Alzheimer's disease (AD) emerges from multi-scale interactions between molecular pathology and disruptions in large-scale brain network dynamics. Understanding how these processes co-evolve and relate to disease stages is essential for advancing complex systems models of aging and AD, and for developing system-informed interventions. However, progress has been limited by a lack of large-scale longitudinal data. To address this, we examined the longitudinal relationship between subsystems of the default mode network (DMN) (posterior DMN, ventral DMN, anterior dorsal DMN) using task-free functional MRI (fMRI) and amyloid positron emission tomography (PET) imaging in a large longitudinal cohort spanning the clinico-biological spectrum of AD (n = 1,451; 2,763 time points) using mixed-effect models. We also assessed whether patterns of DMN connectivity predicted conversion to amyloid positivity, mild cognitive impairment (MCI), and dementia using Cox proportional hazards models. Our findings reveal a dynamic interplay between amyloid accumulation and connectivity within and between DMN subsystems, with both hyper- and hypoconnectivity emerging across DMN subsystems in association with increasing amyloid burden. Importantly, survival models showed that DMN connectivity patterns predicted conversion to critical stages of the disease, including not only conversion to MCI and dementia, but also conversion to amyloid positivity in otherwise clinically unimpaired individuals who were amyloid negative at baseline. These associations were independent of age, APOE4 status, sex, education, and in-scanner motion. These results support a model in which breakdowns in tightly regulated feedback loops governing DMN physiology represent a core systems-level pathophysiology of AD. Notably, this functional dyshomeostasis precedes detectable amyloidosis on imaging. Future studies should focus on the development of robust biomarkers of brain function that can be applied at the individual level, which could in turn help support the development of therapeutic approaches targeting system-level pathophysiology.

Default mode network connectivity is associated with executive and language performance in mild cognitive impairment.

This study investigates the relationship between gestational age (GA) and resting-state functional connectivity (rsFC) in a cohort of very preterm children at school age, and how these neural patterns relate to cognitive and theory of mind (ToM) performance. Resting-state functional magnetic resonance imaging (fMRI) data were collected from 52 children (GA < 32 weeks, birth weight <1500 g) and independent component analysis was applied to extract the resting-state networks. Results showed that GA was positively associated with rsFC of the precuneus and the paracentral region within the left posterior cerebellar network (lpCER), while negatively associated with rsFC of the insula and putamen within the anterior default mode network (DMN), and with rsFC of the postcentral gyrus within the right frontoparietal network (rFPN). Cognitive and neuropsychological assessments revealed that increased connectivity involving the lpCER correlated with better verbal comprehension, visuospatial ability, fluid reasoning, working memory, and ToM performance. Conversely, increased aDMN connectivity was associated with lower working memory and decreased rFPN connectivity was found associated with lower intelligence quotient. These results underscore the influence of GA on intrinsic brain networks supporting cognitive and socio-cognitive functions, and highlight potential neural markers that could inform targeted intervention strategies for preterm children.

Drug cue reactivity (DCR) is the most widely applied fMRI task in addiction neuroscience, yet its translational potential remains limited by unresolved methodological and clinical heterogeneity. In this systematic review and activation likelihood estimation (ALE) meta-analysis of 92 fMRI studies comprising 3647 participants, we examined how design-related factors (fMRI design, control condition valence, stimulus matching) and clinical factors (treatment compliance, drug use severity, common substance classes) shape neural DCR. Beyond identifying the core DCR pattern and its meta-analytic connectivity profiles, we conducted contrast analyses and penalised logistic regression to test whether these factors predicted regional replicability. Our results revealed that both design-related and clinical factors exert systematic modulatory influences. Default-mode network (DMN) regions dominated the core DCR pattern, yet anterior DMN contributions declined with increasing drug use severity. Conversely, amygdala involvement was more frequently observed in severe drug use and in substance classes other than alcohol and nicotine. Treatment-compliant samples showed heightened DCR in superior parietal regions. Importantly, temporo-occipital and fusiform activations were consistently linked to insufficiently matched task designs, revealing that the literature is densely interspersed with visual confounds. Taken together, these findings demonstrate that heterogeneity in task design and clinical characteristics systematically shapes neural DCR. They also illustrate the promise of extending beyond prevailing conditioning accounts toward models that emphasise context, motivation, and value-based encoding. We propose that advancing the translational utility of DCR will depend on rigorous task validation and design, consistent reporting standards, and theoretical frameworks expansive enough to embrace the multifaceted processes reflected in DCR.

