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Purpose: glial activation is one of the earliest mechanisms to be altered in Alzheimer's disease (AD). Glial fibrillary acidic protein (GFAP) relates to reactive astrogliosis and can be measured in both cerebrospinal fluid (CSF) and blood. Plasma GFAP has been suggested to become altered earlier in AD than its CSF counterpart. Although astrocytes consume approximately half of the glucose-derived energy in the brain, the relationship between reactive astrogliosis and cerebral glucose metabolism is poorly understood. Here, we aimed to investigate the association between fluorodeoxyglucose ([18F]FDG) uptake and reactive astrogliosis, by means of GFAP quantified in both plasma and CSF for the same participants. Methods: we included 314 cognitively unimpaired participants from the ALFA + cohort, 112 of whom were amyloid-β (Aβ) positive. Associations between GFAP markers and [18F]FDG uptake were studied. We also investigated whether these associations were modified by Aβ and tau status (AT stages). Results: plasma GFAP was positively associated with glucose consumption in the whole brain, while CSF GFAP associations with [18F]FDG uptake were only observed in specific smaller areas like temporal pole and superior temporal lobe. These associations persisted when accounting for biomarkers of Aβ pathology but became negative in Aβ-positive and tau-positive participants (A + T +) in similar areas of AD-related hypometabolism. Conclusions: higher astrocytic reactivity, probably in response to early AD pathological changes, is related to higher glucose consumption. With the onset of tau pathology, the observed uncoupling between astrocytic biomarkers and glucose consumption might be indicative of a failure to sustain the higher energetic demands required by reactive astrocytes. The project leading to these results has received funding from “la Caixa” Foundation (ID 100010434), under agreement LCF/PR/GN17/50300004 and the Alzheimer’s Association and an international anonymous charity foundation through the TriBEKa Imaging Platform project (TriBEKa-17–519007). Additional support has been received from the Universities and Research Secretariat, Ministry of Business and Knowledge of the Catalan Government under the grant no. 2017-SGR-892. JDG is supported by the Spanish Ministry of Science and Innovation (RYC-2013–13054). MSC receives funding from Instituto de Salud Carlos III (PI19/00155) and from the Spanish Ministry of Science, Innovation and Universities (Juan de la Cierva programme grant IJC2018-037478-I). CM receives funding within the context of EURO-FINGERS, an 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 #733051102). HZ is a Wallenberg Scholar supported by grants from the Swedish Research Council (#2018–02532); the European Research Council (#681712); the Swedish State Support for Clinical Research (#ALFGBG-720931); the Alzheimer Drug Discovery Foundation (ADDF), USA (#201809–2016862); the AD Strategic Fund and the Alzheimer’s Association (#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 (#FO2019-0228); the European Union’s Horizon 2020 research and innovation programme under the Marie Skłodowska-Curie grant agreement no 860197 (MIRIADE), and the UK Dementia Research Institute at UCL. KB is supported by the Swedish Research Council (#2017–00915); the Alzheimer Drug Discovery Foundation (ADDF), USA (#RDAPB-201809–2016615); the Swedish Alzheimer Foundation (#AF-742881); Hjärnfonden, Sweden (#FO2017-0243); the Swedish state under the agreement between the Swedish government and the County Councils, the ALF-agreement (#ALFGBG-715986); the European Union Joint Program for Neurodegenerative Disorders (JPND2019-466–236); and the National Institute of Health (NIH), USA (grant #1R01AG068398-01).

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).

Higher grey matter volumes/cortical thickness and fluorodeoxyglucose uptake have been consistently found in cognitively unimpaired individuals with abnormal Alzheimer’s disease biomarkers compared with those with normal biomarkers. It has been hypothesized that such transient increases may be associated with neuroinflammatory mechanisms triggered in response to early Alzheimer’s pathology. Here, we evaluated, in the earliest stages of the Alzheimer’s continuum, associations between grey matter volume and fluorodeoxyglucose uptake with CSF biomarkers of several pathophysiological mechanisms known to be altered in preclinical Alzheimer’s disease stages. We included 319 cognitively unimpaired participants from the ALFA+ cohort with available structural MRI, fluorodeoxyglucose PET and CSF biomarkers of amyloid-β and tau pathology (phosphorylated tau and total tau), synaptic dysfunction (neurogranin), neuronal and axonal injury (neurofilament light), glial activation (soluble triggering receptor on myeloid cells 2, YKL40, GFAP, interleukin-6 and S100b) and α-synuclein using the Roche NeuroToolKit. We first used the amyloid-β/tau framework to investigate differences in the neuroimaging biomarkers between preclinical Alzheimer’s disease stages. Then, we looked for associations between the neuroimaging markers and all the CSF markers. Given the non-negative nature of the concentrations of CSF biomarkers and their high collinearity, we clustered them using non-negative matrix factorization approach (components) and sought associations with the imaging markers. By groups, higher grey matter volumes were found in the amyloid-β-positive tau-negative participants with respect to the reference amyloid-β-negative tau-negative group. Both amyloid-β and tau-positive participants showed higher fluorodeoxyglucose uptake than tau-negative individuals. Using the obtained components, we observed that tau pathology accompanied by YKL-40 (astrocytic marker) was associated with higher grey matter volumes and fluorodeoxyglucose uptake in extensive brain areas. Higher grey matter volumes in key Alzheimer-related regions were also found in association with two other components characterized by a higher expression of amyloid-β in combination with different glial markers: one with higher GFAP and S100b levels (astrocytic markers) and the other one with interleukin-6 (pro-inflammatory). Notably, these components’ expression had different behaviours across amyloid-β/tau stages. Taken together, our results show that CSF amyloid-β and phosphorylated tau, in combination with different aspects of glial response, have distinctive associations with higher grey matter volumes and increased glucose metabolism in key Alzheimer-related regions. These mechanisms combine to produce transient higher grey matter volumes and fluorodeoxyglucose uptake at the earliest stages of the Alzheimer’s continuum, which may revert later on the course of the disease when neurodegeneration drives structural and metabolic cerebral changes.