Abstract
Background:
The primary manifestations of Alzheimer’s disease (AD) include cognitive decline and brain gray matter volume (GMV) atrophy. Recent studies have found that plasma phosphorylated-tau (p-tau) concentrations perform better in diagnosing, differentiating, and monitoring the progression of AD. However, the correlation between plasma p-tau, GMV, and cognition remains unclear.
Objective:
To investigate whether GMV plays a mediating role in the association between plasma p-tau concentrations and cognition.
Methods:
In total, 99 participants (47 patients with AD and 52 cognitively unimpaired [CU] individuals) were included. All participants underwent neuropsychological assessments, laboratory examinations, and magnetic resonance imaging scans. Plasma p-tau217 and p-tau181 concentrations were measured using an enzyme-linked immunosorbent assay kit. Voxel-based morphometry was performed to assess participants’ brain GMV. Partial correlation and mediation analyses were conducted in AD group.
Results:
Plasma p-tau concentrations were significantly higher in the AD group than in the CU group. Patients with AD had significant brain GMV atrophy in the right hippocampus, bilateral middle temporal gyrus, and right inferior temporal gyrus. In the AD group, there were significant correlations between plasma p-tau217 concentrations, GMV, and Mini-Mental State Examination (MMSE) scores. Brain GMV of the right hippocampus mediated the association between plasma p-tau217 concentrations and MMSE scores. A significant correlation between plasma p-tau181 and MMSE scores was not identified.
Conclusion:
The findings indicate that p-tau217 is a promising biomarker for central processes affecting brain GMV and cognitive function. This may provide potential targets for future intervention and treatment of tau-targeting therapies in the early stages of AD.
INTRODUCTION
Alzheimer’s disease (AD), a neurodegenerative disease characterized by progressive cognitive impairment, is the most common form of dementia. AD is one of the leading causes of mortality and disability in the older adults [1, 2], and the number of patients with dementia in China accounts for approximately a quarter of the global population with dementia [3]. It is estimated that the worldwide prevalence of AD will triple by 2050, presenting a great challenge for policymakers, healthcare professionals, and family members [4, 5]. Therefore, it is imperative to identify and diagnose the early phases of AD and to monitor its disease progression.
One of the core pathological hallmarks of AD is intracellular neurofibrillary tangles, which are made up of hyperphosphorylated tau proteins [2]. Normal tau binds to microtubules in the healthy brain, providing stability and facilitating axonal transport. However, in the AD brain, phosphorylated-tau (p-tau) is disassociated from microtubules and aggregates [6]. The accumulation of p-tau can induce synaptic impairment, neuronal dysfunction, and dementia development [7, 8]. Accumulated evidence has demonstrated that tau pathology is spatially and temporally correlated with neurodegeneration and clinical manifestations of AD [9–12]. Hence, tau pathological biomarkers may improve the diagnostic accuracy and prognostication of AD in clinical practice.
Previously, biomarkers for tau pathology in patients with AD mainly included tau-positron emission tomography (PET) for measuring insoluble tau aggregates and cerebrospinal fluid (CSF)-based tau biomarkers for identifying p-tau isoforms [13]. In accordance with autopsy-based studies, tau-PET was strongly associated with cognitive decline in cognitively impaired individuals [14–16]. Tau phosphorylated at threonine 181 and 217 (p-tau181 and p-tau217) were the predominant tau biomarkers measured in the CSF, and these were found to correlate strongly with baseline and longitudinal tau-PET measures [17, 18]. In addition, these biomarkers can better distinguish AD from other neurodegenerative diseases [19, 20]. However, these methods are expensive, invasive, inaccessible, and difficult to implement. Therefore, researchers are increasingly focusing on the identification of plasma biomarkers. Compelling pieces of evidence have suggested that plasma p-tau181 and p-tau217 concentrations are highly associated with tau pathology [21, 22]. These plasma biomarkers share excellent consistency with CSF and tau-PET in the diagnosis and differentiation of AD [23–27], and they are also closely related to cognition [28, 29] and brain atrophy [30, 31] in the early stages of AD.
Brain gray matter atrophy, assessed using structural magnetic resonance imaging (MRI), has been demonstrated as a cardinal trait of AD-related neurodegeneration [32, 33] that can allow clinicians to track patients’ AD progression [34]. Atrophy is also related to tau accumulation in specific brain regions and is correlated with in vivo biomarkers of CSF p-tau levels and deposition on tau-PET [33]. Brain gray matter volume (GMV) decreases in typical AD-related brain regions, particularly the medial temporal regions and hippocampus, which are regions closely related to cognitive decline and in which changes can be detected up to 10 years before clinical diagnosis of AD [33, 36]. According to these studies, atrophy of the GMV in different brain regions may vary slightly across the disease stages of the AD continuum.