Functional dysconnectivity in triple and reward networks among adolescents with borderline personality disorder.

Distinct within- and between-network functional dysconnectivity of the default-mode and frontoparietal networks in young individuals with first-episode bipolar disorder and major depressive disorder.

Dissecting Fear and Emotional Pain in Posttraumatic Stress Disorder: From Symptom Networks to Neural Signatures.

Adolescent depression presented higher risk of suicide than adult depression. However, the neurophysiological mechanisms underlying this phenomenon have not been elucidated. We aimed to identify structural covariance network alterations in depressed adolescents with suicidal behaviors to provide novel neuroimaging evidence for this condition. 64 first-episode, treatment-naïve depressed adolescent patients with suicidal behaviors and 48 healthy controls were enrolled. Nonnegative matrix factorization was used to identify the structural covariance networks. The Kullback-Leibler divergence method was applied to estimate the interregional relationships between the altered brain networks. Correlation analyses were conducted between altered brain networks and clinical characteristics. Patients had lower gray matter volumes in the anterior default mode network (DMN), visual network, sensorimotor network, and right executive control network than healthy controls. Morphological connections were altered in the anterior DMN, visual network, and right executive control network in patients. Correlation analyses revealed negative associations between morphological connections in anterior DMN-visual networks and illness duration in the patient group. This study revealed abnormal gray matter attributes in the anterior DMN, visual network, sensorimotor network, and executive control network in first-episode and treatment-naïve adolescent depression with suicide, which might reflect disease traits and provide essential neurobiological evidence for behavioral disturbances in depression.

This study aimed to investigate differences in verbal episodic memory and brain functioning during a word recognition task in women who have survived intimate partner violence compared to a control group of women. All participants carried out a violence and mental health assessment, which included questionnaires measuring the severity of intimate partner violence, possible traumatic brain injury and strangulation, adverse childhood events, post-traumatic stress disorder, generalized anxiety, depression, and alcohol consumption. All participants also carried out a verbal episodic recognition task consisting of two learning trials. The verbal episodic memory test included both a free recall and a recognition trial, conducted concurrently with functional magnetic resonance imaging (fMRI). Survivors of intimate partner violence showed higher levels of anxiety, depression, and post-traumatic stress symptomology. Significant differences were found between groups in verbal episodic memory, such that intimate partner violence survivors performed with lower scores in initial recognition trials and free recall. Lower scores in recognition were associated with a greater severity of physical intimate partner violence. Notably, survivors showed greater deactivation in areas related to the anterior default mode network during the fMRI verbal recognition task compared to the control group. Our findings suggest an association between intimate partner violence and memory tasks, such that survivors show poorer performance in verbal learning and increased brain deactivation during this task. More research is needed to understand the implications of these findings on daily living, such as levels of fatigue and efficacy in completing tasks in which verbal memory is necessary (such as remembering a grocery list).

