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Research into hippocampal self-regulation abilities may help determine the clinical significance of hippocampal hyperactivity throughout the pathophysiological continuum of Alzheimer's disease. In this study, we aimed to identify the effects of amyloid-β peptide 42 (amyloid-β42) and phosphorylated tau on the patterns of functional connectomics involved in hippocampal downregulation. We identified 48 cognitively unimpaired participants (22 with elevated CSF amyloid-β peptide 42 levels, 15 with elevated CSF phosphorylated tau levels, mean age of 62.705 ± 4.628 years), from the population-based 'Alzheimer's and Families' study, with baseline MRI, CSF biomarkers, APOE genotyping and neuropsychological evaluation. We developed a closed-loop, real-time functional MRI neurofeedback task with virtual reality and tailored it for training downregulation of hippocampal subfield cornu ammonis 1 (CA1). Neurofeedback performance score, cognitive reserve score, hippocampal volume, number of apolipoprotein ε4 alleles and sex were controlled for as confounds in all cross-sectional analyses. First, using voxel-wise multiple regression analysis and controlling for CSF biomarkers, we identified the effect of healthy ageing on eigenvector centrality, a measure of each voxel's overall influence based on iterative whole-brain connectomics, during hippocampal CA1 downregulation. Then, controlling for age, we identified the effects of abnormal CSF amyloid-β42 and phosphorylated tau levels on eigenvector centrality during hippocampal CA1 downregulation. Across subjects, our main findings during hippocampal downregulation were: (i) in the absence of abnormal biomarkers, age correlated with eigenvector centrality negatively in the insula and midcingulate cortex, and positively in the inferior temporal gyrus; (ii) abnormal CSF amyloid-β42 (19.2) correlated with eigenvector centrality positively in the ventral striatum, anterior cingulate and somatosensory cortex, and negatively in the precuneus and orbitofrontal cortex. During resting state functional MRI, similar eigenvector centrality patterns in the cingulate had previously been associated to CSF biomarkers in mild cognitive impairment and dementia patients. Using the developed closed-loop paradigm, we observed such patterns, which are characteristic of advanced disease stages, during a much earlier presymptomatic phase. In the absence of CSF biomarkers, our non-invasive, interactive, adaptive and gamified neuroimaging procedure may provide important information for clinical prognosis and monitoring of therapeutic efficacy. We have released the developed paradigm and analysis pipeline as open-source software to facilitate replication studies. ; This work has received funding from the European Union's Horizon 2020 research and innovation programme under the Marie Sklodowska-Curie action grant agreement No 707730. 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). JDG is supported by the Spanish Ministry of Economy, and Competitiveness (RYC-2013-13054).

The ε4 allele of the gene Apolipoprotein E is the major genetic risk factor for Alzheimer's Disease. APOE ε4 has been associated with changes in brain structure in cognitively impaired and unimpaired subjects, including atrophy of the hippocampus, which is one of the brain structures that is early affected by AD. In this work we analyzed the impact of APOE ε4 gene dose and its association with age, on hippocampal shape assessed with multivariate surface analysis, in a ε4‐enriched cohort of n = 479 cognitively healthy individuals. Furthermore, we sought to replicate our findings on an independent dataset of n = 969 individuals covering the entire AD spectrum. We segmented the hippocampus of the subjects with a multi‐atlas‐based approach, obtaining high‐dimensional meshes that can be analyzed in a multivariate way. We analyzed the effects of different factors including APOE, sex, and age (in both cohorts) as well as clinical diagnosis on the local 3D hippocampal surface changes. We found specific regions on the hippocampal surface where the effect is modulated by significant APOE ε4 linear and quadratic interactions with age. We compared between APOE and diagnosis effects from both cohorts, finding similarities between APOE ε4 and AD effects on specific regions, and suggesting that age may modulate the effect of APOE ε4 and AD in a similar way. ; "la Caixa" Foundation, Grant/Award Number: LCF/PR/GN17/50300004; Ministry of Business and Knowledge of the Catalan Government, Grant/Award Number: 2017‐SGR‐892; Spanish Ministry of Economy and Competitiveness, Grant/Award Number: MDM‐2015‐0502; Spanish Ministry of Science, Innovation and Universities, Grant/Award Number: RYC‐2013‐13054

