magnetic resonance imaging (MRI) examination, blood sampling for general and biochemical analysis, APOE genotyping, and polygenic risk score (PRS) evaluation. The APOE ε4/ε4 genotype was found to be associated with a diminished overall cognitive scores initial assessment and negative cognitive dynamics. No associations were found between cognitive changes and the PRS. The progression of cognitive impairment was associated with the width of the third ventricle and hematological parameters, specifically, hematocrit and erythrocyte levels. The absence of significant associations between the dynamics of cognitive decline and PRS over three years can be attributed to the provided suitable medical care for the prevention of cognitive impairment. Adding other risk factors and their inclusion in panels assessing the risk of progression of cognitive impairment should be considered. [ABSTRACT FROM AUTHOR]

Background: The VALCODIS (Valencian Cognitive Diseases Study) cohort was designed and studied at the Hospital Universitari i Politècnic La Fe (Valencia, Spain) for the research of cognitive diseases, especially in the search for new biomarkers of Alzheimer's disease (AD). Methods: Participants in the VALCODIS cohort had cerebrospinal fluid (CSF) and blood samples, neuroimaging, and neuropsychological tests. The ApoE genotype was evaluated to identify its relationship with CSF biomarkers and neuropsychological tests in AD and non-AD participants. Results: A total of 1249 participants were included. They were mainly AD patients (n = 547) but also patients with other dementias (frontotemporal lobar dementia (n = 61), Lewy body dementia without AD CSF signature (n = 10), vascular dementia (n = 24) and other specific causes of cognitive impairment (n = 442), and patients with subjective memory complaints (n = 165)). In the ApoE genotype evaluation, significant differences were found for Aβ42 levels between genotypes in both AD and non-AD patients, as well as a negative correlation between tau values and a cognitive test in non-carriers and ε4 heterozygous. Conclusions: The VALCODIS cohort provides biologically diagnosed patients with demographical, clinical and biochemical data, and biological samples for further studies on early AD diagnosis. Also, the ApoE genotype evaluation showed correlations between CSF biomarkers and neuropsychological tests. [ABSTRACT FROM AUTHOR]

Coronary artery disease (CAD) is the leading cause of death in India. Many genetic polymorphisms play a role in regulating oxidative stress, blood pressure and lipid metabolism, contributing to the pathophysiology of CAD. This study examined the association between ten polymorphisms and CAD in the Jat Sikh population from Northern India, also considering polygenic risk scores. This study included 177 CAD cases and 175 healthy controls. The genetic information of GSTM1 (rs366631), GSTT1 (rs17856199), ACE (rs4646994), AGT M235T (rs699), AGT T174M (rs4762), AGTR1 A1166C (rs5186), APOA5 (rs3135506), APOC3 (rs5128), APOE (rs7412) and APOE (rs429358) and clinical information was collated. Statistical analyses were performed using SPSS version 27.0 and SNPstats. Significant independent associations were found for GST*M1, GST*T1, ACE, AGT M235T, AGT T174M, AGTR1 A1166C and APOA5 polymorphisms and CAD risk (all p < 0.05). The AGT CT haplotype was significantly associated with a higher CAD risk, even after controlling for covariates (adjusted OR = 3.93, 95% CI [2.39–6.48], p < 0.0001). The APOA5/C3 CC haplotype was also significantly associated with CAD (adjusted OR = 1.86, 95% CI [1.14–3.03], p < 0.05). A higher polygenic risk score was associated with increased CAD risk (adjusted OR = 1.98, 95% CI [1.68–2.34], p < 0.001). Seven polymorphisms were independently associated with an increase in the risk of CAD in this North Indian population. A considerable risk association of AGT, APOA5/C3 haplotypes and higher genetic risk scores is documented, which may have implications for clinical and public health applications. [ABSTRACT FROM AUTHOR]

One of the major causes of vision impairment among elderly people in developed nations is age-related macular degeneration (AMD). The distinctive features of AMD are the accumulation of extracellular deposits called drusen and the gradual deterioration of photoreceptors and nearby tissues in the macula. AMD is a complex and multifaceted disease influenced by several factors such as aging, environmental risk factors, and a person's genetic susceptibility to the condition. The interaction among these factors leads to the initiation and advancement of AMD, where genetic predisposition plays a crucial role. With the advent of high-throughput genotyping technologies, many novel genetic loci associated with AMD have been identified, enhancing our knowledge of its genetic architecture. The common genetic variants linked to AMD are found on chromosome 1q32 (in the complement factor H gene) and 10q26 (age-related maculopathy susceptibility 2 and high-temperature requirement A serine peptidase 1 genes) loci, along with several other risk variants. This review summarizes the common genetic variants of complement pathways, lipid metabolism, and extracellular matrix proteins associated with AMD risk, highlighting the intricate pathways contributing to AMD pathogenesis. Knowledge of the genetic underpinnings of AMD will allow for the future development of personalized diagnostics and targeted therapeutic interventions, paving the way for more effective management of AMD and improved outcomes for affected individuals. [ABSTRACT FROM AUTHOR]

Numerous studies have tried to evaluate the potential role of thrombophilia-related genes in retinal vein occlusion (RVO); however, there is limited research on genes related to different pathophysiological mechanisms involved in RVO. In view of the strong contribution of oxidative stress and inflammation to the pathogenesis of RVO, the purpose of the present study was to investigate the association of inflammation- and oxidative-stress-related polymorphisms from three different genes [apolipoprotein E (APOE), paraoxonase 1 (PON1) and stromal cell-derived factor 1 (SDF-1)] and the risk of RVO in a Greek population. Participants in this case-control study were 50 RVO patients (RVO group) and 50 healthy volunteers (control group). Blood samples were collected on EDTA tubes and genomic DNA was extracted. Genotyping of rs854560 (L55M) and rs662 (Q192R) for the PON1 gene, rs429358 and rs7412 for the APOE gene and rs1801157 [SDF1-3′G(801)A] for SDF-1 gene was performed using the polymerase chain reaction–restriction fragment length polymorphism (PCR-RFLP) method. Multiple genetic models (codominant, dominant, recessive, overdominant and log-additive) and haplotype analyses were performed using the SNPStats web tool to assess the correlation between the genetic polymorphisms and the risk of RVO. Binary logistic regression analysis was used for the association analysis between APOE gene variants and RVO. Given the multifactorial nature of the disease, our statistical analysis was adjusted for the most important systemic risk factors (age, hypertension and diabetes mellitus). The dominant genetic model for the PON1 Q192R single nucleotide polymorphism (SNP) of the association analysis revealed that there was a statistically significant difference between the RVO group and the control group. Specifically, after adjusting for age and hypertension, the PON1 192 R allele (QR + RR) was found to be associated with a statistically significantly higher risk of RVO compared to the QQ genotype (OR = 2.51; 95% CI = 1.02–6.14, p = 0.04). The statistically significant results were maintained after including diabetes in the multivariate model in addition to age and hypertension (OR = 2.83; 95% CI = 1.01–7.97, p = 0.042). No statistically significant association was revealed between the other studied polymorphisms and the risk of RVO. Haplotype analysis for PON1 SNPs, L55M and Q192R, revealed no statistically significant correlation. In conclusion, PON1 192 R allele carriers (QR + RR) were associated with a statistically significantly increased risk of RVO compared to the QQ homozygotes. These findings suggest that the R allele of the PON1 Q192R is likely to play a role as a risk factor for retinal vein occlusion. [ABSTRACT FROM AUTHOR]

Early-onset Alzheimer's disease (EOAD), defined as Alzheimer's disease onset before 65 years of age, has been significantly less studied than the "classic" late-onset form (LOAD), although EOAD often presents with a more aggressive disease course, caused by variants in the APP, PSEN1, and PSEN2 genes. EOAD has significant differences from LOAD, including encompassing diverse phenotypic manifestations, increased genetic predisposition, and variations in neuropathological burden and distribution. Phenotypically, EOAD can be manifested with non-amnestic variants, sparing the hippocampi with increased tau burden. The aim of this article is to review the different genetic bases, risk factors, pathological mechanisms, and diagnostic approaches between EOAD and LOAD and to suggest steps to further our understanding. The comprehension of the monogenic form of the disease can provide valuable insights that may serve as a roadmap for understanding the common form of the disease. [ABSTRACT FROM AUTHOR]