BackgroundBeta‐thalassemia major (β‐TM) is a hereditary blood disorder characterized by chronic anemia and hypoxia, which may have profound effects on brain function. This study systematically evaluates alterations in both intra‐brain network functional connectivity (FC) and inter‐network functional connectivity (FNC) in β‐TM patients using resting‐state functional magnetic resonance imaging (rs‐fMRI) and independent component analysis (ICA), aiming to uncover the potential mechanisms underlying their neurofunctional impairments.MethodsThis study included 72 β‐TM patients and 50 age‐ and gender‐matched healthy controls (HC). rs‐fMRI was used to collect brain functional data, and ICA was applied to extract 14 resting‐state functional networks (RSNs). Differences in FC within networks and FNC between the two groups were further compared to investigate the brain network abnormalities in β‐TM patients.ResultsIn β‐TM patients, FC within brain networks was significantly reduced in the anterior default mode network (aDMN), posterior default mode network (pDMN), left frontoparietal network (lFPN), right frontoparietal network (rFPN), ventral attention network (VAN), and executive control network (ECN). In contrast, FC was significantly increased in the dorsal sensorimotor network (dSMN) and posterior visual network (pVN). FNC analysis revealed that β‐TM patients exhibited enhanced connectivity between the lFPN and rFPN, as well as between the dorsal attention network (DAN) and VAN. However, connectivity was significantly weakened between the DAN and lFPN, ECN, auditory network (AN), and salience network (SN); as well as between the pVN and dSMN. These findings suggest impairments in cognitive control, attention allocation, and sensory integration, with specific disruptions in the SN that may contribute to the observed dysfunctions.ConclusionBrain network abnormalities in β‐TM patients manifest as an alternating pattern of enhanced and weakened connectivity, revealing the profound impact of chronic anemia and hypoxia on cognitive, emotional, and sensory functions.

Both elevated inflammatory markers and aberrant functional connectivity have been detected in patients with schizophrenia, but there is limited knowledge on the relationship between the two phenomena. Some positive symptoms may arise from external misattribution of self-generated actions mediated by decoupling of the default mode network (DMN) with sensory processing regions. Since the anterior DMN also exhibits bidirectional interaction with the immune system, we hypothesized its decoupling would be associated with elevated inflammatory markers as well as the burden of positive symptomatology. Resting-state functional magnetic resonance imaging, diffusion tensor imaging (DTI), clinical and laboratory data (serum concentrations of interleukin-6 and C-reactive protein) were collected within a neuroimaging trial on schizophrenia. Neuroimaging data were assessed applying seed-to-voxel and region-of-interest-to-region-of-interest functional connectivity analyses as well as DTI tractography. Associations between neuroimaging and laboratory as well as behavioral data were studied employing regression analyses. For both inflammatory markers, a consistent pattern of hypo-connectivity emerged between the anterior DMN and different brain regions involved in sensory processing and self-monitoring. The strongest association was detected for the connectivity between the anterior DMN and the right parietal operculum which was not explained by the structural integrity of the respective white matter tract. Finally, this functional connection was correlated both with the burden of positive and negative symptoms. Our findings reveal a mechanistically plausible neurobiological link between inflammation and psychopathology in schizophrenia.

Patients with ulcerative colitis (UC) often exhibit affective disorders, such as depression and anxiety. The underlying neurological mechanisms of these symptoms, however, remain poorly understood. This study aimed to explore alterations in functional connectivity (FC) both within and between resting-state networks (RSNs) in individuals with ulcerative colitis. Twelve meaningful RSNs were identified from 22 ulcerative colitis patients and 23 healthy controls using independent component analysis of functional magnetic resonance imaging data. Correlation analyses were performed between clinical indices, neuropsychological assessments and neuroimaging data. Compared with healthy controls, UC patients showed increased intranetwork FC, mainly located in the right temporal pole, orbitofrontal cortex, and left superior temporal and Rolandic opercular cortices within the auditory network. Increased intranetwork FC in the Rolandic opercular cortex was also observed in UC patients during remission phase, while no significant alterations were detected in patients with active-phase UC. In addition, UC patients exhibited increased connectivity between the dorsal attention and the left frontoparietal network, as well as between the anterior default mode network and the posterior default mode network, with distinct patterns of internetwork connectivity observed across different clinical phases. No significant correlations were found between altered brain regions and psychological scales in UC patients. These findings imply that UC patients may undergo functional network alterations, affecting both intranetwork connectivity within RSNs and internetwork connectivity between RSNs.