In Alzheimer's disease (AD), tau phosphorylation in the brain and its subsequent release into cerebrospinal fluid (CSF) and blood is a dynamic process that changes during disease evolution. The main aim of our study was to characterize the pattern of changes in phosphorylated tau (p-tau) in the preclinical stage of the Alzheimer's continuum. We measured three novel CSF p-tau biomarkers, phosphorylated at threonine-181 and threonine-217 with an N-terminal partner antibody and at threonine-231 with a mid-region partner antibody. These were compared with an automated mid-region p-tau181 assay (Elecsys) as the gold standard p-tau measure. We demonstrate that these novel p-tau biomarkers increase more prominently in preclinical Alzheimer, when only subtle changes of amyloid-β (Aβ) pathology are detected, and can accurately differentiate Aβ-positive from Aβ-negative cognitively unimpaired individuals. Moreover, we show that the novel plasma N-terminal p-tau181 biomarker is mildly but significantly increased in the preclinical stage. Our results support the idea that early changes in neuronal tau metabolism in preclinical Alzheimer, likely in response to Aβ exposure, can be detected with these novel p-tau assays. ; This publication is part of the ALzheimer's and FAmilies (ALFA) study. The authors would like to express their most sincere gratitude to the ALFA project participants and relatives without whom this research would have not been possible. We also thank Tania Menchón, Carolina Herrero, Noemí Carranza, Charlotte Frick, Linnéa Lagerstedt, Irina Nilsson and Cindy François for technical assistance. Collaborators of the ALFA study are Annabella Beteta, Raffaele Cacciaglia, Alba Cañas, Carme Deulofeu, Irene Cumplido, Ruth Dominguez, Maria Emilio, Carles Falcon, Sherezade Fuentes, Laura Hernandez, Gema Huesa, Jordi Huguet, Paula Marne, Tania Menchón, Grégory Operto, Albina Polo, Sandra Pradas, Anna Soteras, Marc Vilanova and Natalia Vilor‐Tejedor. The authors thank Roche Diagnostics International Ltd. for providing the kits to measure CSF biomarkers. ELECSYS, COBAS, and COBAS E are registered trademarks of Roche. Authors also thank GE Healthcare for kindly providing the [18F]flutemetamol doses of ALFA+ study participants. 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. MS‐C received funding from the European Union's Horizon 2020 Research and Innovation Program under the Marie Sklodowska‐Curie action grant agreement No 752310 and currently 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). TTK holds a Brightfocus postdoctoral fellowship (#A2020812F) and was further supported by the Swedish Alzheimer Foundation (Alzheimerfonden; #AF‐930627), the Swedish Dementia Foundation (Demensförbundet), Gamla Tjänarinnor, the Aina (Ann) Wallströms and Mary‐Ann Sjöbloms Foundation, the Gun and Bertil Stohnes foundation, and the Anna Lisa and Brother Björnsson's Foundation. JDG is supported by the Spanish Ministry of Science and Innovation (RYC‐2013‐13054). OGR is supported by the Spanish Ministry of Science, Innovation and Universities (FJCI‐2017‐33437). ASV is the recipient of an Instituto de Salud Carlos III Miguel Servet II fellowship (CP II 17/00029). EMAU is supported by the Spanish Ministry of Science, Innovation and Universities—Spanish State Research Agency (RYC2018‐026053‐I). CM was supported by the Spanish Ministry of Economy and Competitiveness (grant no IEDI‐2016‐00690). 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), 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), and European Union Joint Program for Neurodegenerative Disorders (JPND2019‐466‐236).