Melatonin (MLT), a natural compound found in the animal and vegetable kingdom, participates in several physiological processes. MLT exerts antioxidant and anti-inflammatory activities, among others, but information about its action on lipid metabolism is still scarce. For this reason, mice deficient in apolipoprotein E (ApoE−/−) fed a Western diet (WD) were intragastrically treated with different concentrations of MLT (2 and 9 mg/kg) for 12 weeks. The lipid parameters were quantified, and, since links between cardiovascular risk and immune function and oxidative stress have been established, we also analyzed the population of leukocytes and the oxidative stress status. Although there was no change in the weight of the mice, a significant reduction in low-density lipoprotein cholesterol (LDL-C) was observed in mice treated with the higher concentration of MLT tested in this study. Additionally, an improvement in cardiovascular risk indexes was observed. A reduction in the hepatic total cholesterol (TC) and LDL-C levels was also observed in the treated mice. Finally, a decrease in leukocytes and lymphocytes in particular, as well as an increase in the antioxidant status, were shown in MLT-treated mice. In conclusion, MLT is a promising candidate that could be considered as a possible functional ingredient capable of preventing cardiovascular risk. [ABSTRACT FROM AUTHOR]

Alzheimer's disease (AD) is a debilitating neurodegenerative disease characterized by the accumulation of extracellular amyloid-β peptides (Aβ) within the cerebral parenchyma and vasculature, which is known as cerebral amyloid angiopathy (CAA). This study utilized confocal imaging to investigate heparan sulfate (HS) expression within the cerebrovasculature and its associations with Aβ, gender, and ApoE4 genotype in AD. Our investigation revealed elevated levels of HS in the cerebrovasculature of AD patients with severe CAA. Additionally, these patients exhibited higher HS colocalization with Aβ in the cerebrovasculature, including both endothelial and vascular smooth muscle cell compartments. Intriguingly, a reversal in the polarized expression of HS within the cerebrovasculature was detected in AD patients with severe CAA. Furthermore, male patients exhibited lower levels of both parenchymal and cerebrovascular HS. Additionally, ApoE4 carriers displayed heightened cerebrovascular Aβ expression and a tendency of elevated cerebrovascular HS levels in AD patients with severe CAA. Overall, these findings reveal potential intricate interplay between HS, Aβ, ApoE, and vascular pathology in AD, thereby underscoring the potential roles of cerebrovascular HS in CAA development and AD pathology. Further study of the underlying mechanisms may present novel therapeutic avenues for AD treatment. [ABSTRACT FROM AUTHOR]

The e4 allele of the apolipoprotein E gene is the strongest genetic risk factor for sporadic Alzheimer's disease. Nevertheless, how APOE is regulated is still elusive. In a trans-eQTL analysis, we found a genome-wide significant association between transmembrane protein 106B (TMEM106B) genetic variants and cortical APOE mRNA levels in human brains. The goal of this study is to determine whether TMEM106B is mis-regulated in Alzheimer's disease or in other neurodegenerative conditions. Available genomic, transcriptomic and proteomic data from human brains were downloaded from the Mayo Clinic Brain Bank and the Religious Orders Study and Memory and Aging Project. An in-house mouse model of the hippocampal deafferentation/reinnervation was achieved via a stereotaxic lesioning surgery to the entorhinal cortex, and mRNA levels were measured using RNAseq technology. In human temporal cortices, the mean TMEM106B expression was significantly higher in Alzheimer's disease compared to cognitively unimpaired individuals. In the mouse model, hippocampal Tmem106b reached maximum levels during the early phase of reinnervation. These results suggest an active response to tissue damage that is consistent with compensatory synaptic and terminal remodeling. [ABSTRACT FROM AUTHOR]

Novel technologies such as single-cell RNA and single-nucleus RNA sequencing have shed new light on the complexity of different microglia populations in physiological and pathological states. The transcriptomic profiling of these populations has led to the subclassification of specific disease-associated microglia and microglia clusters in neurodegenerative diseases. A common profile includes the downregulation of homeostasis and the upregulation of inflammatory markers. Furthermore, there is concordance in few clusters between murine and human samples. Apolipoprotein E, which has long been considered a high-risk factor for late-onset Alzheimer's disease, is strongly regulated in both these murine and human clusters. Transforming growth factor-β plays an essential role during the development and maturation of microglia. In a pathological state, it attenuates their activation and is involved in numerous cell regulatory processes. Transforming growth factor-β also has an influence on the deposition of amyloid-beta, as it is involved in the regulation of key proteins and molecules. Taken together, this review highlights the complex interaction of apolipoprotein E, the triggering receptor on myeloid cells 2, and transforming growth factor-β as part of a regulatory axis in microglia at the onset and over the course of Alzheimer's disease. [ABSTRACT FROM AUTHOR]

Background: An application of artificial intelligence is machine learning, which allows computer programs to learn and create data. Methods: In this work, we aimed to evaluate the performance of the MySLR machine learning platform, which implements the Latent Dirichlet Allocation (LDA) algorithm in the identification and screening of papers present in the literature that focus on mutations of the apolipoprotein E (ApoE) gene in Italian Alzheimer's Disease patients. Results: MySLR excludes duplicates and creates topics. MySLR was applied to analyze a set of 164 scientific publications. After duplicate removal, the results allowed us to identify 92 papers divided into two relevant topics characterizing the investigated research area. Topic 1 contains 70 papers, and topic 2 contains the remaining 22. Despite the current limitations, the available evidence suggests that articles containing studies on Italian Alzheimer's Disease (AD) patients were 65.22% (n = 60). Furthermore, the presence of papers about mutations, including single nucleotide polymorphisms (SNPs) ApoE gene, the primary genetic risk factor of AD, for the Italian population was 5.4% (n = 5). Conclusion: The results show that the machine learning platform helped to identify case-control studies on ApoE gene mutations, including SNPs, but not only conducted in Italy. [ABSTRACT FROM AUTHOR]

The clinical features and pathophysiology of neuropsychiatric symptoms (NPSs) in dementia have been extensively studied. However, the genetic architecture and underlying neurobiological mechanisms of NPSs at preclinical stages of cognitive decline and Alzheimer's disease (AD) remain largely unknown. Mild behavioral impairment (MBI) represents an at-risk state for incident cognitive impairment and is defined by the emergence of persistent NPSs among non-demented individuals in later life. These NPSs include affective dysregulation, decreased motivation, impulse dyscontrol, abnormal perception and thought content, and social inappropriateness. Accumulating evidence has recently begun to shed more light on the genetic background of MBI, focusing on its potential association with genetic factors related to AD. The Apolipoprotein E (APOE) genotype and the MS4A locus have been associated with affective dysregulation, ZCWPW1 with social inappropriateness and psychosis, BIN1 and EPHA1 with psychosis, and NME8 with apathy. The association between MBI and polygenic risk scores (PRSs) in terms of AD dementia has been also explored. Potential implicated mechanisms include neuroinflammation, synaptic dysfunction, epigenetic modifications, oxidative stress responses, proteosomal impairment, and abnormal immune responses. In this review, we summarize and critically discuss the available evidence on the genetic background of MBI with an emphasis on AD, aiming to gain insights into the potential underlying neurobiological mechanisms, which till now remain largely unexplored. In addition, we propose future areas of research in this emerging field, with the aim to better understand the molecular pathophysiology of MBI and its genetic links with cognitive decline. [ABSTRACT FROM AUTHOR]

