Associations Between Changes in Levels of Phosphorylated Tau and Severity of Cognitive Impairment in Early Alzheimer Disease.

Decision letter: Stage-dependent differential influence of metabolic and structural networks on memory across Alzheimer’s disease continuum

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.

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.

Cerebral small vessel disease, particularly characterized by white matter hyperintensities (WMHs), is a prominent contributor to cognitive impairment. The concurrent role of Alzheimer's disease (AD) pathology, as measured by hyperphosphorylated tau species (pTau), in vascular cognitive impairment remains unclear. While plasma pTau217 is an established biomarker for AD, its relevance in vascular disease-enriched populations has not been extensively studied. This study investigates plasma pTau217 as a biomarker for distinguishing cognitive impairment and dementia in a cohort de-enriched for AD but enriched for vascular disease, focusing on its relationship with cognitive status and Fazekas scores. A cohort of 72 participants (mean age: 70.4, SD 7.9, 58% female) from the MarkVCID Consortium study were selected with 75% having a Fazekas score ≥ 2. pTau217 levels were quantified using the Meso Scale Discovery S Plex assay. Individuals were classified based on their cognitive status into cognitively normal, mild cognitive impairment (MCI), or dementia. Receiver operating characteristic (ROC) curve analysis was performed to assess the ability of pTau217 to distinguish between these groups. Linear regression models were used to examine the association between pTau217 levels and Clinical Dementia Rating (CDR) global scores. Plasma pTau217 levels were found to be elevated in individuals with MCI and dementia. The ROC curve analysis showed pTau217 could distinguish between patients with MCI (AUC: 0.74) and dementia (AUC: 0.72), suggesting moderate diagnostic accuracy in this vascular disease-enriched cohort. No significant relationship was observed between pTau217 levels and Fazekas scores. Regression analysis revealed plasma pTau217 levels were significantly associated with CDR global scores (β=0.337; p=0.0007), a correlation that remained significant after adjusting for sex, age, and education, underscoring pTau217 as an independent predictor of cognitive decline. Additionally, 75% of participants with an AD diagnosis (6/8) had pTau217 levels &gt;10 pg/mL (consistent with prior studies) ranging from 12.2 to 35.3 pg/mL. In conclusion, for this cohort enriched for vascular disease and de-enriched for AD, plasma pTau217 exhibited accuracy in distinguishing patients with MCI and dementia, independent of Fazekas scores. These findings support the utility of plasma pTau217 as a biomarker for cognitive impairment, even in populations with a significant vascular pathology.

BackgroundTo assess the performance of plasma neurofilament light (NfL) and phosphorylated tau 181 (p-tau181) to inform about cerebral Alzheimer’s disease (AD) pathology and predict clinical progression in a memory clinic setting.MethodsPlasma NfL and p-tau181, along with established cerebrospinal fluid (CSF) biomarkers of AD pathology, were measured in participants with normal cognition (CN) and memory clinic patients with cognitive impairment (mild cognitive impairment and dementia, CI). Clinical and neuropsychological assessments were performed at inclusion and follow-up visits at 18 and 36 months. Multivariate analysis assessed associations of plasma NfL and p-tau181 levels with AD, single CSF biomarkers, hippocampal volume, and clinical measures of disease progression.ResultsPlasma NfL levels were higher in CN participants with an AD CSF profile (defined by a CSF p-tau181/Aβ1–42 > 0.0779) as compared with CN non-AD, while p-tau181 plasma levels were higher in CI patients with AD. Plasma NfL levels correlated with CSF tau and p-tau181 in CN, and with CSF tau in CI patients. Plasma p-tau181 correlated with CSF p-tau181 in CN and with CSF tau, p-tau181, Aβ1–42, and Aβ1–42/Aβ1–40 in CI participants. Compared with a reference model, adding plasma p-tau181 improved the prediction of AD in CI patients while adding NfL did not. Adding p-tau181, but not NfL levels, to a reference model improved prediction of cognitive decline in CI participants.ConclusionPlasma NfL indicates neurodegeneration while plasma p-tau181 levels can serve as a biomarker of cerebral AD pathology and cognitive decline. Their predictive performance depends on the presence of cognitive impairment.

