Aims

To examine the accuracy of plasma phospho-tau217 (P-tau217) for predicting Alzheimer’s disease dementia (AD) when combined with other non-invasive biomarkers. The accuracy was compared to the clinical diagnostic prediction.

Methods

328 participants with subjective cognitive decline (SCD, n=155) or mild cognitive impairment (MCI, n=173) at baseline were included from the Swedish BioFINDER study. Plasma P-tau217, cognitive tests, demographics, plasma Aβ42/40, plasma neurofilament light (NfL), and MRI (AD-signature cortical thickness) were examined using logistic regression models with conversion to AD at 2, 4 and 6 years, respectively, as outcomes. Model selection and area under the ROC curve (AUC) were validated in 531 participants with SCD or MCI from the ADNI study using plasma P-tau181 instead of P-tau217.

Results

Plasma P-tau217 predicted conversion to AD with an AUC of 0.78 (95%CI 0.72-0.85) at 2 years, 0.82 (0.77-0.88) at 4 years and 0.85 (0.80-0.90) at 6 years. 2-year prediction of AD was improved by adding MRI, memory, executive function, and gender to P-tau217 (0.88, 0.83-0.94). 4-year prediction was improved by adding MRI, memory, and executive function (0.90, 0.86-0.93). 6-year prediction was improved by adding plasma Aβ42/40 and NfL, MRI, and memory (0.91, 0.87-0.94). In ADNI, similar models were selected with similar accuracies. The diagnostic prediction of memory clinic physicians blinded to biomarker data were inferior to all models (AUCs 0.68-0.73).

Conclusions

Plasma P-tau can accurately predict future AD, better than a clinical diagnostic prediction. The accuracy can be improved further by adding brief cognitive tests and MRI, and to a lesser extent plasma Aβ42/40 and NfL.

Aims

Donanemab is an antibody targeting a modified form of Aβ called N3pG. This study aimed to assess the potential treatment effects of donanemab on disease progression in individuals with early symptomatic Alzheimer’s Disease (AD).

Methods

TRAILBLAZER-ALZ (NCT03367403) was a randomized, placebo-controlled, double-blind, multi-center Phase 2 study assessing the safety, tolerability and efficacy of donanemab in patients with early symptomatic AD. The trial enrolled 272 patients, selected based on cognitive assessments in conjunction with amyloid and tau positron emission tomography (PET). The primary efficacy endpoint was change from baseline to 76 weeks in the Integrated AD Rating Scale (iADRS), a composite tool combining the AD Assessment Scale-Cognitive subscale (ADAS-Cog13) and the AD Cooperative Study - instrumental Activities of Daily Living (ADCS-iADL) for function. Secondary endpoints included changes in CDR-SB, ADAS-Cog13, ADCS-iADL, MMSE, amyloid PET, tau PET, and volumetric MRI.

Results

Donanemab significantly slowed the clinical decline compared to placebo on the primary outcome, iADRS, by 32%. On average, patients who received donanemab showed an 84 centiloid reduction of amyloid plaque at 76 weeks. In the donanemab treatment group, amyloid-related imaging abnormalities – edema (ARIA-E) occurred in 27% of treated participants. Secondary and exploratory outcome measures will be presented.

Conclusions

Aims

It is currently unclear whether plasma biomarkers can be used as prognostic tools for Alzheimer’s disease (AD). Here we address this question by examining plasma amyloid-β 42/40 (Aβ42/40), phosphorylated-tau 181 (P-tau181), phosphorylated-tau 217 (P-tau217) and neurofilament light (NfL) in non-demented individuals who underwent longitudinal amyloid and tau positron emission tomography (PET), magnetic resonance imaging (MRI) and cognitive testing.

Methods

Blood was collected at baseline from all participants to determine the levels of Aβ42/40, P-tau181, P-tau217 and NfL. All subjects underwent longitudinal ¹⁸F-RO948 PET, structural MRI and cognitive assessment. In addition, a subsample also had longitudinal ¹⁸F-flutemetamol PET scans. Linear mixed effects models and voxel-wise analyses were applied to assess the relationship between plasma biomarkers and longitudinal changes in imaging and cognition.