Antimicrobial peptides (AMPs) hold promise as alternatives to combat bacterial infections, addressing the urgent global threat of antibiotic resistance. COG1410, a synthetic peptide derived from apolipoprotein E, has exhibited potent antimicrobial properties against various bacterial strains, including Mycobacterium smegmatis. However, our study reveals a previously unknown resistance mechanism developed by M. smegmatis against COG1410 involving ClpC. Upon subjecting M. smegmatis to serial passages in the presence of sub-MIC COG1410, resistance emerged. The comparative genomic analysis identified a point mutation in ClpC (S437P), situated within its middle domain, which led to high resistance to COG1410 without compromising bacterial fitness. Complementation of ClpC in mutant restored bacterial sensitivity. In-depth analyses, including transcriptomic profiling and in vitro assays, uncovered that COG1410 interferes with ClpC at both transcriptional and functional levels. COG1410 not only stimulated the ATPase activity of ClpC but also enhanced the proteolytic activity of Clp protease. SPR analysis confirmed that COG1410 directly binds with ClpC. Surprisingly, the identified S437P mutation did not impact their binding affinity. This study sheds light on a unique resistance mechanism against AMPs in mycobacteria, highlighting the pivotal role of ClpC in this process. Unraveling the interplay between COG1410 and ClpC enriches our understanding of AMP-bacterial interactions, offering potential insights for developing innovative strategies to combat antibiotic resistance. [ABSTRACT FROM AUTHOR]

Spatial navigation (SN) has been reported to be one of the first cognitive domains to be affected in Alzheimer's disease (AD), which occurs as a result of progressive neuropathology involving specific brain areas. Moreover, the epsilon 4 isoform of apolipoprotein-E (APOE-ε4) has been associated with both sporadic and familial late-onset AD, and patients with mild cognitive impairment (MCI) due to AD are more likely to progressively deteriorate. Spatial navigation performance will be examined on a sample of 76 community-dwelling senior citizens (25 healthy controls; 25 individuals with subjective cognitive decline (SCD); and 26 patients with MCI due to AD) via a virtual computer-based task (i.e., the AppleGame) and a naturalistic task (i.e., the Detour Navigation Test—modified version) for which a wearable device with sensors will be used for recording gait data and revealing physiological parameters that may be associated with spatial disorientation. We expect that patients with MCI due to AD and APOE-ε4 carriers will show altered SN performances compared to individuals with SCD and healthy controls in the experimental tasks, and that VR testing may predict ecological performance. Impaired SN performances in people at increased risk of developing AD may inform future cognitive rehabilitation protocols for counteracting spatial disorientation that may occur during elders' traveling to unfamiliar locations. The research protocol has been approved by the Ethics Committee of the Istituto Auxologico Italiano. Findings will be published in peer-reviewed medical journals and discussed in national and international congresses. [ABSTRACT FROM AUTHOR]

Presenilin, a transmembrane protein primarily known for its role in Alzheimer's disease (AD) as part of the γ-secretase complex, has garnered increased attention due to its multifaceted functions in various cellular processes. Recent investigations have unveiled a plethora of functions beyond its amyloidogenic role. This review aims to provide a comprehensive overview of presenilin's diverse roles in AD and other neurodegenerative disorders. It includes a summary of well-known substrates of presenilin, such as its involvement in amyloid precursor protein (APP) processing and Notch signaling, along with other functions. Additionally, it highlights newly discovered functions, such as trafficking function, regulation of ferritin expression, apolipoprotein E (ApoE) secretion, the interaction of ApoE and presenilin, and the Aβ42-to-Aβ40-converting activity of ACE. This updated perspective underscores the evolving landscape of presenilin research, emphasizing its broader impact beyond established pathways. The incorporation of these novel findings accentuates the dynamic nature of presenilin's involvement in cellular processes, further advancing our comprehension of its multifaceted roles in neurodegenerative disorders. By synthesizing evidence from a range of studies, this review sheds light on the intricate web of presenilin functions and their implications in health and disease. [ABSTRACT FROM AUTHOR]

Simple Summary: Glaucoma is a common eye condition linked to genes and aging. We studied genetic factors related to primary open-angle glaucoma (POAG) in adult Arabs from Saudi Arabia. We focused on two specific variations in apolipoprotein gene (APOE), namely rs429358 and rs7412, to examine whether these variations are more common in people with POAG. We compared the DNA from 179 people with POAG and 251 without. Our results showed that these genetic changes were not significantly linked to POAG. We also checked different combinations of these variations but did not observe a strong connection with POAG risk. The gene variations also did not affect eye pressure or other eye indicators, such as cup/disc, ratio linked to POAG. Overall, in our Saudi group, these specific gene variations do not seem to be major factors causing POAG. However, more studies with larger groups are needed to confirm this. Adult-onset glaucoma, an age-related neurodegenerative disease, is very prevalent among the elderly Arabs of Saudi origin. This study investigated the association between apolipoprotein E (APOE) gene variants (rs429358 and rs7412) and primary open-angle glaucoma (POAG) in Arabs of Saudi origin. A case-control genetic association study involving 179 POAG patients and 251 controls utilized Sanger sequencing to genotype APOE gene variants. The allele frequencies and genotype distributions for rs429358 and rs7412 did not show significant associations with POAG. The haplotype analysis revealed apoε3 (87.6% and 87.4%) as the most prevalent, followed by ε4 (2.8% and 3.6%) and ε2 (9.6% and 8.9%) in the controls and POAG patients, respectively. Although the ε2/ε3 genotype and ε2-carriers displayed a more than two-fold increased risk, statistical significance was not reached. Notably, these polymorphisms did not affect clinical markers, such as intraocular pressure and cup/disc ratio. The logistic regression analysis demonstrated no significant influence of age, sex, rs429358, or rs7412 polymorphisms on POAG. In conclusion, within the Saudi cohort, APOE variants (rs429358 and rs7412) do not appear to be associated with POAG and are not substantial risk factors for its development. However, additional population-based studies are required to validate these findings. [ABSTRACT FROM AUTHOR]

Recent advancements in genome analysis technology have revealed the presence of read-through transcripts in which transcription continues by skipping the polyA signal. We here identified and characterized a new read-through transcript, TOMM40-APOE. With cDNA amplification from THP-1 cells, the TOMM40-APOE3 product was successfully generated. We also generated TOMM40-APOE4, another isoform, by introducing point mutations. Notably, while APOE3 and APOE4 exhibited extracellular secretion, both TOMM40-APOE3 and TOMM40-APOE4 were localized exclusively to the mitochondria. But functionally, they did not affect mitochondrial membrane potential. Cell death induction studies illustrated increased cell death with TOMM40-APOE3 and TOMM40-APOE4, and we did not find any difference in cellular function between the two isoforms. These findings indicated that the new mitochondrial protein TOMM40-APOE has cell toxic ability. [ABSTRACT FROM AUTHOR]

APOE ε4 polymorphism has been recently described as a possible association with cognitive deficits in COVID-19 patients. This research aimed to establish the correlation between COVID-19 and cognitive impairment, and the APOE gene polymorphism among outpatients. We performed a cross-sectional study with confirmed COVID-19 patients and neurological symptoms that persisted for more than three months from onset. APOE genotypes were determined. The final number of patients included in this study was 219, of which 186 blood samples were collected for APOE genotyping, evaluated 4.5 months after COVID-19. Among the participants, 143 patients (65.3%) reported memory impairment symptoms as their primary concern. However, this complaint was objectively verified through screening tests (Addenbrooke Cognitive Examination-Revised and Mini-Mental State Examination) in only 36 patients (16.4%). The group experiencing cognitive decline exhibited a higher prevalence of the APOE ε4 allele than the normal group (30.8% vs. 16.4%, respectively, p = 0.038). Furthermore, the APOE ε4 allele and anxiety symptoms remained significant after multivariate analysis. This study assessed an outpatient population where cognitive changes were the primary complaint, even in mild cases. Moreover, the ε4 allele, sleep disorders, and anxiety symptoms were more frequent in the cognitive decline group. [ABSTRACT FROM AUTHOR]