Previous studies have indicated that the brain GMV may play a mediating role between biomarkers and cognitive function. One study found that tau 18F-AV-1451-PET uptake and cognitive performance were partially mediated by brain GMV atrophy in patients with AD [38]. Another study showed that the GMV of the hippocampus mediates the effect of amyloid-β (Aβ) on cognition in patients with mild cognitive impairment (MCI) [39]. In addition, another study showed that GMV atrophy of the right accumbens area completely mediated the higher plasma p-tau and impaired executive function in patients with Parkinson’s disease [40]. However, correlations among plasma p-tau181 and p-tau217 concentrations, brain GMV and cognition in patients with AD still require further validation and clarification in diverse populations [24, 41]. Therefore, we aimed to examine the following hypothesis among the Chinese population: 1) patients with AD have higher plasma p-tau concentrations than healthy individuals; 2) increased plasma p-tau concentrations are correlated with GMV atrophy of AD-related brain regions and cognitive decline; and 3) brain GMV mediates the correlation between plasma p-tau concentrations and cognitive function.
MATERIALS AND METHODS
Subjects
All participants (aged 50–80 years, right-handed, and of Chinese Han origin) were enrolled in the Department of Neurology at the First Affiliated Hospital of Anhui Medical University from April 2021 to May 2022. All the patients underwent detailed cognitive assessments, laboratory examinations, and brain MRI scans. Demographic information, such as age, sex, years of education, and medical history, including hypertension, diabetes, hyperlipidemia, and heart disease, was recorded for each participant.
The diagnosis of probable AD fulfilled the criteria of the 2011 National Institute of Aging and Alzheimer’s Association (NIA-AA) [42]. The inclusion criteria for the AD group were as follows: 1) gradual onset of cognitively impaired symptoms for over 1 year; 2) Mini-Mental State Examination (MMSE) score ≤26 points; 3) Clinical Dementia Rating (CDR) [43] score of 0.5–1.0 points; 4) Hachinski Ischemic Scale [44] score less than 4 points; and 5) Geriatric Depression Scale [45] score less than 10 points. The inclusion criteria for the cognitively unimpaired (CU) group were as follows: 1) no complaints of memory loss; 2) MMSE >26 points; and 3) CDR = 0. The exclusion criteria for both groups were as follows: 1) history of brain tumor, traumatic brain injury, stroke, epilepsy, psychiatric illness, or treatment with electroconvulsive therapy; 2) other neuropsychiatric disorders resulting in cognitive decline; 3) severe liver and kidney diseases, thyroid diseases, tumors, immune, and digestive disease; and 4) presence of multiple lacunar cerebral infarctions or severe white matter hyperintensity (Fazekas grade ≥2) [46].
This study was approved by the Institutional Ethics Committee of the First Affiliated Hospital of Anhui Medical University (ethical approval number: Quick-PJ 2022-13-30) and was conducted following the Declaration of Helsinki. Signed informed consents were obtained from all participants or their legal guardians.
Blood sample collection and analyses
Peripheral venous blood (2 mL) from each participant was collected using an ethylenediaminetetraacetic acid tube after an overnight fast. First, 500μL of the whole blended blood sample was extracted into EP tubes and stored at –80°C for apolipoprotein E (APOE) genotyping. Centrifugation at 3,500 r/min for 8 min was completed within 1 h of blood collection. After centrifugation, the 500μL plasma sample was extracted into EP tubes and stored at –80°C for p-tau testing. The samples in EP tubes were sent to the Beijing Genomics Institution Gene Technology Co., Ltd. for testing. According to the protocols, genotype data of APOE ɛ4 status was obtained using a BigDyeTM Direct cycle sequencing kit (Applied BiosystemsTM, USA). Plasma p-tau concentrations were examined using human p-tau181 and p-tau217 enzyme-linked immunosorbent assay (ELISA) kits (Shanghai Lianshuo Biotechnology Co., Ltd. China), respectively. The coefficient of variations was 7.3% (inter-assay) and 5.5% (intra-assay) for plasma p-tau181, and 7.1% (inter-assay) and 5.2% (intra-assay) for plasma p-tau217, respectively.
