Distinctive associations between plasma p-tau181 levels and hippocampal subfield volume across the Alzheimer’s disease continuum

BackgroundPlasma p-tau181 is a promising diagnostic marker of Alzheimer's disease (AD) pathology, reflecting amyloid accumulation, tau deposition, and downstream neurodegeneration that leads to cognitive impairment. However, the specificity of plasma p-tau181 to AD-related tau pathology remains unclear.ObjectiveTo assess whether plasma p-tau181 is differentially associated with volumetric changes in distinct structures of the hippocampal formation and whether these structures mediate the relationship between plasma p-tau181 and cognition across the AD continuum.Methods213 participants with normal cognition (N = 57), mild cognitive impairment (N = 109), and AD (N = 47) from the Alzheimer's Disease Neuroimaging Initiative (ADNI) were included for cross-sectional analyses of hippocampal formation volume that was quantified using the Automatic Segmentation of Hippocampal Subfields (ASHS) software. A subset (n = 89) was evaluated for one-year longitudinal changes in hippocampal formation volume.ResultsHigher plasma p-tau181 levels (pg/mL) were associated with decreased volumes in the CA1 and dentate gyrus, bilaterally, and right entorhinal cortex (ps < 0.05). Additionally, volumes of these subfields partially mediated the relationship between plasma p-tau181 and ADNI memory and executive function composite scores. Baseline plasma p-tau181, however, did not predict longitudinal atrophy of hippocampal formation structures across diagnostic groups.ConclusionsPlasma p-tau181 is differentially associated with regions of the hippocampal formation that are closely related to both age- and AD-related neurodegeneration. Elevated plasma p-tau181 levels may reflect tau pathology, and volumetric changes in CA1 and DG may mediate the detrimental effect of tau pathology on cognition.

BackgroundPlasma p‐tau181 is an increasingly established diagnostic marker for Alzheimer’s disease (AD); however, its precise relationship with brain tau pathology and the neural mechanisms underlying its association with cognitive impairment remain elusive. Our objective was to assess the association between plasma p‐tau181 and hippocampal (HC) subfield integrity and to investigate whether the subfields mediate the relationship between plasma p‐tau181 and cognition.MethodA total of 213 participants (57 cognitively normal, 109 mild cognitive impairment, and 47 AD) with plasma p‐tau181 measurements and high‐resolution T2‐weighted scans were selected from the Alzheimer’s Disease Neuroimaging Initiative (ADNI). HC subfield volume was measured at baseline using the Automatic Segmentation of Hippocampal Subfields (ASHS) software. Follow‐up HC subfield volume collected around one year was measured for eighty‐nine participants. A linear regression adjusted for age and sex evaluated the relationship between plasma p‐tau181 and HC subfields at baseline, as well as HC volume rate of change over one year. A mediation model assessed whether HC subfields mediate the association between plasma p‐tau181 and memory and executive functioning.ResultOur findings indicate that increasing levels of plasma p‐tau181(pg/mL) are associated with decreased volume in the left CA1 (β = ‐0.119, p = 0.019, Fig. 1a), right CA1 (β = ‐0.154, p = 0.005, Fig. 1b), left dentate gyrus (β = ‐0.120, p = 0.016, Fig. 1g), right dentate gyrus (β = ‐0.146, p = 0.005, Fig. 1h), and right entorhinal cortex (β = ‐0.091, p = 0.048, Fig. 1l). Moreover, these subfields partially mediate the relationship between plasma p‐tau181 and memory and executive functioning composite scores. Baseline plasma p‐tau181 did not predict longitudinal atrophy of the HC subfields across diagnostic groups.ConclusionOur study reveals consistent associations between plasma p‐tau181 levels and vulnerable HC subfields, including CA1, entorhinal cortex, and dentate gyrus, collectively implicated in normal aging and Alzheimer’s disease pathologies. Volumetric changes in CA1, dentate gyrus, and right entorhinal cortex were shown to underlie the association of plasma p‐tau181 with both memory and executive functioning. Together, our findings indicate that selective changes in HC subfield volume serve as a neural basis underlying the relationship between plasma p‐tau181 levels and cognitive impairment.