Background: Air quality contributes to incidence of Alzheimer's disease (AD) although the underlying neurobiological mechanisms are unclear. This study was aimed to examine the association between air pollution and concentrations of cerebrospinal fluid (CSF) AD biomarkers and amyloid-β (Aβ) deposition. Participants and methods The sample included 156 cognitively unimpaired adults aged 57 years (61 at biomarkers assessment) with increased risk of AD from the ALFA + Study. We examined CSF levels of Aβ42, Aβ40, p-Tau, t-Tau, neurofilament light (NfL) and cerebral amyloid load (Centiloid). A Land Use Regression model from 2009 was used to estimate residential exposure to air pollutants including nitrogen dioxide (NO2,) and particulate matter (PM2.5, PM2.5 abs, PM10). This model was considered a surrogate of long-term exposure until time of data collection in 2013-2014. Participants have resided in the same residence for at least the previous 3 years. Multiple linear regression models were used to estimate associations between air pollutants and biomarkers. The effect modification by CSF Aβ status and APOE-ε4 carriership was also assessed. Results: A consistent pattern of results indicated that greater exposure to NO2 and PM2.5 absorbance was associated with higher levels of brain Aβ deposition, while greater exposure to PM10 and PM2.5was associated with higher levels of CSF NfL. Most associations were driven by individuals that were Aβ-positive. Although APOE-ε4 status did not significantly modify these associations, the effect of air pollutants exposure on CSF NfL levels was stronger in APOE-ε4 carriers. Conclusion: In a population of cognitively unimpaired adults with increased risk of AD, long-term exposure to air pollution was associated with higher levels in biomarkers of AD pathology. While further research is granted to elucidate the mechanisms involved in such associations, our results reinforce the role of air pollution as an environmental risk factor for AD. ; 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. SA is funded by a Juan de la Cierva – Incorporación Postdoctoral Contract awarded by Ministry of Economy, Industry and Competitiveness (IJCI-2017-34068). NV-T is funded by a post-doctoral grant, Juan de la Cierva Programme (FJC2018-038085-I), Ministry of Science and Innovation– Spanish State Research Agency. MS-C received funding from the European Union's Horizon 2020 Research and Innovation Program under the Marie Sklodowska-Curie action grant agreement No 752310, and currently 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). EMA-U is supported by the Spanish Ministry of Science, Innovation and Universities - Spanish State Research Agency (RYC2018-026053-I). OG-R is supported by the Spanish Ministry of Science, Innovation and Universities (FJCI-2017-33437). JDG is supported by the Spanish Ministry of Science and Innovation (RYC-2013-13054). 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), 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), and European Union Joint Program for Neurodegenerative Disorders (JPND2019-466-236). 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. ISGlobal acknowledge support from the Spanish Ministry of Science and Innovation through the "Centro de Excelencia Severo Ochoa 2019–2023" Program (CEX2018-000806-S), and support from the Generalitat de Catalunya through the CERCA Program

Introduction: Amyloid beta (Aβ) pathology is an Alzheimer's disease early hallmark. Here we assess the value of longitudinal self- and informant reports of cognitive decline to predict Aβ positron emission tomography (PET) outcome in cognitively unimpaired middle-aged individuals. Methods: A total of 261 participants from the ALFA+ study underwent [18F]flutemetamol PET and Subjective Cognitive Decline Questionnaire (SCD-Q) concurrently, and 3 years before scan. We used logistic regressions to evaluate the ability of SCD-Q scores (self and informant) to predict Aβ PET visual read, and repeated analysis of variance to assess whether changes in SCD-Q scores relate to Aβ status. Results: Self-perception of decline in memory (odds ratio [OR] = 1.2), and informant perception of executive decline (OR = 1.6), increased the probability of a positive scan. Informant reports 3 years before scanning predicted Aβ PET outcome. Longitudinal increase of self-reported executive decline was predictive of Aβ in women (P = .003). Discussion: Subjective reports of cognitive decline are useful to predict Aβ and may improve recruitment strategies. ; 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. Marc Suárez‐Calvet received funding from the European Union's Horizon 2020 Research and Innovation Program under the Marie Sklodowska‐Curie action grant agreement No 752310, and currently 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). Juan Domingo Gispert is supported by the Spanish Ministry of Science and Innovation (RYC‐2013‐13054). Oriol Grau‐Rivera is supported by the Spanish Ministry of Science, Innovation, and Universities (FJCI‐2017‐33437). ASV is the recipient of an Instituto de Salud Carlos III Miguel Servet II fellowship (CP II 17/00029). Eider M. Arenaza‐Urquijo is supported by the Spanish Ministry of Science, Innovation and Universities–Spanish State Research Agency (RYC2018‐026053‐I). Carolina Minguillon was supported by the Spanish Ministry of Economy and Competitiveness (grant n° IEDI‐2016‐00690).

