Both Alzheimer's disease (AD) and osteoporosis (OP) are common age‐associated degenerative diseases and are strongly correlated with clinical epidemiology. However, there is a lack of clear pathological relationship between the brain and bone in the current understanding. Here, it is found that young osteocyte, the most abundant cells in bone, secretes extracellular vesicles (OCYYoung‐EVs) to ameliorate cognitive impairment and the pathogenesis of AD in APP/PS1 mice and model cells. These benefits of OCYYoung‐EVs are diminished in aged osteocyte‐derived EVs (OCYAged‐EVs). Based on the self‐constructed OCY‐EVs tracer transgenic mouse models and the in vivo fluorescent imaging system, OCY‐EVs have been observed to be transported to the brain under physiological and pathological conditions. In the hippocampal administration of Aβ40 induced young AD model mice, the intramedullary injection of Rab27a‐shRNA adenovirus inhibits OCYYoung‐EVs secretion from bone and aggravates cognitive impairment. Proteomic quantitative analysis reveals that OCYYoung‐EVs, compared to OCYAged‐EVs, enrich multiple protective factors of AD pathway. The study uncovers the role of OCY‐EV as a regulator of brain health, suggesting a novel mechanism in bone‐brain communication.

Inadequate osteogenesis and excessive adipogenesis of bone marrow mesenchymal stem cells (BMSCs) are key factors in the pathogenesis of osteoporosis. Patients with Alzheimer's disease (AD) have a higher incidence of osteoporosis than healthy adults, but the underlying mechanism is not clear. Here, we show that brain-derived extracellular vesicles (EVs) from adult AD or wild-type mice can cross the blood-brain barrier to reach the distal bone tissue, while only AD brain-derived EVs (AD-B-EVs) significantly promote the shift of the BMSC differentiation fate from osteogenesis to adipogenesis and induce a bone-fat imbalance. MiR-483-5p is highly enriched in AD-B-EVs, brain tissues from AD mice, and plasma-derived EVs from AD patients. This miRNA mediates the anti-osteogenic, pro-adipogenic, and pro-osteoporotic effects of AD-B-EVs by inhibiting Igf2. This study identifies the role of B-EVs as a promoter of osteoporosis in AD by transferring miR-483-5p.

Background: Alzheimer’s disease (AD) is a chronic and fatal neurodegenerative disease; accumulating evidence suggests that vitamin deficiency is associated with the risk of AD. However, studies attempting to elucidate the relationship between vitamins and AD varied widely. Objective: This study aimed to investigate the relationship between serum vitamin levels and AD in a cohort of the Chinese population. Methods: A total of 368 AD patients and 574 healthy controls were recruited in this study; serum vitamin A, B1, B6, B9, B12, C, D, and E were measured in all participants. Results: Compared with the controls, vitamin B2, B9, B12, D, and E were significantly reduced in AD patients. Lower levels of vitamin B2, B9, B12, D, and E were associated with the risk of AD. After adjusting for age and gender, low levels of vitamin B2, B9, and B12 were still related to the risk of AD. In addition, a negative correlation was determined between vitamin E concentration and Activity of Daily Living Scale score while no significant association was found between serum vitamins and age at onset, disease duration, Mini-Mental State Examination, and Neuropsychiatric Inventory Questionnaire score. Conclusion: We conclude that lower vitamin B2, B9, B12, D, and E might be associated with the risk of AD, especially vitamin B2, B9, and B12. And lower vitamin E might be related to severe ability impairment of daily activities.

Background: Three polymorphisms in the Methylenetetrahydrofolate reductase (MTHFR) gene (C677T, A1298C, and A1793G) were reported associated with AD. However, their genotype distributions and associations with age at onset (AAO), homocysteine, and white matter lesions (WML) were unclear in the Chinese AD population. Method: We determined the presence of C677T, A1298C, and A1793G polymorphisms in the MTHFR gene using Sanger sequencing in a Chinese cohort comprising 721 AD patients (318 early-onset AD patients (EOAD) and 403 late-onset AD patients (LOAD)) and 365 elderly controls. Additionally, the homocysteine level and WML were evaluated in 121 AD patients. Results: The frequency of allele T of C677T polymorphism was significantly higher in AD patients than in controls ( P = 0.040), while no statistical difference was observed in A1298C and A1793G ( P > 0.05). Besides, genotype distributions of C677T and A1298C polymorphisms statistically varied between AD patients and controls ( P = 0.021, P = 0.012). Moreover, the AAO was significantly lower in CT/TT (C677T) genotypes carriers ( P = 0.042) and higher in AC/CC (A1298C) and AG/GG (A1793G) genotypes carriers ( P = 0.034, P = 0.009) in patients with LOAD. We also found that patients with CT/TT (C677T) genotypes were prone to present an increased homocysteine level ( P = 0.036) and higher Fazekas score ( P = 0.024). In comparison, patients with AG/GG genotypes (A1793G) had a significantly lower Fazekas score ( P = 0.013). Conclusions: The genotype distributions of C677T and A1298C polymorphisms are associated with AD in the Chinese population. Moreover, AD patients with C677T polymorphism are prone to present an earlier onset, higher homocysteine level, and more severe WML.

BackgroundThe pathogenic missense mutations of the gelsolin (GSN) gene lead to familial amyloidosis of the Finnish type (FAF); however, our previous study identifiedGSNframeshift mutations existed in patients with Alzheimer’s disease (AD). TheGSNgenotype–phenotype heterogeneity and the role ofGSNframeshift mutations in patients with AD are unclear.MethodIn total, 1192 patients with AD and 1403 controls were screened through whole genome sequencing, and 884 patients with AD were enrolled for validation. Effects ofGSNmutations were evaluated in vitro. GSN, Aβ42, Aβ40 and Aβ42/40 were detected in both plasma and cerebrospinal fluid (CSF).ResultsSix patients with AD withGSNP3fs and K346fs mutations (0.50%, 6/1192) were identified, who were diagnosed with AD but not FAF. In addition, 13 patients with AD withGSNframeshift mutations were found in the validation cohort (1.47%, 13/884). Further in vitro experiments showed that both K346fs and P3fs mutations led to theGSNloss of function in inhibiting Aβ-induced toxicity. Moreover, a higher level of plasma (p=0.001) and CSF (p=0.005) GSN was observed in AD cases than controls, and a positive correlation was found between the CSF GSN and CSF Aβ42 (r=0.289, p=0.009). Besides, the GSN level was initially increasing and then decreasing with the disease course and cognitive decline.ConclusionsGSNframeshift mutations may be associated with AD. An increase in plasma GSN is probably a compensatory reaction in AD, which is a potential biomarker for early AD.