Type 2 diabetes mellitus (DM) is a chronic metabolic disorder posing multifaceted challenges to global public health. Among its numerous complications, infected diabetic foot ulcers (IDFUs) represent a particularly debilitating consequence. Beyond cardiovascular implications, there is an emerging understanding of the interconnectedness among IDFUs, neuropathy, atherosclerosis, and dyslipidemia. IDFUs, peripheral neuropathy, and atherosclerosis share common risk factors and mechanistic pathways. The primary objective of this study was to characterize the lipid profiles in DM patients with IDFUs, comparing them with DM patients without foot ulcers, and with a control group of healthy subjects. The secondary objectives included evaluating apolipoprotein E (ApoE) levels across these study groups and comparing lipid profiles within IDFU subgroups. A total of 160 patients were assessed for this study. After applying exclusion criteria, 140 participants were included, divided into three groups: Group IDFU (80 patients with IDFUs), Group DM (32 patients with DM but no foot ulcers), and Group Controls (28 healthy controls). Compared to Group DM, Group IDFU demonstrated lower levels of high-density lipoprotein cholesterol (HDL-C) (30.9 ± 12.6 mg/dL vs. 40.8 ± 16.6 mg/dL, p = 0.002), but improved levels of ApoE (160.9 ± 68.4 mg/dL vs. 197.2 ± 69.6 mg/dL, p = 0.01), triglycerides (TG) (126.9 ± 56.2 mg/dL vs. 165.8 ± 79.0 mg/dL, p = 0.004), low-density lipoprotein cholesterol (LDL-C) (84.2 ± 32.3 mg/dL vs. 92.3 ± 39.3 mg/dL, p = 0.1), and total cholesterol (133.6 ± 43 mg/dL vs. 164.6 ± 44.4 mg/dL, p = 0.002). The IDFU patients exhibit improved lipid profiles, excepting HDL-C, which is unusual because IDFU follows complications related to dyslipidemia for DM patients. Anemia, impaired renal function, and elevated TG levels were identified as biomarkers for mortality among patients with IDFUs. The data suggest that a lower level of HDL-C and an improved lipid profile may indicate a systemic end-stage disease manifestation in DM patients with IDFUs. [ABSTRACT FROM AUTHOR]

The genetic etiology of Keratoconus (KC) in Middle Eastern Arabs of Saudi origin is still unclear. A recent genome-wide study identified two significant loci in the region of PNPLA2 (rs61876744) and CSNK1E (rs138380) for KC that may be associated with KC in the Saudi population. In addition, polymorphisms in the apolipoprotein E (APOE) gene, namely, rs429358 and rs7412, responsible for APOE allelic variants ε2, ε3, and ε4, may influence KC via oxidative stress mechanism(s). Thus, we investigated the possible association of polymorphisms rs61876744, rs138380, rs429358, rs7412, and APOE genotypes in KC patients of the Saudi population. This study included 98 KC cases and 167 controls. Polymorphisms rs6187644 and rs138380 were genotyped using TaqMan assays, and rs429358 and rs7412 were genotyped via Sanger sequencing. Although the allele frequency of rs61876744(T) in PNPLA2 was a protective effect against KC (odds ratio (OR) = 0.64, 95% confidence interval (CI) = 0.44–0.93), the p-value (p = 0.020) was not significant for multiple testing correction (p = 0.05/4 = 0.015). However, rs6187644 genotype showed a modestly significant protective effect in the dominant model (OR = 0.53, 95% CI = 0.32–0.88, p = 0.013). Polymorphisms rs138380, rs429358, and rs7412 showed no significant allelic or genotype association with KC. However, the ε2-carriers (ε2/ε2 and ε2/ε3 genotypes) exhibited a greater than 5-fold increased risk of KC, albeit non-significantly (p = 0.055). Regression analysis showed no significant effect of age, gender, and the four polymorphisms on KC. Our results suggest that polymorphism rs6187644 in PNPLA2 might be associated with KC in the Middle Eastern Arabs of Saudi origin but warrant a large-scale association analysis at this locus. [ABSTRACT FROM AUTHOR]

Alzheimer's disease (AD) is a complex multifactorial disorder that poses a substantial burden on patients, caregivers, and society. Considering the increased aging population and life expectancy, the incidence of AD will continue to rise in the following decades. However, the molecular pathogenesis of AD remains controversial, superior blood-based biomarker candidates for early diagnosis are still lacking, and effective therapeutics to halt or slow disease progression are urgently needed. As powerful genetic regulators, microRNAs (miRNAs) are receiving increasing attention due to their implications in the initiation, development, and theranostics of various diseases, including AD. In this review, we summarize miRNAs that directly target microtubule-associated protein tau (MAPT), amyloid precursor protein (APP), and β-site APP-cleaving enzyme 1 (BACE1) transcripts and regulate the alternative splicing of tau and APP. We also discuss related kinases, such as glycogen synthase kinase (GSK)-3β, cyclin-dependent kinase 5 (CDK5), and death-associated protein kinase 1 (DAPK1), as well as apolipoprotein E, that are directly targeted by miRNAs to control tau phosphorylation and amyloidogenic APP processing leading to Aβ pathologies. Moreover, there is evidence of miRNA-mediated modulation of inflammation. Furthermore, circulating miRNAs in the serum or plasma of AD patients as noninvasive biomarkers with diagnostic potential are reviewed. In addition, miRNA-based therapeutics optimized with nanocarriers or exosomes as potential options for AD treatment are discussed. [ABSTRACT FROM AUTHOR]

Autism spectrum disorder (ASD) is a neurodevelopmental disability and recent evidence suggests that autistic adults are more likely to develop Alzheimer's disease (Alz) and other dementias compared to neurotypical (NT) adults. The ε4-allele of the Apolipoprotein E (APOE) gene is the strongest genetic risk factor for Alz and negatively impacts cognition in middle-aged and older (MA+) adults. This study aimed to determine the impact of the APOE ε4-allele on verbal learning and memory in MA+ autistic adults (ages 40–71 years) compared to matched NT adults. Using the Auditory Verbal Learning Test (AVLT), we found that ε4 carriers performed worse on short-term memory and verbal learning across diagnosis groups, but there was no interaction with diagnosis. In exploratory analyses within sex and diagnosis groups, only autistic men carrying APOE ε4 showed worse verbal learning (p = 0.02), compared to autistic men who were not carriers. Finally, the APOE ε4-allele did not significantly affect long-term memory in this sample. These findings replicate previous work indicating that the APOE ε4-allele negatively impacts short-term memory and verbal learning in MA+ adults and presents new preliminary findings that MA+ autistic men may be vulnerable to the effects of APOE ε4 on verbal learning. Future work with a larger sample is needed to determine if autistic women may also be vulnerable. [ABSTRACT FROM AUTHOR]

Tightly regulated and highly adaptive lipid metabolic and transport pathways are critical to maintaining brain cellular lipid homeostasis and responding to lipid and inflammatory stress to preserve brain function and health. Deficits in the lipid handling genes APOE and GBA1 are the most significant genetic risk factors for Lewy body dementia and related dementia syndromes. Parkinson's disease patients who carry both APOE4 and GBA1 variants have accelerated cognitive decline compared to single variant carriers. To investigate functional interactions between brain ApoE and GBA1, in vivo GBA1 inhibition was tested in WT versus ApoE-deficient mice. The experiments demonstrated glycolipid stress caused by GBA1 inhibition in WT mice induced ApoE expression in several brain regions associated with movement and dementia disorders. The absence of ApoE in ApoE-KO mice amplified complement C1q elevations, reactive microgliosis and astrocytosis after glycolipid stress. Mechanistically, GBA1 inhibition triggered increases in cell surface and intracellular lipid transporters ABCA1 and NPC1, respectively. Interestingly, the absence of NPC1 in mice also triggered elevations of brain ApoE levels. These new data show that brain ApoE, GBA1 and NPC1 functions are interconnected in vivo, and that the removal or reduction of ApoE would likely be detrimental to brain function. These results provide important insights into brain ApoE adaptive responses to increased lipid loads. [ABSTRACT FROM AUTHOR]

