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Brain-age can be inferred from structural neuroimaging and compared to chronological age (brain-age delta) as a marker of biological brain aging. Accelerated aging has been found in neurodegenerative disorders like Alzheimer's disease (AD), but its validation against markers of neurodegeneration and AD is lacking. Here, imaging-derived measures from the UK Biobank dataset (N=22,661) were used to predict brain-age in 2,314 cognitively unimpaired (CU) individuals at higher risk of AD and mild cognitive impaired (MCI) patients from four independent cohorts with available biomarker data: ALFA+, ADNI, EPAD and OASIS. Brain-age delta was associated with abnormal amyloid-b, more advanced stages (AT) of AD pathology and APOE-e4 status. Brain-age delta was positively associated with plasma neurofilament light, a marker of neurodegeneration, and sex differences in the brain effects of this marker were found. These results validate brain-age delta as a non-invasive marker of biological brain aging in non-demented individuals with abnormal levels of biomarkers of AD and axonal injury. Marc Suárez-Calvet: Horizon 2020 - Research and Innovation Framework Programme 948677, Instituto de Salud Carlos III PI19/00155, La Caixa Foundation 100010434, Horizon 2020 - Research and Innovation Framework Programme 847648 / Juan Domingo Gispert: EU/EFPIA Innovative Medicines Initiative Joint Undertaking AMYPAD 115952 / Marc Suárez-Calvet: La Caixa Foundation 100010434; LCF/PR/ GN17/50300004 / Irene Cumplido-Mayoral: TriBEKa Imaging Platform project TriBEKa-17-519007, Universities and Research Secretariat, Ministry of Business and Knowledge of the Catalan Government 2017-SGR-892 / Juan Domingo Gispert: EIT Digital Grant 2021, Spanish Ministry of Science and Innovation (MCIN)/Spanish Research Agency (AEI) MCIN/AEI /10.13039/501100011033 RTI2018-102261, cofunded by the European Regional Development Fund (FEDER) / Marc Suárez-Calvet: NIHR biomedical research center at UCLH Frederik Barkhof Instituto de Salud Carlos III PI22/00456 / Raffaele Cacciaglia: Spanish Ministry of Science and Innovation (MCIN)/Spanish Research Agency (AEI) MCIN/ AEI/10.13039/501100011033 PID2021-125433OA-100 / Verónica Vilaplana: Spanish Research Agency (AEI) PID2020-116907RB-I00 of the call MCIN/ AEI /10.13039/501100011033 Peer Reviewed Article signat per 27 autors/es: Irene Cumplido-Mayoral, Barcelonaβeta Brain Research Center, Pasqual Maragall Foundation, Barcelona, Spain; Marina García-Prat, Barcelonaβeta Brain Research Center, Pasqual Maragall Foundation, Barcelona, Spain; Grégory Operto, Barcelonaβeta Brain Research Center, Pasqual Maragall Foundation, Barcelona, Spain; Carles Falcon, Barcelonaβeta Brain Research Center, Pasqual Maragall Foundation, Barcelona, Spain; Mahnaz Shekari, Barcelonaβeta Brain Research Center, Pasqual Maragall Foundation, Barcelona, Spain; Raffaele Cacciaglia, Barcelonaβeta Brain Research Center, Pasqual Maragall Foundation, Barcelona, Spain; Marta Milà-Alomà, Barcelonaβeta Brain Research Center, Pasqual Maragall Foundation, Barcelona, Spain; Luigi Lorenzini, Department of Radiology and Nuclear Medicine, Amsterdam University Medical Centers, Amsterdam, Netherlands; Silvia Ingala, Department of Radiology and Nuclear Medicine, Amsterdam University Medical Centers, Amsterdam, Netherlands; Alle Meije Wink, Department of Radiology and Nuclear Medicine, Amsterdam University Medical Centers, Amsterdam, Netherlands; Henk JMM Mutsaerts, Department of Radiology and Nuclear Medicine, Amsterdam University Medical Centers, Amsterdam, Netherlands; Carolina Minguillón, Barcelonaβeta Brain Research Center, Pasqual Maragall Foundation, Barcelona, Spain; Karine Fauria, Barcelonaβeta Brain Research Center, Pasqual Maragall Foundation, Barcelona, Spain; José