Background/Purpose: Sporadic early-onset Alzheimer disease (sEOAD) and its visual variant, posterior cortical atrophy (PCA), have a disease onset at less than 65 years of age with no familial aggregation. The etiology and genetic basis of these diseases remain poorly understood. Our study aimed to identify additional mutations or variants associated with sEOAD and PCA and to further examine their genetic and phenotypic spectrums. Methods: We performed whole-exome sequencing and analyzed the clinical and neuroimaging features of mutation carriers with 29 patients having sEOAD and 25 having PCA. Results: Nine rare damaging variants were identified in 4 patients with sEOAD and 3 with PCA. A novel mutation (p.A136V) in PSEN1 was identified in a patient with sEOAD and a likely pathogenic variant (p.M239T) was identified for PSEN2 in a patient with PCA. In addition, 7 rare damaging variants were detected in other genes related to neurodegenerative diseases. The patient carrying the PSEN1 p.A136V mutation presented with typical clinical and imaging features of sEOAD, and the PCA patient with the PSEN2 p.M239T mutation presented with visuospatial impairment as the initial symptom. Conclusion: Our study expands the PSEN1 mutation spectrum of sEOAD and highlights the importance of screening PSEN1 and/or PSEN2 mutations in PCA patients.

Background: Lectin-like oxidized low density lipoprotein receptor 1 (OLR1) locates within the area of chromosome 12p, which has been identified as the AD-susceptible region, and plays a role in lipid metabolism. Therefore, it has been suggested to be a good candidate gene for Alzheimer’s disease (AD). Several SNPs within OLR1 have been reported to have association with AD among Caucasians. Methods: We selected and genotyped three SNPs (rs1050283, rs1050286, rs17808009) in OLR1 to investigate its possible relationship with the onset of late-onset Alzheimer disease(LOAD) in 984 LOAD cases and 1,354 healthy controls among northern Han Chinese. Results: No significant association was found between the OLR1 (rs1050283, rs1050286, rs17808009) polymorphisms and LOAD, even after adjustment for gender and age and stratification for apolipoprotein E (APOE) status. Conclusions: Our study showed that the SNPs (rs1050283, rs1050286, rs17808009) located in the 3’UTR of OLR1 may not involve in the mechanism of LOAD in Han Chinese population.

Background: Parkinson’s disease (PD) is the second most common neurodegenerative disorder, after Alzheimer’s disease. Many individuals with PD experience cognitive impairment, significantly threatening both their physical and mental well-being. Research has shown that abnormal DNA methylation is closely linked to neurodegenerative conditions such as Alzheimer’s and Parkinson’s disease. The RIN3 gene, which encodes a guanine nucleotide exchange factor, plays a role in inhibiting amyloid-beta formation and affects protein endocytosis, both of which are linked to cognitive impairment. However, the potential connection between RIN3 gene methylation and cognitive impairment in Parkinson’s disease has not yet been explored. This study aims to explore whether the methylation status of the RIN3 gene is connected to cognitive decline in Parkinson’s patients, thereby shedding light on the gene’s crucial role in the disease’s development and identifying potential targets for diagnosing and treating cognitive impairment in this context. Purpose: This study aims to explore whether the methylation status of the RIN3 gene is associated with cognitive impairment in Parkinson’s disease and to further clarify the gene’s significant role in the disease’s pathogenesis. Methods: This study involved 50 control subjects and 51 Parkinson’s disease (PD) patients, who were assessed using a cognitive scale. Additionally, DNA methylation in whole blood was analyzed. The research compared RIN3 methylation levels between the PD group and the normal control group (NC), as well as between the subgroups of PD-Mild Cognitive Impairment (PD-MCI), PD-Normal Cognition (PD-NC), and the control group. Results: The DNA methylation level of the RIN3 gene in the whole blood of patients with PD was lower than that in healthy controls (22.3%vs.23.6%, P=0.009). Moreover, individuals with PD-MCI had significantly lower RIN3 methylation levels than both the control group (21.3%vs.23.6%, P< 0.001) and those in the PD-NC group (21.3%vs.23.3%, P=0.001). Conclusion: RIN3 methylation is associated with PD-MCI. With appropriate lifestyle changes and clinical interventions, methylation may influence disease progression, suggesting that RIN3 gene methylation could serve as a predictor for the development of PD-MCI.

Tau is a microtubule-binding protein that is critical to the organization and stabilization of microtubules physiologically. Cerebrospinal fluid (CSF) total tau (t-tau) and CSF phosphorylated tau (p-tau) have been recommended as diagnostic biomarkers for AD according to the 2018 National Institute on Aging and Alzheimer’s Association (NIA-AA) research framework. We performed a genome-wide association study (GWAS) of longitudinal change in CSF t-tau among 317 non-demented elders from the Alzheimer’s Disease Neuroimaging Initiative (ADNI) cohort in non-Hispanic Caucasians. We employed the linear regression model to identify novel variants associated with longitudinal change of t-tau in CSF. One single nucleotide polymorphism (SNP) (rs17149074) in the region of C9orf171 (CFAP77) gene was found to reach genome-wide significance associated with longitudinal change of CSF t-tau. Five SNPs (rs10916844, rs10916846, rs9425869, rs3744474, rs8078303) were identified as potential candidate loci associated with longitudinal change of CSF t-tau. Validation of the identified loci in larger samples and various races was needed in future research.