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An unresolved question for the understanding of Alzheimer’s disease (AD) pathophysiology is why a significant percentage of amyloid-β (Aβ)-positive cognitively unimpaired (CU) individuals do not develop detectable downstream tau pathology and, consequently, clinical deterioration. In vitro evidence suggests that reactive astrocytes unleash Aβ effects in pathological tau phosphorylation. Here, in a biomarker study across three cohorts (n = 1,016), we tested whether astrocyte reactivity modulates the association of Aβ with tau phosphorylation in CU individuals. We found that Aβ was associated with increased plasma phosphorylated tau only in individuals positive for astrocyte reactivity (Ast+). Cross-sectional and longitudinal tau–positron emission tomography analyses revealed an AD-like pattern of tau tangle accumulation as a function of Aβ only in CU Ast+ individuals. Our findings suggest astrocyte reactivity as an important upstream event linking Aβ with initial tau pathology, which may have implications for the biological definition of preclinical AD and for selecting CU individuals for clinical trials.

Microglial activation and tau accumulation propagate together in patients with Alzheimer's disease, suggesting an interaction that determines disease progression. Compelling experimental evidence suggests that microglial activation is involved in the spread of tau tangles over the neocortex in Alzheimer's disease (AD). We tested the hypothesis that the spatial propagation of microglial activation and tau accumulation colocalize in a Braak-like pattern in the living human brain. We studied 130 individuals across the aging and AD clinical spectrum with positron emission tomography brain imaging for microglial activation ([C-11]PBR28), amyloid-beta (A beta) ([F-18]AZD4694) and tau ([F-18]MK-6240) pathologies. We further assessed microglial triggering receptor expressed on myeloid cells 2 (TREM2) cerebrospinal fluid (CSF) concentrations and brain gene expression patterns. We found that [C-11]PBR28 correlated with CSF soluble TREM2 and showed regional distribution resembling TREM2 gene expression. Network analysis revealed that microglial activation and tau correlated hierarchically with each other following Braak-like stages. Regression analysis revealed that the longitudinal tau propagation pathways depended on the baseline microglia network rather than the tau network circuits. The co-occurrence of A beta, tau and microglia abnormalities was the strongest predictor of cognitive impairment in our study population. Our findings support a model where an interaction between A beta and activated microglia sets the pace for tau spread across Braak stages.

