Background:The Centiloid (CL) value offers a standardized metric for quantifying amyloid-β (Aβ) levels in the brain. We aimed to investigate the associations of plasma phosphorylated tau 217 (P-tau217) and glial fibrillary acidic protein (GFAP) with Aβ (A) deposition, Tau (T) accumulation, cortical atrophy (N), and cognitive decline across varying CL scales. Methods:This study involved 1346 participants who underwent [18F]florbetapir PET, plasma P-tau217 and GFAP measurements, structural MRI (sMRI), and cognitive assessments. A subset of 604 participants additionally completed [18F]MK6240 PET. CL values were stratified into three scales: CL ≤ 10, 10 < CL ≤ 30, and CL > 30. ROC analyses assessed the discriminative abilities of plasma P-tau217 and GFAP across various CL scales. Adjusted regression models examined their associations with Aβ/Tau burden, cortical atrophy, and cognitive decline among different CL scales. Findings:Plasma levels of P-tau217 and GFAP exhibited a progressive increase across the groups of CL ≤ 10, 10 < CL ≤ 30, and CL > 30 (P < 0.0001), and were most positively associated with CL values within the 10 < CL ≤ 30 range (β = 0.236, P = 0.016; β = 0.206, P = 0.027, respectively). Plasma P-tau217 effectively differentiated between CL > 30 and CL ≤ 30 in cognitively normal (CN) and mild cognitive impairment (MCI) participants (AUC = 0.919 and 0.926, respectively), whereas in dementia participants, it more effectively separated CL > 10 from CL ≤ 10 (AUC = 0.959). A sequential mediation model indicated that CL values influenced the MK6240-SUVR (temporal-meta-ROI) through plasma GFAP, followed by P-tau217, with the most significant effects observed within the 10 < CL ≤ 30 range. Elevated GFAP levels were correlated with reduced cortical thickness and poorer cognitive performance in the CL ≤ 10 group, while increased P-tau217 levels were associated with atrophy and non-executive cognitive deficits in the CL > 10 group. Interpretation:Plasma P-tau217 and GFAP track early Aβ accumulation, downstream Tau pathology, neurodegeneration, and cognitive deterioration across different CL scales. These biomarkers may provide valuable information for risk stratification and therapeutic targeting of AD within specific CL contexts. Funding:National Natural Science Foundation of China (Grant No. 82171198, 82501892), Shanghai Municipal Commission of Health Research Project (Grant No. 202440009, 202440010), Shanghai Municipal Science Technology Major Project (Grant No. 2018SHZDZX01), STI2030-Major Projects (Grant No. 2022ZD0213800), and Shanghai Medical Innovation and Development Foundation "Brain Health Youth Fund-Precision Diagnosis and Treatment Research on Alzheimer's Disease" (Grant No. SMIDF-150-2025A30).

INTRODUCTION:Blood-based phosphorylated tau 217 (p-tau217), glial fibrillary acidic protein (GFAP), and neurofilament light chain (NfL) show promise for Alzheimer's disease (AD), while their links to brain amyloid beta (Aβ)/tau, hippocampal atrophy, and cognitive decline need further investigation. METHODS:A cohort of 1275 participants, representing various cognitive stages, was recruited to examine the links between plasma biomarkers and brain Aβ/tau stages, tau progression, hippocampal atrophy, and cognitive decline. RESULTS:Plasma p-tau217 effectively distinguished A-T-/A-T+ individuals and A+T+Braak III-VI patients, though it identified early A+T-/A+T+Braak I-II stages only in Aβ+ subjects. Plasma GFAP levels plateau beyond a certain tau threshold, while Aβ-induced tau progression occurred only in those with high GFAP. Plasma NfL showed a weak link to brain Aβ and tau pathology, hippocampal atrophy, and typical AD cognitive decline. DISCUSSION:Plasma p-tau217 aids in disease stratification, and GFAP promotes tau progression, while NfL is inadequate as a neuronal injury biomarker for AD. HIGHLIGHTS:Plasma p-tau217 is strongly linked to brain Aβ/tau burdens and effectively differentiates between various Aβ/tau stages. Elevated plasma levels of GFAP consistently contributed to the Aβ-induced tau progression across various Braak stages. Plasma NfL exhibits limited associations with Aβ/tau pathology, AD-specific hippocampal atrophy, and cognitive decline.

