P-Tau217 Continues to Show Benefit as Predictor of Cognitive Decline in Preclinical Alzheimer Disease

Oskar Hansson, MD, PhD

A recently published prospective population-based prognostic study evaluating combinations of different plasma biomarkers showed that phosphorylated tau 217 (P-tau217) was the best marker to predict cognitive decline in patients with preclinical Alzheimer disease (AD). Investigators concluded that plasma P-tau217 may be used as a complement to cerebrospinal fluid (CSF) or PET for participation selection in clinical trials of novel disease-modifying therapies.

Senior investigator Oskar Hansson, MD, PhD, professor of neurology, Lund University and Skåne University Hospital, and colleagues evaluated data from 2 prospective longitudinal cohort studies: the Swedish BioFINDER-1 and the Wisconsin Registry for Alzheimer Prevention (WRAP). A total of 171 amyloid-ß-positive, cognitively unimpaired participants were included in the main analyses, with biomarkers such as P-tau181, P-tau217, P-tau231, glial fibrillary filament protein, and neurofilament light measured in plasma. Additional CSF biomarkers in the BioFINDER-1 cohort and PiB PET uptake in the WRAP cohort were also evaluated.

The Mini-Mental State Examination (MMSE) and modified Preclinical Alzheimer Cognitive Composite (mPACC) over a median of 6 years made up the primary outcome of the study, with conversion to AD dementia as a secondary end point. Models were adjusted for age, sex, years of education, apolipoprotein ε4 allele status, and baseline cognition. In the BioFINDER-1 cohort, after adjustment, plasma P-tau217 was found to be the strongest biomarker to predict cognitive decline in both the mPACC (R2 = 0.41 vs 0.23 for the covariates-only model; P <.001) and the MMSE (R2 = 0.34 vs 0.04 for the covariates-only model; P <.001), yielding significantly improved model fits. Additionally, P-Tau217 was the strongest CSF biomarker to predict cognitive decline for both tests (mPACC: R2 = 0.37; P <.001; MMSE: R2 = 0.24; P <.001).

The inclusion of plasma P-tau217 (ß = –0.098 [SE, 0.018]; P <.001), APOE4 status (ß = 0.110 [SE, 0.050]; P = .03), sex (ß = 0.090 [SE, 0.051]; P = .08) and baseline mPACC scores (ß = 0.078 [E, 0.019]; P <.001) was found to be the optimal biomarker combination to predict mPACC slopes. For the MMSE, the best combination model included plasma P-tau217 (ß = –0.400 [SE, 0.065]; P <.001), and CAS Aß42/40 (ß = 0.090 [SE, 0.058]; P = .13).

In total, 30 of the 118 amyloid-ß-positive individuals from the BioFINDER-1 cohort who were evaluated for dementia converted to AD dementia at follow-up. Baseline plasma P-tau217 was associated with significant conversion to AD dementia compared with no conversion or conversion to non-AD dementias (HR, 2.03%; 95% CI, 1.57-2.63; P <.001). Plasma P-tau217 was also the only biomarker included in an optimal survival model.

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To validate findings from the BioFINDER-1 analysis, predictive models of cognitive decline in the WRAP cohort showed that both plasma P-tau217 (R2 = 0.13; P = .01) and amyloid PET (R2 = 0.10; P = .02) were associated with the mPACC and improved the model fit when compared with the covariates-only model. Using plasma P-tau217, baseline mPACC score, and APOE4 status from BioFINDER-1, findings from WRAP showed that only P-tau217 was a significant predictor of mPACC slopes (ß = –0.045 [SE, 0.015]; P = .005). Compared with the covariates-only model (R2 = 0.24), plasma P-tau217 (R2 = 0.29; P = .046) was also associated with MMSE slopes, but amyloid PET (R2 = 0.28; P = .07) was not.

In simulated trials of amyloid-ß-positive cognitively unimpaired individuals, the inclusion of P-tau217 produced substantial reductions in sample sizes. Using the BioFINDER-1 cohort, the relative sample sizes when using mPACC slopes as the outcome were 79% when including the 3 highest quartiles of baseline plasma P-tau217, 55% when including the 2 highest, and 42% when including the highest quartile.

"This finding suggests that plasma P-tau217 could increase the power of early-stage AD trials, which is a logical extension of how biomarkers have been integrated in previous AD trials," Hansson et al wrote. "Clinical trials are needed to assess whether specific treatment principles are actually effective. A possible caveat is that individuals with steeper declines in cognition could hypothetically have conditions that have progressed beyond certain disease events for which certain treatments are less effective."

REFERENCE
1. Mattsson-Carlgren N, Salvado G, Ashton NJ, et al. Prediction of longitudinal cognitive decline in preclinical Alzheimer disease using plasma biomarkers. JAMA Neurol. Published online February 6, 2023. doi:10.1001/jamaneurol.2022.5272.