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. 2025 Feb 10;82(4):344-354.
doi: 10.1001/jamaneurol.2024.5017. Online ahead of print.

Detection of Alzheimer Neuropathology in Alzheimer and Non-Alzheimer Clinical Syndromes With Blood-Based Biomarkers

Lawren VandeVrede  1 , Hanna Cho  1   2 , Mark Sanderson-Cimino  1 , Fattin Wekselman  1 , Yann Cobigo  1 , Maria Luisa Gorno-Tempini  1 , Hilary W Heuer  1 , Joel H Kramer  1 , Argentina Lario Lago  1 , Dana Leichter  1 , Peter Ljubenkov  1 , Bruce L Miller  1 , David C Perry  1 , Gil D Rabinovici  1   3 , Julio C Rojas  1 , Howard J Rosen  1 , Rowan Saloner  1 , Adam Staffaroni  1 , Gallen Triana-Baltzer  4 , Salvatore Spina  1 , William W Seeley  1 , Lea T Grinberg  1   5 , Hartmuth C Kolb  4 , Renaud La Joie  1 , Adam L Boxer  1
Affiliations

Detection of Alzheimer Neuropathology in Alzheimer and Non-Alzheimer Clinical Syndromes With Blood-Based Biomarkers

Lawren VandeVrede et al. JAMA Neurol. .

Abstract

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 < .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 < .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.

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Conflict of interest statement

Conflict of Interest Disclosures: Dr VandeVrede reported nonfinancial support from Biogen (site principal investigator for Biogen-sponsored clinical trial) outside the submitted work. Dr Gorno Tempini reported grants from the National Institute on Deafness and Other Communication Disorders (K24DC015544), the National Institute of Neurological Disorders and Stroke (RF1NS050915 and RF1NS100440), the National Institutes of Health Center for Scientific Review (R01AG075775, R01AG071756, R01AG080469, and R01NS131604) during the conduct of the study. Dr Miller reported serving on the scientific advisory board of the Bluefield Project to Cure Frontotemporal Dementia; the John Douglas French Alzheimer’s Foundation; Fundación Centro de Investigación Enfermedades Neurológicas, Madrid, Spain; Genworth; the Kissick Family Foundation; the Larry L. Hillblom Foundation; and the Tau Consortium of the Rainwater Charitable Foundation; serving as a scientific advisor for the Arizona Alzheimer’s Consortium; Massachusetts General Hospital Alzheimer’s Disease Research Center; and the Stanford University Alzheimer’s Disease Research Center; receiving royalties from Cambridge University Press, Elsevier, Guilford Publications, Johns Hopkins Press, Oxford University Press, and the Taylor & Francis Group; serving as editor for Neurocase and section editor for Frontiers in Neurology; and receiving grants for the University of California San Francisco Frontotemporal Dementia Core, from the Bluefield Project to Cure Frontotemporal Dementia, and from the National Institute on Aging for the US–South American Initiative for Genetic-Neural-Behavioral Interactions in Human Neurodegenerative Diseases. Dr Rabinovici reported grants from National Institutes of Health during the conduct of the study; consulting fees from C2N, Eli Lilly, Alector, Merck, Roche, and Novo Nordisk; data safety monitoring board fees from Johnson & Johnson; and grants from Avid Radiopharmaceuticals, GE Healthcare, Life Molecular Imaging, and Genentech outside the submitted work; and served as Associate Editor at JAMA Neurology. Dr Rojas reported serving as site principal investigator for clinical trials sponsored by Eli Lilly, Eisai, and Amylyx during the conduct of the study. Dr Rosen reported consulting fees from Genentech and Eisai outside the submitted work. Dr Staffaroni reported grants from the National Institutes of Health, the Bluefield Project to Cure Frontotemporal Dementia, and the Association for Frontotemporal Degeneration; personal fees from Alector, Prevail Therapuetics/Eli Lilly, Passage Bio, Takeda, and the Alzheimer's Drug Discovery Foundation; and other from Datacubed Health (licensing fees) outside the submitted work. Dr Triana-Baltzer reported salary from Johnson & Johnson outside the submitted work; in addition, Dr Triana-Baltzer had a patent for JAB7156 pending (plasma p217tau assay patent). Dr Seeley reported grants from the National Institutes of Health, the Chan-Zuckerberg Initiative, the Bluefield Project to Cure Frontotemporal Dementia, and the Rainwater Charitable Foundation during the conduct of the study and personal fees from Biogen, Atheneum (consulting), and from Lyterian Therapeutics outside the submitted work; in addition, Dr Seeley had a patent for US 63/085,749 pending. Dr Grinberg reported personal fees from Guidepoint (consulting), Otsuka (educational event), Medscape, and Weill Neurohub outside the submitted work. Dr Kolb reported employment at Johnson & Johnson during the conduct of the study and at Enigma Biomedical Group outside the submitted work; in addition, Dr Kolb had a patent for Pantent on plasma p217Tau assays pending (former employer filed patents on this topic). Dr La Joie reported grants from the National Institute on Aging, the Alzheimer’s Association, the US Department of Defense as well as personal fees from GE Healthcare outside the submitted work. Dr Boxer reported grants from the National Institutes of Health, the Rainwater Charitable Foundation, the GHR Foundation, and the Bluefield Project and personal fees from Alector, Arvinas, Alchemab, Alexion, Amylyx, Arkuda, Arrowhead, Eli Lilly, Muna, Neurocrine, Ono, Oscotec, Pfizer, Switch, Transposon, and Unlearn AI outside the submitted work. No other disclosures were reported.