Background Urinary formic acid (FA) has been reported to be a biomarker for Alzheimer's disease (AD). However, the association between FA and pathological changes in memory clinic patients is currently unclear. Objective This study aims to investigate associations between FA and pathological changes across different cognitive statuses in memory clinic patients. Methods A cohort of patients with mild cognitive impairment (MCI-Aβ- n = 37, MCI-Aβ+ n = 33), AD dementia (n = 39), and cognitively normal subjects (CN-Aβ- n = 98, CN-Aβ+ n = 50) were included. Comprehensive neuropsychological assessment, urinary FA, AD-related plasma biomarkers, MRI scans, [18F]-flurbetapir and [18F]-FDG PET scan data were collected from all participants. Results Urinary FA levels were higher in patients with MCI and AD than in CN subjects and higher in Aβ+ (CN- Aβ+, MCI-Aβ+, AD dementia) subjects than in Aβ-subjects (CN- Aβ-, MCI-Aβ-). Urinary FA was positively associated with cerebral Aβ deposition and negatively associated with glucose metabolism, both at the global level and in multiple regions of interest cortical regions in participants with different cognitive statuses. Additionally, urinary FA levels were positively correlated with the severity of white matter hyperintensities and hippocampal atrophy. Urinary FA combined with age, Mini-Mental State Examination, plasma p-tau181, and neurofilament light chain could be used to predict Aβ deposition in the brain. Conclusions Urinary FA is associated with brain pathological changes in memory clinic patients, including cerebral Aβ deposition, glucose metabolism, white matter hyperintensities, and hippocampal atrophy. It could be used as a biomarker for the early diagnosis of AD and predicting Aβ deposition.

BackgroundBlood-based biomarkers (BBBs) of Alzheimer’s disease (AD) provide a promising, minimally invasive alternative for detecting cerebral amyloid-β (Aβ) pathology. However, a lack of robust validation across diverse platforms and populations has hindered their broader clinical adoption.ObjectiveThis study aimed to cross-platform validation of the robustness of BBBs for predicting Aβ positivity in a Chinese population.MethodsThe whole cohort (N = 1,254) of AD clinical spectrum underwent cognitive assessments, cranial MRI scans, and Aβ PET scans. Subcohort 1 (N = 504) underwent Simoa-based quantification of peripheral blood Aβ40, Aβ42, p-tau181, and NfL. Subcohort 2 (N = 262) underwent additional single molecule assays (Simoa) based quantification of p-tau217 and GFAP. The whole cohorts (Subcohort 1, Subcohort 2, and the remaining population) were measured for the aforementioned six biomarkers (Aβ40, Aβ42, p-tau181, p-tau217, NfL, and GFAP) using light-initiated chemiluminescent assays (LiCA). We validated the robustness of BBBs for predicting Aβ positivity in Chinese populations, with a focus on p-tau217.ResultsThe BBBs of Aβ42/40, p-tau181, p-tau217, GFAP, and NfL have demonstrated remarkable robustness in identifying Aβ positivity within the Chinese population, as evidenced by both LiCA and Simoa assays. Among these markers, p-tau217 has emerged as the most accurate, performing robustness in both the whole cohort and cognitively normal individuals. Utilizing a dual-threshold approach for p-tau217, only 16% of samples fell into the intermediate range, thus requiring additional Aβ PET testing.ConclusionBlood-based biomarkers have demonstrated good robustness for predicting Aβ pathology in the Chinese population, with plasma p-tau217 standing out as the most promising marker for early detection of AD-related changes.