Neuropsychological scale assessment
All participants underwent the following neuropsychological tests, which were administered by two clinical neuropsychologists with extensive experience: the MMSE for evaluating the cognitive function, the CDR for assessing the severity of the disease [47, 48], the Hachinski Ischemic Scale for excluding vascular dementia [49], and the Geriatric Depression Scale for excluding emotional disorders [50].
MRI data acquisition and analysis
MRI scans were acquired using a 3.0-Tesla MR system (Discovery MR750w, General Electric, Milwaukee, WI, USA) with a 24-channel head coil. Earplugs and foam padding were used to reduce scanner noise and minimize head motion, respectively. High-resolution three-dimensional T1-weighted structural images were obtained by employing a brain volume sequence with the following parameters: repetition time (TR) = 8.5 ms; echo time (TE) = 3.2 ms; inversion time = 450 ms; flip angle (FA) = 12°; field of view (FOV) = 256 mm×256 mm; matrix size = 256×256; slice thickness = 1 mm, no gap; and 188 sagittal slices. The T2 fluid-attenuated inversion recovery (FLAIR) parameters were as follows: TR = 9,000 ms, TE = 119.84 ms, FOV = 225×225 mm, FA = 160°, matrix = 512×512, number of layers = 19, layer thickness = 7 mm, and acquisition time = 1 min 57 s. All images were visually inspected for artefacts, motion problems, or structural abnormalities.
Voxel-based morphometry (VBM) analysis was performed using the VBM8 toolbox (https://dbm.neuro.uni-jena.de/vbm8/) based on statistical parametric mapping software (SPM8, https://www.fil.ion.ucl.ac.uk/spm) according to our previous study [51]. A multiple regression model in SPM8 was used to identify brain structural changes between the different groups while controlling age, sex, education, APOE, and total intracranial volume (TIV) as covariates. Multiple comparison correction was performed using the cluster-level family-wise error (FWE) method. The statistical significance was set at p < 0.05, and this was corrected at the cluster level to a threshold of p = 0.001 at the voxel level. Data processing and analysis for brain imaging (DPABI) (https://rfmri.org/dpabi) software were used to extract the GMV of specific structurally changed brain regions for further region-of-interest analysis [52].
The time interval between the blood sample collection, neuropsychological assessment, and MRI scan procedures was less than 1 week.
Statistical analyses
Comparisons between groups were performed using the χ2 test for categorical variables (sex, APOE ɛ4 status, and comorbidities), and a two-sample t-test for continuous variables (age, education, MMSE, CDR, and TIV). Statistical significance was defined as a two-tailed p < 0.05.
The variables with significant differences between the AD and CU groups, including p-tau217 and p-tau181, the GMV of the right hippocampus, bilateral middle temporal gyrus, and right inferior temporal gyrus, and MMSE scores, were included in the partial correlation analyses. Partial correlation analyses were performed at the region-of-interest level, adjusting for age, sex, education, APOE status, and TIV as covariates. The correlation coefficients were also shown. Statistical product service solutions (SPSS) software (version 23.0; IBM SPSS Inc., Armonk, NY, United States) was used for all analyses.
Mediation analyses
In this study, we aimed to investigate whether the effect of plasma p-tau concentrations (independent variable, X) on MMSE scores (dependent variable, Y) was indirectly explained by the GMV of brain structural changes (mediator, M). Variables that showed a significant correlation with others in the partial correlation analyses were considered in the mediation analyses.
Mediation analysis of a linear regression model [53] was performed to test whether the association between variables was mediated by other variables using the PROCESS macro (https://www.processmacro.org/), a versatile modelling tool freely available for SPSS 23.0. PROCESS uses an ordinary least squares path analytic framework to estimate direct and indirect mediation effects. In the mediation analysis model, all paths were reported as unstandardized ordinary least squares regression coefficients, namely the total effect of X on Y (c) = indirect effect of X on Y through M (a×b) + direct effect of X on Y (c’). The significance analysis was based on 5000 bootstrap realizations, and the significance of the indirect effects was assessed using a bootstrap 95% confidence interval (CI). In the PROCESS analysis, a significant indirect effect was indicated when the bootstrap 95% CI did not include zero. The statistical significance threshold was set at 0.05 for all the relevant paths. Mediation analyses were performed, controlling for age, sex, education, APOE, and TIV as covariates in this study.
