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Though clinical trials for\n                      <jats:italic>GRN<\/jats:italic>\n                      \u2010related therapies are underway, there is an unmet need for biomarkers that can predict symptom onset and track disease progression. We previously showed that asymptomatic\n                      <jats:italic>GRN<\/jats:italic>\n                      variant carriers exhibit thalamocortical hyperconnectivity that increases with age, presumably as they are approaching symptom onset. Whether hyperconnectivity arises concomitantly with markers of neurodegeneration remains unclear.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Methods<\/jats:title>\n                    <jats:p>\n                      Utilizing T1 and task\u2010free functional magnetic resonance imaging from 49 asymptomatic and 26 symptomatic\n                      <jats:italic>GRN<\/jats:italic>\n                      variant carriers, we determined the relationships between functional connectivity, as measured by voxelwise whole\u2010brain degree, and\n                      <jats:italic>GRN<\/jats:italic>\n                      \u2010relevant markers of disease progression, including plasma neurofilament light chain concentrations, cerebrospinal fluid complement C1q and C3b protein levels, obsessive\u2010compulsive disorder symptom severity, and gray matter volume.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Results<\/jats:title>\n                    <jats:p>\n                      Neurofilament light chain concentrations were associated with frontotemporoparietal and thalamic hyperconnectivity in asymptomatic\n                      <jats:italic>GRN<\/jats:italic>\n                      variant carriers and extensive regions of atrophy in symptomatic carriers. Complement levels were associated with regions of hyperconnectivity, but not gray matter volume, in symptomatic carriers. Obsessive\u2010compulsive disorder symptom severity was associated with hypoconnectivity across all\n                      <jats:italic>GRN<\/jats:italic>\n                      carriers. Asymptomatic carriers with thalamic hyperconnectivity tended to have lower gray matter volume in the bilateral insula and left lateral parietal cortex, early regions of atrophy in\n                      <jats:italic>GRN<\/jats:italic>\n                      \u2010frontotemporal dementia.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Interpretation<\/jats:title>\n                    <jats:p>In asymptomatic carriers, the co\u2010occurrence of hyperconnectivity, high neurofilament light chain, and low gray matter volume suggests that functional hyperconnectivity may portend the onset of clinical decline. These findings point toward hyperconnectivity as an indicator of approaching symptomatic onset.<\/jats:p>\n                  <\/jats:sec>","DOI":"10.1002\/acn3.70170","type":"journal-article","created":{"date-parts":[[2025,9,17]],"date-time":"2025-09-17T04:30:02Z","timestamp":1758083402000},"page":"2575-2588","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":2,"title":["Functional Connectivity Associations With Markers of Disease Progression in\n                    <i>GRN<\/i>\n                    Pathogenic Variant Carriers"],"prefix":"10.1002","volume":"12","author":[{"ORCID":"https:\/\/orcid.org\/0009-0003-6566-9696","authenticated-orcid":false,"given":"Taru M.","family":"Flagan","sequence":"first","affiliation":[{"name":"Department of Neurology, Weill Institute for Neurosciences, Memory and Aging Center University of California, San Francisco  San Francisco California 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