INTRODUCTION:Various indicators of neurodegeneration (N) are used in the assessment of neuronal injury in Alzheimer's disease (AD). The heterogeneity of such indicators is less clear. METHODS:A total of 416 individuals with different cognitive statuses were recruited for this study. Differential associations of hippocampal volume (HV), 18F-fluorodeoxyglucose positron emission tomography (FDG PET) standardized uptake value ratios (SUVRs), and plasma neurofilament light chain (NfL) levels with amyloid beta (Aβ)-tau pathology and cognitive impairment were examined. RESULTS:HV decreased early during the high Aβ burden but tau-negative stage. FDG PET SUVRs and plasma NfL levels notably changed at tau-positive stages. HV and plasma NfL correlated with cognitive scores in the early to middle stages, while FDG PET SUVRs aligned with cognitive decline from the middle to late stages. Hippocampal atrophy and inferior parietal hypometabolism increased the risk of cognitive impairment in A+T+, while adding NfL+ had no additional impact within the distinct A/T groups. DISCUSSION:Different indicators of N have varying relationships to AD pathology and cognitive impairment. HIGHLIGHTS:Hippocampal atrophy emerges early with a high amyloid beta burden and exacerbates during the tau-positive phase. Brain hypometabolism and elevated plasma neurofilament light chain (NfL) levels appear mainly in tau-positive stages. Hippocampal volume and plasma NfL levels correlate with cognitive decline in the early to middle stages, while 18F-fluorodeoxyglucose positron emission tomography standardized uptake value ratios in the middle to late stages. Hippocampal atrophy and inferior parietal hypometabolism raise the risk of cognitive impairment in amyloid/tau-positive individuals while adding NfL+ shows no additional effect.

Alzheimer’s disease (AD) is a common cause of dementia, characterised by cerebral amyloid-β deposition, pathological tau and neurodegeneration. The prodromal stage of AD (pAD) refers to patients with mild cognitive impairment (MCI) and evidence of AD’s pathology. At this stage, disease-modifying interventions should be used to prevent the progression to dementia. Given the inherent heterogeneity of MCI, more specific biomarkers are needed to elucidate the underlying AD’s pathology. Although the uses of cerebrospinal fluid and positron emission tomography are widely accepted methods for detecting AD’s pathology, their clinical applications are limited by their high costs and invasiveness, particularly in low-income areas in China. Therefore, to improve the early detection of Alzheimer's disease (AD) pathology through cost-effective screening methods, a panel of 45 neurologists, psychiatrists and gerontologists was invited to establish a formal consensus on the screening of pAD in China. The supportive evidence and grades of recommendations are based on a systematic literature review and focus group discussion. National meetings were held to allow participants to review, vote and provide their expert opinions to reach a consensus. A majority (two-thirds) decision was used for questions for which consensus could not be reached. Recommended screening methods are presented in this publication, including neuropsychological assessment, peripheral biomarkers and brain imaging. In addition, a general workflow for screening pAD in China is established, which will help clinicians identify individuals at high risk and determine therapeutic targets.

A newly developed SV2A radiotracer, 18F-SynVesT-1, was used in this study to investigate synaptic density and its association with Alzheimer's disease (AD) "A/T/N" biomarkers. The study included a cohort of 97 subjects, consisting of 64 patients with cognitive impairment (CI) and 33 individuals with normal cognition (CU). All subjects underwent 18F-SynVesT-1 PET/MR and 18F-florbetapir PET/CT scans. Additionally, a subgroup of individuals also underwent 18F-MK-6240, 18F-FDG PET/CT, plasma Aβ42/Aβ40 and p-tau181 tests. The differences in synaptic density between the groups and the correlations between synaptic density and AD "A/T/N" biomarkers were analyzed. The results showed that compared to the CU group, the CI with Aβ+ (CI+) group exhibited the most pronounced synapse loss in the hippocampus, with some loss also observed in the neocortex. Furthermore, synaptic density in the hippocampus and parahippocampal gyrus showed associations with AD biomarkers detected by both imaging and plasma tests in the CI group. The associations between synaptic density and FDG uptake and hippocampal volume were also observed in the CI+ group. In conclusion, the study demonstrated significant synaptic density loss, as measured by the promising tracer 18F-SynVesT-1, and its close correlation with "A/T/N" biomarkers in patients with both Alzheimer's clinical syndrome and pathological changes.

