Associations of CSF BACE1 with amyloid pathology, neurodegeneration, and cognition in Alzheimer's disease.

Β-site amyloid precursor protein (APP) cleaving enzyme (BACE1) is a crucial protease in the production of amyloid-ß (Aß) in Alzheimer's disease (AD) patients. However, the side effects observed in clinical trials of BACE1 inhibitors, including reduction in brain volume and cognitive worsening, suggest that the exact role of BACE1 in AD pathology is not fully understood. To further investigate this, we examined cerebrospinal fluid (CSF) levels of BACE1 and its cleaved product sAPPß that reflects BACE1 activity in the China Aging and Neurodegenerative Disorder Initiative cohort. We found significant correlations between CSF BACE1 or sAPPß levels and CSF Aß40, Aß42, and Aß42/Aß40 ratio, but not with amyloid deposition detected by 18F-Florbetapir PET. Additionally, CSF BACE1 and sAPPß levels were positively associated with cortical thickness in multiple brain regions, and higher levels of sAPPß were linked to increased cortical glucose metabolism in frontal and supramarginal areas. Interestingly, individuals with higher baseline levels of CSF BACE1 exhibited slower rates of brain volume reduction and cognitive worsening over time. This suggests that increased levels and activity of BACE1 may not be the determining factor for amyloid deposition, but instead, may be associated with increased neuronal activity and potentially providing protection against neurodegeneration in AD.

Changes in CSF sPDGFRß level and their association with blood-brain barrier breakdown in Alzheimer's disease with or without small cerebrovascular lesions.

BACKGROUND: CSF-soluble platelet-derived growth factor receptor beta (sPDGFRß) is closely associated with pericyte damage. However, the changes in CSF sPDGFRß levels and their role in blood-brain barrier (BBB) leakage at different stages of Alzheimer's disease (AD), with or without cerebral small vessel disease (CSVD) burden, remain unclear. METHODS: A total of 158 individuals from the China Aging and Neurodegenerative Disorder Initiative cohort were selected, including 27, 48, and 83 individuals with a clinical dementia rating (CDR) score of 0, 0.5, and 1-2, respectively. CSF total tau, phosphorylated tau181 (p-tau181), Aß40, and Aß42 were measured using the Simoa assay. Albumin and CSF sPDGFRß were measured by commercial assay kits. CSVD burden was assessed by magnetic resonance imaging. RESULTS: CSF sPDGFRß was the highest level in the CDR 0.5 group. CSF sPDGFRß was significantly correlated with the CSF/serum albumin ratio (Q-alb) in the CDR 0-0.5 group (ß = 0.314, p = 0.008) but not in the CDR 1-2 group (ß = - 0.117, p = 0.317). In the CDR 0-0.5 group, CSF sPDGFRß exhibited a significant mediating effect between Aß42/Aß40 levels and Q-alb (p = 0.038). Q-alb, rather than CSF sPDGFRß, showed a significant difference between individuals with or without CSVD burden. Furthermore, in the CDR 0.5 group, CSF sPDGFRß was higher in subjects with progressive mild cognitive impairment than in those with stable mild cognitive impairment subjects (p < 0.001). Meanwhile, CSF sPDGFRß was significantly associated with yearly changes in MMSE scores in the CDR 0.5 group (ß = - 0.400, p = 0.020) and CDR 0.5 (A+) subgroup (ß = - 0.542, p = 0.019). CONCLUSIONS: We provide evidence that increased CSF sPDGFRß is associated with BBB leakage in the early cognitive impairment stage of AD, which may contribute to cognitive impairment in AD progression.

Increased ß-site APP cleaving enzyme 1-mediated insulin receptor cleavage in type 2 diabetes mellitus with cognitive impairment.

INTRODUCTION: Patients with type 2 diabetes mellitus (T2DM) are at a high risk of cognitive impairment, with insulin resistance playing a pivotal role. ß-site amyloid precursor protein cleaving enzyme 1 (BACE1) is considered a predictor of Alzheimer's disease. However, the potential roles of BACE1 in insulin resistance and the risk of cognitive impairment in T2DM remain unclear. METHODS: We measured plasma BACE1 levels, BACE1 cleavage activities for Swedish mutant amyloid precursor protein (APPsw) and insulin receptor ß subunit (INSR-ß), and soluble INSR (sINSR) levels in a clinical cohort study. RESULTS: T2DM patients with or without cognitive impairment exhibited elevated plasma BACE1 levels and BACE1 enzymatic activities for APPsw and INSR-ß, and sINSR levels. Moreover, the glycemic status correlated with elevated BACE1 levels and BACE1-mediated INSR cleavage, which was associated with insulin resistance. DISCUSSION: The elevated BACE1 levels in T2DM may contribute to increasing the cognitive impairment risk through both amyloidogenesis and insulin resistance.

A New Neurovascular Panel Discriminates Between Patients with Type 2 Diabetes Mellitus with Cognitive Impairment and Cognitive Impairment Alone.

BACKGROUND: Recent studies showed that type 2 diabetes mellitus (T2DM) may increase the risk of cognitive impairment, but there are few biomarkers to diagnostically discriminate T2DM-associated cognitive impairment and cognitive impairment alone. In this study, we assessed certain cytokines involved in inflammation and vascular diseases and identified special panel of cytokines that could differentiate between T2DM and cognitive impairment. OBJECTIVE: To investigate associations and differences between T2DM and cognitive impairment by cytokines analysis. METHODS: A total of 264 participants were recruited, their blood samples were collected, and plasma and serum were separated and stored at - 80°C until the assessment of amyloid-ß (Aß)42, Aß40 and 8 kinds of cytokines by Luminex multiplex assays. RESULTS: Plasma Aß40 is higher whereas Aß42/40 ratio is lower in cognitive impairment and T2DM-associated cognitive impairment compared to other groups. As compared to health control, YKL-40 level was upregulated in cognitive impairment, PRGN was downregulated in T2DM associated cognitive impairment, OPN was substantially decreased in T2DM, and IL-6 was elevated in cognitive impairment and T2DM-associated cognitive impairment. Interestingly, VEGF and S100B were induced in T2DM when compared with cognitive impairment, and NSE level in T2DM-associated cognitive impairment is significantly lower than in T2DM or cognitive impairment. CONCLUSION: Aß42, Aß40, and Aß42/40 ratio cannot distinguish T2DM-associated cognitive impairment from cognitive impairment. Certain cytokines (YKL-40, NSE, and VEGF) have good performance in distinguishing T2DM-associated cognitive impairment from simple cognitive impairment. Taken together, this may improve the accuracy of the diagnosis and establishment of individualized therapy.