BACKGROUND: The spread of tau pathology closely correlates with the disease course and cognitive decline in Alzheimer's disease (AD). Tau-targeting immunotherapies are being developed to stop the spread of tau pathology and thus halt disease progression. In this post hoc analysis of the ADAMANT clinical trial, we examined the performance of AADvac1, an active immunotherapy targeting the microtubule-binding region (MTBR) of tau, in a subgroup of participants with elevated plasma p-tau217, indicating AD-related neuropathological changes. METHODS: ADAMANT was a 24-month, randomized, placebo-controlled, parallel-group, double-blinded, multicenter, phase 2 clinical trial in subjects with mild AD. The trial participants were randomized 3:2 to receive six doses of AADvac1 or placebo at 4-week intervals, followed by five booster doses at 14-week intervals. The primary outcome was safety. The secondary outcomes were the Clinical Dementia Rating-Sum of Boxes (CDR-SB), the Alzheimer's Disease Cooperative Study - Activities of Daily Living score for Mild Cognitive Impairment 18-item version (ADCS-ADL-MCI-18), and immunogenicity. Volumetric MRI, plasma neurofilament light (NfL), and glial fibrillary acidic protein (GFAP) were exploratory outcomes. The inclusion criterion for this post-hoc analysis was a baseline plasma p-tau217 level above the cutoff for AD. RESULTS: Among 196 ADAMANT participants, 137 were positive for plasma p-tau217 (mean age 71.4 years, 59% women). AADvac1 was safe and well tolerated in this subgroup. AADvac1 reduced the rate of accumulation of log-plasma NfL by 56% and that of GFAP by 73%. The treatment differences in the CDR-SB and ADCS-ADL-MCI-18 scores favored AADvac1 but were not statistically significant. AADvac1 had no effect on whole-brain volume but nonsignificantly reduced the loss of brain cortical tissue in several regions. Importantly, the impact on the study outcomes was more pronounced in participants with higher anti-tau antibody levels. CONCLUSIONS: These results suggest that AADvac1 tau immunotherapy can reduce plasma biomarkers of neurodegeneration and neuroinflammation. These findings and possible observations on brain atrophy and cognition are hypothesis-generating and warrant further evaluation in a larger clinical trial. TRIAL REGISTRATION: EudraCT 2015-000630-30 (primary) and NCT02579252.

ADx NeuroSciences NV Technologiepark 6 9052 Ghent Belgium

Axon Neuroscience R and D Services SE Dvorakovo Nabr 10 81102 Bratislava Slovakia

Axon Neuroscience R and D Services SE Dvorakovo Nabr 10 81102 Bratislava Slovakia and Institute of Neuroimmunology Slovak Academy of Sciences Dubravska Cesta 9 Bratislava 84510 Slovakia

Axon Neuroscience SE 4 Arch Makariou and Kalogreon 6016 Larnaca Cyprus

Clinical Memory Research Unit Department of Clinical Sciences Lund University Clinical Research Centre Jan Waldenströms Gata 35 202 13 Malmö Sweden

Department of Mathematics and Statistics Axon Neuroscience R and D Services SE Bratislava Slovakia and Masaryk University Kotlářská 267 2 Brno 611 37 Czech Republic

Department of Neurosciences Alzheimer's Disease Cooperative Study University of California San Diego 9500 Gilman Drive La Jolla CA 92093 USA

Division of Neurogeriatrics Department of Neurobiology Care Sciences and Society Karolinska Institutet BioClinicum 171 64 Solna Sweden

Theme Inflammation and Aging Karolinska University Hospital 141 86 Stockholm Sweden

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