Background: Understanding the changes that occur in the transitional stage between absent and overt amyloid-β (Aβ) pathology within the Alzheimer's continuum is crucial to develop therapeutic and preventive strategies. The objective of this study is to test whether cognitively unimpaired individuals with a low burden of Aβ pathology have a distinct CSF, structural, and functional neuroimaging biomarker profile. Methods: Cross-sectional study of 318 middle-aged, cognitively unimpaired individuals from the ALFA+ cohort. We measured CSF Aβ42/40, phosphorylated tau (p-tau), total tau (t-tau), neurofilament light (NfL), neurogranin, sTREM2, YKL40, GFAP, IL6, S100B, and α-synuclein. Participants also underwent cognitive assessments, APOE genotyping, structural MRI, [18F]-FDG, and [18F]-flutemetamol PET. To ensure the robustness of our results, we used three definitions of low burden of Aβ pathology: (1) positive CSF Aβ42/40 and < 30 Centiloids in Aβ PET, (2) positive CSF Aβ42/40 and negative Aβ PET visual read, and (3) 20-40 Centiloid range in Aβ PET. We tested CSF and neuroimaging biomarker differences between the low burden group and the corresponding Aβ-negative group, adjusted by age and sex. Results: The prevalence and demographic characteristics of the low burden group differed between the three definitions. CSF p-tau and t-tau were increased in the low burden group compared to the Aβ-negative in all definitions. CSF neurogranin was increased in the low burden group definitions 1 and 3, while CSF NfL was only increased in the low burden group definition 1. None of the defined low burden groups showed signs of atrophy or glucose hypometabolism. Instead, we found slight increases in cortical thickness and metabolism in definition 2. Conclusions: There are biologically meaningful Aβ-downstream effects in individuals with a low burden of Aβ pathology, while structural and functional changes are still subtle or absent. These findings support considering individuals with a low burden of Aβ pathology for clinical trials. Trial registration: NCT02485730. ; 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 the grant no. 2017-SGR-892. JDG holds a "Ramón y Cajal" fellowship (RYC-2013-13054). EMA-U is supported by the Spanish Ministry of Science, Innovation and Universities - Spanish State Research Agency (RYC2018-026053-I). NV-T is funded by a post-doctoral grant, Juan de la Cierva Programme (FJC2018-038085-I), Ministry of Science and Innovation–Spanish State Research Agency. OG-R is supported by the Spanish Ministry of Science, Innovation and Universities (FJCI-2017-33437), and receives funding from the Alzheimer's Association Research Fellowship Program (2019-AARF-644568). ASV is the recipient of an Instituto de Salud Carlos III Miguel Servet II fellowship (CP II 17/00029). 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), and the UK Dementia Research Institute at UCL. KB is supported by 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), and European Union Joint Program for Neurodegenerative Disorders (JPND2019-466-236). MSC receives funding from the European Research Council (ERC) under the European Union's Horizon 2020 research and innovation program (Grant agreement No. 948677). MSC 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).

Background: Perivascular spaces (PVS) have an important role in the elimination of metabolic waste from the brain. It has been hypothesized that the enlargement of PVS (ePVS) could be affected by pathophysiological mechanisms involved in Alzheimer's disease (AD), such as abnormal levels of CSF biomarkers. However, the relationship between ePVS and these pathophysiological mechanisms remains unknown. Objective: We aimed to investigate the association between ePVS and CSF biomarkers of several pathophysiological mechanisms for AD. We hypothesized that ePVS will be associated to CSF biomarkers early in the AD continuum (i.e., amyloid positive cognitively unimpaired individuals). Besides, we explored associations between ePVS and demographic and cardiovascular risk factors. Methods: The study included 322 middle-aged cognitively unimpaired participants from the ALFA + study, many within the Alzheimer's continuum. NeuroToolKit and Elecsys® immunoassays were used to measure CSF Aβ42, Aβ40, p-tau and t-tau, NfL, neurogranin, TREM2, YKL40, GFAP, IL6, S100, and α-synuclein. PVS in the basal ganglia (BG) and centrum semiovale (CS) were