Luis Molinuevo, Barcelonaβeta Brain Research Center, Pasqual Maragall Foundation, Barcelona, Spain; Sven Haller, CIRD Centre d'Imagerie Rive Droite, Geneva, Switzerland; Gael Chetelat, Normandie Univ, UNICAEN, INSERM, U1237, Caen, France; Adam Waldman, Centre for Dementia Prevention, University of Edinburgh, Edinburgh, United Kingdom; Adam J Schwarz, Takeda Pharmaceutical Company Ltd, Cambridge, United States; Frederik Barkhof, Department of Radiology and Nuclear Medicine, Amsterdam University Medical Centers, Amsterdam, Netherlands; Ivonne Suridjan, Roche Diagnostics International Ltd, Rotkreuz, Switzerland; Gwendlyn Kollmorgen, Roche Diagnostics GmbH, Penzberg, Germany; Anna Bayfield, Roche Diagnostics GmbH, Penzberg, Germany; Henrik Zetterberg, Institute of Neuroscience and Physiology, University of Gothenburg, Gothenburg, Sweden; Kaj Blennow, Institute of Neuroscience and Physiology, University of Gothenburg, Mölndal, Sweden; Marc Suárez-Calvet, Barcelonaβeta Brain Research Center, Pasqual Maragall Foundation, Barcelona, Spain; Verónica Vilaplana, Department of Signal Theory and Communications, Universitat Politècnica de Catalunya, Barcelona, Spain; Juan Domingo Gispert López, Barcelonaβeta Brain Research Center, Pasqual Maragall Foundation, Barcelona, Spain

Brain-age can be inferred from structural neuroimaging and compared to chronological age (brain-age delta) as a marker of biological brain aging. Accelerated aging has been found in neurodegenerative disorders like Alzheimer's disease (AD), but its validation against markers of neurodegeneration and AD is lacking. Here, imaging-derived measures from the UK Biobank dataset (N=22,661) were used to predict brain-age in 2,314 cognitively unimpaired (CU) individuals at higher risk of AD and mild cognitive impaired (MCI) patients from four independent cohorts with available biomarker data: ALFA+, ADNI, EPAD, and OASIS. Brain-age delta was associated with abnormal amyloid-β, more advanced stages (AT) of AD pathology and APOE-ε4 status. Brain-age delta was positively associated with plasma neurofilament light, a marker of neurodegeneration, and sex differences in the brain effects of this marker were found. These results validate brain-age delta as a non-invasive marker of biological brain aging in non-demented individuals with abnormal levels of biomarkers of AD and axonal injury.

Purpose: To determine whether the APOE-ε4 allele modulates the relationship between regional β-amyloid (Aβ) accumulation and cognitive change in middle-aged cognitively unimpaired (CU) participants. Methods: The 352 CU participants (mean aged 61.1 [4.7] years) included completed two cognitive assessments (average interval 3.34 years), underwent [18F]flutemetamol Aβ positron emission tomography (PET), T1w magnetic resonance imaging (MRI), as well as APOE genotyping. Global and regional Aβ PET positivity was assessed across five regions-of-interest by visual reading (VR) and regional Centiloids. Linear regression models were developed to examine the interaction between regional and global Aβ PET positivity and APOE-ε4 status on longitudinal cognitive change assessed with the Preclinical Alzheimer's Cognitive Composite (PACC), episodic memory, and executive function, after controlling for age, sex, education, cognitive baseline scores, and hippocampal volume. Results: In total, 57 participants (16.2%) were VR+ of whom 41 (71.9%) were APOE-ε4 carriers. No significant APOE-ε4*global Aβ PET interactions were associated with cognitive change for any cognitive test. However, APOE-ε4 carriers who were VR+ in temporal areas (n = 19 [9.81%], p = 0.04) and in the striatum (n = 8 [4.14%], p = 0.01) exhibited a higher decline in the PACC. The temporal areas findings were replicated when regional PET positivity was determined with Centiloid