RESULTS
Demographics
A total of 99 participants were included in this study, including 52 CU individuals and 47 patients at an early stage of clinically probable AD. The demographic characteristics of all participants are presented in Table 1. The CU and AD groups showed no significant differences in age, years of education, TIV, or comorbidities. Patients with AD had significantly lower MMSE scores and higher CDR scores than CU individuals. In addition, the proportion of women and APOE ɛ4 carriers in the AD group was significantly higher than that in the CU group.
Demographic and clinical data of all participants
CU, cognitively unimpaired; AD, Alzheimer’s disease; MMSE, Mini-Mental State Examination; CDR, Clinical Dementia Rating; TIV, total intracranial volume. Age, education, and scores of MMSE, CDR, and TIV were compared between different groups by two sample t-test; sex, APOE status, and comorbidities by χ2 test.
Group differences in plasma p-tau concentrations and brain GMV
As shown in Fig. 1, the plasma p-tau181 and p-tau217 concentrations in the AD group were significantly higher than in the CU group.
The voxel-wise whole gray matter analysis revealed a significant main effect of diagnosis (CU > AD) on the right hippocampus, bilateral middle temporal gyrus, and right inferior temporal gyrus (Fig. 2). A detailed description of each brain region, including cluster size (voxels), Montreal neurological institute peak coordinate (X/Y/Z), and peak T-value were displayed in Table 2.
Violin plot of plasma concentrations of p-tau181 and p-tau217 between the AD and the CU groups. P-tau concentrations are presented as mean (pg/mL)±standard deviation. A) Group difference of plasma p-tau181 between AD and CU; B) Group difference of plasma p-tau217 between AD and CU. AD, Alzheimer’s disease; CU, cognitively unimpaired. *p < 0.05, ***p < 0.001.
Patients with Alzheimer’s disease exhibited significant brain gray matter atrophy in the right hippocampus, bilateral middle temporal gyrus, and right inferior temporal gyrus compared with cognitively unimpaired individuals. L, left; R, right.
Peak point coordinates of significant clusters in intergroup comparison
AAL, anatomical automatic labelling; MNI, Montreal Neurological Institute; AD, Alzheimer’s disease; CU, cognitively unimpaired.
Correlations between plasma p-tau concentrations and brain GMV in the AD group
In the AD group, there was a significant negative correlation between plasma p-tau217 concentrations and GMV in the right hippocampus (Fig. 3A), and plasma p-tau217 was also significantly negatively correlated with GMV in the right inferior temporal gyrus (Fig. 3B). However, plasma p-tau217 levels were not significantly correlated with the GMV of the right middle temporal gyrus (Supplementary Figure 1A) nor with the GMV of the left middle temporal gyrus (Supplementary Figure 1B). A significant negative correlation was found between plasma p-tau181 concentration and the GMV in the right middle temporal gyrus (Fig. 3C). However, plasma p-tau181 levels were not significantly correlated with the GMV of the right hippocampus (Supplementary Figure 1C), the GMV of the right inferior temporal gyrus (Supplementary Figure 1D), or the GMV of the left middle temporal gyrus (Supplementar Figure 1E).
Scatter plot of the association between plasma p-tau concentration, gray matter volume (GMV) of different brain regions, and Mini-Mental State Examination (MMSE) scores in the AD group. A) Correlation between plasma p-tau217 and the GMV of the right hippocampus. B) Correlation between plasma p-tau217 and the GMV of the right inferior temporal gyrus. C) Correlation between plasma p-tau181 and the GMV of the right middle temporal gyrus. D) Correlation between the GMV of the right hippocampus and MMSE scores. E) Correlation between the GMV of the right inferior temporal gyrus and MMSE scores. F) Correlation between the GMV of the right middle temporal gyrus and MMSE scores. G) Correlation between plasma p-tau217 and MMSE scores. H) Correlation between plasma p-tau181 and MMSE scores. AD, Alzheimer’s disease; CU, cognitively unimpaired. *p < 0.05, **p < 0.01.
Correlations between brain GMV and cognitive function in the AD group
In the AD group, the GMV of the right hippocampus had a strongly significantly positive correlation with MMSE scores (Fig. 3D), and the GMV of the right inferior temporal gyrus and the right middle temporal gyrus were significantly positively correlated with MMSE scores (Fig. 3E, F). However, we did not find a significant correlation between the GMV of the left middle temporal gyrus and MMSE scores (Supplementary Figure 1F).
Correlations between plasma p-tau concentrations and cognitive function in the AD group
Plasma p-tau217 concentrations had significantly negative correlations with MMSE scores (Fig. 3G), whereas p-tau181 was not significantly associated with MMSE scores (Fig. 3H) in the AD group.