While Cannabis use disorder (CUD) is twice as prevalent in males, females transition more quickly from heavy use to CUD and experience more severe withdrawal. These clinically relevant sex differences contrast the lack of knowledge about the underlying brain mechanisms. This study investigated the relationship between CUD and resting-state functional brain connectivity (RSFC), assessing potential sex differences herein. RSFC of the Salience Network (SN), Basal Ganglia Network (BGN), Executive Control Network (ECN), and Default Mode Network (DMN) was compared between 152 individuals (76 males) with CUD and 114 matched controls (47 males). Within the CUD group, relationships between RSFC and heaviness of cannabis use, age of onset, and CUD symptom severity, along with their associations with sex, were investigated. CUD and control groups showed similar RSFC across all networks, regardless of sex. In the CUD group, heavier cannabis use correlated with higher RSFC across all networks and earlier age of onset was related to higher RSFC in the anterior SN, BGN, left ECN, and dorsal DMN. These associations were similar for males and females. CUD severity was related to higher RSFC in the anterior SN, which was moderated by sex, with a positive association seen only in males. In conclusion, CUD may not necessarily be associated with altered RSFC. Individual use characteristics such age of onset and severity of use may determine the potential impact of cannabis use on RSFC in a largely similar way in males and females.

The weak link between subjective symptom-based diagnostics for posttraumatic psychopathology and objective neurobiological indices hinders the development of effective personalized treatments. To identify early neural networks associated with posttraumatic stress disorder (PTSD) development among recent trauma survivors. This prognostic study used data from the Neurobehavioral Moderators of Posttraumatic Disease Trajectories (NMPTDT) large-scale longitudinal neuroimaging dataset of recent trauma survivors. The NMPTDT study was conducted from January 20, 2015, to March 11, 2020, and included adult civilians who were admitted to a general hospital emergency department in Israel and screened for early PTSD symptoms indicative of chronic PTSD risk. Enrolled participants completed comprehensive clinical assessments and functional magnetic resonance imaging (fMRI) scans at 1, 6, and 14 months post trauma. Data were analyzed from September 2023 to March 2024. Traumatic events included motor vehicle incidents, physical assaults, robberies, hostilities, electric shocks, fires, drownings, work accidents, terror attacks, or large-scale disasters. Connectome-based predictive modeling (CPM), a whole-brain machine learning approach, was applied to resting-state and task-based fMRI data collected at 1 month post trauma. The primary outcome measure was PTSD symptom severity across the 3 time points, assessed with the Clinician-Administered PTSD Scale for DSM-5 (CAPS-5). Secondary outcomes included Diagnostic and Statistical Manual of Mental Disorders (Fifth Edition) (DSM-5) PTSD symptom clusters (intrusion, avoidance, negative alterations in mood and cognition, hyperarousal). A total of 162 recent trauma survivors (mean [SD] age, 33.9 [11.5] years; 80 women [49.4%] and 82 men [50.6%]) were included at 1 month post trauma. Follow-up assessments were completed by 136 survivors (84.0%) at 6 months and by 133 survivors (82.1%) at 14 months post trauma. Among the 162 recent trauma survivors, CPM significantly predicted PTSD severity at 1 month (ρ = 0.18, P < .001) and 14 months (ρ = 0.24, P < .001) post trauma, but not at 6 months post trauma (ρ = 0.03, P = .39). The most predictive edges at 1 month included connections within and between the anterior default mode, motor sensory, and salience networks. These networks, with the additional contribution of the central executive and visual networks, were predictive of symptoms at 14 months. CPM predicted avoidance and negative alterations in mood and cognition at 1 month, but it predicted intrusion and hyperarousal symptoms at 14 months. In this prognostic study of recent trauma survivors, individual differences in large-scale neural networks shortly after trauma were associated with variability in PTSD symptom trajectories over the first year following trauma exposure. These findings suggest that CPM may identify potential targets for interventions.