Objective:The aim of this study was to examine the structural change in the hippocampal subfields in early-onset (EO) mild cognitive impairment (MCI) patients associated with the APOE ε4 carrier state.Methods:This study had 50 subjects aged 55-63 years, all of whom were diagnosed with amnestic MCI at baseline via the Korean version of the Consortium to Establish a Registry for Alzheimer’s Disease Assessment Packet (CERAD-K). The EO-MCI patients were divided into the MCI continued (MCIcont) and Alzheimer’s disease (AD) converted (ADconv) groups 2 years later. The volumes of hippocampal subfields were measured for all the subjects. The calculations were based on the change of the volumes between the 2-year-interval brain Magnetic resonance image (MRI) scans between MCIcont and ADconv groups according to the Apolipoprotein ε4 (APOE ε4) carrier state.Results:There was a significant correlation between APOE ε4 allele and structural changes in several hippocampal subfields. The volume reduction in cornus ammonis 1 (CA1) field and subiculum, especially in the APOE ε4 carriers. The significance was more prominent in ADconv group.Conclusion:These results suggest that the possession of APOE ε4 allele may lead to significantly greater predilection for the structural changes in hippocampal subfields, showing significant changes, especially in the ADconv patients compared with MCIcont patients.

There is an urgent need for inexpensive and minimally invasive blood biomarkers for Alzheimer disease (AD) that could be used to detect early disease changes. To assess how early in the course of AD plasma levels of tau phosphorylated at threonine 217 (P-tau217) start to change compared with levels of established cerebrospinal fluid (CSF) and positron emission tomography (PET) biomarkers of AD pathology. This cohort study included cognitively healthy control individuals (n = 225) and participants with subjective cognitive decline (n = 89) or mild cognitive impairment (n = 176) from the BioFINDER-2 study. Participants were enrolled at 2 different hospitals in Sweden from January 2017 to October 2019. All study participants underwent plasma P-tau217 assessments and tau- and amyloid-β (Aβ)-PET imaging. A subcohort of 111 participants had 2 or 3 tau-PET scans. Changes in plasma P-tau217 levels in preclinical and prodromal AD compared with changes in CSF P-tau217 and PET measures. Of 490 participants, 251 were women (51.2%) and the mean (SD) age was 65.9 (13.1) years. Plasma P-tau217 levels were increased in cognitively unimpaired participants with abnormal Aβ-PET but normal tau-PET in the entorhinal cortex (Aβ-PET+/ tau-PET- group vs Aβ-PET-/ tau-PET- group: median, 2.2 pg/mL [interquartile range (IQR), 1.5-2.9 pg/mL] vs 0.7 pg/mL [IQR, 0.3-1.4 pg/mL]). Most cognitively unimpaired participants who were discordant for plasma P-tau217 and tau-PET were positive for plasma P-tau217 and negative for tau-PET (P-tau217+/tau-PET-: 36 [94.7%]; P-tau217-/tau-PET+: 2 [5.3%]). Event-based modeling of cross-sectional data predicted that in cognitively unimpaired participants and in those with mild cognitive impairment, both plasma and CSF P-tau217 would change before the tau-PET signal in the entorhinal cortex, followed by more widespread cortical tau-PET changes. When testing the association with global Aβ load in nonlinear spline models, both plasma and CSF P-tau217 were increased at lower Aβ-PET values compared with tau-PET measures. Among participants with normal baseline tau-PET, the rates of longitudinal increase in tau-PET in the entorhinal cortex were higher in those with abnormal plasma P-tau217 at baseline (median standardized uptake value ratio, 0.029 [IQR, -0.006 to 0.041] vs -0.001 [IQR, -0.021 to 0.020]; Mann-Whitney U, P = .02). In this cohort study, plasma P-tau217 levels were increased during the early preclinical stages of AD when insoluble tau aggregates were not yet detectable by tau-PET. Plasma P-tau217 may hold promise as a biomarker for early AD brain pathology.