Background: A socioeconomic crisis in Russia lasted from 1991 to 1998 and was accompanied by a sharp drop in the birth rate. The main factor that influenced the refusal to have children during this period is thought to be prolonged social stress. Methods: comparing frequencies of common gene variants associated with stress-induced diseases among generations born before, after, and during this crisis may show which genes may be preferred under the pressure of natural selection during periods of increased social stress in urban populations. Results: In the "crisis" group, a statistically significant difference from the other two groups was found in rs6557168 frequency (p = 0.001); rs4522666 was not in the Hardy–Weinberg equilibrium in this group, although its frequency did not show a significant difference from the other groups (p = 0.118). Frequencies of VNTRs in SLC6A3 and MAOA as well as common variants rs17689918 in CRHR1, rs1360780 in FKBP5, rs53576 in OXTR, rs12720071 and rs806377 in CNR1, rs4311 in ACE, rs1800497 in ANKK1, and rs7412 and rs429358 in APOE did not differ among the groups. Conclusions: a generation born during a period of prolonged destructive events may differ from the rest of the gene pool of the population in some variants associated with personality traits or stress-related disorders. [ABSTRACT FROM AUTHOR]

The underlying genetic susceptibility for Alzheimer's disease (AD) is not yet fully understood. The heterogeneous nature of the disease challenges genetic association studies. Endophenotype approaches can help to address this challenge by more direct interrogation of biological traits related to the disease. AD endophenotypes based on amyloid-β, tau, and neurodegeneration (A/T/N) biomarkers and cognitive performance were selected from the Alzheimer's Disease Neuroimaging Initiative (ADNI) cohort (N = 1565). A genome-wide association study (GWAS) of quantitative phenotypes was performed using an SNP main effect and an SNP by Diagnosis interaction (SNP × DX) model to identify disease stage-specific genetic effects. Nine loci were identified as study-wide significant with one or more A/T/N endophenotypes in the main effect model, as well as additional findings significantly associated with cognitive measures. These nine loci include SNPs in or near the genes APOE, SRSF10, HLA-DQB1, XKR3, and KIAA1671. The SNP × DX model identified three study-wide significant genetic loci (BACH2, EP300, and PACRG-AS1) with a neuroprotective effect in later AD stage endophenotypes. An endophenotype approach identified novel genetic associations and provided insight into the molecular mechanisms underlying the genetic associations that may otherwise be missed using conventional case-control study designs. [ABSTRACT FROM AUTHOR]

This study explores the potential impact of metformin on the development of severe dementia in individuals with Alzheimer's disease (AD) and type 2 diabetes mellitus (T2DM). With an emerging interest in the role of the APOE genotype in mediating metformin's effects on cognitive decline in AD patients, we sought to investigate whether metformin usage is associated with a reduced risk of severe dementia. Using data from the National Alzheimer's Coordinating Center (NACC) database (2005–2021), we identified 1306 participants with both AD and T2DM on diabetes medications. These individuals were categorized based on metformin usage, and a propensity score-matched cohort of 1042 participants was analyzed. Over an average follow-up of 3.6 years, 93 cases of severe dementia were observed. A Kaplan–Meier analysis revealed that metformin users and non-users had similar probabilities of remaining severe dementia-free (log-rank p = 0.56). Cox proportional hazards models adjusted for covariates showed no significant association between metformin usage and a lower risk of severe dementia (HR, 0.96; 95% CI, 0.63–1.46; p = 0.85). A subgroup analysis based on APOE ε4 carrier status demonstrated consistent results, with metformin use not correlating with a reduced severe dementia risk. In conclusion, our findings from a substantial cohort of AD and T2DM patients suggest that metformin usage is not significantly associated with a decreased risk of severe dementia. This observation persists across APOE ε4 carriers and non-carriers, indicating a lack of genotype-mediated effect. [ABSTRACT FROM AUTHOR]

Purpose: To investigate the relationship between the apolipoprotein E (APOE) ε4 allele and retinal structural and vascular characteristics in older adult participants from several research studies. We also studied the relationship between these structural and vascular characteristics with multifocal visual evoked potential (mfVEP) indices, neuropsychological parameters and MRI brain volumes in these participants. Methods: In this study, 109 participants with a mean (SD) age of 67.1 (9.0) years were recruited. Participants were classified as APOE ε4 carriers or non-carriers based on the presence or absence of the ε4 allele. Baseline measurements included peripapillary retinal nerve fibre layer optical coherence tomography (RNFL OCT), and OCT–angiography (OCT-A) for evaluation of the retinal layer thickness and vessel density (VD) parameters. A multifocal visual evoked potential (mfVEP) test, including amplitude and latency, was used to assess the visual pathway function. Finally, cognitive function was evaluated using a battery of neuropsychological tests. OCT-A images were analysed in ImageJ to quantify VD in the superficial and deep vascular plexus and the size of the foveal avascular zone (FAZ). The relationship between carriers of APOE ε4 allele and these ocular parameters was analysed using generalised estimating equation (GEE) models and data adjusted for age, sex and inter-eye differences as within-subject variables (p < 0.05). Results: Twenty-four participants were APOE ε4 carriers. Temporal RNFL thickness was decreased in APOE ε4 carriers (p < 0.01). Vessel density between carriers and non-carriers was not significantly different at either the superficial or deep level. The FAZ area was significantly smaller in ε4 carriers in both superficial (p < 0.01) and deep layers (p < 0.003). Conclusions: Retinal abnormalities were present in participants with increased genetic risk of dementia due to presence of the ε4 allele. These findings provide preliminary evidence for their potential role in the diagnosis of dementia. [ABSTRACT FROM AUTHOR]

The polygenic risk score (PRS), together with the ɛ4 allele of the APOE gene (APOE-ɛ4), has shown high potential for Alzheimer's disease (AD) risk prediction. The aim of this study was to validate the model of polygenic risk in Russian patients with dementia. A microarray-based assay was developed to identify 21 markers of polygenic risk and ɛ alleles of the APOE gene. This case–control study included 348 dementia patients and 519 cognitively normal volunteers. Cerebrospinal fluid (CSF) amyloid-β (Aβ) and tau protein levels were assessed in 57 dementia patients. PRS and APOE-ɛ4 were significant genetic risk factors for dementia. Adjusted for APOE-ɛ4, individuals with PRS corresponding to the fourth quartile had an increased risk of dementia compared to the first quartile (OR 1.85; p-value 0.002). The area under the curve (AUC) was 0.559 for the PRS model only, and the inclusion of APOE-ɛ4 improved the AUC to 0.604. PRS was positively correlated with tTau and pTau181 and inversely correlated with Aβ42/Aβ40 ratio. Carriers of APOE-ɛ4 had higher levels of tTau and pTau181 and lower levels of Aβ42 and Aβ42/Aβ40. The developed assay can be part of a strategy for assessing individuals for AD risk, with the purpose of assisting primary preventive interventions. [ABSTRACT FROM AUTHOR]

Background: APOE polymorphism and the Kynurenine pathway (KP) are associated with many disorders, but little is known about associations between APOE polymorphism and the KP. This study explored the associations between the KP and APOE polymorphism in disorders associated with APOE polymorphism and changes in the KP. Methods: Subjects with morbid obesity before and after bariatric surgery (numbers 139 and 95, respectively), depression (number 49), and unspecified neurological symptoms (number 39) were included. The following grouping of the APOE genotypes was used: E2 = ɛ2ɛ2 + ɛ2ɛ3, E3 = ɛ3ɛ3 + ɛ2ɛ4, and E4 = ɛ3ɛ4 + ɛ4ɛ4. The KP metabolites Tryptophan, Kynurenine, Kynurenic acid, Quinolinic acid, and Xanthurenic acid were quantified in serum. Results: The main findings were a significant positive association between E3 and Quinolinic acid (difference between E3 and E2E4: 12.0 (3.5; 18.6) ng/mL); p = 0.005), and a negative association between E4 and Kynurenine (difference between E4 and E2E3: −31.3 (−54.2; −3.2) ng/mL; p = 0.008). Quinolinic acid has been ascribed neurotoxic and inflammatory effects, and Kynurenine is a marker of inflammation. Conclusions: The findings indicate that APOE polymorphism might cause changes in the KP that contribute to the disease. Inflammation could be the link between APOE and the KP. [ABSTRACT FROM AUTHOR]