Neurometabolic network (NMetNet) for functional neurological disorder in children and adolescents.

Abstract BackgroundWe aim to describe the imaging findings in pre‐symptomatic and early‐symptomatic individuals carrying a recently described novel APP duplication rearrangement causing early‐onset AD (EOAD).MethodWe studied individuals from one pedigree that carry APP duplication and CH 5 mutation gain that had structural and resting state functional (rs‐f) brain MRI. Non‐carrier family members were assessed as controls. Volumetric analysis was performed using Freesurfer and normalized to total intracranial volume. Fazekas scores for white matter hyperintensities (WMH) and microbleed count were performed visually by two neuroradiologists. rs‐fMRI seed to whole brain analysis was used to create functional connectivity maps of the default mode network (DMN). F18‐Flutemetamol amyloid‐PET was available for two of the mutation carriers. Amyloid deposition was quantified using SUVR with the pons as reference region and compared to SUVR of young adults and amyloid‐positive older adults (Ab+OA).ResultFourteen mutation carriers (mean age 29.8[19‐39], 8 (57%) F, median education 12Y[11‐14Y], mean MMSE 28[23‐30]), and nine non‐carrier family members were included (36.8Y[19‐56Y], 5 (55%)F, 12Y[12‐19], 29[27‐30]). Volumetric analysis revealed an increase in amygdala volume (log) (estimate = 0.01, p = 0.03) and a (non‐statistically significant) trend toward decrease in the putamen, globus pallidus, and pons volume with age in mutation carriers (Figure 1A). WMHs and microbleeds were found in some mutation carriers from the age of 28Y (Figure 1B). rs‐fMRI showed a trend toward a disconnection between the anterior and the posterior component of the DMN in the APP‐dup carriers &gt;30Y (n = 6) compared with non‐carrier (n = 8; U = 10, p = 0.08). Moreover, increased connectivity was found between the anterior component of the DMN and the striatum compared to carriers &lt;30Y (n = 8, U = 9, p = 0.06) and to non‐carriers (U = 9, p = 0.06) (Figure 2). Cortical amyloid deposition was high but within the range of Ab+OA, and extremely high, above the level of deposition in Ab+OA in the putamen, caudate, and thalamus (Figure 3).ConclusionWe found early basal ganglia abnormalities in presymptomatic and early symptomatic novel APP duplication mutation carriers, including high amyloid deposition, DMN disconnection, increased connectivity between anterior DMN and striatum, and volumetric alterations. These findings point to the basal ganglia as a region of early pathology that requires further research.

Abstract BackgroundCognitive Reserve (CR) refers to the brain's ability to maintain optimal cognitive function despite damage or pathology. The neural implementation of CR is a major research focus, and resting‐state functional connectivity (RSFC) has emerged as a promising imaging correlate of CR. We assessed RSFC as a function of two different proxy measures of CR and further assessed the impact of these brain networks on longitudinal cognitive performance in a sample of cognitively unimpaired (CU) individuals at risk of Alzheimer's disease (AD).MethodAnalyses were conducted in 328 CU individuals from the ALFA cohort (mean age=60.8, SD=4.74) with available CSF Aβ, p‐tau, resting‐state fMRI and longitudinal cognitive assessment (average follow‐up time=3.35 years, SD=0.53). CSF Aβ42 and Aβ40 were assessed with the exploratory NeuroToolKit, while p‐tau181 was measured with the Elecsys® Phospho‐Tau (181P) CSF immunoassay (both Roche Diagnostics International Ltd). We examined the impact of years of education (YOE) and global score of the Cognitive Reserve Questionnaire (CRQ) on the RSFC amongst 246 brain regions of the Brainnetome atlas using the CONN toolbox, selecting a cluster threshold of p&lt;0.005, and adjusting or the effects of age, sex, and APOE status.ResultOf the entire sample, 38.4% had positive CSF Aβ42/40 markers. YOE was related to an increased RSFC between regions of the salience network and the anterior default‐mode network (DMN). Increased negative RSFC was found as a function of YOE between primary visual areas and regions of the executive control as well as dorsal attention (Figure 1). In models adjusted by CSF biomarkers, the increased RSFC between the anterior DMN and salience regions predicted better PACC score over time and further modulated the association between CSF Aβ42/40 and longitudinal PACC (Figure 2). CRQ score was associated with a decreased RSFC between the posterior DMN and inferior temporal areas. These patterns of reduced RSFC significantly mediated the impact of CSF Aβ42/40 on longitudinal memory performance (Figure 3).ConclusionRSFC may provide insights into the mechanisms relating CR and cognitive resilience in preclinical AD. Further, the expression of RSFC patterns may serve as an outcome in intervention studies aiming to boost CR.