Results

Our results show that plasma P-tau217 predicts increases in amyloid (p=0.017) and tau (p=0.004) PET, medial temporal atrophy (p<0.001) and global cognitive decline (p=0.005). The results for the other plasma markers were more variable, with plasma Aβ42/40 predicting amyloid (p=0.002) and tau (p=0.003) PET signal increases as well as cognition (p=0.020), whereas P-tau181 predicts hippocampal atrophy (p=0.008) and cognitive decline (p=0.003), and finally NfL predicts atrophy (p=0.001) and tau PET increases (p=0.020). The comparison between the models showed that the ones that included P-tau217 as a predictor had a significantly better fit to the data as indicated by lower Bayesian Information Criterion values.

Conclusions

These findings suggest that plasma P-tau217 could be useful in clinical trials to determine whether an individual is on the pathophysiological pathway of AD.

Aims

Blood-based Alzheimer’s disease (AD) biomarkers provide opportunities for community studies and across ethnic groups.

We investigated blood biomarker concentrations in the Washington Heights, Inwood, Columbia Aging Project (WHICAP), a

multi-ethnic community study of aging and dementia. The goal was to determine the effectiveness of state-of-the-art ADrelated

plasma biomarkers, including Aβ40 and ββ42 as markers of amyloid pathology, total tau and neurofilament light

chain (NfL) as markers of neurodegeneration, and phospho-tau (P-tau) 181 and 217 as markers of tau pathology. We

compared plasma biomarker concentrations between clinically- and pathologically-defined diagnostic groups and

examined differences by race/ethnicity groups.

Methods

We measured plasma Aβ40, Aβ42,T-tau, P-tau181 and P-tau217, and neurofilament light chain (NfL) in 113 autopsied

participants, (29% with high AD neuropathological changes) and in 300 clinically evaluated individuals (42% with clinical

AD). Receiver operating characteristics were used to evaluate each biomarker. We also investigated biomarkers as

predictors of incident clinical AD.

Results

P-tau181, P-tau217 and NfL concentrations were elevated in pathologically diagnosed AD and to a lesser extent in

clinically diagnosed AD. Decreased Aβ42/Aβ40 ratio and increased P-tau217 and P-tau181 were associated with

subsequent AD diagnosis in a follow-up of previously unaffected individuals.

Conclusions

Blood-based AD biomarker concentrations of the Aβ42/Aβ40 ratio, P-tau217 and P-tau181 are associated with

pathological and clinical diagnoses and can predict future development of clinical AD, providing evidence that they can be

incorporated into multi-ethnic, community-based studies.

Aims

We assessed the utility of plasma phosphorylated tau (P-tau) 181 and 217 as biomarkers of AD pathophysiology in a population-based setting and examined interclass correlation coefficients (ICC) to determine intra-individual variability over serial samples.

Methods

We included 1,329 Mayo Clinic Study on Aging participants (1,161 cognitively unimpaired, 153 MCI, 15 dementia), median age of 69 (range 30-98); 1,066 had amyloid PET and 495 tau PET. P-tau 181 and 217 was measured on the MSD platform; previous cutpoints were used for analyses. Elevated amyloid (A+) was defined as SUVR≥1.48 using PiB PET; elevated tau (T+) as SUVR≥1.25 using F-18-AV-1451. Area under the Receiver Operating Curve (AUROC) and diagnostic statistics were used to assess the accuracy of plasma P-tau for amyloid and tau PET. ICCs of P-tau levels were calculated.

Results

Among all participants, plasma P-tau181 predicted A+ with an AUROC of 0.71, 51% sensitivity, 92% specificity, and 81% positive predictive value (PPV). For P-tau217 and A+, the AUROC was 0.74, 51% sensitivity, 96% specificity, 90% PPV. Plasma P-tau181 predicted T+ with an AUROC of 0.59, 22% sensitivity, 95% specificity, 54% PPV. For P-tau 217, the AUROC was 0.63, 34% sensitivity, 92% specificity, 53% PPV. Both P-tau181 and 217 levels increased with clinical severity (CU<MCI<dementia, p<0.001). The ICC (95% CI) for Ptau181 was 0.92 (0.92, 0.93) and for Ptau217 was 0.95 (0.95, 0.96).

Conclusions

In this population-based sample, both plasma P-tau181 and 217 had good discrimination for A+, but discrimination for T+ was lower. There was low intra-individual variability over serial samples.

