Citations

Abstract We present a comprehensive global analysis of genetic variants associated with autosomal-dominant Alzheimer’s disease (ADAD). A total of 550 variants in the APP, PSEN1 and PSEN2 genes were identified, of which 279 were classified as pathogenic or likely pathogenic based on American College of Medical Genetics and Genomics and the Association for Molecular Pathology criteria, utilizing data from the Dominantly Inherited Alzheimer Network (DIAN), literature and public databases. Symptomatic age at onset (AAO) data were estimated for 227 of these variants, allowing detailed characterization of their frequency, pathogenicity and AAO. Importantly, 226 variants met eligibility criteria for inclusion in disease-modifying clinical trials. Furthermore, we demonstrated the predictive value of mean variant AAO and parental AAO in predicting symptomatic AAO, validated against converters who became symptomatic during follow-up in the DIAN Observational Study. This dataset provides critical insights into the global landscape of ADAD and reveals the genetic and AAO heterogeneity of ADAD variants while refining variant trial eligibility criteria.

Background: Immune cell–driven inflammation is a key mediator of metabolic dysfunction–associated steatohepatitis (MASH) progression. We have previously demonstrated that pharmacological sphingosine 1-phosphate (S1P) receptor modulation ameliorates MASH and is associated with attenuated accumulation of intrahepatic macrophage and T-cell subsets. Although S1P receptors are expressed on several immune cell types, given the prominent role of monocyte-derived recruited macrophages in the sterile inflammation of MASH, we hypothesized that deletion of S1P receptor 1 (S1P 1 ) on myeloid cells may ameliorate MASH by reducing the accumulation of proinflammatory monocyte-derived macrophages in the liver. Methods: The LyzMCre approach was used to generate myeloid cell–specific knockout mice, termed S1pr1 MKO . Littermate S1pr1 loxp/loxp mice were used as wild-type controls. MASH was established by feeding mice a high-fat, -fructose, and -cholesterol (FFC) diet for 24 weeks, which led to the development of steatohepatitis and MASH-defining cardiometabolic risk factors. Liver injury and inflammation were determined by histological and gene expression analyses. Intrahepatic leukocyte populations were analyzed by mass cytometry and immunohistochemistry. Results: Histological examination demonstrated a reduction in liver inflammatory infiltrates and fibrosis in high-fat, -fructose, and -cholesterol–fed S1pr1 MKO compared to wild-type. There was a corresponding reduction in alanine aminotransferase, a sensitive marker for liver injury. As determined by mass cytometry, a significant decrease in recruited macrophages was noted in the livers of high-fat, -fructose, and -cholesterol–fed S1pr1 MKO mice compared to wild-type. Gene ontology pathway analysis revealed significant suppression of the peroxisome proliferator–activated receptor gamma and mitogen-activated protein kinase pathways in S1pr1 MKO consistent with attenuated MASH in mice. Conclusions: Deletion of S1P 1 in myeloid cells is sufficient to attenuate intrahepatic accumulation of monocyte-derived macrophages and ameliorate murine MASH.

OBJECTIVE Tobacco smoking is among the factors known to significantly augment the risk of untreated intracranial aneurysm (IA) growth and rupture. Smoking appears to have a variable effect on different endovascular treatment modalities. The impact of smoking on the safety, efficacy, and outcomes of Woven EndoBridge (WEB) device use for wide-neck IAs has not been evaluated. This study aimed to investigate the outcomes of WEB devices by smoking status. METHODS A retrospective multicenter analysis was conducted on the data of patients from 36 sites worldwide treated with the WEB device for intracranial saccular aneurysms. Patients were stratified based on smoking status (current, former, and never smokers). The Student t-test and chi-square test were performed for continuous and categorical variables, respectively. Multivariable logistic regression was used to adjust for confounders. RESULTS Of 1376 patients with available smoking status, 504 were current smokers, 358 were former smokers, and 514 were never smokers. Upon adjusting for significant confounders, no association was found between smoking and recurrence outcomes (OR 1.39, 95% CI 0.69–2.80; p = 0.36), thromboembolic and hemorrhagic complications, and mortality among IAs treated with the WEB device. There was no statistically significant difference in outcomes between former and never smokers (OR 1.23, 95% CI 0.70–2.18; p = 0.46). The location of aneurysms differed between smoking groups, with former smokers having more anterior circulation aneurysms compared with current and never smokers (99.0% vs 96.9% vs 95.3%; p = 0.01). In terms of clinical symptoms, headache and dizziness were more common in the never smokers compared with current and former smokers (13.9% vs 8.9% vs 7.7%, p = 0.01). CONCLUSIONS This large-scale study suggests no significant correlation between smoking and the recurrence of IAs treated with the WEB device. Biological studies are warranted to better understand the biological impact of smoking on the growth and rupture of treated IAs.