It has been well documented that atrophy of hippocampus and hippocampal subfields is closely linked to cognitive decline in normal aging and patients with mild cognitive impairment (MCI) and Alzheimer's disease (AD). However, evidence is still sparce regarding the atrophy of hippocampus and hippocampal subfields in normal aging adults who later developed MCI or AD. To examine whether atrophy of hippocampus and hippocampal subfields has occurred in normal aging before a diagnosis of MCI or AD. We analyzed structural magnetic resonance imaging (MRI) data of cognitively normal (CN, n = 144), MCI (n = 90), and AD (n = 145) participants obtained from the Alzheimer's Disease Neuroimaging Initiative. The CN participants were categorized into early dementia converters (CN-C) and non-converters (CN-NC) based on their scores of clinical dementia rating after an average of 36.2 months (range: 6-105 months). We extracted the whole hippocampus and hippocampal subfields for each participant using FreeSurfer, and analyzed the differences in volumes of hippocampus and hippocampal subfields between groups. We then examined the associations between volume of hippocampal subfields and delayed recall scores in each group separately. Hippocampus and most of the hippocampal subfields demonstrated significant atrophy during the progression of AD. The CN-C and CN-NC groups differed in the left hippocampus-amygdala transition area (HATA). Furthermore, the volume of presubiculum was significantly correlated with delayed recall scores in the CN-NC and AD groups, but not in the CN-C and MCI groups. Hippocampal subfield atrophy (i.e., left HATA) had occurred in cognitively normal elderly individuals before clinical symptoms were recognized. Significant associations of presubiculum with delayed recall scores in the CN-NC and AD groups highlight the essential role of the hippocampal subfields in both early dementia detection and AD progression.

BackgroundRecent studies suggest that plasma phosphorylated tau181 (p-tau181) is a highly specific biomarker for Alzheimer’s disease (AD)-related tau pathology. It has great potential for the diagnostic and prognostic evaluation of AD, since it identifies AD with the same accuracy as tau PET and CSF p-tau181 and predicts the development of AD dementia in cognitively unimpaired (CU) individuals and in those with mild cognitive impairment (MCI). Plasma p-tau181 may also be used as a biomarker in studies exploring disease pathogenesis, such as genetic or environmental risk factors for AD-type tau pathology. The aim of the present study was to investigate the relation between polygenic risk scores (PRSs) for AD and plasma p-tau181.MethodsData from the Alzheimer’s Disease Neuroimaging Initiative (ADNI) was used to examine the relation between AD PRSs, constructed based on findings in recent genome-wide association studies, and plasma p-tau181, using linear regression models. Analyses were performed in the total sample (n = 818), after stratification on diagnostic status (CU (n = 236), MCI (n = 434), AD dementia (n = 148)), and after stratification on Aβ pathology status (Aβ positives (n = 322), Aβ negatives (n = 409)).ResultsAssociations between plasma p-tau181 and APOE PRSs (p = 3e−18–7e−15) and non-APOE PRSs (p = 3e−4–0.03) were seen in the total sample. The APOE PRSs were associated with plasma p-tau181 in all diagnostic groups (CU, MCI, and AD dementia), while the non-APOE PRSs were associated only in the MCI group. The APOE PRSs showed similar results in amyloid-β (Aβ)-positive and negative individuals (p = 5e−5–1e−3), while the non-APOE PRSs were associated with plasma p-tau181 in Aβ positives only (p = 0.02).ConclusionsPolygenic risk for AD including APOE was found to associate with plasma p-tau181 independent of diagnostic and Aβ pathology status, while polygenic risk for AD beyond APOE was associated with plasma p-tau181 only in MCI and Aβ-positive individuals. These results extend the knowledge about the relation between genetic risk for AD and p-tau181, and further support the usefulness of plasma p-tau181 as a biomarker of AD.

