Sex Differences in Cortical Thickness and Neuropsychiatric Symptom Burden Based on APOE4 Homozygosity in Alzheimer's Disease.

Sex differences in patterns of cortical thickness and neuropsychiatric symptom (NPS) burden were examined among individuals with Alzheimer's disease (AD) and two copies (homozygote carriers) of the e4 allele of the apolipoprotein gene (APOE). A total of 752 participants with a clinical etiologic diagnosis of AD were selected from the National Alzheimer's Coordinating Center (NACC) database. Bayesian multilevel regression was used to examine both the within- and between-sex differences in gray-matter cortical thickness and total NPS burden associated with APOE homozygosity. Female homozygote carriers displayed a high probability of having reduced cortical thickness primarily in medial-lateral temporal regions and a greater burden of NPS, relative to both non-homozygous females and homozygous males. These findings support the notion that APOE4 status affects cortical thickness and symptom burden in men and women with AD differentially, with females showing more pronounced effects in brain areas known to be vulnerable in early AD. Future investigations should attempt to elucidate the proposed pattern of decline longitudinally.

18F-fluorodeoxyglucose PET-MR characterization of aortic inflammation in ApoE-/- mouse models of accelerated atherosclerosis: comparison of Western diet vs. uremia.

ApoE-/- mice are a widely used preclinical model of atherosclerosis, potentially accelerated by a Western diet (WD) or uremia. We aimed to compare hybrid 18F-fluorodeoxyglucose (18F-FDG) positron emission tomography-magnetic resonance (PET-MR) and immunostaining in ApoE-/- models of accelerated atherosclerosis. Five groups were studied: standard diet-fed ApoE-/- (n = 7), standard diet-fed and uremic ApoE-/- (n = 7), WD ApoE-/- (n = 7), WD and uremic ApoE-/- (n = 6), and control C57BL/6J mice (n = 6). Uremia was induced by electrocoagulation of the right kidney at 8 weeks old, followed 2 weeks later by a contralateral nephrectomy. 18F-FDG PET-MR imaging and histological staining (anti-CD4, -CD8, -CD11c, -CD20, -CD31, -CD68, -CD163, -interferon-γ, interleukin-1α, -1ß, -6, -17 A antibodies) were performed in 18-week-old mice, i.e., 8 weeks after 5/6 nephrectomy and/or WD. 18F-FDG uptake was similar in all groups. In contrast, histological staining highlighted higher percentages of CD8-, CD68-, or CD11c-positive cells in ApoE-/- aortic samples than in wild-type aortic samples. In addition, immunostaining revealed some differences between ApoE-/- mouse groups. Only the WD seemed to contribute to these differences. Using immunostaining, WD appeared to be a stronger accelerator of atherosclerosis than uremia. However, 18F-FDG PET-MR imaging failed to demonstrate in vivo increased aortic glucose uptake in these models.

Cardiorespiratory fitness, independent of APOE genotype, is associated with better neurocognitive function in older adults: An ERP study.

This study assessed the association between cardiorespiratory fitness and carriage of the apolipoprotein-E ε4 allele (APOE ε4) and cognitive function using behavioral and neuroelectric measures obtained from cognitively normal older adults. A total of 159 adults aged 50-70 years were categorized into four groups based on cardiorespiratory fitness (i.e., higher vs. lower fitness) and APOE genotype (i.e., APOE ε4 carrier vs. non-carrier). Neurocognitive functions were indexed using response time and accuracy measures from the Stroop Test and averaged mean P3 amplitudes of event-related potentials obtained during task performance. A significant main effect of cardiorespiratory fitness (p = .02) and Stroop congruency (p < .001), but not APOE genotype status, with shorter response times for the higher fitness group than for the lower fitness group and for the congruent condition relative to the incongruent condition, were observed. Similar findings were also revealed, with larger averaged mean P3 amplitudes for the higher fitness group than those in the lower fitness group, and in the congruent condition than in the incongruent condition. These findings suggest that higher cardiorespiratory fitness is linked to better neurocognitive function, and the positive association is evident regardless of APOE ε4 status and the cognitive domain assessed in cognitively normal older adults.

Comparing PCR With High-resolution Melting Analysis for Apolipoprotein E Genotyping in Alzheimer's: A Case-control Study.

