With the potential development of new disease-modifying Alzheimer’s Disease (AD) therapies, simple, widely available screening tests are needed to identify which individuals who are experiencing symptoms of cognitive or behavioral decline should be further evaluated for initiation of treatment. A blood-based test for AD would be a less invasive and less expensive screening tool than the currently approved CSF or amyloid β-PET diagnostic tests. We examined whether plasma phosphorylated tau at residue 181 (pTau181) could differentiate between clinically diagnosed or autopsy confirmed AD and Frontotemporal Lobar Degeneration (FTLD). Plasma pTau181 concentrations were increased by 3.5 fold in AD compared to controls and differentiated AD from both clinically diagnosed (Receiver Operating Characteristic Area Under the Curve [AUC]=0.894) and autopsy confirmed FTLD (AUC=0.878). Plasma pTau181 identified amyloid β-PET positive individuals regardless of clinical diagnosis and correlated with cortical tau protein deposition measured by 18 F-Flortaucipir PET. Plasma pTau181 may be useful to screen for tau pathology associated with AD.

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Summary Background Davunetide (AL-108, NAP) is an eightamino acid peptide that promotes microtubule stability and decreases tau phosphorylation in pre-clinical studies. Since PSP is tightly linked to tau pathology, davunetide could be an effective treatment for PSP.The goals of this study were to evaluate the efficacy and safety of davunetide in PSP. Methods A phase 2/3 double-blind, parallel group, clinical trial of davunetide 30 mg or placebo (randomized 1:1) administered intranasally twice daily for 52 weeks was conducted at 48centers. Participants met modifiedNNIPPS criteria for possible or probable PSP. Co-primary endpointswere the change from baseline in PSP Rating Scale (PSPRS) and Schwab and England ADL(SEADL) scale at up to 52 weeks. Data from all individuals who received at least one dose of medication and had a post-baseline efficacy assessment were compared using a rank-based method.Secondary outcomes included the Clinical Global Impression of Change (CGIC) and the change in regional brain volumeon MRI. Clinicaltrials.gov identifier: NCT01110720. Findings 360 participants were screened, 313 were randomized and 243 (77.6%) completed the study. There were no group differences in PSPRS (mean difference: 0.49 [95% CI: −1.5, 2.5], p = 0.72) or SEADL (1% [−2, 4%], p = 0.76) change from baseline (CFB) and mean 52 week CFB PSPRS scores were similar between the davunetide (11.3 [9.8,12.8]) and placebo groups (10.9 [9.1, 13.0]). There wereno differences in any of the secondary or exploratory endpoints. There were 11deaths in the davunetide group and tenin the placebo group. There were more nasal adverse events in the davunetide group. Interpretation Davunetide is well tolerated but is not an effective treatment for PSP. Clinical trials of disease modifying therapy are feasible in PSP and should be pursued with other promising tau-directed therapies. Funding Allon Therapeutics