Mediation analyses
The results of the mediation analyses are presented in Fig. 4. In the AD group, the GMV of the right hippocampus mediated the association between plasma p-tau217 concentrations and MMSE scores (Fig. 4B). However, the association between plasma p-tau181 concentrations and MMSE scores was not significantly mediated by the GMV in the right middle temporal gyrus (Fig. 4C), and there was no significant mediation effect of the GMV in the right inferior temporal gyrus on the association between plasma p-tau217 concentrations and MMSE scores (Fig. 4D).
Mediation path diagram showing different brain region gray matter atrophy serves as a potential mediator (M) between plasma p-tau concentrations (independent variable, X) and MMSE scores (dependent variable, Y). A) Conceptual diagram of a mediation analysis model with one mediator. The total effect of X on Y (c) = indirect effect of X on Y through M (a×b) + direct effect of X on Y (c’). B) GMV of the right hippocampus mediated the correlation between plasma p-tau217 concentration and MMSE scores. C) Correlation between plasma p-tau181 concentration and MMSE scores was not mediated by GMV of the right middle temporal gyrus. D) Correlation between plasma p-tau217 concentration and MMSE scores was not mediated by GMV of the right inferior temporal gyrus. *p < 0.05, **p < 0.01.
DISCUSSION
To the best of our knowledge, this was the first study to investigate the mediating relationship between plasma p-tau concentrations, brain GMV, and cognitive function in patients with early AD. The main findings are consistent with our hypothesis. Plasma p-tau217 outperformed p-tau181 in terms of its correlation with cognitive changes in the early stages of AD and was significantly correlated with the GMV of AD-related brain regions. The GMV of the right hippocampus, a key brain region that affects cognition, mediated the correlation between plasma p-tau217 concentrations and cognitive function in patients with early AD.
Our mediation analyses revealed that GMV atrophy of the right hippocampus was a significant mediator of the correlation between higher plasma p-tau217 concentrations and cognitive impairment (less MMSE scores) in patients with AD. However, in this study, the relationship between increased plasma p-tau217 and cognitive decline in AD was not mediated by the GMV atrophy of the right inferior temporal gyrus. Based on the results of previous studies [54–56], we speculated that increased plasma p-tau217 levels strongly contributed to tau pathology, contributing to neuronal death and regional atrophy in the right hippocampus and further affecting the cognitive deficit in patients with early AD. Bejanin et al. proposed that tau pathology may lead to cognitive decline through gray matter loss [38]. Brain atrophy is also common in older CU participants; however, in patients with AD, increased plasma p-tau217 concentrations may induce cognitive decline by indirectly affecting the location and rate of brain atrophy.
In this study, we compared the concentrations of plasma p-tau between patients with early AD and CU participants and analysed the GMV of discrepant brain regions in the two groups. Our study is highly consistent with previous robust evidence from direct comparisons. Both plasma p-tau181 and p-tau217 were increased in patients with AD, with p-tau217 outperforming p-tau181 in differentiating and accurately diagnosing AD [21, 27]. In this study, we found that plasma p-tau217 concentrations had significantly negative correlations with cognitive function in patients with AD, whereas p-tau181 concentrations only exhibited slightly negative correlations with cognitive function. A multicohort study [27] showed that plasma p-tau217 was more strongly correlated with cognitive performance than p-tau181, and a recent study also reported no significant correlation between plasma p-tau181 and MMSE scores [57], despite the fact that a significant correlation between plasma p-tau181 and MMSE scores was found in another dataset [31].
We speculated that the relationship with cognition might vary due to the heterogeneity of the population, testing methods, and the time course of AD [58]. In our study, baseline p-tau217 levels were not significantly related to cognition in CU individuals. However, according to a Swedish BioFINDER study [30], a longitudinal increase in plasma p-tau217 was correlated with worsening cognition in CU participants. Notably, the MMSE is a comprehensive cognitive assessment that cannot reflect the impairment of a specific cognitive domain. Thus, longitudinal and diverse assessments are required to validate these results.
We observed that higher plasma p-tau217 concentrations were significantly correlated with brain GMV atrophy in the right hippocampus and right inferior temporal gyrus, and a significant correlation was observed between higher p-tau181 levels and GMV in the right middle temporal gyrus in patients with AD. A postmortem study revealed that patients with a high likelihood of AD showed significantly higher p-tau217 area fraction in four brain areas, including the cornu ammonis 1 (CA1) region of the hippocampus [59]. This postmortem study also concluded that plasma p-tau217 concentration, a peripheral biomarker level, most likely reflected the accumulation of p-tau217 in the brain. In addition, it concluded that plasma p-tau217 levels were moderately correlated with the p-tau217 area fraction in the CA1 of the hippocampus [59].