Introduction: The apolipoprotein E (APOE) genotype has a heterogeneous distribution throughout the world. The present study aimed to characterize the APOE genotype (rs429358, rs7412) in healthy individuals compared with Alzheimer cases in Kerman, southeastern Iran, by two standard mutation scanning methods. Methods: In this case-control study, 90 Alzheimer patients as a case group and 90 healthy individuals as a control group were examined. APOE genotyping was carried out using high-resolution melting (HRM) analysis assay and multiplex tetra-primer amplification-refractory mutation system polymerase chain reaction (T-ARMS PCR) techniques. Results: In contrast to Multiplex T-ARMS PCR, HRM analysis was not efficient in rs7412 genotyping. The results of multiplex T-ARMS showed that ɛ2ɛ3 genotype (P=0.006, odd ratio [OR]=0.119) and ɛ2 allele (P=0.004, OR=0.129) were more prevalent in the control group compared with the case ones, whereas ɛ4 allele was associated with borderline risk of Alzheimer disease (P=0.099, OR=1.76). Conclusion: We concluded that Multiplex T-ARMS PCR could be considered as a better option than HRM analysis for APOE genotyping in terms of speed, accuracy, simplicity, and cheapness in large-scale use. Also, the present study revealed that ɛ2 ɛ3 genotype and ɛ2 allele are protective against Alzheimer whereas the ɛ4 allele cannot be strongly considered as Alzheimer genetic risk factor in Kerman, Iran. The results may help to choose a better technique for APOE genotyping.

Association of hemoglobin with plasma neurofilament light and white matter hyperintensities in Alzheimer's disease continuum.

Objective: This study aimed to investigate the association of hemoglobin (Hb) with axonal injury marker plasma neurofilament light (PNFL) and brain structure measurements in the Alzheimer's disease (AD) continuum. Methods: The data used in this study were collected from the Alzheimer's Disease Neuroimaging Initiative database. Participants with cognitively normal, mild cognitive impairment, and mild dementia were included in the data analyses. All participants had available data on blood tests, PNFL levels, neuropsychological assessments, brain structure measurements (including volumes of white matter hyperintensities [WMH], hippocampus, gray matter, and total brain), and Aß positron emission tomography standardized uptake value ratio (SUVR) at baseline. Aß-positive was defined as SUVR threshold value > 1.11. Linear regression, restricted cubic spline, and causal mediation analyses were conducted to investigate the association of Hb concentration with PNFL levels and brain structure measurements. Stratified analyses were also employed to evaluate the association between Hb concentration and PNFL levels across different APOE genotypes and sex. Results: In the Aß-positive group, Hb concentration was associated with PNFL levels (ß = -0.022, p = 0.002). Stratified analyses suggested an association between Hb concentration and PNFL in APOE ɛ4 carriers (ß = -0.031, p < 0.001) and males (ß = -0.030, p < 0.001) but not in non-carriers and females (p > 0.05). Hb concentration was also associated with WMH volume (ß = -0.04, p = 0.028), especially in APOE ɛ4 carriers, with mediation analysis revealing that PNFL mediated the association between Hb concentration and WMH volume. The association of Hb concentration with other brain structure measurements was minimal. Conclusion: In the AD continuum, Hb was associated with axonal injury marker PNFL and WMH volume, particularly in APOE ɛ4 carriers.

In 2024, the amyloid-cascade-hypothesis still remains a working hypothesis, no less but certainly no more.

The amyloid-cascade-hypothesis of the pathogenesis of Alzheimer's disease (AD) was introduced 32 years ago, in 1992. From early on, this clear and straight forward hypothesis received a lot of attention, but also a lot of substantial criticism. Foremost, there have always been massive doubts that a complex age-associated disorder of the most intricate organ of the human body, the brain, can be explained by a linear, one-dimensional cause-and-effect model. The amyloid-cascade defines the generation, aggregation, and deposition of the amyloid beta peptide as the central pathogenic mechanism in AD, as the ultimate trigger of the disease, and, consequently, as the key pharmacological target. Certainly, the original 1992 version of this hypothesis has been refined by various means, and the 'formulating fathers' followed up with a few reappraisals and partly very open reflections in 2002, 2006, 2009, and 2016. However, up until today, for the supporters of this hypothesis, the central and initial steps of the cascade are believed to be driven by amyloid beta-even if now displayed somewhat more elaborate. In light of the recently published clinical results achieved with anti-amyloid antibodies, the controversy in the field about (1) the clinical meaningfulness of this approach, (2) the significance of clearance of the amyloid beta peptide, and last but not least (3) the relevance of the amyloid-cascade-hypothesis is gaining momentum. This review addresses the interesting manifestation of the amyloid-cascade-hypothesis as well as its ups and downs over the decades.

