{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,14]],"date-time":"2026-09-14T18:28:27Z","timestamp":1789410507427,"version":"build-2803163510"},"reference-count":92,"publisher":"Wiley","issue":"4","license":[{"start":{"date-parts":[[2026,2,9]],"date-time":"2026-02-09T00:00:00Z","timestamp":1770595200000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by\/4.0\/"},{"start":{"date-parts":[[2026,2,9]],"date-time":"2026-02-09T00:00:00Z","timestamp":1770595200000},"content-version":"tdm","delay-in-days":0,"URL":"http:\/\/doi.wiley.com\/10.1002\/tdm_license_1.1"}],"funder":[{"DOI":"10.13039\/501100010969","name":"Alzheimer Nederland","doi-asserted-by":"publisher","award":["WE.03\u20102020\u201002"],"award-info":[{"award-number":["WE.03\u20102020\u201002"]}],"id":[{"id":"10.13039\/501100010969","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["onlinelibrary.wiley.com"],"crossmark-restriction":true},"short-container-title":["Brain Pathology"],"published-print":{"date-parts":[[2026,7]]},"abstract":"<jats:title>Abstract<\/jats:title>\n                  <jats:p>\n                    Synaptic loss in the (para)hippocampus is a major contributor to cognitive decline in Alzheimer's disease (AD), yet its regional specificity and pathological correlates remain poorly understood. Here, we quantified synaptophysin\u2010positive puncta across hippocampal subregions (CA4, CA2, CA1, and subiculum) and parahippocampal cortex (entorhinal cortex, parahippocampal and fusiform gyrus) in postmortem tissue from 28 AD and 17 controls, and assessed relationships to neuropathological severity and cognitive decline. Amyloid\u2010\u03b2, phosphorylated tau (p\u2010tau) load and neurofilament light (NfL) immunoreactivity were quantified, and Clinical Dementia Rating scores were collected as a cognitive measure. Group differences were analyzed with linear mixed models; correlations between synaptic puncta, pathology and cognitive scores with linear regressions, corrected for age, sex and multiple comparisons. We found selective synaptic loss in the entorhinal cortex (\u221214%,\n                    <jats:italic>p<\/jats:italic>\n                    \u2009=\u20090.017) and parahippocampal gyrus (\u221214%,\n                    <jats:italic>p\u2009=<\/jats:italic>\n                    \u20090.021) in AD versus controls. Hippocampal synaptic density negatively correlated with amyloid\u2010\u03b2 in controls (\n                    <jats:italic>r<\/jats:italic>\n                    \u2009=\u2009\u22120.52,\n                    <jats:italic>p<\/jats:italic>\n                    \u2009&lt;\u20090.001) and positively in AD (\n                    <jats:italic>r<\/jats:italic>\n                    \u2009=\u20090.25,\n                    <jats:italic>p<\/jats:italic>\n                    \u2009=\u20090.007), suggesting a disease\u2010dependent shift. In AD, hippocampal, but not parahippocampal, subregions with higher p\u2010tau burden showed greater synaptic density (\n                    <jats:italic>r<\/jats:italic>\n                    \u2009=\u20090.21,\n                    <jats:italic>p<\/jats:italic>\n                    \u2009=\u20090.003), raising questions about the role of p\u2010tau in synaptic loss at late stages. Axonal damage (i.e., higher NfL load) in the parahippocampal cortex associated with synaptic loss locally and in interconnected subregions. Worse cognitive performance was strongly associated with synaptic loss in the CA1 (\n                    <jats:italic>r<\/jats:italic>\n                    \u2009=\u2009\u22120.64,\n                    <jats:italic>p<\/jats:italic>\n                    \u2009=\u20090.003), subiculum (\n                    <jats:italic>r<\/jats:italic>\n                    \u2009=\u2009\u22120.62,\n                    <jats:italic>p<\/jats:italic>\n                    \u2009=\u20090.012), entorhinal cortex (\n                    <jats:italic>r<\/jats:italic>\n                    \u2009=\u2009\u22120.60,\n                    <jats:italic>p<\/jats:italic>\n                    \u2009=\u20090.008), parahippocampal (\n                    <jats:italic>r<\/jats:italic>\n                    \u2009=\u2009\u22120.48,\n                    <jats:italic>p<\/jats:italic>\n                    \u2009=\u20090.041) and fusiform gyrus (\n                    <jats:italic>r<\/jats:italic>\n                    \u2009=\u2009\u22120.67,\n                    <jats:italic>p<\/jats:italic>\n                    \u2009=\u20090.002). These findings highlight the vulnerability of the entorhinal cortex and parahippocampal gyrus to synaptic loss in AD. Our results suggest that amyloid\u2010\u03b2 and p\u2010tau pathology may play a limited role in synaptic loss at end\u2010stage disease, and the strong link between synaptic loss in (para)hippocampal subregions and cognitive decline underscores the need for monitoring synaptic change in light of disease progression and evaluating therapeutic interventions.\n                  <\/jats:p>","DOI":"10.1111\/bpa.70081","type":"journal-article","created":{"date-parts":[[2026,2,10]],"date-time":"2026-02-10T07:29:30Z","timestamp":1770708570000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":2,"title":["Distinct regional patterns of synaptic vulnerability across hippocampal and parahippocampal subregions in Alzheimer's disease"],"prefix":"10.1111","volume":"36","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-9481-0332","authenticated-orcid":false,"given":"Maud M. A.","family":"Bouwman","sequence":"first","affiliation":[{"name":"Department of Anatomy and Neurosciences, Section Clinical Neuroanatomy and Biobanking Amsterdam UMC, Vrije University Amsterdam  Amsterdam The Netherlands"},{"name":"Amsterdam Neuroscience, Program Neurodegeneration  Amsterdam The Netherlands"},{"name":"Amsterdam Neuroscience, Program Brain Imaging  Amsterdam The Netherlands"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Irene","family":"Frigerio","sequence":"additional","affiliation":[{"name":"Department of Anatomy and Neurosciences, Section Clinical Neuroanatomy and Biobanking Amsterdam UMC, Vrije University Amsterdam  Amsterdam The Netherlands"},{"name":"Amsterdam Neuroscience, Program Neurodegeneration  Amsterdam The Netherlands"},{"name":"Amsterdam Neuroscience, Program Brain Imaging  Amsterdam The Netherlands"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yvon Galis\u2010de","family":"Graaf","sequence":"additional","affiliation":[{"name":"Department of Anatomy and Neurosciences, Section Clinical Neuroanatomy and Biobanking Amsterdam UMC, Vrije University Amsterdam  Amsterdam The Netherlands"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Wilma D. J.","family":"van de Berg","sequence":"additional","affiliation":[{"name":"Department of Anatomy and Neurosciences, Section Clinical Neuroanatomy and Biobanking Amsterdam UMC, Vrije University Amsterdam  Amsterdam The Netherlands"},{"name":"Amsterdam Neuroscience, Program Neurodegeneration  Amsterdam The Netherlands"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Laura E.","family":"Jonkman","sequence":"additional","affiliation":[{"name":"Department of Anatomy and Neurosciences, Section Clinical Neuroanatomy and Biobanking Amsterdam UMC, Vrije University Amsterdam  Amsterdam The Netherlands"},{"name":"Amsterdam Neuroscience, Program Neurodegeneration  Amsterdam The Netherlands"},{"name":"Amsterdam Neuroscience, Program Brain Imaging  Amsterdam The 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