assessed based on a validated 4-point visual rating scale. Odds ratios were calculated for associations of cardiovascular and AD risk factors with ePVS using logistic and multinomial models adjusted for relevant confounders. Models were stratified by Aβ status (positivity defined as Aβ42/40 < 0.071). Results: The degree of PVS significantly increased with age in both, BG and CS regions independently of cardiovascular risk factors. Higher levels of p-tau, t-tau, and neurogranin were significantly associated with ePVS in the CS of Aβ positive individuals, after accounting for relevant confounders. No associations were detected in the BG neither in Aβ negative participants. Conclusions: Our results support that ePVS in the CS are specifically associated with tau pathophysiology, neurodegeneration, and synaptic dysfunction in asymptomatic stages of the Alzheimer's continuum. ; 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 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 Programme (FJC2018-038085-I), Ministry of Science and Innovation– Spanish State Research Agency. MS-C received funding from the European Union's Horizon 2020 Research and Innovation Program under the Marie Sklodowska-Curie action grant agreement No 752310, and currently 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). EMAU is supported by the Spanish Ministry of Science, Innovation and Universities—Spanish State Research Agency (RYC2018-026053-I). OGR is supported by the Spanish Ministry of Science, Innovation and Universities (FJCI-2017–33437). JDG is supported by the Spanish Ministry of Science and Innovation (RYC-2013–13054). 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), and European Union Joint Program for Neurodegenerative Disorders (JPND2019-466–236). HZ is a Wallenberg Scholar supported by grants from the Swedish Research Council (#2018–02532), the European Research Council (#681712), the Swedish state under the agreement between the Swedish government and the County Councils, the ALF-agreement (#ALFGBG-720931), the ADDF, USA (#201809–2016862), and the UK Dementia Research Institute at UCL.

Background: Current evidence supports the involvement of brain-derived neurotrophic factor (BDNF) Val66Met polymorphism, and the ε4 allele of APOE gene in hippocampal-dependent functions. Previous studies on the association of Val66Met with whole hippocampal volume included patients of a variety of disorders. However, it remains to be elucidated whether there is an impact of BDNF Val66Met polymorphism on the volumes of the hippocampal subfield volumes (HSv) in cognitively unimpaired (CU) individuals, and the interactive effect with the APOE-ε4 status. Methods: BDNF Val66Met and APOE genotypes were determined in a sample of 430 CU late/middle-aged participants from the ALFA study (ALzheimer and FAmilies). Participants underwent a brain 3D-T1-weighted MRI scan, and volumes of the HSv were determined using Freesurfer (v6.0). The effects of the BDNF Val66Met genotype on the HSv were assessed using general linear models corrected by age, gender, education, number of APOE-ε4 alleles and total intracranial volume. We also investigated whether the association between APOE-ε4 allele and HSv were modified by BDNF Val66Met genotypes. Results: BDNF Val66Met carriers showed larger bilateral volumes of the subiculum subfield. In addition, HSv reductions associated with APOE-ε4 allele were significantly moderated by BDNF Val66Met status. BDNF Met carriers who were also APOE-ε4 homozygous showed patterns of higher HSv than BDNF Val carriers. Conclusion: To our knowledge, the present study is the first to show that carrying the BDNF Val66Met polymorphisms partially compensates the decreased on HSv associated with APOE-ε4 in middle-age cognitively unimpaired individuals. ; The research leading to these results has received funding from "la Caixa" Foundation (LCF/PR/GN17/10300004) and the Health Department of the Catalan Government (Health Research and Innovation Strategic Plan (PERIS) 2016–2020 grant# SLT002/16/00201). CM was supported by the Spanish Ministry of Economy and Competitiveness (grant n° IEDI-2016-00690). MSC received funding from the European Union's Horizon 2020 Research and Innovation Program under the Marie Sklodowska-Curie action grant agreement No 752310. H.H.H.A. was supported by ZonMW grant numbers 916.19.15 and 916.19.151. J.D.G. holds a 'Ramón y Cajal' fellowship (RYC-2013-13054).