Blood biomarkers indicating elevated amyloid-β (Aβ) pathology in preclinical Alzheimer's disease are needed to facilitate the initial screening process of participants in disease-modifying trials. Previous biofluid data suggest that phosphorylated tau231 (p-tau231) could indicate incipient Aβ pathology, but a comprehensive comparison with other putative blood biomarkers is lacking. In the ALFA+ cohort, all tested plasma biomarkers (p-tau181, p-tau217, p-tau231, GFAP, NfL and Aβ42/40) were significantly changed in preclinical Alzheimer's disease. However, plasma p-tau231 reached abnormal levels with the lowest Aβ burden. Plasma p-tau231 and p-tau217 had the strongest association with Aβ positron emission tomography (PET) retention in early accumulating regions and associated with longitudinal increases in Aβ PET uptake in individuals without overt Aβ pathology at baseline. In summary, plasma p-tau231 and p-tau217 better capture the earliest cerebral Aβ changes, before overt Aβ plaque pathology is present, and are promising blood biomarkers to enrich a preclinical population for Alzheimer's disease clinical trials. The research leading to these results received funding from ‘la Caixa’ Foundation (ID 100010434), under agreement LCF/PR/GN17/10300004 and the Alzheimer’s Association, and an international anonymous charity foundation through the TriBEKa Imaging Platform project (TriBEKa-17-519007). E.V. was supported by Flanders Innovation and Entrepreneurship (VLAIO grant no. 140105). C.M. received funding within the context of EURO-FINGERS, a EU Joint Programme–Neurodegenerative Disease Research (JPND) project. The EURO-FINGERS project is supported through the following funding organizations under the aegis of JPND—www.jpnd.eu: Finland: Academy of Finland; Germany: Federal Ministry of Education and Research; Spain: National Institute of Health Carlos III; Luxembourg: National Research Fund; Hungary: National Research, Development and Innovation Office; and The Netherlands: Netherlands Organisation for Health Research and Development (ZonMW-Memorabel no. 733051102). H.Z. is a Wallenberg Scholar supported by grants from the Swedish Research Council (grant no. 2018-02532), the European Research Council (ERC, grant no. 681712), Swedish State Support for Clinical Research (grant no. ALFGBG-720931), the Alzheimer Drug Discovery Foundation (ADDF), USA (grant no. 201809-2016862), the AD Strategic Fund and the Alzheimer’s Association (grant nos. ADSF-21-831376-C, ADSF-21-831381-C and ADSF-21-831377-C), the Olav Thon Foundation, the Erling–Persson Family Foundation, Stiftelsen för Gamla Tjänarinnor, Hjärnfonden, Sweden (grant no. FO2019-0228), the EU’s Horizon 2020 research and innovation program under the Marie Skłodowska-Curie grant agreement no. 860197 (MIRIADE) and the UK Dementia Research Institute at University College London (UCL). J.D.G. is supported by the Spanish Ministry of Economy and Competitiveness (RYC-2013-13054) and received research support from the EU/EFPIA Innovative Medicines Initiative Joint Undertaking AMYPAD (grant no. 115952) and from Ministerio de Ciencia, Innovación y Universidades (grant no. RTI2018-102261). M.S.C. receives funding from the European Research Council (ERC) under the European Union’s Horizon 2020 research and innovation program (grant agreement no. 948677), the Instituto de Salud Carlos III (PI19/00155), and from the ERC under the EU’s ‘la Caixa’ Foundation (ID 100010434) and from the EU’s Horizon 2020 research and innovation program under the Marie Skłodowska-Curie grant (no. 847648, LCF/BQ/PR21/11840004). K.B. is supported by the Swedish Research Council (grant no. 2017-00915), the ADDF, USA (grant no. RDAPB-201809-2016615), the Swedish Alzheimer Foundation (grant no. AF-742881) (grant nos. AF-930351, AF-939721 and AF-968270), Hjärnfonden, Sweden (grant nos. FO2017-0243 and ALZ2022-0006), the Swedish state under the agreement between the Swedish government and the County Councils, the ALF agreement (grant nos. ALFGBG-715986 and ALFGBG-965240), the EU Joint Program for Neurodegenerative Disorders (JPND2019-466-236), the National Institutes of Health (grant no. 1R01AG068398-01) and the Alzheimer’s Association 2021 Zenith Award (ZEN-21-848495).

Blood biomarkers indicative of Alzheimer’s disease (AD) pathology are altered in both preclinical and symptomatic stages of the disease. Distinctive biomarkers may be optimal for the identification of AD pathology or monitoring of disease progression. Blood biomarkers that correlate with changes in cognition and atrophy during the course of the disease could be used in clinical trials to identify successful interventions and thereby accelerate the development of efficient therapies. When disease-modifying treatments become approved for use, efficient blood-based biomarkers might also inform on treatment implementation and management in clinical practice. In the BioFINDER-1 cohort, plasma phosphorylated (p)-tau231 and amyloid-β42/40 ratio were more changed at lower thresholds of amyloid pathology. Longitudinally, however, only p-tau217 demonstrated marked amyloid-dependent changes over 4–6 years in both preclinical and symptomatic stages of the disease, with no such changes observed in p-tau231, p-tau181, amyloid-β42/40, glial acidic fibrillary protein or neurofilament light. Only longitudinal increases of p-tau217 were also associated with clinical deterioration and brain atrophy in preclinical AD. The selective longitudinal increase of p-tau217 and its associations with cognitive decline and atrophy was confirmed in an independent cohort (Wisconsin Registry for Alzheimer’s Prevention). These findings support the differential association of plasma biomarkers with disease development and strongly highlight p-tau217 as a surrogate marker of disease progression in preclinical and prodromal AD, with impact for the development of new disease-modifying treatments.