values. Regionally, VR+ in the striatum was associated with higher memory decline. As for executive function, interactions between APOE-ε4 and regional VR+ were found in temporal and parietal regions, and in the striatum. Conclusion: CU APOE-ε4 carriers with a positive Aβ PET VR in regions known to accumulate amyloid at later stages of the Alzheimer's disease (AD) continuum exhibited a steeper cognitive decline. This work supports the contention that regional VR of Aβ PET might convey prognostic information about future cognitive decline in individuals at higher risk of developing AD. Clinicaltrials: gov Identifier: NCT02485730. Registered 20 June 2015 https://clinicaltrials.gov/ct2/show/NCT02485730 and ClinicalTrials.gov Identifier:NCT02685969. Registered 19 February 2016 https://clinicaltrials.gov/ct2/show/NCT02685969 . The research leading to these results has received funding from “la Caixa” Foundation (LCF/PR/GN17/10300004) 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 grant 2021 SGR 00913. NV-T is funded by a postdoctoral grant, Juan de la Cierva Programme (FJC2018-038085-I), Ministry of Science and Innovation-Spanish State Research Agency. Her research has received additional support of “la Caixa” Foundation (LCF/PR/GN17/10300004) and the Health Department of the Catalan Government (Health Research and Innovation Strategic Plan 2016–2020 Grant SLT002/16/00201). OG-R is supported by the Spanish Ministry of Science, Innovation and Universities (IJC2020-043417-I) and receives funding from the Alzheimer’s Association Research Fellowship Program (2019-AARF-644568). EA-U is supported by Alzheimer’s Association research grants (AARG 2019-AARG-644641, AARG 2019-AARG-644641-RAPID), a “Ramón y Cajal” fellowship (RYC2018-026053-I) and by a grant of the Ministry of Science and Innovation (PID2019-111514RA-I00). MS-C receives funding from the European Research Council under the European Union’s Horizon 2020 research and innovation programme (Grant agreement No. 948677), the Instituto de Salud Carlos III (PI19/00155), and from a fellowship from “la Caixa” Foundation (ID 100010434) and from the European Union’s Horizon 2020 research and innovation programme under the Marie Skłodowska-Curie grant agreement No 847648 (LCF/BQ/PR21/11840004). JD-G holds a “Ramón y Cajal” fellowship (RYC-2013-13054).

Introduction: Harboring two copies of the apolipoprotein E (APOE) ε2 allele strongly protects against Alzheimer's disease (AD). However, the effect of this genotype on gray matter (GM) volume in cognitively unimpaired individuals has not yet been described. Methods: Multicenter brain magnetic resonance images (MRIs) from cognitively unimpaired ε2 homozygotes were matched (1:1) against all other APOE genotypes for relevant confounders (n = 223). GM volumes of ε2 genotypic groups were compared to each other and to the reference group (APOE ε3/ε3). Results: Carrying at least one ε2 allele was associated with larger GM volumes in brain areas typically affected by AD and also in areas associated with cognitive resilience. APOE ε2 homozygotes, but not APOE ε2 heterozygotes, showed larger GM volumes in areas related to successful aging. Discussion: In addition to the known resistance against amyloid-β deposition, the larger GM volumes in key brain regions may confer APOE ε2 homozygotes additional protection against AD-related cognitive decline. The project leading to this study has received funding from “la Caixa” Foundation (ID 100010434), under the agreement LCF/PR/GN17/50300004. Additional support has been received from the Universities and Research Secretariat, Ministry of Business and Knowledge of the Catalan Government under the grant number 2017-SGR-892. EMAU is supported by the Spanish Ministry of Science, Innovation and Universities–Spanish State Research Agency (RYC2018-026053-I).