Introduction: The biological pathways involved in the preclinical stage of the Alzheimer's continuum are not well understood. Methods: We used NeuroToolKit and Elecsys® immunoassays to measure cerebrospinal fluid (CSF) amyloid-β (Aβ)42, Aβ40, phosphorylated tau (p-tau), total tau (t-tau), neurofilament light (NfL), neurogranin, sTREM2, YKL40, GFAP, IL6, S100, and α-synuclein in cognitively unimpaired participants of the ALFA+ study, many within the Alzheimer's continuum. Results: CSF t-tau, p-tau, and neurogranin increase throughout aging only in Aβ-positive individuals, whereas NfL and glial biomarkers increase with aging regardless of Aβ status. We modelled biomarker changes as a function of CSF Aβ42/40, p-tau and p-tau/Aβ42 as proxies of disease progression. The first change observed in the Alzheimer's continuum was a decrease in the CSF Aβ42/40 ratio. This is followed by a steep increase in CSF p-tau; t-tau; neurogranin; and, to a lesser extent, in NfL and glial biomarkers. Discussion: Multiple biological pathways are altered and could be targeted very early in the Alzheimer's continuum. ; 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. MSC received funding from the European Union's Horizon 2020 Research and Innovation Program under the Marie Sklodowska‐Curie action grant agreement No 752310, and currently 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). JDG is supported by the Spanish Ministry of Science and Innovation (RYC‐2013‐13054). NVT is supported by the Spanish Ministry of Science, Innovation and Universities—Spanish State Research Agency (FJC2018‐038085‐I). OGR is supported by the Spanish Ministry of Science, Innovation and Universities (FJCI‐2017‐33437). ASV is the recipient of an Instituto de Salud Carlos III Miguel Servet II fellowship (CP II 17/00029). EMAU is supported by the Spanish Ministry of Science, Innovation and Universities—Spanish State Research Agency (RYC2018‐026053‐I). CM was supported by the Spanish Ministry of Economy and Competitiveness (grant n° IEDI‐2016‐00690). KB holds the Torsten Söderberg Professorship in Medicine at the Royal Swedish Academy of Sciences, and is supported by the Swedish Research Council (#2017‐00915); the Swedish Alzheimer Foundation (#AF‐742881), Hjärnfonden, Sweden (#FO2017‐0243); and a grant (#ALFGBG‐715986) from the Swedish state under the agreement between the Swedish government and the County Councils, the ALF‐agreement. HZ is a Wallenberg Academy Fellow supported by grants from the Swedish Research Council (#2018‐02532), the European Research Council (#681712), and a grant (#ALFGBG‐720931) from the Swedish state under the agreement between the Swedish government and the County Councils.

Background: Recognizing clinical manifestations heralding the development of Alzheimer's disease (AD)-related cognitive impairment could improve the identification of individuals at higher risk of AD who may benefit from potential prevention strategies targeting preclinical population. We aim to characterize the association of body weight change with cognitive changes and AD biomarkers in cognitively unimpaired middle-aged adults. Methods: This prospective cohort study included data from cognitively unimpaired adults from the ALFA study (n = 2743), a research platform focused on preclinical AD. Cognitive and anthropometric data were collected at baseline between April 2013 and November 2014. Between October 2016 and February 2020, 450 participants were visited in the context of the nested ALFA+ study and underwent cerebrospinal fluid (CSF) extraction and acquisition of positron emission tomography images with [18F]flutemetamol (FTM-PET). From these, 408 (90.1%) were included in the present study. We used data from two visits (average interval 4.1 years) to compute rates of change in weight and cognitive performance. We tested associations between these variables and between weight change and categorical and continuous measures of CSF and neuroimaging AD biomarkers obtained at follow-up. We classified participants with CSF data according to the AT (amyloid, tau) system and assessed between-group differences in weight change. Results: Weight loss predicted a higher likelihood of positive FTM-PET visual read (OR 1.27, 95% CI 1.00-1.61, p = 0.049), abnormal CSF p-tau levels (OR 1.50, 95% CI 1.19-1.89, p = 0.001), and an A+T+ profile (OR 1.64, 95% CI 1.25-2.20, p = 0.001) and was greater among participants with an A+T+ profile (p < 0.01) at follow-up. Weight change was positively associated with CSF Aβ42/40 ratio (β = 0.099, p = 0.032) and negatively associated with CSF p-tau (β = - 0.141, p = 0.005), t-tau (β = - 0.147 p = 0.004) and neurogranin levels (β = - 0.158, p = 0.002). In stratified analyses, weight loss was significantly associated with higher t-tau, p-tau, neurofilament light, and neurogranin, as well as faster cognitive decline in A+ participants only. Conclusions: Weight loss predicts AD CSF and PET biomarker results and may occur downstream to amyloid-β accumulation in preclinical AD, paralleling cognitive decline. Accordingly, it should be considered as an indicator of increased risk of AD-related cognitive impairment. ; 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. OG-R is supported by the Spanish Ministry of Science, Innovation and Universities (FJCI-2017-33437) and receives funding from the Alzheimer's Association Research Fellowship Program (2019-AARF-644568). MS-C received funding from the European Union's Horizon 2020 Research and Innovation Program under the Marie Sklodowska-Curie action grant agreement No 752310 and currently 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). EMA-U is supported by the Spanish Ministry of Science, Innovation and Universities - Spanish State Research Agency (RYC2018-026053-I). ASV is the recipient of an Instituto de Salud Carlos III Miguel Servet II fellowship (CP II 17/00029). JDG holds a "Ramón y Cajal" fellowship (RYC-2013-13054). 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), and the UK Dementia Research Institute at UCL. KB is supported by 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), and European Union Joint Program for Neurodegenerative Disorders (JPND2019-466-236).