Abstract BackgroundCognitive Reserve (CR) refers to the brain’s ability to maintain optimal cognitive function despite damage or pathology. The neural implementation of CR is a major research focus, and resting‐state functional connectivity (RSFC) has emerged as a promising imaging correlate of CR. We assessed RSFC as a function of two different proxy measures of CR and further assessed the impact of these brain networks on longitudinal cognitive performance in a sample of cognitively unimpaired (CU) individuals at risk of Alzheimer’s disease (AD).MethodAnalyses were conducted in 328 CU individuals from the ALFA cohort (mean age = 60.8, SD = 4.74) with available CSF Aß, p‐tau, resting‐state fMRI and longitudinal cognitive assessment (average follow‐up time = 3.35 years, SD = 0.53). CSF Aß42 and Aß40 were assessed with the exploratory NeuroToolKit, while p‐tau181 was measured with the Elecsys® Phospho‐Tau (181P) CSF immunoassay (both Roche Diagnostics International Ltd). We examined the impact of years of education (YOE) and global score of the Cognitive Reserve Questionnaire (CRQ) on the RSFC amongst 246 brain regions of the Brainnetome atlas using the CONN toolbox, selecting a cluster threshold of p&lt;0.005, and adjusting or the effects of age, sex, and APOE status.ResultOf the entire sample, 38.4% had positive CSF Aß42/40 markers. YOE was related to an increased RSFC between regions of the salience network and the anterior default‐mode network (DMN). Increased negative RSFC was found as a function of YOE between primary visual areas and regions of the executive control as well as dorsal attention (Fig. 1). In models adjusted by CSF biomarkers, the increased RSFC between the anterior DMN and salience regions predicted better PACC score over time and further modulated the association between CSF Aß42/40 and longitudinal PACC (Fig. 2). CRQ score was associated with a decreased RSFC between the posterior DMN and inferior temporal areas. These patterns of reduced RSFC significantly mediated the impact of CSF Aß42/40 on longitudinal memory performance (Fig.3).ConclusionRSFC may provide insights into the mechanisms relating CR and cognitive resilience in preclinical AD. Further, the expression of RSFC patterns may serve as an outcome in intervention studies aiming to boost CR.

