¹NHO Kure Medical Center and Chugoku Cancer Center, Psychiatry, Kure, Japan, ²Kumamoto University, Psychiatry and Neuroscience, Center for Metabolic Regulation of Healthy Aging, Faculty of Life Science, Kumamoto, Japan, ³NHO Kure Medical Center and Chugoku Cancer Center, Division of Psychiatry and Neuroscience, Institute for Clinical Research, Kure, Japan, ⁴Hiroshima City Center for Children’s Health and Development, Department of Psychiatry, Hiroshima, Japan

Background: Differentiating late-life depression (LLD) from prodromal or early Alzheimer’s disease (AD) is clinically difficult because affective and cognitive symptoms overlap and a subset of LLD patients shows amyloid-β (Aβ) positivity, limiting the specificity of core CSF Aβ/tau biomarkers. The p75 neurotrophin receptor (p75NTR) regulates pro-survival and pro-apoptotic signaling. Its soluble ectodomain (p75NTR-ECD), shed via ADAM17/TACE, can bind Aβ and mitigate downstream neurotoxicity. While decreased CSF p75NTR-ECD has been reported in AD, its status in LLD and links to symptom domains remain unclear.

Aims & Objectives: To test whether CSF p75NTR-ECD differs among AD, LLD, and healthy controls (HC), and to explore associations with cognition (Mini-Mental State Examination; MMSE) and depressive symptom domains (Hamilton Depression Rating Scale-21; HAM-D-21). Exploratory receiver-operating-characteristic (ROC) analyses were performed without proposing diagnostic thresholds.

Method: We quantified CSF p75NTR-ECD by ELISA in older Japanese adults (HC, n=19; LLD, n=19; AD, n=12). Multivariable linear regression modeled p75NTR-ECD with diagnosis (reference=AD), adjusting for age, sex, and body mass index (BMI). Age- and BMI-adjusted exploratory regressions related p75NTR-ECD to MMSE and HAM-D-21 domains. ROC analyses contrasted AD vs HC, AD vs LLD, and AD vs non-AD (HC+LLD). The study complied with the principles of the Declaration of Helsinki and was approved by the Ethics Committees of NHO Kure Medical Center and Chugoku Cancer Center and Kumamoto University; all participants provided written informed consent.

Results: CSF p75NTR-ECD was lower in AD than in HC (p=0.005) and LLD (p=0.001), with no HC–LLD difference. Older age (B=−5.19 pg/mL/year, p=0.007) and higher BMI (B=−15.32 pg/mL per kg/m², p=0.014) predicted lower levels; sex was not significant. Higher p75NTR-ECD related to better global cognition (MMSE: B=8.345, p=0.005) and to higher orientation (p=0.021) and recall scores (p<0.001). Lower p75NTR-ECD related to more sleep disturbance (HAM-D items 4–6: p=0.015) and greater psychic anxiety (items 9–10: p=0.006), whereas the HAM-D total was not associated. AUCs were 0.754 (AD vs HC), 0.724 (AD vs LLD), and 0.739 (AD vs non-AD); no cut-points are proposed.

Discussion & Conclusions: In this cohort, CSF p75NTR-ECD distinguished AD from LLD and healthy aging and tracked cognition and specific symptom domains. Given overlapping clinical phenotypes and Aβ positivity in some LLD cases, p75NTR-ECD may provide mechanism-linked information that could complement established Aβ/tau biomarkers; however, findings are cross-sectional, modest in sample size, and Aβ/tau were not measured, so independence and additivity versus core biomarkers were not tested. Validation in larger longitudinal, multimarker cohorts is warranted.