Molecules of senescent glial cells differentiate Alzheimer's disease from ageing.

BACKGROUND: Ageing is a major risk factor for Alzheimer's disease (AD), which is accompanied by cellular senescence and thousands of transcriptional changes in the brain. OBJECTIVES: To identify the biomarkers in the cerebrospinal fluid (CSF) that could help differentiate healthy ageing from neurodegenerative processes. METHODS: Cellular senescence and ageing-related biomarkers were assessed in primary astrocytes and postmortem brains by immunoblotting and immunohistochemistry. The biomarkers were measured in CSF samples from the China Ageing and Neurodegenerative Disorder Initiative cohort using Elisa and the multiplex Luminex platform. RESULTS: The cyclin-dependent kinase inhibitors p16/p21-positive senescent cells in human postmortem brains were predominantly astrocytes and oligodendrocyte lineage cells, which accumulated in AD brains. CCL2, YKL-40, HGF, MIF, S100B, TSP2, LCN2 and serpinA3 are biomarkers closely related to human glial senescence. Moreover, we discovered that most of these molecules, which were upregulated in senescent glial cells, were significantly elevated in the AD brain. Notably, CSF YKL-40 (ß=0.5412, p<0.0001) levels were markedly elevated with age in healthy older individuals, whereas HGF (ß=0.2732, p=0.0001), MIF (ß=0.33714, p=0.0017) and TSP2 (ß=0.1996, p=0.0297) levels were more susceptible to age in older individuals with AD pathology. We revealed that YKL-40, TSP2 and serpinA3 were useful biomarkers for discriminating patients with AD from CN individuals and non-AD patients. DISCUSSION: Our findings demonstrated the different patterns of CSF biomarkers related to senescent glial cells between normal ageing and AD, implicating these biomarkers could identify the road node in healthy path off to neurodegeneration and improve the accuracy of clinical AD diagnosis, which would help promote healthy ageing.

A combination model of AD biomarkers revealed by machine learning precisely predicts Alzheimer's dementia: China Aging and Neurodegenerative Initiative (CANDI) study.

INTRODUCTION: To test the utility of the "A/T/N" system in the Chinese population, we study core Alzheimer's disease (AD) biomarkers in a newly established Chinese cohort. METHODS: A total of 411 participants were selected, including 96 cognitively normal individuals, 94 patients with mild cognitive impairment (MCI) patients, 173 patients with AD, and 48 patients with non-AD dementia. Fluid biomarkers were measured with single molecule array. Amyloid beta (Aß) deposition was determined by 18 F-Flobetapir positron emission tomography (PET), and brain atrophy was quantified using magnetic resonance imaging (MRI). RESULTS: Aß42/Aß40 was decreased, whereas levels of phosphorylated tau (p-tau) were increased in cerebrospinal fluid (CSF) and plasma from patients with AD. CSF Aß42/Aß40, CSF p-tau, and plasma p-tau showed a high concordance in discriminating between AD and non-AD dementia or elderly controls. A combination of plasma p-tau, apolipoprotein E (APOE) genotype, and MRI measures accurately predicted amyloid PET status. DISCUSSION: These results revealed a universal applicability of the "A/T/N" framework in a Chinese population and established an optimal diagnostic model consisting of cost-effective and non-invasive approaches for diagnosing AD.

Correlation of blood-brain barrier leakage with cerebral small vessel disease including cerebral microbleeds in Alzheimer's disease.

Background: Blood-brain barrier (BBB) damage is considered an important part of Alzheimer's disease (AD) progression, and cerebral small-vessel disease (CSVD) is commonly associated with AD. However, the relationship between BBB damage, small cerebrovascular lesions, especially cerebral microbleeds (CMBs), and amyloid and tau biomarkers remains controversial. Therefore, our study aimed to further investigate their association in our cohort of patients with AD. Methods: A total of 139 individuals were divided into probable AD (18F-florbetapir PET positive, n = 101) and control group (cognitively normal, n = 38). The levels of cerebrospinal fluid (CSF) and plasma t-tau, p-tau181, Aß40, Aß42, and albumin were measured using corresponding commercial assay kits, and the CSF/plasma albumin ratio (Qalb), an indicator of BBB dysfunction, was calculated. CSVD burden and the number of CMBs were defined using magnetic resonance imaging. Results: Patients with AD had higher Qalb (p = 0.0024), higher numbers of CMBs (p = 0.03), and greater CSVD burden (p < 0.0001). In the AD group, CMBs and CSVD correlated with a higher Qalb (p = 0.03), and the numbers of CMBs negatively correlated with CSF Aß42 (p = 0.02). Conclusion: Blood-brain barrier damage was accompanied by a more severe burden of CSVD, including CMB, in patients with AD.