Early CA2 Tau Inclusions Do Not Distinguish an Age-Related Tauopathy from Early Alzheimer's Disease.

Background: Neuropathologic studies of brains from autopsy series show tau inclusions (pretangles, neuropils threads, neurofibrillary tangles) are detectable more than a decade before amyloid-ß (Aß) deposition in Alzheimer's disease (AD) and develop in a characteristic manner that forms the basis for AD staging. An alternative position views pathological tau without Aß deposition as a 'primary age-related tauopathy' (PART) rather than prodromal AD. Recently, an early focus of tau inclusions in the Ammon's horn second sector (CA2) with relative sparing of CA1 that occurs before tau inclusions develop in the entorhinal cortex (EC) was proposed as an additional feature of PART. Objective: To test the 'definite PART' hypothesis. Methods: We used AT8-immunohistochemistry in 100µm sections to examine the EC, transentorhinal cortex (TRE), and Ammon's horn in 325 brains with tau inclusions lacking Aß deposits (average age at death 66.7 years for females, 66.4 years for males). Results: 100% of cases displayed tau inclusions in the TRE. In 89% of cases, the CA1 tau rating was greater than or equal to that in CA2. In 25%, CA2 was devoid of tau inclusions. Only 4% displayed a higher tau score in CA2 than in the TRE, EC, and CA1. The perforant path also displayed early tau changes. APOE genotyping was available for 199/325 individuals. Of these, 44% had an ɛ4 allele that placed them at greater risk for developing later NFT stages and, therefore, clinical AD. Conclusions: Our new findings call into question the PART hypothesis and are consistent with the idea that our cases represent prodromal AD.

Dynamics of Cognitive Impairment in MCI Patients over a Three-Year Period: The Informative Role of Blood Biomarkers, Neuroimaging, and Genetic Factors.

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.

Cardiac Autonomic Neuropathy Is Not Associated with Apolipoprotein E Gene Isoforms in the Kazakh Population: A Case-Control Study.

The absence of an early diagnosis of cardiac autonomic neuropathy might increase the risk of the disease, progressing to an irreversible stage. Therefore, this study aims to investigate the APOE gene isoforms in patients with cardiac autonomic neuropathy to identify early markers for predicting this disease in the Kazakh population. A total of 147 patients with cardiac neuropathy and 153 controls were examined in this case-control study. Patients were genotyped for two polymorphisms of the APOE gene using real-time PCR. Statistical calculations were performed using binary logistic regression. As a result of our study, we found that there was no statistically significant difference in the frequency of any APOE gene isoforms (APOE (ε2/ε2), APOE (ε2/ε3), APOE (ε2/ε4), APOE (ε3/ε3), or APOE (ε4/ε4)) between the patient group and the control group (p = 0.69, p = 0.64, p = 0.19, p = 0.22, p = 0.97, respectively). Thus, cardiac autonomic neuropathy is not associated with APOE gene isoforms in the Kazakh population.

Apolipoprotein E and Alzheimer's Disease in Italian Population: Systematic Review and Meta-Analysis.

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.

Wall Shear Stress (WSS) Analysis in Atherosclerosis in Partial Ligated Apolipoprotein E Knockout Mouse Model through Computational Fluid Dynamics (CFD).

Atherosclerosis involves an inflammatory response due to plaque formation within the arteries, which can lead to ischemic stroke and heart disease. It is one of the leading causes of death worldwide, with various contributing factors such as hyperlipidemia, hypertension, obesity, diabetes, and smoking. Wall shear stress (WSS) is also known as a contributing factor of the formation of atherosclerotic plaques. Since the causes of atherosclerosis cannot be attributed to a single factor, clearly understanding the mechanisms and causes of its occurrence is crucial for preventing the disease and developing effective treatment strategies. To better understand atherosclerosis and define the correlation between various contributing factors, computational fluid dynamics (CFD) analysis is primarily used. CFD simulates WSS, the frictional force caused by blood flow on the vessel wall with various hemodynamic changes. Using apolipoprotein E knockout (ApoE-KO) mice subjected to partial ligation and a high-fat diet at 1-week, 2-week, and 4-week intervals as an atherosclerosis model, CFD analysis was conducted along with the reconstruction of carotid artery blood flow via magnetic resonance imaging (MRI) and compared to the inflammatory factors and pathological staining. In this experiment, a comparative analysis of the effects of high WSS and low WSS was conducted by comparing the standard deviation of time-averaged wall shear stress (TAWSS) at each point within the vessel wall. As a novel approach, the standard deviation of TAWSS within the vessel was analyzed with the staining results and pathological features. Since the onset of atherosclerosis cannot be explained by a single factor, the aim was to find the correlation between the thickness of atherosclerotic plaques and inflammatory factors through standard deviation analysis. As a result, the gap between low WSS and high WSS widened as the interval between weeks in the atherosclerosis mouse model increased. This finding not only linked the occurrence of atherosclerosis to WSS differences but also provided a connection to the causes of vulnerable plaques.

