BACKGROUND. Soluble triggering receptor expressed on myeloid cells 2 (sTREM2) plays an important role in the clearance of pathological amyloid-β (Aβ) in Alzheimer’s disease (AD). This study aimed to explore sTREM2 as a central and peripheral predictor of the conversion from mild cognitive impairment (MCI) to AD. METHODS. sTREM2 and Aβ_1–42 levels in cerebrospinal fluid (CSF) and florbetapir-PET (AV45) images were analyzed for healthy control (HCs), patients with MCI, and patients with AD from the ADNI database. Peripheral plasma sTREM2 and Aβ_1–42 levels were determined for our Neurology database of Ruijin Hospital for Alzheimer’s Disease (NRHAD) cohort, and patients with MCI were reevaluated at follow-up visits to assess for progression to AD. The association between CSF and plasma sTREM2 levels was analyzed in data from the Chinese Alzheimer’s Biomarker and Lifestyle (CABLE) database. RESULTS. The results showed that patients with MCI who had low levels of CSF sTREM2 and Aβ_1–42 were more likely to develop AD. Among participants with positive Aβ deposition, as assessed by AV45 imaging, elevated CSF sTREM2 levels were associated with a decreased risk of MCI-to-AD conversion. Meanwhile, in the NRHAD cohort, individuals in the MCI group with high sTREM2 levels in plasma were at a greater risk for AD, whereas low Aβ_1–42 with high sTREM2 levels in plasma were associated with a faster cognitive decline. In addition, CSF sTREM2 levels were highly correlated with plasma sTREM2 levels in the CABLE database. CONCLUSION. These findings suggest that sTREM2 may be useful as a potential predictive biomarker of MCI-to-AD conversion. FUNDING. This study was supported by grants from the National Natural Science Foundation of China (grant nos. 82001341, 82071415, 81873778, and 82201392); the Shanghai Sailing Program (grant no. 22YF1425100); and the China Postdoctoral Science Foundation funded project (grant no. 2021M702169).

α-Synuclein (α-Syn) pathology is present in 30-50 % of Alzheimer's disease (AD) patients, and its interactions with tau proteins may further exacerbate pathological changes in AD. However, the specific role of different aggregation forms of α-Syn in the progression of AD remains unclear. To explore the relationship between various aggregation types of CSF α-Syn and Alzheimer's disease progression. We conducted a retrospective analysis of data from the Alzheimer's Disease Neuroimaging Initiative (ADNI) to examine the association between different α-Syn aggregation forms-Syn0 (no detectable α-Syn aggregates) and Syn1 (α-Syn aggregates detected, resembling those found in Parkinson's disease)-with the pathological and clinical features of AD. Additionally, we evaluated their potential as predictors of conversion from mild cognitive impairment (MCI) to AD. The ADNI database. A total of 250 participants, including 70 cognitively normal controls, 119 patients diagnosed with MCI, and 61 patients diagnosed with AD. Pearson correlation was employed to assess the relationship between α-Syn levels and cerebrospinal fluid (CSF) biomarkers, including total tau (T-tau), phosphorylated tau (p-tau), and amyloid-β₄₂ (Aβ₄₂). Multivariate Cox proportional hazards models were applied, adjusting for APOE4 status, age, and sex, to determine the association between α-Syn forms and AD-related pathological and clinical outcomes. Kaplan-Meier curves were used to evaluate the prognostic value of different α-Syn aggregation states in predicting the conversion from MCI to AD. Compared with controls, overall MCI and AD patients had elevated α-Syn levels. Notably, in the α-Syn0 group, α-Syn levels were increased in the MCI patients and further increased in AD patients, whereas in the α-Syn1 group, α-Syn levels did not significantly differ across diagnostic groups. Both in the α-Syn0 and α-Syn1 groups, α-Syn levels were found to correlate more strongly with CSF tau levels than with Aβ₄₂, indicating a possible role for α-Syn in tau-related pathology in AD. Importantly, α-Syn0-AD patients exhibited more rapid cognitive decline and greater hippocampal atrophy than α-Syn1-AD patients. However, MCI patients with CSF α-Syn1 aggregation status had an increased risk of conversion to AD. CSF α-Syn is associated with tau pathology and neurodegeneration in Alzheimer's disease. The distinct aggregation profiles of α-Syn serve as valuable biomarkers, offering insights into differing prognoses in AD and aiding in the prediction of early disease progression.

Background/Objectives: Genetic factors play an important role in idiopathic rapid eye movement sleep behavior disorder (iRBD) but have not been fully studied. This study aimed to analyze the Parkinson’s disease (PD)-related genetic loci in iRBD in the southern Chinese population. Methods: In this study, we recruited 292 individuals with PD, 62 with iRBD, and 189 healthy controls (HC). Candidate genes were identified primarily from the Parkinson’s Progression Markers Initiative (PPMI) database. Genotypic and allele frequency analyses were conducted to compare the distribution across HC, iRBD, and PD groups. The effects of significant single-nucleotide polymorphisms (SNPs) on gene expression were examined. Clinical manifestations associated with different genotypes were also analyzed. The receiver operating characteristic (ROC) curve and Kaplan–Meier plots were utilized to further verify the diagnostic and predictive value of these SNPs. Results: We identified two significant SNPs associated with iRBD: rs13294100 of SH3GL2 and rs165599 of COMT. Clinical scale and polysomnography data analysis indicated that iRBD patients with the GA or AA genotype at the COMT rs165599 locus have lower RBDSQ scores and higher sleep efficiency. Moreover, we identified that COMT rs165599 and MCCC1 rs12637471 may play an important role in both PD and iRBD, while SNCA rs356181 was different between iRBD and PD. Conclusions: Our research revealed that in the southern Chinese demographic, genetic loci in SH3GL2 and COMT were linked to iRBD and may act as potential biomarkers for iRBD risk. Additionally, there is evidence suggesting a partial genetic overlap between iRBD and PD, indicating a shared genetic predisposition.

Background: Glycosylation is an important post-translational modification of apolipoprotein E (APOE) and APOE in cerebrospinal fluid (CSF) displays an additional secondary glycosylation that is not present in plasma, suggesting a brain-specific regulatory mechanism. This study investigated whether altered APOE glycosylation is associated with early cognitive decline and progression from mild cognitive impairment (MCI) to AD and further explored its potential biological relevance. Methods: APOE glycosylation levels were measured in participants with MCI and healthy controls (HCs). Analyses were stratified by APOE4 genotype and examined in relation to neuroimaging markers. The data-derived cut-off values were used to assess disease progression. Single-cell transcriptomic data from the SEA-AD cohort were analyzed to characterize glycosylation-related alterations in dementia microglia. Results: The total APOE glycosylation in CSF and plasma did not differ significantly between the MCI and control groups. CSF secondary APOE glycosylation was lower in participants with MCI in the unadjusted analysis. It was not significantly associated with baseline white matter hyperintensity (WMH) or hippocampal volume. In exploratory analyses using a data-derived cut-off, lower CSF secondary glycosylation was associated with faster hippocampal volume decline and shorter time to AD conversion. Donor-level pseudobulk analysis of the SEA-AD cohort showed lower ST6GAL1 expression and higher APOE, LPL, and CD9 expression in donors with dementia; MGAT1 was not significantly altered overall. Conclusions: CSF secondary APOE glycosylation may be associated with early pathological changes and disease progression in MCI. Together with alterations in microglial glycosylation-related pathways, these exploratory findings suggest broader glycosylation dysregulation in APOE-related neurodegeneration.