With the approval of Disease Modifying Drugs for Alzheimer's disease (AD), emerging clinical trials and unknowns in etiology, the clinical use of plasma biomarkers is increasingly becoming a reality. Here we explore the implementation of plasma pTau217 as a screening tool for patients at risk of AD in the real-world practice of an experienced memory clinic. The study cohort encompassed 2353 paired cerebrospinal fluid (CSF) and plasma samples collected during 8 years at Ace Alzheimer Center Barcelona memory clinic from real-world patients with subjective cognitive decline (SCD), mild cognitive impairment (MCI), AD dementia and other dementias. Plasma pTau181 and pTau217 were measured using the Lumipulse G1200 automatic platform (Fujirebio Inc.). The study cohort was divided in testing and validation cohorts for the analysis. Plasma pTau217 significantly correlated (p<0.0001) with its CSF homonymous in all phenotypes except the other dementias. ROC curve only defined by A+T+ vs A-T- showed an AUC=0.97, p<0.0001, sensitivity 90.58% and specificity 94.46%. Plasma pTau217 showed a clear improvement against plasma pTau181 in the preclinical stage, not instead in the most advanced AD continuum phase. Moreover, plasma pTau181 levels were more affected by eGFR than plasma pTau217. MRI analysis showed that plasma pTau217 positively correlated with the white matter hypointensities and lateral ventricles volumes (rho>0.40, p<0.0001) and negatively correlated with the amygdala and hippocampus volumes (rho<-0.41, p<0.0001). Survival analysis showed that MCI with the plasma pTau217 value above the pre-defined cut off (0.19 pg/ml) exhibited a 4.75 higher risk to convert to AD dementia than patients under the cut off value. Validation cohort confirmed all these findings. Plasma pTau217 exhibits better results than plasma pTau181 in the preclinical stages of AD continuum. All results together suggest that plasma pTau217 is robust enough to be implemented as a screening tool of AD risk in the memory clinics. However, since plasma biomarkers are not still approved by the international guidelines for their use in the clinical practice, a CSF/PET confirmatory test is mandatory required. Further studies are needed to obtain more clinical data and improve the biomarker's performance to finally substitute CSF/PET biomarkers as diagnostic tests.

PurposeBiomarkers used for predicting longitudinal cognitive change in Alzheimer’s disease (AD) continuum are still elusive. Tau pathology, neuroinflammation, and neurodegeneration are the leading candidate predictors. We aimed to determine these three aspects of biomarkers in cerebrospinal fluid (CSF) and plasma to predict longitudinal cognition status using Alzheimer’s Disease Neuroimaging Initiative (ADNI) cohort.Patients and MethodsA total of 430 subjects including, 96 cognitive normal (CN) with amyloid β (Aβ)-negative, 54 CN with Aβ-positive, 195 mild cognitive impairment (MCI) with Aβ-positive, and 85 AD with amyloid-positive (Aβ-positive are identified by CSF Aβ42/Aβ40 < 0.138). Aβ burden was evaluated by CSF and plasma Aβ42/Aβ40 ratio; tau pathology was evaluated by CSF and plasma phosphorylated-tau (p-tau181); microglial activation was measured by CSF soluble TREM2 (sTREM2) and progranulin (PGRN); neurodegeneration was measured by CSF and plasma t-tau and structural magnetic resonance imaging (MRI); cognition was examined annually over the subsequent 8 years using the Alzheimer’s Disease Assessment Scale Cognition 13-item scale (ADAS13) and Mini-Mental State Exam (MMSE). Linear mixed-effects models (LME) were applied to assess the correlation between biomarkers and longitudinal cognition decline, as well as their effect size on the prediction of longitudinal cognitive decline.ResultsBaseline CSF Aβ42/Aβ40 ratio was decreased in MCI and AD compared to CN, while CSF p-tau181 and t-tau increased. Baseline CSF sTREM2 and PGRN did not show any differences in MCI and AD compared to CN. Baseline brain volumes (including the hippocampal, entorhinal, middle temporal lobe, and whole-brain) decreased in MCI and AD groups. For the longitudinal study, there were significant interaction effects of CSF p-tau181 × time, plasma p-tau181 × time, CSF sTREM2 × time, and brain volumes × time, indicating CSF, and plasma p-tau181, CSF sTREM2, and brain volumes could predict longitudinal cognition deterioration rate. CSF sTREM2, CSF, and plasma p-tau181 had similar medium prediction effects, while brain volumes showed stronger effects in predicting cognition decline.ConclusionOur study reported that baseline CSF sTREM2, CSF, and plasma p-tau181, as well as structural MRI, could predict longitudinal cognitive decline in subjects with positive AD pathology. Plasma p-tau181 can be used as a relatively noninvasive reliable biomarker for AD longitudinal cognition decline prediction.