AbstractThe metabolic implications in Alzheimer’s disease (AD) remain poorly understood. Here, we conducted a metabolomics study on a moderately aging Chinese Han cohort (n = 1397; mean age 66 years). Conjugated bile acids, branch-chain amino acids (BCAAs), and glutamate-related features exhibited strong correlations with cognitive impairment, clinical stage, and brain amyloid-β deposition (n = 421). These features demonstrated synergistic performances across clinical stages and subpopulations and enhanced the differentiation of AD stages beyond demographics and Apolipoprotein E ε4 allele (APOE-ε4). We validated their performances in eight data sets (total n = 7685) obtained from Alzheimer’s Disease Neuroimaging Initiative (ADNI) and Religious Orders Study and Memory and Aging Project (ROSMAP). Importantly, identified features are linked to blood ammonia homeostasis. We further confirmed the elevated ammonia level through AD development (n = 1060). Our findings highlight AD as a metabolic disease and emphasize the metabolite-mediated ammonia disturbance in AD and its potential as a signature and therapeutic target for AD.

Objective: Compare the efficiency of pulse wave velocity (PWV) and ankle-brachial Index (ABI) in diabetes patients and healthy participants. Investigate novel bio-markers for aging related arterial stiffness. JOURNAL/jhype/04.03/00004872-202301001-01307/figure1/v/2023-10-24T163949Z/r/image-jpeg Design and method: PWV, ABI, vascular cell adhesion molecule (VCAM), osteopontin (OPN) and glutathione peroxidase (GPX) were evaluated in elderly Chinese from March to June in 2019. Results: 86 participants were included in the study. There were 69 male participants (80.2%), the mean age is 87.2 ± 0.5 years, the mean BMI is 23.3 ± 0.5. Of the 86 participants, 34 were diagnosed with diabetes mellitus. Compared with non- diabetes mellitus participants, ABI levels declined in left limbs of diabetes mellitus (DM) patients (0.94 ± 0.04 vs 1.02 ± 0.03, P < 0.05, separately). After adjusted by age, SBP, DBP, BMI, FPG, Cholesterol and HCT, serum OPN level was negatively correlated to both L- ABI and R- ABI (r = - 0.317, P = 0.028; r = - 0.362, P = 0.014, separately). Conclusions: Differential use of PWV and ABI should be considered in elderly with diabetes. Serum levels of OPN might be an independent bio-marker for predicting arterial stiffness in elderly Chinese.

BACKGROUND Blood pressure variability (BPV) has been shown to be related to mild cognitive impairment and Alzheimer's disease in a number of studies. However, the relationship between BPV and subtle cognitive decline (SCD) has received minimal attention in this field of research to date and has rarely been reported. AIM To examine whether SCD is independently associated with changes in BPV in older adults. METHODS Participants were selected based on having participated in cognitive function evaluation and ambulatory blood pressure measurement at the Shanghai Sixth People's Hospital Affiliated with Shanghai Jiao Tong University School of Medicine between June 2020 and August 2022. The participants included 182 individuals with SCD as the experimental group and 237 with normal cognitive function as the control group. The basic data, laboratory examinations, scale tests, and ambulatory blood pressure test results of the two groups were analyzed retrospectively, and the relationship between SCD and BPV was subsequently evaluated. RESULTS Significant differences were observed between the two groups of participants (P < 0.05) in terms of age, education level, prevalence rate of diabetes, fasting blood glucose level, 24-h systolic blood pressure standard deviation and coefficient of variation, 24-h diastolic blood pressure standard deviation and coefficient of variation. The scale monitoring results showed significant differences in the scores for memory, attention, and visual space between the experimental and control groups. Logistic regression analysis indicated that age, education level, blood sugar level, and BPV were factors influencing cognitive decline. Linear regression analysis showed that there was an independent correlation between blood pressure variation and SCD, even after adjusting for related factors. Each of the above differences was still significant. CONCLUSION This study suggests that increased BPV is associated with SCD.