Neurofilament light chain (NfL) is an axonal protein that when measured in cerebrospinal fluid (CSF) serves as a biomarker of neurodegeneration. We aimed at investigating the association among CSF NfL, presence of Subjective Cognitive Decline (SCD) and hippocampal volume, and how CSF amyloid-β (Aβ) modifies these associations. We included 278 cognitively unimpaired participants from the Alfa+ cohort (78 SCD and 200 Controls). Linear models accounting for covariates (age, gender, and mood) were used to test the association between CSF NfL and SCD status, and between CSF NfL and bilateral hippocampal volumes. Interactions with Aβ were also explored. Individuals with SCD had higher CSF NfL and lower CSF Aβ42/40 than Controls. There was a significant interaction between SCD and CSF-Aβ42/40 levels. Stratified analyses showed a significant association between SCD and NfL only in Aβ+ individuals. Higher CSF NfL was significantly associated with lower hippocampal volume specifically in Aβ+ individuals with SCD. The presence of SCD in Aβ+ individuals may represent an early symptom in the Alzheimer's continuum related to incipient neurodegeneration. ; The research leading to these results has received funding from "la Caixa" Foundation (LCF/PR/GN17/1030 0 0 04) and the Alzheimer's Association and an international anonymous char ity 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. MS-C received funding from the European Union's Horizon 2020 Research and Innovation Program under the Marie Sklodowska-Curie action grant agreement No 752310, and currently receives funding from the Spanish Ministry of Science, Innovation and Universities (Juan de la Cierva Programme grant IJC2018-037478-I ). EMA-U is supported by the Spanish Ministry of Science, Innovation and Universities - Spanish State Research Agency ( RYC2018-026053-I ) and is recipient of the Alzheimer's Association Research Grant ( AARC 2019-AARG 6 446 41). OG-R is supported by the Spanish Ministry of Science, Innovation and Universities ( FJCI-2017-33437 ). JDG holds a 'Ramón y Cajal' fellowship ( RYC-2013-13054 ). NV-T is funded by a post-doctoral grant, Juan de la Cierva Programme ( FJC2018-038085-I ), Ministry of Science and Innovation–Spanish State Research Agency. ASV is the recipient of an Instituto de Salud Carlos III Miguel Servet II fellowship ( CP II 17/0 0 029 ). 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 ), and the UK Dementia Research Institute at UCL. KB is supported by 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 ), and European Union Joint Program for Neurodegenerative Disorders (JPND2019-466-236 )

Background: The number of APOE-ε4 alleles is a major nonmodifiable risk factor for sporadic Alzheimer disease (AD). There is increasing evidence on the benefits of dietary DHA (22:6n-3) before the onset of AD symptoms, particularly in APOE-ε4 carriers. Brain alterations in the preclinical stage can be detected by structural MRI. Objectives: We aimed, in middle-aged cognitively unimpaired individuals at increased risk of AD, to cross-sectionally investigate whether dietary DHA intake relates to cognitive performance and to MRI-based markers of cerebral small vessel disease and AD-related neurodegeneration, exploring the effect modification by APOE-ε4 status. Methods: In 340 participants of the ALFA (ALzheimer and FAmilies) study, which is enriched for APOE-ε4 carriership (n = 122, noncarriers; n = 157, 1 allele; n = 61, 2 alleles), we assessed self-reported DHA intake through an FFQ. We measured cognitive performance by administering episodic memory and executive function tests. We performed high-resolution structural MRI to assess cerebral small vessel disease [white matter hyperintensities (WMHs) and cerebral microbleeds (CMBs)] and AD-related brain atrophy (cortical thickness in an AD signature). We constructed