Detection of Alzheimer Neuropathology in Alzheimer and Non-Alzheimer Clinical Syndromes With Blood-Based Biomarkers
Authors: Lawren VandeVrede, Hanna Cho, Mark Sanderson-Cimino, Fattin Wekselman, Yann Cobigo, Maria Luisa Gorno-Tempini, Hilary W. Heuer, Joel H. Kramer, Argentina Lario Lago, Dana Leichter, Peter Ljubenkov, Bruce L. Miller, David C. Perry, Gil D. Rabinovici, Julio C. Rojas, Howard J. Rosen, Rowan Saloner, Adam Staffaroni, Gallen Triana-Baltzer, Salvatore Spina, William W. Seeley, Lea T. Grinberg, Hartmuth C. Kolb, Renaud La Joie, Adam L. Boxer
Journal: JAMA Neurology (2025)

Importance Blood-based biomarkers for Alzheimer disease (AD) are clinically available, but their value is not well understood in syndromes typically associated with frontotemporal lobar degeneration syndromes (FTLD). Objective To investigate the clinical importance and detectability of AD in FTLD-related neurodegenerative syndromes using 3 plasma biomarkers, phosphorylated tau 217 (p-tau217), neurofilament light chain (NfL), and glial fibrillary acidic protein (GFAP). Design, Setting, and Participants This clinicopathological study took place at the University of California San Francisco Alzheimer Disease Research Center from August 2008 to July 2022. Autopsied individuals with clinical evaluation and neuropathological examination, diagnosed with clinical syndromes related to AD (n = 125), frontotemporal lobar degeneration (FTLD; n = 198), or cognitively unimpaired (CU) at the time of evaluation (n = 16) were included. Exposures AD-related or FTLD-related clinical syndromes or CU. Main Outcomes and Measures P-tau217, NfL, and GFAP were measured with single-molecule array (SIMOA). AD was defined as intermediate or high AD neuropathological change (ADNC) at autopsy. Clinical biomarker associations were evaluated using linear regressions. Imaging analyses used bayesian linear mixed-effects modeling. Results A total of 349 individuals (191 [55%] male; mean [SD] age at death, 72 [11] years) were included. AD was common in both AD-related syndromes (110/125 [88%]) and FTLD-related syndromes (45/198 [23%]). Neuropathological stage at autopsy was higher in AD-related syndromes (high ADNC: 82/88 [93%] AD vs 13/23 [56%] FTLD), and AD was frequently considered a copathology in FTLD-related syndromes (30/198 [15%]). Plasma p-tau217 concentrations were higher in AD-related syndromes (mean [SD], 0.28 [0.16] pg/mL) than FTLD-related syndromes (mean [SD], 0.10 [0.09] pg/mL) ( P &amp;amp;lt; .05). Plasma p-tau217 concentrations were highest in atypical AD-related syndromes (mean [SD], 0.33 [0.02] pg/mL), followed by typical late-onset amnestic syndromes (mean [SD], 0.27 [0.03] pg/mL). FTLD-related syndromes with AD (mean [SD], 0.19 [0.02] pg/mL) were higher compared to without (mean [SD], 0.07 [0.00] pg/mL). Plasma p-tau217 detected AD neuropathology across syndromes (area under the receiver operating characteristic curve [AUC], 0.95; 95% CI, 0.93-0.97), with slightly better performance in AD-related syndromes (AUC, 0.98; 95% CI, 0.95-1.00) compared to FTLD-related syndromes (AUC, 0.89; 95% CI, 0.83-0.94). NfL and GFAP had lower performance for detecting AD (AUC, 0.73; 95% CI, 0.68-0.78 and AUC, 0.75; 95% CI, 0.67-0.80, respectively) and added little to no diagnostic value either alone or in combinations with p-tau217. The presence of AD in FTLD-related syndromes was associated with lower Mini-Mental State Examination score (mean [SD], −2.90 [1.09]; P &amp;amp;lt; .05), worse performance on memory (mean [SD] z score, −0.64 [0.32]), executive (mean [SD] z score, −0.74 [0.19]), and visuospatial composites (mean [SD] z score, −0.88 [0.37]) as well as increased rates of posterior cortical atrophy. Conclusion Clinically relevant AD was prevalent across neurodegenerative syndromes and detectable with plasma p-tau217. Plasma p-tau217 may be a useful tool to investigate the clinical impact of AD copathology in non-AD neurodegenerative syndromes, including the effect of disease-modifying therapies.