Conflicting findings exist regarding the differences in amyloid burden and cognitive performance based on sex and apolipoprotein E (APOE) genotype. This study aimed to investigate the brain amyloid-β (Aβ) burden and cognitive performances by sex and APOE genotype in a cohort of Aβ-positron emission tomography (PET)-positive participants. Brain Aβ burden was assessed using 18F-florbetapir PET standard uptake value ratios. Cognitive performance was evaluated using standardized neuropsychological tests. In the cognitively normal participants, females had a higher Aβ burden than males in APOE ε4 noncarriers, whereas APOE ε4 carriers had a higher Aβ burden than noncarriers in males. In the cognitively impaired participants, APOE ε4 carriers were more likely to have a higher Aβ burden than noncarriers in the brain regions of the lateral parietal gyrus, frontal gyrus, and precuneus. In addition, females were more likely to have poorer language and visuospatial performance compared to males, while the APOE genotype did not significantly impact cognitive performance. These findings further elucidate the impact of sex and APOE genotype on brain Aβ burden and sex-related cognitive performance should be considered in the Alzheimer's Continuum.

Abstract Background Accurate prediction of cerebral amyloidosis with easily available indicators is urgently needed for diagnosis and treatment of Alzheimer’s disease (AD). Methods We examined plasma Aβ42, Aβ40, T-tau, P-tau181, and NfL, with APOE genotypes, cognitive test scores and key demographics in a large Chinese cohort (N = 609, aged 40 to 84 years) covering full AD spectrum. Data-driven integrated computational models were developed to predict brain β-amyloid (Aβ) pathology. Results Our computational models accurately predict brain Aβ positivity (area under the ROC curves (AUC) = 0.94). The results are validated in Alzheimer’s Disease Neuroimaging Initiative (ADNI) cohort. Particularly, the models have the highest prediction power (AUC = 0.97) in mild cognitive impairment (MCI) participants. Three levels of models are designed with different accuracies and complexities. The model which only consists of plasma biomarkers can predict Aβ positivity in amnestic MCI (aMCI) patients with AUC = 0.89. Generally the models perform better in participants without comorbidities or family histories. Conclusions The innovative integrated models provide opportunity to assess Aβ pathology in a non-invasive and cost-effective way, which might facilitate AD-drug development, early screening, clinical diagnosis and prognosis evaluation.

Subjective cognitive decline (SCD) as an indicator of preclinical Alzheimer’s disease (AD) may precede mild cognitive impairment (MCI) over several decades. Self-reported cognitive decline as a typical clinical manifestation is critical in preclinical AD. Metacognition represents a person’s ability to accurately assess cognition. Our study aimed to examine (1) the alternations of metamemory in a cohort across the Alzheimer’s continuum, (2) the association between metamemory and cognition, and (3) the relationship of cortical thickness in four regions of interest (ROI) with metamemory scores. Six hundred ninety-seven participants were classified as 79 AD dementia, 161 aMCI, 261 SCD, and 196 cognitively unimpaired (CU) individuals, in which 418 participants aged above 65, 131 participants with Aβ+ after receiving positron emission tomography, and 602 participants received sMRI. The degree of confidence (DOC) was measured by calculating discrepancies between judgments and memory performance. We assessed the relationships between DOC tertiles and cognition and analyzed the screening power, then investigated the partial correlation between DOC and ROIs, controlled by age, sex, and cognition. In the Aβ+ subgroup, SCD showed significantly higher DOC scores than the CU group. There was an increasing trend of overconfidence with the decline of cognition across the AD spectrum (P for trend < 0.001). After adjusting for age, sex, and education, the lower degree of confidence-long-term delay recall (DOC-LD) tertiles were associated with lower odds ratio in SCD, aMCI, and AD in the Aβ+ subgroup (all P for trend < 0.05). The area under the curves of DOC scores for screening SCD from CU in the Aβ+ subgroup was better than that in all participants and the age ≥65 subgroup. Partial correlation showed that in the Aβ+ subgroup, DOC-SD (degree of confidence-short-term delay recall) was negatively correlated with the anterior cingulate cortex; DOC-LD was negatively correlated with the cortices of parahippocampal, anterior cingulate, posterior cingulate, and medial orbitofrontal. In individuals with Aβ+, SCD exhibited a detectable metamemory alternation before objective cognitive impairment could be tested, indicated by the overestimation in the memory performance. The pattern of an increasing trend of overconfidence across SCD, aMCI, and AD dementia supports the view of a continuum in Alzheimer’s disease.