Background: Brain-age can be inferred from structural neuroimaging and compared to chronological age (brain-age delta), as a marker of accelerated/decelerated biological brain aging. Accelerated biological aging has been found in Alzheimer’s disease (AD), but validation against biomarkers of AD and neurodegeneration is lacking. We studied the association between brain-age delta vs biomarkers and risk factors for AD, neurodegeneration, and cerebrovascular disease in non-demented individuals. Furthermore, between-sex differences in the brain areas that better predicted age were sought. Method: We trained XGBoost regressor models to predict brain-age separately for females and males using volumes and cortical thickness in regions of the Desikan-Kiliany atlas (obtained with Freesurfer 6.0) from the UKBioBank cohort (n=22,661). Using this trained model, we estimated brain-age delta in cognitively unimpaired (CU) and mild cognitive impaired (MCI) individuals four independent cohorts: ALFA+ (nCU=380), ADNI (nCU=253, nMCI=498), EPAD (nCU=653, nMCI=155) and OASIS (nCU=407). Chronological age, sex, MMSE and APOE categories were available for all subjects. ALFA+, ADNI and EPAD cohorts included data for AD CSF biomarkers (Aß42 and p-tau) and amyloid-b/tau (AT) staging was performed using pre-established cut-off values, whereas for OASIS amyloid-b was determined by PET. White Matter Hyperintensities (WMH) were available as a marker of small vessel disease and plasma (ALFA+ and ADNI) neurofilament light (NfL) as of neurodegeneration. Linear regression models, including chronological age and sex as covariates were used to identify associations between brain-age delta and biomarkers. We identified the individuals at the 10th and 90th deciles to select those with higher (accelerated) and lower (decelerated) brain-age delta and tested for interactions between age and all the variables on brain-age delta. Result: Between-sex differences were found in the most predictive brain regions (Figure 1). Brain-age delta was positively associated with abnormal amyloid-ß status, advanced AT stages and APOE-e4 carriership. Furthermore, brain-age delta was positively associated with plasma NfL in MCI patients and an interaction between age and plasma NfL was found on brain-age delta of CU individuals (Figure 2). Conclusion: Biological brain-age can be estimated from structural neuroimaging and is associated with biomarkers and risk factors of AD pathology and neurodegeneration in non-demented individuals. This project has received support from European Prevention of Alzheimer’s Dementia (EPAD) grant no. 115736, Edinburgh, United Kingdom. Peer Reviewed La publicació està signada per 27 autors/autores: Irene Cumplido-Mayoral 1,2; Marina Garcia 1; Grégory Operto 1,3,4; Carles Falcon 1,3,5; Mahnaz Shekari 1,2,6; Raffaele Cacciaglia 1,3,4; Marta Milà-Alomà 1,2,3,4; Luigi Lorenzini 7; Silvia Ingala 7; Alle Meije Wink 7; Henk-Jan Mutsaerts 7; Carolina Minguillón 1,3,4; Karine Fauria 1,4; Jose Luis Molinuevo 1,3,4,8; Sven Haller 9; Gael Chetelat 10; Adam Waldman 11; Adam J. Schwarz 12; Frederik Barkhof 7,13; Gwendlyn Kollmorgen 14; Ivonne Suridjan 14; Norbert Wild 14; Henrik Zetterberg 15,16,17,18,19; Kaj Blennow 15,19; Marc Suárez-Calvet 1,3,4,20; Verónica Vilaplana 21; Juan Domingo Gispert 1,3,5; ALFA study 22; ADNI study 23 on Behalf Of The EPAD Consortium 24 // 1 Barcelonaβeta Brain Research Center (BBRC), Pasqual Maragall Foundation, Barcelona, Spain; 2 Universitat Pompeu Fabra, Barcelona, Spain; 3 IMIM (Hospital del Mar Medical Research Institute), Barcelona, Spain; 4 Centro de Investigación Biomédica en Red de Fragilidad y Envejecimiento Saludable (CIBERFES), Madrid, Spain; 5 Centro de Investigación Biomédica en Red de Bioingeniería, Biomateriales y Nanomedicina (CIBER-BBN), Madrid, Spain; 6 Hospital del Mar Medical Research Institute (IMIM), Barcelona, Spain; 7 Department of Radiology and Nuclear Medicine, Amsterdam Neuroscience, Vrije Universiteit Amsterdam, Amsterdam UMC, Amsterdam, Netherlands; 8 Lundbeck A/S, Copenhagen, Denmark; 9 CIRD Centre d’Imagerie Rive Droite, Geneva, Switzerland; 10 Normandie Univ, UNICAEN, INSERM, U1237, PhIND "Physiopathology and Imaging of Neurological Disorders", Institut Blood and Brain @ Caen-Normandie, Cyceron, Caen, France; 11 Centre for Dementia Prevention, Edinburgh Imaging, and UK Dementia Research Institute at The University of Edinburgh, Edinburgh, United Kingdom; 12 Takeda Pharmaceutical Company Ltd, Cambridge, MA, USA; 13 Institutes of Neurology and Healthcare Engineering, University College London, London, United Kingdom; 14 Roche Diagnostics International Ltd, Rotkreuz, Switzerland; 15 Clinical Neurochemistry Laboratory, Sahlgrenska University Hospital, Mölndal, Sweden; 16 UK Dementia Research Institute at UCL, London, United Kingdom; 17 Hong Kong Center for Neurodegenerative Diseases, Clear Water Bay, Hong Kong; 18 Department of Neurodegenerative Disease, UCL Queen Square Institute of Neurology, University College London, London, United Kingdom; 19 Institute of Neuroscience and Physiology, University of Gothenburg, Mölndal, Sweden; 20 Servei de Neurologia, Hospital del Mar, Barcelona, Spain; 21 Department of Signal Theory and Communications, Universitat Politècnica de Catalunya, Barcelona, Spain; 22 BarcelonaBeta Brain Research Center (BBRC), Pasqual Maragall Foundation, Barcelona, Spain; 23 Laboratory of Neuroimaging (LONI), University of Southern California, Los Angeles, CA, USA.

