Alzheimer's disease (AD) and cancer have inverse relationship in many aspects. Some tumor suppressors, including miR‐34c, are decreased in cancer but increased in AD. The upstream regulatory pathways and the downstream mechanisms of miR‐34c in AD remain to be investigated. The expression of miR‐34c was detected by RT–qPCR in oxidative stressed neurons, hippocampus of SAMP8 mice, or serum of patients with amnestic mild cognitive impairment (aMCI). Dual luciferase assay was performed to confirm the binding sites of miR‐34c in its target mRNA. The Morris water maze (MWM) was used to evaluate learning and memory in SAMP8 mice administrated with miR‐34c antagomir (AM34c). Golgi staining was used to evaluate the synaptic function and structure. The dramatically increased miR‐34c was mediated by ROS‐JNK‐p53 pathway and negatively regulated synaptotagmin 1 (SYT1) expression by targeting the 3′‐untranslated region (3′‐UTR) of syt1 in AD. The expression of SYT1 protein was reduced by over expression of miR‐34c in the HT‐22 cells and vice versa. Administration of AM34c by the third ventricle injection or intranasal delivery markedly increased the brain levels of SYT1 and ameliorated the cognitive function in SAMP8 mice. The serum miR‐34c was significantly increased in patients with aMCI and might be a predictive biomarker for diagnosis of aMCI. These results indicated that increased miR‐34c mediated synaptic and memory deficits by targeting SYT1 through ROS‐JNK‐p53 pathway and the miR‐34c/SYT1 pathway could be considered as a promising novel therapeutic target for patients with AD.

Background: Age-related hormone changes play important roles in cognitive decline in older men, and apolipoprotein E ɛ4 (APOE ɛ4) is a risk factor for Alzheimer’s disease (AD). Objective: This study aimed to investigate the interactive role of androgen decline and APOE ɛ4 genotype in the pathogenesis of amnestic mild cognitive impairment (aMCI) and AD. Methods: In total, 576 elderly men over 65 years old from communities in Shijiazhuang were enrolled in this study, including 243 with normal cognition (NC), 271 with aMCI, and 62 with probable AD. Cognitive function was evaluated with a battery of neuropsychological tests. The serum levels of androgen and gonadotropin were detected by ELISA and chemiluminescence immunoassay. Results: The levels of free testosterone (FT) and dihydrotestosterone (DHT) were lower in the aMCI group (p <  0.05), and even lower in the AD group (p <  0.001), but the levels of follicle stimulating hormone (FSH) and luteinizing hormone (LH) were higher in AD group (p <  0.01), comparing with that in NC or aMCI group. The interaction of lower FT or DHT levels with APOE ɛ4 had a risk role in global cognitive impairment (p <  0.05). The area under the curve (AUC) of the ROC curve for predicting aMCI by serum FT levels was 0.745. Conclusion: These results indicated that the interaction of androgen decline and APOE ɛ4 genotype play a role in aMCI and AD. Serum FT levels have a predictive value for aMCI and might be a potential biomarker for prodromal AD.

Background: The interactions between environmental factors and genetic variants have been implicated in the pathogenesis of Alzheimer’s disease (AD). The altered gut microbiota (GM) and vitamin D deficiency are closely associated with the higher risk of AD. Objective: This study was performed to evaluate whether the crosstalk between GM and single nucleotide polymorphisms (SNPs) of vitamin D receptor (VDR) or vitamin D binding protein (VDBP) have a link with the risk of amnestic mild cognitive impairment (aMCI) in the Chinese elderly population. Methods: A total of 171 aMCI patients and 261 cognitive normal controls (NC) were enrolled in this study. Six tag SNPs of VDR and VDBP were genotyped by PCR-RFLP. The serum levels of vitamin D, Aβ1-42, and p-tau (181P) were determined by using of ELISA kits. The alterations in the GM were analyzed by full-length 16S ribosomal RNA (rRNA) gene sequencing. Results: The frequencies of AG genotype and A allele of VDR rs1544410 in aMCI group were significantly higher than that in NC group (genotype: p = 0.002, allele: p = 0.003). Patients with aMCI showed an abnormal GM composition compared with NC group. Interestingly, significant differences in GM composition were found between aMCI and NC group among individuals with AG genotype, as well as between individuals with AG and GG genotype of VDR rs1544410 among patients with aMCI. Conclusion: These results implicated that the crosstalk between gut microflora and vitamin D receptor variants are associated with the risk of aMCI in Chinese elderly population.