Figures

Figure 1.
Figure 1.. Neuropathological Distribution of Alzheimer Disease (AD) Primary and Copathology Across Neurodegenerative Clinical Syndromes
Primary neuropathology was defined by an expert neuropathologist. AD copathology was defined as present if intermediate or high AD neuropathological changes were present. For corticobasal syndrome (CBS), other pathology included 1 case of Huntington disease; for behavioral variant frontotemporal dementia (bvFTD), other pathology comprised 8 cases of rarer pathologies, including frontotemporal lobar degeneration (FTLD) fused in sarcoma (n = 4), FTLD with ubiquitinated inclusions (n = 2), FTLD with no inclusions (n = 1), and cerebral amyloid angiopathy (n = 1). Numbers in bars indicate case counts. ALS indicates amyotrophic lateral sclerosis; DLB, dementia with Lewy bodies; EOAD, early-onset Alzheimer disease; LBD, Lewy body dementia; LOAD, late-onset Alzheimer disease; lvPPA, logopenic variant primary progressive aphasia; MCI, mild cognitive impairment; nfvPPA, nonfluent variant primary progressive aphasia; PCA, posterior cortical atrophy; PSP-RS, progressive supranuclear palsy–Richardson syndrome; svPPA, semantic variant primary progressive aphasia; TDP, transactive response DNA-binding protein.
Figure 2.
Figure 2.. Plasma Biomarker Concentrations Across Neurodegenerative Clinical Syndromes
Plasma concentrations of (A) plasma phosphorylated tau217 (p-tau217), (B) neurofilament light chain (NfL), and (C) glial fibrillary acidic protein (GFAP) for each clinical neurodegenerative syndrome and grouped into Alzheimer disease (AD)– and frontotemporal lobar degeneration (FTLD)–related syndromes. Statistical comparisons used linear regression (age, sex, and interval to autopsy as covariates). ADNC indicates AD neuropathological change; ALS, amyotrophic lateral sclerosis; bvFTD, behavioral variant frontotemporal dementia; CBS, corticobasal syndrome; CU, cognitively unimpaired; DLB, dementia with Lewy bodies; EOAD, early-onset Alzheimer disease; LBD, Lewy body dementia; LOAD, late-onset Alzheimer disease; lvPPA, logopenic variant primary progressive aphasia; MCI, mild cognitive impairment; nfvPPA, nonfluent variant primary progressive aphasia; PCA, posterior cortical atrophy; PSP-RS, progressive supranuclear palsy–Richardson syndrome; svPPA, semantic variant primary progressive aphasia; TDP, transactive response DNA-binding protein. aDifferent from each other (P < .05). bDifferent from CU (P < .05).
Figure 3.
Figure 3.. Plasma Biomarker Concentrations Comparing Atypical Alzheimer Disease (AD), Typical Late-Onset AD, and Frontotemporal Lobar Degeneration (FTLD)–Related Syndromes With and Without AD Neuropathology
Plasma concentrations of (A) plasma phosphorylated tau217 (p-tau217), (B) neurofilament light chain (NfL), and (C) glial fibrillary acidic protein (GFAP) for each cohort. Statistical comparisons used linear regression (age, sex, and interval to autopsy as covariates); lines represent significant differences (P < .05). Color represents AD neuropathological change. ADNC indicates AD neuropathological change; CU, cognitively unimpaired; LOAD, late-onset Alzheimer disease.
Figure 4.
Figure 4.. Alzheimer Disease (AD) Copathology in Frontotemporal Lobar Degeneration (FTLD)–Related Syndromes and Increased Rates of Posterior Cortical Atrophy
Voxel-based bayesian linear mixed effects showing differences in rates of atrophy on magnetic resonance imaging in white matter (WM) and gray matter (GM) regions over time in FTLD syndromes with or without AD. Statistical analyses controlled for age and total intracranial volume, and results are masked to show only statistically significant regions (P < .05) after familywise error correction.
See this image and copyright information in PMC

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