BackgroundLewy body disease (LBD) often co‐occurs with Alzheimer’s disease neuropathological change (ADNC), which can be detected using plasma pTau181 and pTau217. Few studies have investigated these biomarkers in LBD, nor have studies investigated plasma pTau217 in Parkinson’s disease (PD) cognitively normal patients (LBD‐CN), or in alpha‐synuclein positive (asyn‐positive) participants. Furthermore, uncertainties remain regarding LBD‐specific cut‐points for these biomarkers.We aimed to determine whether there is a difference in the diagnostic performance of plasma pTau181 and pTau217 for detecting ADNC and amyloidosis in LBD. We also determine whether cut‐points for these biomarkers in LBD differ from those for AD. Finally, we conducted a sensitivity analysis in asyn‐positive participants.MethodWe included 230 Stanford research participants: 110 cognitively normal (CN), 43 LBD‐CN, 41 LBD with cognitive impairment (LBD‐CI), and 36 AD. Plasma pTau181 was measured with the Lumipulse G platform, and pTau217 with the ALZpath pTau217 assay. A‐syn positivity was assessed in CSF with SYNTap®. Diagnostic accuracy of pTau181 and pTau271 in distinguishing ADNC (determined by CSF pTau181/Aβ42) and amyloidosis (determined by CSF Aβ42/Aβ40 or amyloid‐β PET) were evaluated with receiver‐operating characteristic (ROC) analyses. The Youden index was used to determine optimal cut‐points in distinguishing ADNC and amyloidosis, and the DeLong test to compare model performance.ResultIn the LBD‐CI group, plasma pTau181 and pTau217 had similar diagnostic performance in distinguishing ADNC+ from ADNC‐ (Figure 1A). Similarly, in the LBD‐CN and LBD‐CI groups, both biomarkers had similar diagnostic performance in distinguishing Aβ+ from Aβ‐ participants (Figure 1B). However, in the sensitivity analysis, pTau217 outperformed pTau181 for detecting Aβ+ in asyn‐positive participants (AUC: 0.88, 95%‐CI: 0.77‐1 vs 0.77, 95%‐CI: 0.64‐0.90, p=0.045) (Figure 2B). Finally, plasma pTau181 and pTau217 cut‐points for detecting ADNC and amyloidosis in LBD differed from those for AD (Figures 1‐3).ConclusionWe present, for the first time, the diagnostic accuracy of plasma pTau217 in LBD‐CN and asyn‐positive participants. Our results indicate that plasma pTau181 and pTau217 reliably detect concomitant ADNC and amyloidosis in LBD. Particularly, plasma pTau217 appears more sensitive for detecting amyloidosis in asyn‐positive participants. Additionally, our findings underscore the importance of establishing LBD‐specific cut‐points for AD biomarkers.

Heterogeneity of clinical progression in Alzheimer's disease (AD) complicates the assessment of disease progression and treatment effects in trials. This study evaluates the potential of plasma phosphorylated tau-217 (p-tau217) to capture this heterogeneity. We used k-means clustering to analyze cognitive trajectories in amyloid beta -positive (Aβ+) cognitively normal (CN) and mild cognitive impairment (MCI) participants from two independent cohorts. Cohort 1 included 186 participants (71 CN, 115 MCI; 507 observations) and Cohort 2 included 207 participants (64 CN, 144 MCI; 781 observations), both with up to 10 years of follow-up. Three progression clusters emerged in both cohorts: stable cognition, slow decline, and rapid decline-each including cases initially classified as CN or MCI. Baseline plasma p-tau217 was linked to progression risk in both cohorts, whereas longitudinal increases in Cohort 1 were steepest in rapid decliners. Plasma p-tau217 may aid in capturing clinical heterogeneity and support stratification and monitoring of disease progression in clinical trials. k-Means found stable, slow, and rapid cognitive decline clusters in amyloid beta-positive (Aβ+) cases. Higher baseline plasma phosphorylated tau-217 (p-tau217) levels predicted faster cognitive decline. Longitudinal increases in plasma p-tau217 were steepest in rapid decliners. Plasma p-tau217 tracks clinical progression heterogeneity in Aβ+ cases. Cognitive stage and amyloid alone may miss severity and risk in early-stage Alzheimer's disease.