APOE differentially moderates cerebrospinal fluid and plasma phosphorylated tau181 associations with multi-domain cognition

Hippocampal subfields volume changes and its correlation with memory functions in patients with mild cognitive impairment

Studies have shown that women on the Alzheimer’s disease (AD) continuum have more pathological tau in the brain and cerebrospinal fluid (CSF), than men. Some studies have found that higher levels of tau biomarkers are more strongly associated with clinical AD, cognitive decline and neurodegeneration in women than in men. Despite major developments in the use of plasma tau phosphorylated at threonine 181 (p-tau181) as an AD biomarker, it is unknown whether these sex differences apply to plasma p-tau181. In 1060 Alzheimer’s Disease Neuroimaging Initiative (ADNI) participants (47% women, 73.8 ± 7.6 years old), we examined sex differences in plasma p-tau181 levels and their association with other biomarkers, cognitive decline and incident AD. Linear regressions tested for an effect of sex on plasma p-tau181 levels and for plasma p-tau181 × sex interactions on CSF p-tau181, as well as entorhinal cortex tau, cortical amyloid-β (Aβ) deposition, and brain glucose metabolism, quantified using PET imaging. Linear mixed effects models tested for a sex × baseline plasma p-tau181 interaction on change in cognition over time. Finally, Cox models tested for a sex × plasma p-tau181 interaction on the risk of AD dementia in participants who were free of dementia at baseline. Despite similar plasma p-tau181 levels between sexes, women had lower brain glucose metabolism, greater brain Aβ and entorhinal cortex tau deposition, higher CSF p-tau181 and faster cognitive decline in relation to higher baseline plasma p-tau181 levels compared with men. Among Aβ positive, dementia-free participants, women had higher rates of incident AD dementia associated with increasing baseline plasma p-tau181 levels, relative to men. Our results suggest that sex may impact the clinical interpretation of plasma p-tau181 concentrations. If replicated, these findings could have important implications for the use of plasma p-tau181 as an accessible AD biomarker and screening tool for preventive and therapeutic clinical trials.