Abstract BackgroundAmyloid‐β (Aβ) pathology affects resting state functional connectivity (RSFC), even in cognitively unimpaired (CU) individuals. However, the impact of such an aberrant RSFC on cognitive decline is yet to be determined. Moreover, most prior research focused on fibrillary Aβ deposition to predict RSFC, while early Aβ dysmetabolism as reflected by cerebrospinal fluid (CSF) concentrations has received less attention. We assessed RSFC as a function of both CSF Aβ and p‐tau in CU individuals, and further analyzed the impact of biomarker‐dependent RSFC on the longitudinal cognitive performance.MethodAnalyses were conducted in 328 CU individuals from the ALFA cohort (mean age=60.8, SD=4.74) with available CSF Aβ, p‐tau, resting‐state fMRI and longitudinal cognitive assessment (average follow‐up time=3.35 years, SD=0.53). CSF Aβ42 and Aβ40 were assessed with the exploratory NeuroToolKit, while p‐tau181 was measured with the Elecsys® Phospho‐Tau (181P) CSF immunoassay (both Roche Diagnostics International Ltd). RSFC was computed amongst 246 brain regions of the Brainnetome atlas using the CONN toolbox, selecting a cluster threshold of p&lt;0.005. The effects of CSF biomarkers on RSFC were adjusted by age, sex, years of education and APOE‐ε4 status.ResultOf the entire sample, 38.4% had positive CSF Aβ42/40 markers. Low CSF Aβ42/40 ratios were associated to a higher RSFC between visual areas and anterior as well as posterior subdivisions of the default‐mode network (DMN) (Figure 1). These results survived a family‐wise error rate p‐value&lt;0.005. High levels of CSF p‐tau were related to a higher RSFC between inferior temporal areas and the anterior DMN, as well as a reduced RSFC between visual and the somatomotor network. The Aβ‐related higher RSFC significantly predicted longitudinal cognitive decline in PACC, episodic memory (EM) and executive control (EC), in models adjusted by CSF biomarkers (Figure 2), and further modulated the association between CSF Aβ42/40 and PACC longitudinal decline (Figure 3)ConclusionIn CU individuals, CSF Aβ and p‐tau affect RSFC in networks relevant for cognitive performance. Low CSF Aβ42/40 was related to hyperconnectivity between the DMN and the visual system. Lack of DMN segregation as a function of CSF Aβ42/40 may represent a driving mechanism of cognitive decline in the earliest Alzheimer’s continuum.

Abstract BackgroundAmyloid‐ß (Aß) pathology affects resting state functional connectivity (RSFC), even in cognitively unimpaired (CU) individuals. However, the impact of such an aberrant RSFC on cognitive decline is yet to be determined. Moreover, most prior research focused on fibrillary Aß deposition to predict RSFC, while early Aß dysmetabolism as reflected by cerebrospinal fluid (CSF) concentrations has received less attention. We assessed RSFC as a function of both CSF Aß and p‐tau in CU individuals, and further analyzed the impact of biomarker‐dependent RSFC on the longitudinal cognitive performance.MethodAnalyses were conducted in 328 CU individuals from the ALFA cohort (mean age = 60.8, SD = 4.74) with available CSF Aß, p‐tau, resting‐state fMRI and longitudinal cognitive assessment (average follow‐up time = 3.35 years, SD = 0.53). CSF Aß42 and Aß40 were assessed with the exploratory NeuroToolKit, while p‐tau181 was measured with the Elecsys® Phospho‐Tau (181P) CSF immunoassay (both Roche Diagnostics International Ltd). RSFC was computed amongst 246 brain regions of the Brainnetome atlas using the CONN toolbox, selecting a cluster threshold of p&lt;0.005. The effects of CSF biomarkers on RSFC were adjusted by age, sex, years of education and APOE‐e4 status.ResultOf the entire sample, 38.4% had positive CSF Aß42/40 markers. Low CSF Aß42/40 ratios were associated to a higher RSFC between visual areas and anterior as well as posterior subdivisions of the default‐mode network (DMN) (Fig. 1). These results survived a family‐wise error rate p‐value&lt;0.005. High levels of CSF p‐tau were related to a higher RSFC between inferior temporal areas and the anterior DMN, as well as a reduced RSFC between visual and the somatomotor network. The Aß‐related higher RSFC significantly predicted longitudinal cognitive decline in PACC, episodic memory (EM) and executive control (EC), in models adjusted by CSF biomarkers (Fig. 2), and further modulated the association between CSF Aß42/40 and PACC longitudinal decline (Fig. 3)ConclusionIn CU individuals, CSF Aß and p‐tau affect RSFC in networks relevant for cognitive performance. Low CSF Aß42/40 was related to hyperconnectivity between the DMN and the visual system. Lack of DMN segregation as a function of CSF Aß42/40 may represent a driving mechanism of cognitive decline in the earliest Alzheimer’s continuum.