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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 (Aβ) deposition was determined by 18 F-Flobetapir positron emission tomography (PET), and brain atrophy was quantified using magnetic resonance imaging (MRI).Results: Aβ42/Aβ40 was decreased, whereas levels of phosphorylated tau (p-tau) were increased in cerebrospinal fluid (CSF) and plasma from patients with AD. CSF Aβ42/Aβ40, 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 costeffective and non-invasive approaches for diagnosing AD.

Loss of function mutations in the progranulin (PGRN) gene is a risk factor for Alzheimer's disease (AD). Previous works reported that the deficiency of PGRN accelerates βamyloid (Aβ) accumulation in AD transgenic mouse brains while overexpression of PGRN could restrain disease progression. However, mechanisms of PGRN in protecting against Aβ deposition remains unclear. Here, using the 5xFAD AD mouse model, we show that intrahippocampal injection of PGRN protein leads to a reduction of Aβ plaques, downregulation of beta-secretase 1 (BACE1), and enhanced microglia Aβ phagocytosis in the mouse hippocampus. Furthermore, PGRN treatment inhibited BACE1 expression in N2a cells and primary culture neurons and improved the phagocytic capacity of microglia isolated from 5xFAD mouse brains. Collectively, our results provide further evidence that enhancing progranulin could be a promising option for AD therapy.

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BackgroundBlood–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.MethodsA 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, Aβ40, Aβ42, 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.ResultsPatients 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 Aβ42 (p = 0.02).ConclusionBlood–brain barrier damage was accompanied by a more severe burden of CSVD, including CMB, in patients with AD.

The current diagnoses of Alzheimer’s disease (AD) mainly rely on such measures as amyloid-β (Aβ) and tau neuropathology biomarkers in vivo via cerebrospinal fluid (CSF) and positron emission tomography (PET) imaging, which had been systematically studied in Caucasian individuals, whereas diagnostic performances of these approaches in Chinese dementia population still remain unclear. This study investigated the associations between the levels of CSF core AD biomarkers, including phosphorylated tau (p-Tau181), total tau (t-Tau), Aβ42, and Aβ40 measured by the single-molecule array (Simoa) and cerebral Aβ deposition status assessed by 18F-Florbetapir PET (Aβ PET), and evaluated the predictive values of CSF core AD biomarkers in discriminating Aβ PET status in a clinical dementia cohort of the Chinese population, which consisted of patients with mild cognitive impairment (MCI), AD dementia, and non-Alzheimer’s dementia disease (Non-ADD). Global standard uptake value ratios (SUVRs) were calculated by Aβ PET, which was divided into positive (Aβ+) and negative (Aβ−) through visual analysis. CSF p-Tau181 and p-Tau181/t-Tau ratio were positively correlated with the global SUVR, while CSF Aβ42 and Aβ42/Aβ40 ratio were negatively correlated with the global SUVR. CSF Aβ40 has the highest predictive value in discriminating the MCI group from the AD group, while CSF p-Tau181 was applied to discriminate the AD group from the non-ADD group. CSF Aβ42/Aβ40 ratio, as the optimal predictive factor, was combined with APOE ε4 status rather than age and education, which could improve the predictive ability in differentiating the Aβ+ group from the Aβ– group. The results reveal the universal applicability of CSF core AD biomarkers and Aβ PET imaging in Chinese dementia population, which is helpful in clinical practice and drug trials in China.

BackgroundAgeing is a major risk factor for Alzheimer’s disease (AD), which is accompanied by cellular senescence and thousands of transcriptional changes in the brain.ObjectivesTo identify the biomarkers in the cerebrospinal fluid (CSF) that could help differentiate healthy ageing from neurodegenerative processes.MethodsCellular 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.ResultsThe 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 (β=0.5412, p<0.0001) levels were markedly elevated with age in healthy older individuals, whereas HGF (β=0.2732, p=0.0001), MIF (β=0.33714, p=0.0017) and TSP2 (β=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.DiscussionOur 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.

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