Tau phosphorylated at threonine 181 (p-tau181) measured in blood plasma has recently been proposed as an accessible, scalable, and highly specific biomarker for Alzheimer's disease. Longitudinal studies, however, investigating the temporal dynamics of this novel biomarker are lacking. It is therefore unclear when in the disease process plasma p-tau181 increases above physiological levels and how it relates to the spatiotemporal progression of Alzheimer's disease characteristic pathologies. We aimed to establish the natural time course of plasma p-tau181 across the sporadic Alzheimer's disease spectrum in comparison to those of established imaging and fluid-derived biomarkers of Alzheimer's disease. We examined longitudinal data from a large prospective cohort of elderly individuals enrolled in the Alzheimer's Disease Neuroimaging Initiative (ADNI) (n = 1067) covering a wide clinical spectrum from normal cognition to dementia, and with measures of plasma p-tau181 and an 18F-florbetapir amyloid-β PET scan at baseline. A subset of participants (n = 864) also had measures of amyloid-β1-42 and p-tau181 levels in CSF, and another subset (n = 298) had undergone an 18F-flortaucipir tau PET scan 6 years later. We performed brain-wide analyses to investigate the associations of plasma p-tau181 baseline levels and longitudinal change with progression of regional amyloid-β pathology and tau burden 6 years later, and estimated the time course of changes in plasma p-tau181 and other Alzheimer's disease biomarkers using a previously developed method for the construction of long-term biomarker temporal trajectories using shorter-term longitudinal data. Smoothing splines demonstrated that earliest plasma p-tau181 changes occurred even before amyloid-β markers reached abnormal levels, with greater rates of change correlating with increased amyloid-β pathology. Voxel-wise PET analyses yielded relatively weak, yet significant, associations of plasma p-tau181 with amyloid-β pathology in early accumulating brain regions in cognitively healthy individuals, while the strongest associations with amyloid-β were observed in late accumulating regions in patients with mild cognitive impairment. Cross-sectional and particularly longitudinal measures of plasma p-tau181 were associated with widespread cortical tau aggregation 6 years later, covering temporoparietal regions typical for neurofibrillary tangle distribution in Alzheimer's disease. Finally, we estimated that plasma p-tau181 reaches abnormal levels ∼6.5 and 5.7 years after CSF and PET measures of amyloid-β, respectively, following similar dynamics as CSF p-tau181. Our findings suggest that plasma p-tau181 increases are associated with the presence of widespread cortical amyloid-β pathology and with prospective Alzheimer's disease typical tau aggregation, providing clear implications for the use of this novel blood biomarker as a diagnostic and screening tool for Alzheimer's disease.

Plasma phosphorylated tau-181 (p-tau181) associations with global cognition and memory are clear, but the link between p-tau181 with other cognitive domains and subjective cognitive decline (SCD) across the clinical spectrum of Alzheimer's disease (AD) and how this association changes based on genetic and demographic factors is poorly understood. Participants were drawn from the Alzheimer's Disease Neuroimaging Initiative (ADNI) and included 1185 adults >55 years of age with plasma p-tau181 and neuropsychological test data. Linear regression models related plasma p-tau181 to neuropsychological composite and SCD scores with follow-up models examining plasma p-tau181 interactions with cognitive diagnosis, apolipoprotein E (APOE) ε4 carrier status, age, and sex on cognitive outcomes. Higher plasma p-tau181 level was associated with worse memory, executive functioning, and language abilities, and greater informant-reported SCD. Visuospatial abilities and self-report SCD were not associated with plasma p-tau181. Associations were generally stronger in mild cognitive impairment (MCI) or dementia, APOE ε4 carriers, women, and younger participants. Higher levels of plasma p-tau181 are associated with worse neuropsychological test performance across multiple cognitive domains; however, these associations vary based on disease stage, genetic risk status, age, and sex. Greater plasma p-tau181 was associated with lower cognition across most domains.Associations between p-tau181 and cognition were modified by age and sex.Level of p-tau181 was more strongly associated with cognition in people with mild cognitive impairment (MCI) and apolipoprotein E (APOE) ε4.