regression models adjusted for potential confounders, exploring the interaction DHA × APOE-ε4. Results: We observed no significant associations between DHA and cognitive performance or WMH burden. We observed a nonsignificant inverse association between DHA and prevalence of lobar CMBs (OR: 0.446; 95% CI: 0.195, 1.018; P = 0.055). DHA was found to be significantly related to greater cortical thickness in the AD signature in homozygotes but not in nonhomozygotes (P-interaction = 0.045). The association strengthened when analyzing homozygotes and nonhomozygotes matched for risk factors. Conclusions: In cognitively unimpaired APOE-ε4 homozygotes, dietary DHA intake related to structural patterns that may result in greater resilience to AD pathology. This is consistent with the current hypothesis that those subjects at highest risk would obtain the largest benefits from DHA supplementation in the preclinical stage.This trial was registered at clinicaltrials.gov as NCT01835717. ; Supported by "la Caixa" Foundation (ID 100010434) under agreement LCF/PR/GN17/10300004 (to JLM). In addition, supported by Universities and Research Secretariat, Ministry of Business and Knowledge of the Catalan Government grant no. 2017-SGR-892 (to JLM). AS-V is the recipient of Instituto de Salud Carlos III Miguel Servet fellowship grant CP II 17/00029. EMA-U is the recipient of Alzheimer's Association research grant AARG 2019-AARG-644641 and holds "Ramón y Cajal" fellowship RYC2018-026053-I. MS-C received funding from the European Union's Horizon 2020 Research and Innovation Program under Marie Sklodowska-Curie action grant agreement no. 752310 and is currently supported by Instituto de Salud Carlos III grant PI19/00155 and Spanish Ministry of Science, Innovation, and Universities Juan de la Cierva Programme grant IJC2018-037478-I. FB is supported by the National Institute for Health Research University College London Hospitals Biomedical Research Centre. JD-G holds "Ramón y Cajal" fellowship RYC-2013-13054.

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. ; 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 2017-SGR-892. J.D.G. holds a "Ramón y Cajal" fellowship (RYC-2013-13054). E. Arenaza-Urquijo is supported by the Spanish Ministry of Science, Innovation and Universities–Spanish State Research Agency (RYC2018-026053-I). N. Vilor-Tejedor 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). All Centre for Genomic Regulation 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. O. Grau-Rivera is supported by the Spanish Ministry of Science, Innovation and Universities (FJCI-2017-33437) and receives funding from the Alzheimer's Association Research Fellowship Program (2019-AARF-644568). A. Sala-Vila is the recipient of an Instituto de Salud Carlos III Miguel Servet II fellowship (CP II 17/00029). H. Zetterberg is a Wallenberg Scholar supported by grants from the Swedish Research Council (No. 2018-02532), European Research Council (No. 681712), Swedish State Support for Clinical Research (No. ALFGBG-720931), Alzheimer Drug Discovery Foundation (No. 201809-2016862), and the UK Dementia Research Institute at UCL. K. Blennow is supported by the Swedish Research Council (No. 2017-00915), Alzheimer Drug Discovery Foundation (No. RDAPB-201809-2016615), Swedish Alzheimer Foundation (No. AF-742881), Hjärnfonden, Sweden (No. FO2017-0243), the Swedish state under the agreement between the Swedish government and the county councils, the ALF agreement (No. ALFGBG-715986), European Union Joint Program for Neurodegenerative Disorders (JPND2019-466-236), and NIH (No. 1R01AG068398-01). M. Suárez-Calvet receives funding from the European Research Council under the European Union's Horizon 2020 Research and Innovation Programme (grant agreement 948677). M. Suárez-Calvet 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)