Hippocampal atrophy shown on structural MRI is a sensitive marker of neurodegeneration in AD [60]. Moreover, evidence suggests prominent cortical thinning of the inferior and medial temporal regions in AD [61]. Regarding tau-PET imaging studies, longitudinal results from the Alzheimer’s Disease Neuroimaging Initiative database showed that tau-tracer uptake was restricted mainly to the temporal lobe in early AD [62], whereas tau-tracer uptake in the inferior temporal gyrus was associated with more significant clinical cognitive impairment [14]. Future studies examining the use of tau PET in the hippocampus may provide potential evidence for our hypothesis regarding its mediating role. A previous study indicated that p-tau217 levels are associated with brain GMV atrophy measured on MRI scans in typical AD-related brain regions, specifically in temporoparietal areas [27]. In that study, longitudinally increased p-tau217 levels were correlated with accelerated atrophy of the temporal cortex and hippocampus along with worsening cognition [30]. Moreover, a significant negative correlation was reported between the plasma p-tau181 level and cortical volume of the left middle temporal regions, which also played central roles in cognitive impairments during AD development [57]. It is also possible that p-tau181 and p-tau217 may have dynamic correlations at different stages of the course of AD. Longitudinal studies are needed to further validate the relationship between plasma p-tau concentration and brain GMV atrophy.
An intriguing finding in this study was that the brain regions significantly associated with p-tau and MMSE scores were almost always on the right side of the brain. The main reason for this might be that the patient group in this study predominantly included patients with AD at an early stage, which could partly explain the bias toward right hemisphere differences. A meta-analysis found that in patients with MCI, the GMV of the right hippocampus was more atrophic than its left counterpart [37]. Additionally, Apostolova et al. reported more severe atrophy of the right hemisphere in the medial, lateral temporal cortex, and parietal cortex in both patients with MCI and AD [63]. However, Thompson et al. found some evidence for leftward-biased hippocampal GMV atrophy in patients with AD, which was inconsistent with our results [64]. These discrepancies might also result from the subtypes of AD considered (e.g., typical AD or atypical AD), the diagnostic criteria employed, and ethnic differences among patients. Notably, we detected the plasma p-tau concentrations using ELISA, whereas previous studies mainly examined plasma p-tau181 and p-tau217 concentrations using ultrasensitive detection methods, such as single-molecule array (Simoa) or meso scale discovery. Compared with Simoa and meso scale discovery, ELISA is more affordable, more accessible, and can be commendably promoted in clinical practice for monitoring AD progression in China.
The strength of our study was that we collected detailed data from each participant, including blood samples, MRI scans, and neuropsychological evaluation data. Quality controls were performed for all procedures to ensure that the results were accurate and validated. However, this study had some limitations. First, the sample size was small and monocentric. Therefore, these findings need to be confirmed through more extensive studies. Second, this was a cross-sectional study focused on patients in the early stages of AD that lacked longitudinal follow-up data; therefore, changes that occur with further disease progression could not be inferred. Third, the AD diagnosis in this study was based on the 2011 NIA-AA criteria, which lacked comprehensive criteria based on A/T/N/(X) diagnostic framework testing through CSF or PET analyses [65]. In addition, we did not divide the participants into subgroups according to the Aβ accumulation status in their brains. Separate analyses of Aβ-positive or Aβ-negative groups may contribute to the acquisition of more accurate correlation results.
In conclusion, the findings in this study imply that plasma p-tau217 is a useful biomarker for central processes affecting brain GMV and cognitive function. This may provide potential targets for future intervention and treatment with tau-targeting therapies in the early stages of AD.
Footnotes
ACKNOWLEDGMENTS
We would like to thank all participants in this study and their supportive families. We also thank the research group in the Neurology Department of First Affiliated Hospital of Anhui Medical University.
FUNDING
This study was supported by the Key Research and Development Projects of Anhui Province (202104j07020031), the Natural Science Foundation of Anhui Province (1908085QH322), and the Basic and Clinical Cooperative Research Promotion Plan of Anhui Medical University (2020xkjT026).
CONFLICT OF INTEREST
The authors have no conflict of interest to report.
DATA AVAILABILITY
The data supporting the findings of this study are available on request from the corresponding author. The data are not publicly available due to privacy or ethical restrictions.