Whilst cerebrospinal fluid (CSF) and positron emission tomography (PET) biomarkers for amyloid-β (Aβ) and tau pathologies are accurate for the diagnosis of Alzheimer's disease (AD), their broad implementation in clinical and trial settings are restricted by high cost and limited accessibility. Plasma phosphorylated-tau181 (p-tau181) is a promising blood-based biomarker that is specific for AD, correlates with cerebral Aβ and tau pathology, and predicts future cognitive decline. In this study, we report the performance of p-tau181 in >1000 individuals from the Alzheimer's Disease Neuroimaging Initiative (ADNI), including cognitively unimpaired (CU), mild cognitive impairment (MCI) and AD dementia patients characterized by Aβ PET. We confirmed that plasma p-tau181 is increased at the preclinical stage of Alzheimer and further increases in MCI and AD dementia. Individuals clinically classified as AD dementia but having negative Aβ PET scans show little increase but plasma p-tau181 is increased if CSF Aβ has already changed prior to Aβ PET changes. Despite being a multicenter study, plasma p-tau181 demonstrated high diagnostic accuracy to identify AD dementia (AUC = 85.3%; 95% CI, 81.4-89.2%), as well as to distinguish between Aβ- and Aβ+ individuals along the Alzheimer's continuum (AUC = 76.9%; 95% CI, 74.0-79.8%). Higher baseline concentrations of plasma p-tau181 accurately predicted future dementia and performed comparably to the baseline prediction of CSF p-tau181. Longitudinal measurements of plasma p-tau181 revealed low intra-individual variability, which could be of potential benefit in disease-modifying trials seeking a measurable response to a therapeutic target. This study adds significant weight to the growing body of evidence in the use of plasma p-tau181 as a non-invasive diagnostic and prognostic tool for AD, regardless of clinical stage, which would be of great benefit in clinical practice and a large cost-saving in clinical trial recruitment.

Background: Plasma-based biomarkers would be potential biomarkers for early diagnosis of Alzheimer's disease (AD) because they are more available and cost-effective than cerebrospinal fluid (CSF) or neuroimaging. Therefore, we aimed to evaluate whether phosphorylated tau181 (p-tau181) in plasma could be an accurate AD predictor.Methods: Participants from the ADNI database included 185 cognitively unimpaired subjects with negative Aβ (CU–), 66 subjects with pre-clinical AD (CU with positive Aβ), 164 subjects with mild cognitive impairment with negative Aβ (MCI–), 254 subjects with prodromal AD (MCI with positive Aβ), and 98 subjects with dementia. Multiple linear regression models, linear mixed-effects models, and local regression were used to explore cross-sectional and longitudinal associations of plasma p-tau181 with cognition, neuroimaging, or CSF biomarkers adjusted for age, sex, education, and APOE genotype. Besides, Kaplan–Meier and adjusted Cox-regression model were performed to predict the risk of progression to dementia. Receiver operating characteristic analyses were performed to evaluate the predictive value of p-tau181.Results: Plasma p-tau181 level was highest in AD dementia, followed by prodromal AD and pre-clinical AD. In pre-clinical AD, plasma p-tau181 was negatively associated with hippocampal volume (β = −0.031, p-value = 0.017). In prodromal AD, plasma p-tau181 was associated with decreased global cognition, executive function, memory, language, and visuospatial functioning (β range −0.119 to −0.273, p-value < 0.05) and correlated with hippocampal volume (β = −0.028, p-value < 0.005) and white matter hyperintensity volume (WMH) volume (β = 0.02, p-value = 0.01). In AD dementia, increased plasma p-tau181 was associated with worse memory. In the whole group, baseline plasma p-tau181 was significantly associated with longitudinal increases in multiple neuropsychological test z-scores and correlated with AD-related CSF biomarkers and hippocampal volume (p-value < 0.05). Meanwhile, CU or MCI with high plasma p-tau181 carried a higher risk of progression to dementia. The area under the curve (AUC) of the adjusted model (age, sex, education, APOE genotype, and plasma p-tau181) was 0.78; that of additionally included CSF biomarkers was 0.84.Conclusions: Plasma p-tau181 level is related to multiple AD-associated cognitive domains and AD-related CSF biomarkers at the clinical stages of AD. Moreover, plasma p-tau181 level is related to the change rates of cognitive decline and hippocampal atrophy. Thus, this study confirms the utility of plasma p-tau181 as a non-invasive biomarker for early detection and prediction of AD.