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However, a significant proportion of individuals exhibit discordant biomarkers' profiles, such as elevated phosphorylated tau181 (p\u2010tau181) with normal A\u00df42 from cerebrospinal fluid (CSF), posing diagnostic and mechanistic challenges. This study investigated whether functional and structural brain connectivity can distinguish individuals with discordant CSF profiles (A\u2212T+) from those with concordant patterns (A+T+), hypothesizing that distinct connectivity patterns may reflect early divergent pathophysiological processes. Data from cognitively unimpaired or mildly impaired individuals in the ADNI3 repository were analyzed, selecting those with resting\u2010state functional MRI (rsfMRI) and\/or diffusion MRI (dMRI) within 18 months of CSF testing for A\u00df and p\u2010tau181. Participants were grouped into A\u2212T+ or A+T+ groups. Structural and functional connectivity gradients were generated for each participant and summarized using a Euclidean distance measure from reference gradient templates derived from cognitively unimpaired individuals without pathology (A\u2212T\u2212). We applied linear mixed models and analysis of variance to assess connectivity\u2010based gradient differences between A\u2212T+ and A+T+ groups, adjusting for relevant variables. Classification analyzes using logistic regression and support vector machine, along with feature importance via the Boruta algorithm, evaluated the discriminative power of gradient connectivity profiles. Multimodal integration was performed using partial least square canonical analysis (PLSC), and relationships between gradients and cognition were assessed via UMAP\u2010based dimensionality reduction and bootstrapped linear regressions. Results were compared with a classical network analysis examining within\u2010 and between\u2010network connectivity differences. Among 424 participants,\n                    <jats:italic>n<\/jats:italic>\n                    \u2009=\u200967 were classified as A\u2212T+,\n                    <jats:italic>n<\/jats:italic>\n                    \u2009=\u2009106 as A+T+, and\n                    <jats:italic>n<\/jats:italic>\n                    \u2009=\u200956 as cognitively healthy A\u2212T\u2212. The remaining 195 participants (\n                    <jats:italic>n<\/jats:italic>\n                    \u2009=\u200986 A+T+ and\n                    <jats:italic>n<\/jats:italic>\n                    \u2009=\u2009109 cognitively impaired A\u2212T\u2212) were not included. A\u2212T+ individuals (age\u2009=\u200975\u2009\u00b1\u20098.2) exhibited less cognitive impairment but greater functional connectivity gradients' distance to the reference templates (false discovery rate\u2010corrected\n                    <jats:italic>p<\/jats:italic>\n                    \u2009&lt;\u20090.05) in the temporo\u2010occipital axis compared to A+T+ (age\u2009=\u200976.1\u2009\u00b1\u20097.7). Structural connectivity differences were not significant. FC\u2010based models classified A\u2212T+ and A+T+ with good accuracy (AUC\u2009=\u20090.77), loading on the same temporo\u2010occipital regions, unlike SC (AUC\u2009=\u20090.52). The posterior brain involvement in A\u2212T+ was confirmed by PLSC analyzes. A+T+ individuals showed a significant relation between cognitive scores and functional connectivity, primarily mapping the default mode network (DMN). A shift was observed in relation to executive functions and functional connectivity in A\u2212T+. Discordant CSF profiles (A\u2212T+) exhibit distinct functional connectivity patterns, particularly in posterior brain regions, compared to concordant CSF patterns (A+T+), which are characterized by a significant cognitive\u2010DMN connectivity association. These results suggest that CSF p\u2010tau181 accumulation in the absence of A\u00df42 may be associated with specific functional trajectories, suggesting specific pathophysiological patterns.\n                  <\/jats:p>","DOI":"10.1002\/hbm.70406","type":"journal-article","created":{"date-parts":[[2025,11,8]],"date-time":"2025-11-08T12:24:11Z","timestamp":1762604651000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":2,"title":["Brain Connectivity Gradients Alterations in Discordant Cerebrospinal Fluid Profile for Alzheimer's Disease Biomarkers"],"prefix":"10.1002","volume":"46","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-9305-3376","authenticated-orcid":false,"given":"Lorenzo","family":"Pini","sequence":"first","affiliation":[{"name":"Department of Neuroscience University of Padova  Padua Italy"},{"name":"Padova Neuroscience Center, University of Padova  Padua 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