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Lower baseline cerebrospinal fluid (CSF) NPTX2 levels have been shown to be associated with an earlier onset of mild cognitive impairment (MCI), a pre\u2010dementia syndrome, even after CSF Alzheimer's Disease (AD) biomarkers (amyloid beta (A\u03b2\n                      <jats:sub>42\/40<\/jats:sub>\n                      ), and phosphorylated tau (p\u2010tau\n                      <jats:sub>181<\/jats:sub>\n                      )) were considered. To date, however, it is not known whether CSF NPTX2 levels among cognitively unimpaired individuals are associated with longitudinal brain atrophy.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Objective(s)<\/jats:title>\n                    <jats:p>Evaluate the association between baseline CSF NPTX2 levels and measures of long\u2010term brain atrophy in participants who were cognitively unimpaired at baseline.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Methods<\/jats:title>\n                    <jats:p>\n                      Analyses included 213 participants (\n                      <jats:italic>M<\/jats:italic>\n                      baseline age\u2009=\u200957.2\u2009years, 62% female) from the prospective longitudinal BIOCARD study with 13.9\u2009years (max\u2009=\u200922.6\u2009years) of magnetic resonance imaging (MRI) follow\u2010up, on average. CSF NPTX2 was measured as a composite of three correlated peptides obtained by quantitative parallel reaction monitoring mass spectrometry. MRI brain atrophy was measured longitudinally with three composites. This included two spatial patterns of atrophy: (1) a composite of AD\u2010signature regions (SPARE\u2010AD) and (2) a composite of regions sensitive to brain aging (SPARE\u2010BA), with higher values indicating more atrophy. Additionally, (3) a medial temporal lobe (MTL) composite included volumes of the amygdala, hippocampus, and entorhinal cortex. Linear mixed effect models assessed the association of baseline NPTX2 levels with the rate of change in the brain atrophy measures.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Results<\/jats:title>\n                    <jats:p>\n                      When covarying biomarkers of AD pathology (i.e., the ratio of CSF p\u2010tau\n                      <jats:sub>181<\/jats:sub>\n                      \/(A\u03b2\n                      <jats:sub>1\u201042<\/jats:sub>\n                      \/A\u03b2\n                      <jats:sub>1\u201040<\/jats:sub>\n                      ), age, sex, APOE4 genetic status, and years of education), lower baseline NPTX2 levels were associated with greater atrophy over time in both AD\u2010vulnerable regions (SPARE\u2010AD, standardized estimate\u2009=\u2009\u22120.008,\n                      <jats:italic>p<\/jats:italic>\n                      \u2009=\u20090.034) as well as regions sensitive to brain aging (SPARE\u2010BA, standardized estimate\u2009=\u2009\u22120.011,\n                      <jats:italic>p<\/jats:italic>\n                      \u2009=\u20090.014). These associations were independent of participants having follow\u2010up diagnoses of MCI or dementia.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Conclusion<\/jats:title>\n                    <jats:p>Our findings suggest that after accounting for biomarkers of AD pathology, CSF NPTX2 is associated with slower longitudinal atrophy in AD\u2010signature and aging\u2010related regions. These findings are consistent with the view that NPTX2 may be a resilience factor in the presence of pathology and modifies rates of neurodegeneration.<\/jats:p>\n                  <\/jats:sec>","DOI":"10.1002\/acn3.70216","type":"journal-article","created":{"date-parts":[[2025,10,9]],"date-time":"2025-10-09T06:55:14Z","timestamp":1759992914000},"page":"332-342","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":6,"title":["CSF Levels of NPTX2 Are Associated With Less Brain Atrophy Over Time in Cognitively Unimpaired Individuals"],"prefix":"10.1002","volume":"13","author":[{"ORCID":"https:\/\/orcid.org\/0000-0001-8930-8009","authenticated-orcid":false,"given":"Juan P.","family":"Vazquez","sequence":"first","affiliation":[{"name":"Department of Neurology Johns Hopkins University School of Medicine  Baltimore Maryland 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