Synergistic Effect between the APOE ε4 Allele with Genetic Variants of GSK3B and MAPT: Differential Profile between Refractory Epilepsy and Alzheimer Disease.

Temporal Lobe Epilepsy (TLE) is a chronic neurological disorder characterized by recurrent focal seizures originating in the temporal lobe. Despite the variety of antiseizure drugs currently available to treat TLE, about 30% of cases continue to have seizures. The etiology of TLE is complex and multifactorial. Increasing evidence indicates that Alzheimer's disease (AD) and drug-resistant TLE present common pathological features that may induce hyperexcitability, especially aberrant hyperphosphorylation of tau protein. Genetic polymorphic variants located in genes of the microtubule-associated protein tau (MAPT) and glycogen synthase kinase-3ß (GSK3B) have been associated with the risk of developing AD. The APOE ε4 allele is a major genetic risk factor for AD. Likewise, a gene-dose-dependent effect of ε4 seems to influence TLE. The present study aimed to investigate whether the APOE ɛ4 allele and genetic variants located in the MAPT and GSK3B genes are associated with the risk of developing AD and drug-resistant TLE in a cohort of the Mexican population. A significant association with the APOE ε4 allele was observed in patients with AD and TLE. Additional genetic interactions were identified between this allele and variants of the MAPT and GSK3B genes.

APOE4 and Infectious Diseases Jointly Contribute to Brain Glucose Hypometabolism, a Biomarker of Alzheimer's Pathology: New findings from the ADNI.

Introduction: We investigated the interplay between infections and APOE4 on brain glucose hypometabolism, an early preclinical feature of Alzheimer's Disease (AD) pathology. Methods: Multivariate linear regression analysis was performed on 1,509 participants of the Alzheimer's Disease Neuroimaging Initiative (ADNI). The outcomes were the rank-normalized hypometabolic convergence index (HCI) and statistical regions of interest (SROI) for AD and mild cognitive impairment (MCI). Further, the HCI and its change in the presence and absence of APOE4 were evaluated. Results: Infections were associated with greater hypometabolism [0.15, 95% CI: 0.03, 0.27, p=0.01], with a more pronounced effect among APOE4 carriers, indicating an interaction effect. A higher HCI (0.44, p=0.01) was observed in APOE4 carriers with multiple infections, compared to (0.11, p=0.08) for those with a single infection, revealing a dose-response relationship. The corresponding estimates for the association of infections with SROI AD and SROI MCI were -0.01 (p=0.02) and -0.01 (p=0.04) respectively. Conclusion: Our findings suggest that infections and APOE4 jointly contribute to brain glucose hypometabolism and AD pathology, supporting a "multi-hit" mechanism in AD development.

Lost in translation: Inconvenient truths on the utility of mouse models in Alzheimer's disease research.

The recent, controversial approval of antibody-based treatments for Alzheimer's disease (AD) is fueling a heated debate on the molecular determinants of this condition. The discussion should also incorporate a critical revision of the limitations of preclinical mouse models in advancing our understanding of AD. We critically discuss the limitations of animal models, stressing the need for careful consideration of how experiments are designed and results interpreted. We identify the shortcomings of AD models to recapitulate the complexity of the human disease. We dissect these issues at the quantitative, qualitative, temporal, and context-dependent levels. We argue that these models are based on the oversimplistic assumptions proposed by the amyloid cascade hypothesis (ACH) of AD and fail to account for the multifactorial nature of the condition. By shedding light on the constraints of current experimental tools, this review aims to foster the development and implementation of more clinically relevant tools. While we do not rule out a role for preclinical models, we call for alternative approaches to be explored and, most importantly, for a re-evaluation of the ACH.