Blood-based biomarkers have been considered as a promising method for the diagnosis of Alzheimer's disease (AD). The reliability and accuracy of plasma core AD biomarkers, including phosphorylated tau (P-tau181), total tau (T-tau), Aβ42, and Aβ40, have also been confirmed in diagnosing AD and predicting cerebral β-amyloid (Aβ) deposition in Western populations, while fewer research studies have ever been conducted in China's Han population. In this study, we investigated the capability of plasma core AD biomarkers in predicting cerebral Aβ deposition burden among the China Aging and Neurodegenerative Disorder Initiative (CANDI) cohort consisting of cognitively normal (CN), mild cognitive impairment (MCI), AD dementia, and non-Alzheimer's dementia disease (Non-ADD). Body fluid (plasma and CSF) AD core biomarkers were measured via single-molecule array (Simoa) immunoassay. The global standard uptake value ratio (SUVR) was then calculated by 18F-florbetapir PET, which was divided into positive (+) and negative (-). The most significant correlation between plasma and CSF was plasma P-tau181 (r = 0.526, P < 0.0001). Plasma P-tau181 and P-tau181/T-tau ratio were positively correlated with global SUVR (r = 0.257, P < 0.0001; r = 0.263, P < 0.0001, respectively), while Aβ42 and Aβ42/Aβ40 ratio were negatively correlated with global SUVR (r = -0.346, P < 0.0001; r = -0.407, P < 0.0001, respectively). Interestingly, voxel-wise analysis showed that plasma P-tau181 and P-tau181/T-tau ratio were negatively related to 18F-florbetapir PET in the hippocampus and parahippocampal cortex. The optimal predictive capability in distinguishing all Aβ+ participants from Aβ- participants and MCI+ from MCI- subgroups was the plasma P-tau181/T-tau ratio (AUC = 0.825 and 0.834, respectively). Our study suggested that plasma P-tau181 and P-tau181/T-tau ratio possessed better diagnostic and predictive values than plasma Aβ42 and Aβ42/Aβ40 in this cohort, a finding that may be useful in clinical practices and trials in China.

Background:Plasma 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.Objective:To assess whether plasma p-tau181 is differentially associated with volumetric changes in distinct hippocampal subfields and whether they mediate the relationship between plasma p-tau181 and cognition across the AD continuum.Methods:213 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 subfield 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 subfield volume.Results:Higher 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 subfields across diagnostic groups.Conclusions:Plasma p-tau181 is differentially associated with hippocampal subfields that are closely related to both age- and AD-related neurodegeneration. Elevated plasma p-tau181 levels may reflect tau accumulation, and volumetric changes in CA1 and DG may mediate the detrimental effect of tau pathology on cognition.

BackgroundNeuroinflammation is a key process in initiating and propagating Alzheimer’s disease (AD). Even though it is widely known that the deposit of amyloid plaques and CSF levels of amyloid distinguishes patients with AD or mild cognitive impairment (MCI) from cognitively normal (CN) individuals, little is known about the role of amyloid‐specific immune response in cognitive decline.MethodUsing a polyfunctionality assay typically used for detecting virus‐specific T cell responses, we tested participants from the Epidemiology of Mild Cognitive Impairment in Taiwan study (EMCIT) and the Taiwan Precision Medicine Initiative of Cognitive impairment and dementia (TPMIC) study to compare the amyloid‐specific T cell responses between CN and MCI individuals. The abilities of T cell response parameters and plasma p‐Tau181 to distinguish MCI from CN were tested.ResultResults from both cohorts showed an enhanced amyloid‐specific T‐cell response in individuals with MCI. In the EMCIT cohort, the individual’s amyloid‐specific CD4+ response frequency of total CD4+ cells was significantly larger in MCI (n = 69, 0.93%) than in CN (n = 69, 0.51%, p &lt; 0.001). CD4+ T cell response discriminated MCI versus CN (area under curve [AUC], 0.72 [0.64‐0.81]) with significantly higher accuracy than p‐Tau181 (AUC: 0.59 [0.5‐0.69], p &lt; 0.01). In the TPMIC cohort, both CD4+ and CD8+ response frequencies were higher in MCI individuals (n = 21, CD4: 1.2%, CD8: 2.02%) than in CN (n = 30, CD4: 0.14%, CD8:0.27%; both p &lt; 0.001). CD4+ T cell response frequency and CD8+ response frequency also outperform p‐Tau181 in their discriminative accuracy of MCI versus NC (CD4+ AUC, 0.97, [0.94‐1.01]; CD8+ AUC, 0.96, [0.92‐1.01]; p‐Tau181 AUC, 0.83, [0.69‐0.96]; both p &lt; 0.05).ConclusionOur study validates the amyloid hypothesis by showing that amyloid‐associated neuroinflammation is involved in the process of neurodegeneration and demonstrated the accuracy of using amyloid‐specific T cell response to discriminate MCI from CN individuals. The TPMIC cohort is an ongoing longitudinal study that includes amyloid PET results and thus we will investigate the prognostic value of amyloid‐T cell response in the future.