Telomere length (TL) is associated with biological aging, consequently influencing the risk of age-related diseases such as Alzheimer’s disease (AD). We aimed to evaluate the potential causal role of TL in AD endophenotypes (i.e., cognitive performance, N = 2233; brain age and AD-related signatures, N = 1134; and cerebrospinal fluid biomarkers (CSF) of AD and neurodegeneration, N = 304) through a Mendelian randomization (MR) analysis. Our analysis was conducted in the context of the ALFA (ALzheimer and FAmilies) study, a population of cognitively healthy individuals at risk of AD. A total of 20 single nucleotide polymorphisms associated with TL were used to determine the effect of TL on AD endophenotypes. Analyses were adjusted by age, sex, and years of education. Stratified analyses by APOE-ɛ4 status and polygenic risk score of AD were conducted. MR analysis revealed significant associations between genetically predicted longer TL and lower levels of CSF Aβ and higher levels of CSF NfL only in APOE-ɛ4 non-carriers. Moreover, inheriting longer TL was associated with greater cortical thickness in age and AD-related brain signatures and lower levels of CSF p-tau among individuals at a high genetic predisposition to AD. Further observational analyses are warranted to better understand these associations., The project leading to these results has received funding from the Alzheimer’s Association (Grant AARG-19-618265). This project has received funding from Instituto de Salud Carlos III (PI19/00119). Additional support has been received from “la Caixa” Foundation (ID 100010434), under agreement LCF/PR/GN17/50300004, the Alzheimer’s Association and an international anonymous charity foundation through the TriBEKa Imaging Platform project (TriBEKa-17-519007), the Health Department of the Catalan Government (Health Research and Innovation Strategic Plan (PERIS) 2016-2020 grant# SLT002/16/00201), and the Universities and Research Secretariat, Ministry of Business and Knowledge of the Catalan Government under the grant no. 2017-SGR-892. All CRG authors acknowledge the support of the Spanish Ministry of Science, Innovation and Universities to the EMBL partnership, the Centro de Excelencia Severo Ochoa, and the CERCA Programme/Generalitat de Catalunya. NV-T is funded by a post-doctoral grant, Juan de la Cierva Incorporación Programme (IJC2020-043216-I), Ministry of Science and Innovation–Spanish State Research Agency. EMAU is supported by the Spanish Ministry of Science, Innovation and Universities - Spanish State Research Agency (RYC2018-026053-I). MS-C receives funding from the European Research Council (ERC) under the European Union’s Horizon 2020 research and innovation programme (Grant agreement no. 948677). MS-C also receives funding from the 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). HZ is a Wallenberg Scholar supported by grants from the Swedish Research Council (#2018-02532); the European Research Council (#681712); 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). JDG is supported by the Spanish Ministry of Science and Innovation (RYC-2013-13054). AS-V. is the recipient of an Instituto de Salud Carlos III Miguel Servet II fellowship (CP II 17/00029).