Aims

To investigate whether plasma phospho-tau217 (P-tau217) and phospho-tau181 (P-tau181) can detect Alzheimer’s disease (AD) co-pathology in patients with dementia with Lewy bodies and Parkinson’s disease with dementia (i.e. Lewy body disease with dementia).

Methods

In this cross-sectional study we investigated the plasma levels of P-tau217 and P-tau181 in 35 patients with dementia with Lewy bodies or Parkinson’s disease with dementia, recruited as part of the Swedish BioFINDER2 study. All patients also underwent tau-PET imaging using ¹⁸F-RO948, and cerebrospinal fluid (CSF) was analyzed for P-tau217, P-tau181 and β-amyloid_42/40 (Aβ₄₂/Aβ₄₀), biomarkers that reliably detect AD pathology in vivo. Abnormal β-amyloid status was defined as CSF Aβ₄₂/Aβ₄₀ <0.752, determined using mixture modeling.

Results

Plasma P-tau217 correlated with plasma P-tau181 (r_s=0.68, p<0.001), CSF P-tau217 (r_s=0.68, p<0.001) and negatively with CSF Aβ₄₂/Aβ₄₀ (r_s=-0.52, p=0.001). Plasma P-tau181 correlated with CSF P-tau181 (r_s=0.55, p<0.001). Both plasma P-tau217 and plasma P-tau181 correlated with ¹⁸F-RO948 retention in the temporal meta ROI corresponding to Braak stage I-IV (r_s=0.57, p<0.001 and r_s=0.66, p<0.001, respectively). Additionally, plasma P-tau217 and plasma P-tau181 predicted abnormal tau-PET status in the temporal meta ROI (AUC 0.84 and 0.78, respectively) as well as abnormal CSF β-amyloid status (AUC 0.88 and 0.81, respectively).

Conclusions

Plasma P-tau might be a useful marker for the detection of AD co-pathology in Lewy body disease with dementia, and could be used for stratification of patients in clinical trials. Further studies are needed to determine whether plasma P-tau provides important prognostic information in patients with Lewy body disease.

Aims

To study if the accuracy of blood amyloid-β (Aβ) to detect Alzheimer disease (AD) at early stages could be improved by other blood biomarkers including phospho-tau217 (P-tau217), neurofilament light (NfL) and glial fibrillary acidic protein (GFAP).

Methods

We measured plasma Aβ42/Aβ40 (Araclon mass spectrometry [MS] or Euroimmun ELISA [EL]), Ptau-217 (Lilly assay), NfL (Simoa assay) and GFAP (Simoa assay) in cognitively unimpaired elderly from the Swedish BioFINDER-1 (n=242) and BioFINDER-2 (n=338) studies. In BioFINDER-1, out of 239 individuals followed longitudinally, 12 converted to AD dementia. CSF Aβ42/Aβ40 measures were available in all study participants, 568 individuals underwent Aβ-PET.

Results

In BioFINDER-1, plasma Aβ42/Aβ40^MS identified individuals with abnormal CSF Aβ status with AUC of 0.79 (AIC=260). We observed a better performance (higher AUC and lower AIC) for models including plasma Aβ42/Aβ40^MS and P-tau217 (AUC=0.83, AIC=230) or plasma Aβ42/Aβ40^MS, P-tau217 and GFAP (AUC=0.85, AIC=224). In BioFINDER-2, the model with plasma Aβ42/Aβ40^EL and P-tau217 as predictors provided better fit (AUC=0.84, AIC=319) for CSF Aβ status than plasma Aβ42/Aβ40^EL alone (AUC=0.74, AIC=354). The results when using Aβ-PET instead of CSF Aβ status were very similar. In BioFINDER-1, a combination of plasma Aβ42/Aβ40^MS and P-tau217 (AUC=0.82, AIC=88) better modelled conversion to AD dementia than plasma Aβ42/Aβ40^MS (AUC=0.79, AIC=90). There was no further improvement when adding plasma NfL to the models.

Conclusions

The accuracy of blood test to detect preclinical cerebral Aβ pathology could be improved by combining plasma measurements of Aβ42/Aβ40, Ptau-217 and potentially GFAP.