BackgroundAlthough blood-based biomarkers can be used to detect early Alzheimer’s disease (AD), population differences affect their clinical value in early diagnosis of the disease spectrum.AimsTo examine the potential of plasma biomarkers to detect different stages along the AD continuum in a Chinese population.MethodsWe enrolled 113 adults from the Shenzhen community (53 cognitively unimpaired [CU], 45 with mild cognitive impairment [MCI], and 15 with AD). We used the single-molecule array technique to detect the levels of glial fibrillary acidic protein (GFAP), neurofilament light (NfL), and phosphorylated-tau181 (p-tau181), and performed APOE genotyping. We assessed the association between plasma biomarkers and cognitive scores, and used receiver operating characteristic curves to measure performance for early AD diagnosis.ResultsThe plasma GFAP, NfL, and p-tau181 levels increased significantly in AD and were slightly higher in MCI than in CU (GFAP p = 0.811, NfL p = 0.909, p-tau181 p = 0.696). The plasma GFAP and p-tau181 levels negatively correlated with cognitive scores. Blood markers demonstrated higher performance in identifying AD than CU or MCI. Plasma p-tau181 displayed the highest diagnostic value for AD. Predictions of cognitive impairment were more robust when blood markers were combined with clinical indicators for AD (age, sex, body mass index, years of education, and APOE ε4 carrier status).DiscussionThe expression of plasma GFAP, NfL, and p-tau181 increased in the AD continuum. Importantly, plasma p-tau181 could identify individuals with AD from the general population, with superior predictive performance when combined with age or sex.ConclusionsPlasma biomarkers are useful screening indicators for early AD in Chinese adults.

Association between head trauma, amyloid and neurodegeneration in a population-based study of cognitively normal and mild cognitive impairment participants

Accurate Assessments of Healthcare Use Along the Course of Cognitive Decline

BackgroundCrucial to the success of clinical trials targeting early Alzheimer’s disease (AD) is recruiting participants who are more likely to progress over the course of the trials. We hypothesize that a combination of plasma and structural MRI biomarkers, which are less costly and non-invasive, is predictive of longitudinal progression measured by atrophy and cognitive decline in early AD, providing a practical alternative to PET or cerebrospinal fluid biomarkers.MethodsLongitudinal T1-weighted MRI, cognitive (memory-related test scores and clinical dementia rating scale), and plasma measurements of 245 cognitively normal (CN) and 361 mild cognitive impairment (MCI) patients from ADNI were included. Subjects were further divided into β-amyloid positive/negative (Aβ+/Aβ−)] subgroups. Baseline plasma (p-tau181 and neurofilament light chain) and MRI-based structural medial temporal lobe subregional measurements and their association with longitudinal measures of atrophy and cognitive decline were tested using stepwise linear mixed effect modeling in CN and MCI, as well as separately in the Aβ+/Aβ− subgroups. Receiver operating characteristic (ROC) analyses were performed to investigate the discriminative power of each model in separating fast and slow progressors (first and last terciles) of each longitudinal measurement.ResultsA total of 245 CN (35.0% Aβ+) and 361 MCI (53.2% Aβ+) participants were included. In the CN and MCI groups, both baseline plasma and structural MRI biomarkers were included in most models. These relationships were maintained when limited to the Aβ+ and Aβ− subgroups, including Aβ− CN (normal aging). ROC analyses demonstrated reliable discriminative power in identifying fast from slow progressors in MCI [area under the curve (AUC): 0.78–0.93] and more modestly in CN (0.65–0.73).ConclusionsThe present data support the notion that plasma and MRI biomarkers, which are relatively easy to obtain, provide a prediction for the rate of future cognitive and neurodegenerative progression that may be particularly useful in clinical trial stratification and prognosis. Additionally, the effect in Aβ− CN indicates the potential use of these biomarkers in predicting a normal age-related decline.

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.