Many studies aim to detect the early phase of dementia. One of the major ways to achieve this is to identify corresponding biomarkers, particularly immune blood biomarkers. The objective of this study was to identify such biomarkers in patients with mild cognitive impairment (MCI) in an experiment that included cognitive training. A group of patients with MCI diagnoses over the age of 65 participated in the study (n = 136). Measurements of cognitive functions (using the Mini-Mental State Examination scale and Montreal Cognitive Assessment) and determination of 27 serum biomarkers were performed twice: on the first visit and on the second visit, one year after the cognitive training. APOE genotypes were also determined. Concentrations of EGF (F = 17; p = 0.00007), Eotaxin (F = 7.17; p = 0.008), GRO (F = 13.42; p = 0.0004), IL-8 (F = 8.16; p = 0.005), MCP-1 (F = 13.46; p = 0.0001) and MDC (F = 5.93; p = 0.016) increased after the cognitive training in MCI patients. All these parameters except IL-8 demonstrated a weak correlation with other immune parameters and were poorly represented in the principal component analysis. Differences in concentrations of IP-10, FGF-2, TGFa and VEGF in patients with MCI were associated with APOE genotype. Therefore, the study identified several immune blood biomarkers that could potentially be associated with changes in cognitive function. [ABSTRACT FROM AUTHOR]

Familial dysbetalipoproteinemia (FD) is a highly atherogenic genetically based lipid disorder with an underestimated actual prevalence. In recent years, several biochemical algorithms have been developed to diagnose FD using available laboratory tests. The practical applicability of FD diagnostic criteria and the prevalence of FD in Russia have not been previously assessed. We demonstrated that the diagnostic algorithms of FD, including the diagnostic apoB levels, require correction, taking into account the distribution of apoB levels in the population. At the same time, a triglycerides cutoff ≥ 1.5 mmol/L may be a useful tool in identifying subjects with FD. In this study, a high prevalence of FD was detected: 0.67% (one in 150) based on the ε2ε2 haplotype and triglycerides levels ≥ 1.5 mmol/L. We also analyzed the presence and pathogenicity of APOE variants associated with autosomal dominant FD in a large research sample. [ABSTRACT FROM AUTHOR]

Black/African American (AA) individuals have a higher risk of Alzheimer's disease (AD) than White non-Hispanic persons of European ancestry (EUR) for reasons that may include economic disparities, cardiovascular health, quality of education, and biases in the methods used to diagnose AD. AD is also heritable, and some of the differences in risk may be due to genetics. Many AD-associated variants have been identified by candidate gene studies, genome-wide association studies (GWAS), and genome-sequencing studies. However, most of these studies have been performed using EUR cohorts. In this paper, we review the genetics of AD and AD-related traits in AA individuals. Importantly, studies of genetic risk factors in AA cohorts can elucidate the molecular mechanisms underlying AD risk in AA and other populations. In fact, such studies are essential to enable reliable precision medicine approaches in persons with considerable African ancestry. Furthermore, genetic studies of AA cohorts allow exploration of the ways the impact of genes can vary by ancestry, culture, and economic and environmental disparities. They have yielded important gains in our knowledge of AD genetics, and increasing AA individual representation within genetic studies should remain a priority for inclusive genetic study design. [ABSTRACT FROM AUTHOR]

The definition of Alzheimer's disease (AD) now considers the presence of the markers of amyloid (A), tau deposition (T), and neurodegeneration (N) essential for diagnosis. AD patients have been reported to have increased blood–brain barrier (BBB) dysfunction, but that has not been tested within the ATN framework so far. As the field is moving towards the use of blood-based biomarkers, the relationship between BBB disruption and AD-specific biomarkers requires considerable attention. Moreover, other factors have been previously implicated in modulating BBB permeability, including age, gender, and ApoE status. A total of 172 cognitively impaired individuals underwent cerebrospinal fluid (CSF) analysis for AD biomarkers, and data on BBB dysfunction, demographics, and ApoE status were collected. Our data showed that there was no difference in BBB dysfunction across different ATN subtypes, and that BBB damage was not correlated with cognitive impairment. However, patients with BBB disruption, if measured with a high Qalb, had low Aβ40 levels. ApoE status did not affect BBB function but had a dose-dependent effect on the Aβ42/40 ratio. These results might highlight the importance of understanding dynamic changes across the BBB in future studies in patients with AD. [ABSTRACT FROM AUTHOR]

Background: Past studies identified a link between weight loss and dementia, but lacked consistent conclusions. We sought to establish this link by examining the weight change profiles before and after dementia diagnosis. Methods: Using data from the Health and Retirement Study (1996–2020), we examined 13,123 participants. We conducted a nested case–control analysis to assess differences in biennial weight change profile while controlling for BMI, longevity polygenic risk scores, and APOE gene variants. Results: Participants with a memory disorder lost weight (−0.63%) biennially, whereas those without a diagnosis did not (+0.013%, p-value < 0.0001). Our case–control study shows a significant difference (p-value < 0.01) in pre-dementia % weight changes between the cases (−0.29%) and controls (0.19%), but not in post-dementia weight changes. The weight loss group have the highest risk (OR = 2.01; p-value < 0.0001) of developing a memory disorder compared to the stable weight and weight gain groups. The observations hold true after adjusting for BMI, longevity polygenic risk scores, and APOE variant in a multivariable model. Conclusions: We observe that weight loss in dementia is a physiological process independent of genetic factors associated with BMI and longevity. Pre-dementia weight loss may be an important prognostic criterion to assess a person's risk of developing a memory disorder. [ABSTRACT FROM AUTHOR]

The ε2 allele of apolipoprotein E (ε2) has neuroprotective effects against beta-amyloid (Aβ) pathology in Alzheimer's disease (AD). However, its impact on the functional connectivity and hub efficiency in cognitively normal older adults (CN) with ε2 is unclear. We investigated the functional connectivity differences in the default mode network (DMN), salience network, and central executive network (CEN) between A-PET-negative (N = 29) and A-PET-positive (N = 15) CNs with ε2/ε2 or ε2/ε3 genotypes. The A-PET-positive CNs exhibited a lower anterior DMN functional connectivity, higher posterior DMN functional connectivity, and increased CEN functional connectivity compared to the A-PET-negative CNs. Cerebral Aβ retention was negatively correlated with anterior DMN functional connectivity and positively correlated with posterior DMN and anterior CEN functional connectivity. A graph theory analysis showed that the A-PET-positive CNs displayed a higher betweenness centrality in the middle frontal gyrus (left) and medial fronto-parietal regions (left). The betweenness centrality in the middle frontal gyrus (left) was positively correlated with Aβ retention. Our findings reveal a reversed anterior–posterior dissociation in the DMN functional connectivity and heightened CEN functional connectivity in A-PET-positive CNs with ε2. Hub efficiencies, measured by betweenness centrality, were increased in the DMN and CEN of the A-PET-positive CNs with ε2. These results suggest unique functional connectivity responses to Aβ pathology in CN individuals with ε2. [ABSTRACT FROM AUTHOR]

