{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,8,5]],"date-time":"2026-08-05T06:51:51Z","timestamp":1785912711198,"version":"3.56.0"},"reference-count":12,"publisher":"Frontiers Media SA","license":[{"start":{"date-parts":[[2026,8,5]],"date-time":"2026-08-05T00:00:00Z","timestamp":1785888000000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":["frontiersin.org"],"crossmark-restriction":true},"short-container-title":["Front. Aging Neurosci."],"abstract":"<jats:sec>\n                    <jats:title>Background<\/jats:title>\n                    <jats:p>Behavioral and psychological symptoms of dementia (BPSD) critically complicate Alzheimer\u2019s disease care, yet the precise biological correlates for highly heterogeneous symptom domains remain largely unexplored.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Objective<\/jats:title>\n                    <jats:p>To investigate an exploratory \u201cdual-pathway framework\u201d to map how macroscopic immunosenescence and elevated latent viral antibody titers parallelly correlate with distinct neurobehavioral phenotypes.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Methods<\/jats:title>\n                    <jats:p>\n                      We evaluated 103 older adults diagnosed with mild cognitive impairment (n = 40) or probable Alzheimer\u2019s disease (\n                      <jats:italic>n<\/jats:italic>\n                      = 63). The severity and frequency of behavioral domains were assessed using the Neuropsychiatric Inventory (NPI). These profiles were correlated with peripheral blood lymphocyte subsets and serological markers of neurotropic Herpesviridae.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Results<\/jats:title>\n                    <jats:p>\n                      Macroscopic immunosenescence, reflected by an elevated CD4\/CD8 ratio (&amp;gt;1.58), differentiated Alzheimer\u2019s disease from mild cognitive impairment (\n                      <jats:italic>p<\/jats:italic>\n                      = 0.028), indicating cross-sectional clinical status. To address the highly zero-inflated distribution of BPSD symptoms, we employed a two-step hurdle-like approach. Initial comparisons revealed that elevated EBV-VCA IgM titers were significantly associated with the occurrence of BPSD symptoms (\n                      <jats:italic>p<\/jats:italic>\n                      = 0.0475). However, subsequent severity analyses exclusively within symptomatic subsets showed that viral titers lacked a continuous linear correlation with symptom severity. Instead, the reduced absolute counts of adaptive immune cells (CD3+, CD4+, and CD19+) exhibited a robust, dose-dependent negative correlation with the global neurobehavioral burden (Total NPI score).\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Conclusion<\/jats:title>\n                    <jats:p>Behavioral and psychological symptoms of dementia are associated with an exploratory dual-pathway model. Elevated viral antibody titers act as an immunological priming factor associated with symptom occurrence, whereas the reduction of adaptive immune reserves continuously modulates the global neuropsychiatric severity in Alzheimer\u2019s disease.<\/jats:p>\n                  <\/jats:sec>","DOI":"10.3389\/fnagi.2026.1867226","type":"journal-article","created":{"date-parts":[[2026,8,5]],"date-time":"2026-08-05T06:27:25Z","timestamp":1785911245000},"update-policy":"https:\/\/doi.org\/10.3389\/crossmark-policy","source":"Crossref","is-referenced-by-count":0,"title":["Translating peripheral blood biomarkers into Alzheimer\u2019s disease care: an exploratory dual-pathway model of immune and viral dynamics in behavioral and psychological symptoms of dementia"],"prefix":"10.3389","volume":"18","author":[{"given":"Ching-Tse","family":"Wu","sequence":"first","affiliation":[{"name":"Institute of Biotechnology, National Tsing Hua University","place":["Hsinchu, Taiwan"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Shuo-Peng","family":"Chou","sequence":"additional","affiliation":[{"name":"Department of Laboratory Medicine, National Taiwan University Hospital Hsin-Chu Branch","place":["Hsinchu, Taiwan"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Chuang-Rung","family":"Chang","sequence":"additional","affiliation":[{"name":"Institute of Biotechnology, National Tsing Hua University","place":["Hsinchu, Taiwan"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Chien-Chung","family":"Chang","sequence":"additional","affiliation":[{"name":"Institute of Cellular Biology, National Tsing Hua University","place":["Hsinchu, Taiwan"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Cheng-I","family":"Chu","sequence":"additional","affiliation":[{"name":"Department of Neurology, National Taiwan University Hospital Hsin-Chu Branch","place":["Hsinchu, Taiwan"]}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1965","published-online":{"date-parts":[[2026,8,5]]},"reference":[{"key":"B1","doi-asserted-by":"publisher","first-page":"1027","DOI":"10.1016\/j.neuron.2019.12.031","article-title":"Human herpesvirus 6 detection in Alzheimer\u2019s disease cases and controls across multiple cohorts.","volume":"105","author":"Allnutt","year":"2020","journal-title":"Neuron"},{"key":"B2","doi-asserted-by":"publisher","first-page":"122","DOI":"10.1016\/j.neurobiolaging.2013.06.024","article-title":"Herpes virus in Alzheimer\u2019s disease: Relation to progression of the disease.","volume":"35","author":"Carbone","year":"2014","journal-title":"Neurobiol. 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