Cerebral microvascular changes in healthy carriers of the APOE-ɛ4 Alzheimer's disease risk gene.

APOE-ɛ4 is a genetic risk factor for Alzheimer's disease (AD). AD is associated with reduced cerebral blood flow (CBF) and with microvascular changes that limit the transport of oxygen from blood into brain tissue: reduced microvascular cerebral blood volume and high relative transit time heterogeneity (RTH). Healthy APOE-ɛ4 carriers reveal brain regions with elevated CBF compared with carriers of the common ɛ3 allele. Such asymptomatic hyperemia may reflect microvascular dysfunction: a vascular disease entity characterized by suboptimal tissue oxygen uptake, rather than limited blood flow per se. Here, we used perfusion MRI to show that elevated regional CBF is accompanied by reduced capillary blood volume in healthy APOE-ɛ4 carriers (carriers) aged 30-70 years compared with similarly aged APOE-ɛ3 carriers (noncarriers). Younger carriers have elevated hippocampal RTH and more extreme RTH values throughout both white matter (WM) and cortical gray matter (GM) compared with noncarriers. Older carriers have reduced WM CBF and more extreme GM RTH values than noncarriers. Across all groups, lower WM and hippocampal RTH correlate with higher educational attainment, which is associated with lower AD risk. Three days of dietary nitrate supplementation increased carriers' WM CBF but caused older carriers to score worse on two of six aggregate neuropsychological scores. The intervention improved late recall in younger carriers and in noncarriers. The APOE-ɛ4 gene is associated with microvascular changes that may impair tissue oxygen extraction. We speculate that vascular risk factor control is particularly important for APOE-ɛ4 carriers' healthy aging.

APOE contributes to longitudinal impulse control disorders progression in Parkinson's disease.

BACKGROUND: Impulse control disorders (ICDs) are an increasingly recognized complication in Parkinson disease (PD). The pathogenesis of ICDs is currently unclear. Few genetic studies have been conducted in this area. OBJECTIVE: We aimed to ascertain the correlation between APOE and ICDs, and identify clinical predictors of ICDs in PD. METHODS: This study included 287 PD patients from the Parkinson's Progression Markers Initiative. They were followed up to investigate the progression of ICDs over a period of 5 years. The cumulative incidence of ICDs and potential risk factors were evaluated using Kaplan-Meier and Cox regression analyses. RESULTS: 44.3% (31/70) patients with APOE ɛ4 and 32.3% (70/217) patients without APOE ɛ4 developed ICDs during the five-year follow up period. There were significant differences between the PD with and without ICDs development group in age, MSEADLG score, ESS score, GDS score, and STAI score at baseline. In multivariable Cox regression analysis, APOE ε4 (HR = 1.450, p = 0.048) and STAI score (HR = 1.017, p = 0.001) were predictors of the development of ICDs. Patients with APOE ɛ4 group showed significantly lower CSF Aß42 and CSF α-syn level than patients without APOE ɛ4 group at baseline. In patients with APOE ɛ4 group, the "low α-syn level" group and the "low ptau/tau ratio" group had a significantly higher incidence of ICDs, respectively. CONCLUSIONS: This study provides important insights into the potential role of the APOE gene in the development of ICDs in PD. Further studies are needed to confirm our findings and to investigate the underlying mechanisms in more detail.

Thyroid Hormone and Alzheimer Disease: Bridging Epidemiology to Mechanism.

The identification of critical factors that can worsen the mechanisms contributing to the pathophysiology of Alzheimer disease is of paramount importance. Thyroid hormones (TH) fit this criterion. Epidemiological studies have identified an association between altered circulating TH levels and Alzheimer disease. The study of human and animal models indicates that TH can affect all the main cellular, molecular, and genetic mechanisms known as hallmarks of Alzheimer disease. This is true not only for the excessive production in the brain of protein aggregates leading to amyloid plaques and neurofibrillary tangles but also for the clearance of these molecules from the brain parenchyma via the blood-brain barrier and for the escalated process of neuroinflammation-and even for the effects of carrying Alzheimer-associated genetic variants. Suboptimal TH levels result in a greater accumulation of protein aggregates in the brain. The direct TH regulation of critical genes involved in amyloid beta production and clearance is remarkable, affecting the expression of multiple genes, including APP (related to amyloid beta production), APOE, LRP1, TREM2, AQP4, and ABCB1 (related to amyloid beta clearance). TH also affects microglia by increasing their migration and function and directly regulating the immunosuppressor gene CD73, impacting the immune response of these cells. Studies aiming to understand the mechanisms that could explain how changes in TH levels can contribute to the brain alterations seen in patients with Alzheimer disease are ongoing. These studies have potential implications for the management of patients with Alzheimer disease and ultimately can contribute to devising new interventions for these conditions.