Introduction: Cerebral Amyloid Angiopathy (CAA) is caused by the progressive deposition of β-amyloid in the walls of small to medium-sized cerebral vessels. Although seizures represent a debilitating manifestation of CAA, little is known about their prevalence or associated factors. We aim to fill this gap by determining the prevalence of seizures in CAA and identify factors associated with an increased risk of seizures. Methods: We identified consecutive patients with CAA, evaluated within the Mayo Clinic health system between January 2010 and December 2023 using the ICD-10 code. Data on demographics and comorbidities were compared between those with and without seizures using the chi-square test for categorical variables and independent samples t-test for continuous variables. Odds ratios (OR) were estimated after adjusting for age, sex, and race in multivariable logistic regression. Results: We included 1,914 patients with CAA with a mean age of 75.4 ± 8.6 years, of whom 52.3% were female and 87.5% were white. Seizures were observed in 347 patients (18.1%). Individuals with seizures were significantly younger (mean age 67.7 ± 9.1 vs. 77.2 ± 7.5 years, p < 0.001). Multivariable modeling identified alcohol abuse (OR 1.92, 95% CI 1.03-3.56, p=0.04), diabetes mellitus (OR 2.14, 95% CI 1.13-4.06, p=0.02), hypertension (OR 1.79, 95% CI 1.33 - 2.41, p= <0.001), liver disease (OR 1.75, 95% CI 1.14-2.69, p=0.01), and ischemic stroke (OR 1.33, 95% CI 1.01-1.74, p=0.04) as independently associated with an increased risk of seizures. Conclusion: We found that seizures affect nearly one in five patients with CAA. Also, comorbidities such as alcohol abuse, diabetes mellitus, hypertension, liver disease, and ischemic stroke were found to be significantly associated with an increased risk of seizures. Longitudinal studies are warranted to confirm these risk factors, some of which may be modifiable.

Introduction: Coagulation factor XI (FXI) inhibitors have shown a better safety profile than other anticoagulants, offering similar reductions in ischemic stroke (IS) risk with a lower risk of intracerebral hemorrhage (ICH). The APOE ε4 genotype is associated with increased risks of both IS and ICH, likely due to its effects on lipid levels, intracranial atherosclerosis, and cerebral amyloid angiopathy. We hypothesized that APOE ε4 carriers would gain greater therapeutic benefit from genetically reduced FXI levels compared to non-carriers. Methods: We conducted a two-stage Mendelian randomization (MR) analysis using the random-effects, inverse-variance weighted method. First, we estimated the effect of genetically proxied FXI inhibition on IS and ICH risk in the general population using summary data from genome-wide association studies of FXI levels (16,169 participants), IS (1,503,898 controls and 110,182 cases), and ICH (3,745 controls and 3,226 cases). Second, we performed stratified analyses to estimate the effect of genetically determined FXI levels on IS (10,343 cases and 476,838 controls) and ICH (2,236 cases and 484,945 controls) risk across APOE ε4 carriership strata (0, 1, or 2 alleles) using UK Biobank data. Results: In the general population, random-effects, inverse-variance weighted MR analyses showed that every 1 unit decrease in natural log-transformed FXI levels was associated with a 37% reduction in IS risk (OR:0.63; 95%CI:0.52–0.77; p <0.001) without a significant increase in ICH risk (OR:0.86; 95%CI:0.37–2.00; p =0.73). Stratified MR analyses indicated that genetically determined reductions in FXI levels had varying protective effects on IS risk based on APOE ε4 status: 31% in non-carriers (OR:0.69, 95%CI:0.53–0.91; p =0.008), 43% in carriers of 1 allele (OR:0.57, 95%CI:0.36–0.91; p =0.02), and 75% in carriers of 2 alleles (OR:0.25, 95%CI:0.06–1.06; p =0.06). Similar MR analyses showed no significant increase in ICH risk with genetically determined reductions in FXI levels in any APOE ε4 strata (all p >0.38, Figure 1). Conclusion: This two-stage genetic study provides causal evidence that lower FXI levels reduce IS risk in the general population, with an even stronger effect among APOE ε4 carriers, while not increasing ICH risk. These results indicate that FXI inhibitors might be a safer and more effective alternative to other anticoagulants among APOE ε4 carriers, who are known to be at higher risk for both ischemic and hemorrhagic events.