Urine-based formaldehyde has been reported to be a potential biomarker for Alzheimer’s disease (AD). However, there is a lack of research about the correlation between urine formaldehyde and cognitive abilities in the clinical spectrum of AD, especially the preclinical period. The relationship of urine formaldehyde with APOE genotype, brain Aβ status and plasma pathological markers in AD are also not clear. This study intends to explore the correlation between urine formaldehyde and cognitive abilities throughout the AD continuum, to evaluate the role of APOE genotype and Aβ accumulation on urine formaldehyde, and further to clarify the relationship between urine formaldehyde level and AD plasma pathological markers. We recruited 72 cognitively normal controls (NC), 110 subjective cognitive decline (SCD), 140 objectively defined subtle cognitive decline (Obj-SCD), 171 mild cognitive impairment (MCI) and 136 AD dementia participants. Next, we collected the data of clinical materials, neuropsychological examination, APOE genotyping, urine formaldehyde concentration, 18F-florbetapir PET imaging and plasma biomarkers. Compared with NC, Obj-SCD and MCI groups, the level of urine formaldehyde was found to be significantly upregulated in SCD group. In addition, the level of urine formaldehyde was significantly higher in AD group compared to both NC and MCI groups. Further subgroup analysis showed that, the level of urine formaldehyde was higher in APOE ε4+ subgroup compared to APOE ε4– subgroup in both NC and AD groups. There was no difference in urine formaldehyde level between the brain Aβ+ subgroup and Aβ– subgroup in each group. In addition, regression analysis showed urine formaldehyde level was correlated with gender, plasma Aβ42 and p-Tau181/T-tau. The dynamic change of urine formaldehyde in the AD continuum could be used as a potential biomarker, and combined with comprehensive cognitive evaluation could become a useful method to distinguish SCD from NC and Obj-SCD, and to distinguish MCI from AD.

Plasma amyloid-β (Aβ) was associated with brain Aβ deposition and Alzheimer’s disease (AD) development. However, changes of plasma Aβ over the course of cognitive decline in the Alzheimer’s continuum remained uncertain. We recruited 449 participants to this study, including normal controls (NC), subjective cognitive decline (SCD), mild cognitive impairment (MCI), AD, and non-AD dementia. All the participants underwent plasma Aβ42, Aβ40, and t-tau measurements with single-molecule array (Simoa) immunoassay and PET scan with 18F-florbetapir amyloid tracer. In the subgroup of Aβ-PET positive, plasma Aβ42 and Aβ42/Aβ40 ratio was significantly lower in AD than NC, SCD and MCI, yet SCD had significantly higher levels of plasma Aβ42 than both NC and MCI. In the diagnostic groups of MCI and dementia, participants with Aβ-PET positive had lower plasma Aβ42 and Aβ42/40 ratio than participants with Aβ-PET negative, and the increasing levels of plasma Aβ42 and Aβ42/40 ratio indicated lower risks of Aβ-PET positive. However, in the participants with SCD, plasma Aβ42 and Aβ40 were higher in the subgroup of Aβ-PET positive than Aβ-PET negative, and the increasing levels of plasma Aβ42 and Aβ40 indicated higher risks of Aβ-PET positive. No significant association was observed between plasma Aβ and Aβ-PET status in normal controls. These findings showed that, in the continuum of AD, plasma Aβ42 had a significantly increasing trend from NC to SCD before decreasing in MCI and AD. Furthermore, the predictive values of plasma Aβ for brain amyloid deposition were inconsistent over the course of cognitive decline.