Background and Objectives Increased anxious-depressive symptomatology is observed in the preclinical stage of Alzheimer disease (AD), which may accelerate disease progression. We investigated whether β-amyloid, cortical thickness in medial temporal lobe structures, neuroinflammation, and sociodemographic factors were associated with greater anxious-depressive symptoms during the COVID-19 confinement. Methods This retrospective observational study included cognitively unimpaired older adults from the Alzheimer's and Families cohort, the majority with a family history of sporadic AD. Participants performed the Hospital Anxiety and Depression Scale (HADS) during the COVID-19 confinement. A subset had available retrospective (on average: 2.4 years before) HADS assessment, amyloid [18F] flutemetamol PET and structural MRI scans, and CSF markers of neuroinflammation (interleukin-6 [IL-6], triggering receptor expressed on myeloid cells 2, and glial fibrillary acidic protein levels). We performed multivariable linear regression models to investigate the associations of prepandemic AD-related biomarkers and sociodemographic factors with HADS scores during the confinement. We further performed an analysis of covariance to adjust by participants' prepandemic anxiety-depression levels. Finally, we explored the role of stress and lifestyle changes (sleep patterns, eating, drinking, smoking habits, and medication use) on the tested associations and performed sex-stratified analyses. Results We included 921 (254 with AD biomarkers) participants. β-amyloid positivity (B = 3.73; 95% CI = 1.1 to 6.36; p = 0.006), caregiving (B = 1.37; 95% CI 0.24–2.5; p = 0.018), sex (women: B = 1.95; 95% CI 1.1–2.79; p < 0.001), younger age (B = −0.12; 95% CI −0.18 to −0.052; p < 0.001), and lower education (B = −0.16; 95% CI −0.28 to −0.042; p = 0.008) were associated with greater anxious-depressive symptoms during the confinement. Considering prepandemic anxiety-depression levels, we further observed an association between lower levels of CSF IL-6 (B = −5.11; 95% CI −10.1 to −0.13; p = 0.044) and greater HADS scores. The results were independent of stress-related variables and lifestyle changes. Stratified analysis revealed that the associations were mainly driven by women. Discussion Our results link AD-related pathophysiology and neuroinflammation with greater anxious-depressive symptomatology during the COVID-19-related confinement, notably in women. AD pathophysiology may increase neuropsychiatric symptomatology in response to stressors. This association may imply a worse clinical prognosis in people at risk for AD after the pandemic and thus deserves to be considered by clinicians., This research was supported by Alzheimer's Association research grants (AARG 2019-AARG-644641 and AARG 2019-AARG-644641-RAPID) to E.M. Arenaza-Urquijo. E.M. Arenaza-Urquijo holds a Ramón y Cajal fellowship (RYC2018-026053-I) and a grant of the Ministry of Science and Innovation (PID2019-111514RA-I00). The research leading to these results has received funding from la Caixa Foundation (LCF/PR/GN17/10300004), the Alzheimer's Association, and an international anonymous charity foundation through the TriBEKa Imaging Platform project. Additional support has been received from the Universities and Research Secretariat, Ministry of Business and Knowledge of the Catalan Government under grant 2017-SGR-892.

Background and Objectives To determine whether CSF synaptic biomarkers are altered in the early preclinical stage of the Alzheimer continuum and associated with Alzheimer disease (AD) risk factors, primary pathology, and neurodegeneration markers. Methods This cross-sectional study was performed in the Alzheimer's and Families (ALFA+) cohort, comprising middle-aged cognitively unimpaired participants. CSF neurogranin and growth-associated protein-43 (GAP-43) were measured with immunoassays, and synaptosomal-associated protein-25 (SNAP-25) and synaptotagmin-1 were measured with immunoprecipitation mass spectrometry. AD CSF biomarkers β-amyloid (Aβ)42/40, phosphorylated tau (p-tau), and total tau and the neurodegeneration biomarker neurofilament light chain (NfL) were also measured. Participants underwent structural MRI and fluorodeoxyglucose and Aβ PET imaging. General linear modeling was used to test the associations between CSF synaptic biomarkers and risk factors, Aβ pathology, tau pathology, and neurodegeneration markers. Results All CSF synaptic biomarkers increased with age. CSF neurogranin was higher in females, while CSF SNAP-25 was higher in APOE ε4 carriers. All CSF synaptic biomarkers increased with higher Aβ load (as measured by CSF Aβ42/40 and Aβ PET Centiloid values), and it is important to note that the synaptic biomarkers were increased even in individuals in the earliest stages of Aβ deposition. Higher CSF synaptic biomarkers were also associated with higher CSF p-tau and NfL. Higher CSF neurogranin and GAP-43 were significantly associated with higher brain metabolism but lower cortical thickness in AD-related brain regions. Discussion CSF synaptic biomarkers increase in the early preclinical stages of the Alzheimer continuum even when a low burden of Aβ pathology is present, and they differ in their association with age, sex, APOE ε4, and markers of neurodegeneration. Trial Registration Information ClinicalTrials.gov Identifier NCT02485730.