Statins are common drugs that are clinically used to reduce elevated plasma cholesterol levels. Based on their solubility, statins are considered to be either hydrophilic or lipophilic. Amongst them, simvastatin has the highest lipophilicity to facilitate its ability to cross the blood-brain barrier. Recent studies have suggested that simvastatin could be a promising therapeutic option for different brain complications and diseases ranging from brain tumors (i.e., medulloblastoma and glioblastoma) to neurological disorders (i.e., Alzheimer's disease, Parkinson's disease, and Huntington's disease). Specific mechanisms of disease amelioration, however, are still unclear. Independent studies suggest that simvastatin may reduce the risk of developing certain neurodegenerative disorders. Meanwhile, other studies point towards inducing cell death in brain tumor cell lines. In this review, we outline the potential therapeutic effects of simvastatin on brain complications and review the clinically relevant molecular mechanisms in different cases. [ABSTRACT FROM AUTHOR]

Cholesterol metabolism dysregulation is associated with several neurological disorders. In Huntington's disease (HD), several enzymes involved in cholesterol metabolism are downregulated, among which the neuronal cholesterol 24-hydroxylase, CYP46A1, is of particular interest. The restoration of CYP46A1 expression in striatal neurons of HD mouse models is beneficial for motor behavior, cholesterol metabolism, transcriptomic activity, and alleviates neuropathological hallmarks induced by mHTT. Among the genes regulated after CYP46A1 restoration, those involved in cholesterol synthesis and efflux may explain the positive effect of CYP46A1 on cholesterol precursor metabolites. Since cholesterol homeostasis results from a fine-tuning between neurons and astrocytes, we quantified the distribution of key genes regulating cholesterol metabolism and efflux in astrocytes and neurons using in situ hybridization coupled with S100β and NeuN immunostaining, respectively. Neuronal expression of CYP46A1 in the striatum of HD zQ175 mice increased key cholesterol synthesis driver genes (Hmgcr, Dhcr24), specifically in neurons. This effect was associated with an increase of the srebp2 transcription factor gene that regulates most of the genes encoding for cholesterol enzymes. However, the cholesterol efflux gene, ApoE, was specifically upregulated in astrocytes by CYP46A1, probably though a paracrine effect. In summary, the neuronal expression of CYP46A1 has a dual and specific effect on neurons and astrocytes, regulating cholesterol metabolism. The neuronal restoration of CYP46A1 in HD paves the way for future strategies to compensate for mHTT toxicity. [ABSTRACT FROM AUTHOR]

The Apolipoprotein E (APOE) locus has garnered significant clinical interest because of its association with Alzheimer's disease (AD) and longevity. This genetic association appears across multiple genes in the APOE locus. Despite the apparent differences between AD and longevity, both conditions share a commonality of aging-related changes in mitochondrial function. This commonality is likely due to accumulative biological effects partly exerted by the APOE locus. In this study, we investigated changes in mitochondrial structure/function-related markers using oxidative stress-induced human cellular models and postmortem brains (PMBs) from individuals with AD and normal controls. Our results reveal a range of expressional alterations, either upregulated or downregulated, in these genes in response to oxidative stress. In contrast, we consistently observed an upregulation of multiple APOE locus genes in all cellular models and AD PMBs. Additionally, the effects of AD status on mitochondrial DNA copy number (mtDNA CN) varied depending on APOE genotype. Our findings imply a potential coregulation of APOE locus genes possibly occurring within the same topologically associating domain (TAD) of the 3D chromosome conformation. The coordinated expression of APOE locus genes could impact mitochondrial function, contributing to the development of AD or longevity. Our study underscores the significant role of the APOE locus in modulating mitochondrial function and provides valuable insights into the underlying mechanisms of AD and aging, emphasizing the importance of this locus in clinical research. [ABSTRACT FROM AUTHOR]

Alzheimer's disease (AD) is the most common neurodegenerative dementia, for which the molecular origins, genetic predisposition and therapeutic approach are still debated. In the 1980s, cells from AD patients were reported to be sensitive to ionizing radiation. In order to examine the molecular basis of this radiosensitivity, the ATM-dependent DNA double-strand breaks (DSB) signaling and repair were investigated by applying an approach based on the radiation-induced ataxia telangiectasia-mutated (ATM) protein nucleoshuttling (RIANS) model. Early after irradiation, all ten AD fibroblast cell lines tested showed impaired DSB recognition and delayed RIANS. AD fibroblasts specifically showed spontaneous perinuclear localization of phosphorylated ATM (pATM) forms. To our knowledge, such observation has never been reported before, and by considering the role of the ATM kinase in the stress response, it may introduce a novel interpretation of accelerated aging. Our data and a mathematical approach through a brand-new model suggest that, in response to a progressive and cumulative stress, cytoplasmic ATM monomers phosphorylate the APOE protein (pAPOE) close to the nuclear membrane and aggregate around the nucleus, preventing their entry in the nucleus and thus the recognition and repair of spontaneous DSB, which contributes to the aging process. Our findings suggest that pATM and/or pAPOE may serve as biomarkers for an early reliable diagnosis of AD on any fibroblast sample. [ABSTRACT FROM AUTHOR]

The role of genetics as a predisposing factor related to an increased risk of developing long COVID symptomatology is under debate. The aim of the current secondary analysis was to identify the association between the Apolipoprotein E (ApoE) gene, a gene affecting cholesterol metabolism and previously associated with a higher risk of SARS-CoV-2 infection and COVID-19 severity, and the development of long COVID in a cohort of individuals who had been hospitalized by SARS-CoV-2 infection. Unstimulated whole saliva samples were collected from 287 previously hospitalized COVID-19 survivors. Three genotypes of the ApoE gene (ApoE ε2, ε3, ε4) were obtained based on the combination of ApoE rs429358 and ApoE rs7412 polymorphisms. Participants were asked to self-report the presence of any post-COVID symptom in a face-to-face interview at 17.8 ± 5.2 months after hospital discharge and medical records were obtained. Each participant reported 3.0 (1.9) post-COVID symptoms. Overall, no significant differences in long COVID symptoms were observed depending on the ApoE genotype (ApoE ε2, ApoE ε3, ApoE ε4). The presence of the ApoE ε4 genotype, albeit associated with a higher risk of SARS-CoV-2 infection and COVID-19 severity, did not appear to predispose for the presence of long COVID in our cohort of previously hospitalized COVID-19 survivors. [ABSTRACT FROM AUTHOR]

Alzheimer's disease (AD) is the most prevalent neurodegenerative disease worldwide, but therapeutic strategies to slow down AD pathology and symptoms have not yet been successful. While attention has been focused on neurodegeneration in AD pathogenesis, recent decades have provided evidence of the importance of microglia, and resident immune cells in the central nervous system. In addition, new technologies, including single-cell RNA sequencing, have revealed heterogeneous cell states of microglia in AD. In this review, we systematically summarize the microglial response to amyloid-β and tau tangles, and the risk factor genes expressed in microglia. Furthermore, we discuss the characteristics of protective microglia that appear during AD pathology and the relationship between AD and microglia-induced inflammation during chronic pain. Understanding the diverse roles of microglia will help identify new therapeutic strategies for AD. [ABSTRACT FROM AUTHOR]

KLOTHO-VS heterozygosity (KL-VShet+) promotes longevity and protects against cognitive decline in aging. To determine whether KL-VShet+ mitigates Alzheimer's disease (AD) progression, we used longitudinal linear-mixed models to compare the rate of change in multiple cognitive measures in AD patients stratified by APOE ε4 carrier status. We aggregated data on 665 participants (208 KL-VShet−/ε4−, 307 KL-VShet−/ε4+, 66 KL-VShet+/ε4−, and 84 KL-VShet+/ε4+) from two prospective cohorts, the National Alzheimer's Coordinating Center and the Alzheimer's Disease Neuroimaging Initiative. All participants were initially diagnosed with mild cognitive impairment, later developed AD dementia during the study, and had at least three subsequent visits. KL-VShet+ conferred slower cognitive decline in ε4 non-carriers (+0.287 MMSE points/year, p = 0.001; −0.104 CDR-SB points/year, p = 0.026; −0.042 ADCOMS points/year, p < 0.001) but not in ε4 carriers who generally had faster rates of decline than non-carriers. Stratified analyses showed that the protective effect of KL-VShet+ was particularly prominent in male participants, those who were older than the median baseline age of 76 years, or those who had an education level of at least 16 years. For the first time, our study provides evidence that KL-VShet+ status has a protective effect on AD progression and interacts with the ε4 allele. [ABSTRACT FROM AUTHOR]