The effects of APOEe4 allele on cerebral structure, function, and related interactions with cognition in young adults.

In the last decade, extensive research has emerged into understanding the impact of risk factors for Alzheimer's Disease (AD) on brain in pre-symptomatic stages. We investigated the neuroimaging correlates of the APOEe4 genetic risk factor for AD in young adulthood, its relationship with cognition, and potential effects of other variables on the findings. While conventional volumetric analyses revealed no consistent differences, more sophisticated analyses identified subtle structural differences between APOEe4 carriers and non-carriers. Findings from diffusion studies were limited, but functional studies demonstrated consistent alterations in connectivity and activity. The complex relationship between APOE genotype, neuroimaging variables, and cognition revealed no consensus on the directionality of findings. Methodological choices, including analytical approaches, sample size, and the influence of other genes, gender, and ethnicity, varied across studies, impacting comparability and generalizability. Recommendations for future research include multimodal and longitudinal imaging, standardisation of pipelines, advanced analytical techniques, and collaborative data pooling.

Reversibility of cognitive worsening observed with BACE inhibitor umibecestat in the Alzheimer's Prevention Initiative (API) Generation Studies.

INTRODUCTION: The Alzheimer's Prevention Initiative (API) Generation Studies evaluated the BACE inhibitor umibecestat for Alzheimer's disease (AD) prevention. The studies were terminated early, and the reversibility of umibecestat's side effects was assessed. METHODS: Cognitively unimpaired 60- to 75-year-old apolipoprotein E (APOE) Îµ4 homozygotes and heterozygotes (the latter with elevated brain amyloid deposition) (n = 1556) received umibecestat (50 or 15 mg daily) or placebo for 7 months on average and were followed for a median (interquartile range) of 4 (3 to 6) months after washout. RESULTS: Compared to placebo, umibecestat-treated participants had small, non-progressive, but statistically significant decline in performance on certain cognitive batteries including Repeatable Battery for the Assessment of Neuropsychological Status (RBANS) and API Preclinical Composite Cognitive test, but not Clinical Dementia Rating-Sum of Boxes. RBANS differences were no longer significant at the end of follow-up. DISCUSSION: In people at genetic risk for AD, high-dose beta-site amyloid precursor protein cleaving enzyme (BACE) inhibition was associated with early mild cognitive worsening, which reversed shortly after washout, suggesting a symptomatic side effect not associated with neurodegeneration. Fully anonymized data, images, and samples are available upon request for further research on BACE inhibition. HIGHLIGHTS: This is the first trial with blinded assessment of reversibility of BACE inhibitor side effects. Umibecestat was tested in cognitively unimpaired persons at genetic risk for AD. Umibecestat led to early mild cognitive decline that reversed shortly after washout. This suggests a potentially manageable effect not associated with neurodegeneration. Further research may determine the future of BACE inhibition in AD prevention.

Apo E protein and related markers show the prognosis of stress urinary incontinence rats treated with modified Buzhong Yiqi Decoction.

Stress urinary incontinence (SUI) is a common disease that seriously affects the quality of life of patients. In recent years, studies have shown that apolipoprotein E (ApoE) plays a role in neuroprotection and repair, but its specific role in SUI remains unclear. The aim of this study was to investigate the effect of macromolecular protein ApoE related markers on the prognosis of rats with SUI treated by modified Buzhong Yiqi Decoction (MBZYQD), in order to provide a new target for the treatment of SUI. Healthy rats were selected to establish a SUI model and divided into groups. The levels of ApoE related metabolites in blood of rats were detected by Metabolomics analysis and Lipidomics analysis. The urine leakage point pressure (LPP) were compared in each group, and the therapeutic effect of MBZYQD was evaluated. Compared with the model group, the LPP of rats in MBZYQD supplemented group was significantly higher. Compared with the control group, the LPP of MBZYQD was not statistically significant before and after treatment. The macromolecular protein ApoE may plays a key role in the treatment of SUI by MBZYQD, which can improve symptoms by regulating lipid metabolism repair.