Abstract Background For detecting mild cognitive impairment (MCI), brief cognitive screening tools are increasingly required for the advantage of time saving and no need for special equipment or trained raters. We aimed to develop a modified Chinese version of Mini‐Addenbrooke's Cognitive Examination (C‐MACE) and further evaluate its validation in detecting MCI. Methods A total of 716 individuals aged from 50 to 90 years old were recruited, including 431 cognitively normal controls (NC) and 285 individuals with MCI. The effect size of Cramer's V was used to explore which items in the Chinese version of Addenbrooke's Cognitive Examination‐III (ACE‐III‐CV) best associated with MCI and to form the C‐MACE. Receiver operating characteristic (ROC) analyses were carried out to explore the ability of C‐MACE, ACE‐III‐CV, Chinese version of Montreal Cognitive Assessment‐Basic (MoCA‐BC), and Mini‐Mental State Examination (MMSE) in discriminating MCI from NC. Results Five items with greatest effect sizes of Cramer's V were selected from ACE‐III‐CV to form the C‐MACE: Memory Immediate Recall, Memory Delayed Recall, Memory Recognition, Verbal Fluency Animal and Language Naming. With a total score of 38, the C‐MACE had a satisfactory classification accuracy in detecting MCI (area under the ROC curve, AUC = 0.892), superior to MMSE (AUC = 0.782) and comparable to ACE‐III‐CV (AUC = 0.901) and MoCA‐BC (AUC = 0.916). In the subgroup of Age > 70 years, Education ≤ 12 years, the C‐MACE got a highest classification accuracy (AUC = 0.958) for detecting MCI. Conclusion In the Chinese‐speaking population, C‐MACE derived from ACE‐III‐CV may identify MCI with a good classification accuracy, especially in aged people with low education.

Abstract Background Blood based biomarkers for Alzheimer’s disease (AD) are becoming increasingly promising. Although plasma amyloid-β (Aβ) and total tau (t-tau) showed a potential ability in identifying cerebral amyloid deposition and AD. Comparisons of these plasma biomarkers along with Aβ-PET in a cohort of normal controls (NC), subjective cognitive decline (SCD), objectively-defined subtle cognitive decline (Obj-SCD), mild cognitive impairment (MCI) and AD remained lacking. Methods A total of 407 individuals aged from 40 to 90 years old were recruited, including 76 of NC, 77 of SCD, 61 of obj-SCD, 92 of MCI and 101 of AD. Plasma Aβ40, Aβ42 and t-tau were examined via single-molecule array (Simoa) immunoassay. A subset of 132 individuals underwent cerebral amyloid scans with 18F-florbetapir PET. Comparisons of plasma t-tau, Aβ40, Aβ42 and Aβ42/Aβ40 ratio were conducted between different diagnostic groups and cerebral Aβ burdens. Pearson correlation analysis was used to evaluate the correlation between Aβ42, Aβ42/Aβ40 ratio and 18F-florbetapir SUVR. Receiver operating characteristic (ROC) curve analyses were carried out to evaluate the capacity of plasma biomarkers in identifying high brain Aβ burden and diagnosis of AD. Results Plasma Aβ42 was significantly higher in SCD and obj-SCD than NC, MCI and AD. Plasma Aβ40 was significantly higher in SCD and obj-SCD than NC and AD. The lowest levels of plasma Aβ42 and Aβ42/Aβ40 ratio were found in AD. No significant difference of plasma t-tau was found among groups. Plasma Aβ42 and Aβ42/Aβ40 ratio were inversely correlated with 18F-florbetapir SUVR (r=-0.272, P = 0.003; r=-0.211, P = 0.021 respectively). Aβ42/Aβ40 ratio performed well in predicting high brain Aβ burden (area under the curve, AUC = 0.762). Plasma Aβ42 and Aβ42/Aβ40 ratio had acceptable diagnostic accuracy for AD (AUC = 0.714 and 0.706 respectively), even in Aβ-PET (+) individuals (AUC = 0.728 and 0.808 respectively). Conclusions Plasma Aβ40 and Aβ42 measured by Simoa immunoassay showed a significantly bidirectional trend of initially increasing from NC to SCD and obj-SCD, and then declining to MCI and AD. In addition, plasma Aβ was significantly correlated with 18F-florbetapir PET SUVR and showed potential value in predicting cerebral Aβ deposition and risk of AD.