There is a lack of effective diagnostic biomarkers for neurodegenerative disorders (NDDs). Here, we established gene expression profiles for diagnosing Alzheimer's disease (AD), Parkinson's disease (PD), and vascular (VaD)/mixed dementia. Patients with AD had decreased APOE, PSEN1, and ABCA7 mRNA expression. Subjects with VaD/mixed dementia had 98% higher PICALM mRNA levels, but 75% lower ABCA7 mRNA expression than healthy individuals. Patients with PD and PD-related disorders showed increased SNCA mRNA levels. There were no differences in mRNA expression for OPRK1, NTRK2, and LRRK2 between healthy subjects and NDD patients. APOE mRNA expression had high diagnostic accuracy for AD, and moderate accuracy for PD and VaD/mixed dementia. PSEN1 mRNA expression showed promising accuracy for AD. PICALM mRNA expression was less accurate as a biomarker for AD. ABCA7 and SNCA mRNA expression showed high-to-excellent diagnostic accuracy for AD and PD, and moderate-to-high accuracy for VaD/mixed dementia. The APOE E4 allele reduced APOE expression in patients with different APOE genotypes. There was no association between PSEN1, PICALM, ABCA7, and SNCA gene polymorphisms and expression. Our study suggests that gene expression analysis has diagnostic value for NDDs and provides a liquid biopsy alternative to current diagnostic methods. [ABSTRACT FROM AUTHOR]

Gut microbiome alterations have recently been linked to many chronic conditions including cardiovascular disease (CVD). There is an interplay between diet and the resident gut microbiome, where the food eaten affects populations of certain microbes. This is important, as different microbes are associated with various pathologies, as they can produce compounds that are disease-promoting or disease-protecting. The Western diet negatively affects the host gut microbiome, ultimately resulting in heightened arterial inflammation and cell phenotype changes as well as plaque accumulation in the arteries. Nutritional interventions including whole foods rich in fiber and phytochemicals as well as isolated compounds including polyphenols and traditional medicinal plants show promise in positively influencing the host gut microbiome to alleviate atherosclerosis. This review investigates the efficacy of a vast array of foods and phytochemicals on host gut microbes and atherosclerotic burden in mice. Reduction in plaque by interventions was associated with increases in bacterial diversity, reduction in the Firmicutes/Bacteroidetes (F/B) ratio, and upregulation of Akkermansia. Upregulation in CYP7 isoform in the liver, ABC transporters, bile acid excretion, and the level of acetic acid, propionic acid, and butyric acid were also noted in several studies reducing plaque. These changes were also associated with attenuated inflammation and oxidative stress. In conclusion, an increase in the abundance of Akkermansia with diets rich in polyphenols, fiber, and grains is likely to reduce plaque burden in patients suffering from CVD. [ABSTRACT FROM AUTHOR]

Cholesterol efflux capacity (CEC) is of interest given its potential relationship with several important clinical conditions including Alzheimer's disease. The inactivation of the APOE locus in mouse models supports the idea that it is involved in determining the CEC. With that in mind, we examine the impact of the plasma metabolome profile and the APOE genotype on the CEC in cognitively healthy elderly subjects. The study subjects were 144 unrelated healthy individuals. The plasma CEC was determined by exposing cultured mouse macrophages treated with BODIPY-cholesterol to human plasma. The metabolome profile was determined using NMR techniques. Multiple regression was performed to identify the most important predictors of CEC, as well as the NMR features most strongly associated with the APOE genotype. Plasma 3-hydroxybutyrate was the variable most strongly correlated with the CEC (r = 0.365; p = 7.3 × 10−6). Male sex was associated with a stronger CEC (r = −0.326, p = 6.8 × 10−5). Most of the NMR particles associated with the CEC did not correlate with the APOE genotype. The NMR metabolomics results confirmed the APOE genotype to have a huge effect on the concentration of plasma lipoprotein particles as well as those of other molecules including omega-3 fatty acids. In conclusion, the CEC of human plasma was associated with ketone body concentration, sex, and (to a lesser extent) the other features of the plasma lipoprotein profile. The APOE genotype exerted only a weak effect on the CEC via the modulation of the lipoprotein profile. The APOE locus was associated with omega-3 fatty acid levels independent of the plasma cholesterol level. [ABSTRACT FROM AUTHOR]

The aim of this study was to disentangle the effects of various genetic factors on hippocampal subfield volumes using three different approaches: a biologically driven candidate gene approach, a hypothesis-free GWAS approach, and a polygenic approach, where AD risk alleles are combined with a polygenic risk score (PRS). The impact of these genetic factors was investigated in a large dementia-free general population cohort from the Study of Health in Pomerania (SHIP, n = 1806). Analyses were performed using linear regression models adjusted for biological and environmental risk factors. Hippocampus subfield volume alterations were found for APOE ε4, BDNF Val, and 5-HTTLPR L allele carriers. In addition, we were able to replicate GWAS findings, especially for rs17178139 (MSRB3), rs1861979 (DPP4), rs7873551 (ASTN2), and rs572246240 (MAST4). Interaction analyses between the significant SNPs as well as the PRS for AD revealed no significant results. Our results confirm that hippocampal volume reductions are influenced by genetic variation, and that different variants reveal different association patterns that can be linked to biological processes in neurodegeneration. Thus, this study underlines the importance of specific genetic analyses in the quest for acquiring deeper insights into the biology of hippocampal volume loss, memory impairment, depression, and neurodegenerative diseases. [ABSTRACT FROM AUTHOR]

Alzheimer's disease (AD) is a genetically complex disorder. In addition to the relatively small number of pathogenic variants causing autosomal dominant AD, many others have been associated with the much more common sporadic form. The E4 allele of the Apolipoprotein E (APOE) is the first discovered genetic risk factor for AD. In addition, more than 70 genetic risk loci contributing to AD have been identified. Current guidelines do not recommend AD susceptibility genetic testing in cognitively healthy adults because the implications for clinical care are limited. However, secondary prevention clinical trials of disease-modifying therapies enrol individuals based on genetic criteria, and participants are often informed of APOE testing results. Moreover, the availability of direct-to-consumer genetic testing allows individuals to learn their own AD genetic risk profile without medical supervision. A number of research protocols for AD susceptibility genetic testing have been proposed. In Italy, disclosure processes and protocols beyond those developed for inherited dementia have not been established yet. We reviewed the literature on the current practice and clinical issues related to disclosing AD genetic risk to cognitively healthy individuals and provide suggestions that may help to develop specific guidelines at the national level. [ABSTRACT FROM AUTHOR]

Hypertension is an independent risk factor for atherosclerosis. However, few models of hypertensive atherosclerosis have been established in medical research. In this study, we crossed the ApoE knockout (ApoE-KO; ApoE−/−) atherosclerotic mouse model with the NOS3 knockout (NOS3-KO; NOS3−/−) hypertensive mouse model to establish an ApoE/NOS3 double knockout (ApoE/NOS3-KO; ApoE/NOS3−/−) hypertensive atherosclerosis mouse model. We found that ApoE/NOS3−/− mice reproduced normally, had a blood pressure of 133.00 ± 3.85 mmHg, and developed hypertensive fundus retinopathy and hypertensive nephropathy. In addition, serum total cholesterol (TC) and low-density lipoprotein (LDL) levels in the blood were abnormally elevated, steatosis was observed in the liver cells, and atherosclerotic lesions were observed in the aortic vessels in ApoE/NOS3−/− adult mice. In conclusion, ApoE/NOS3−/− adult mice are a satisfactory model of hypertension and atherosclerosis and can be utilized for studies on cardiovascular diseases. [ABSTRACT FROM AUTHOR]