ArticleGeroScience2026
Age-adjusted neurofilament light chain cutoffs for diagnosing neurodegenerative dementia: a two-threshold machine learning approach.
Article in GeroScience, 2026. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Not yet cited in PubMed.
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13 authors.
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Abstract
Clinical implementation of neurofilament light chain (NfL), a biomarker of neurodegeneration, remains challenging due to absence of reliable cutoffs and influence of confounding factors, particularly age. We aimed to develop an age-adjusted, two-threshold classification framework to support clinical interpretation of NfL in the neurodegenerative dementia diagnosis. We retrospectively enrolled subjects with cognitive/behavioral disturbances and cognitively unimpaired controls (CTR). Participants underwent a baseline diagnostic workup, including at least a neuropsychological assessment, blood test, CSF and serum NfL measurement, and MRI, and were followed up for 2 years. At follow-up, they were diagnosed with either a neurodegenerative dementia [Alzheimer's Disease (AD), Frontotemporal Dementia (FTD), or Lewy Body Dementia (LBD)] or a non-neurodegenerative condition [Other Etiology (OE)]. AD, FTD, and LBD were grouped as Neurodegenerative (NDG), while OE and CTR were grouped as Non-Neurodegenerative (non-NDG). Bayesian regression models assessed the effects of age, disease duration, renal function, and gender on NfL. A weighted support vector machine (SVM) with leave-one-out cross-validation defined age-adjusted cutoffs using a two-threshold strategy constraining sensitivity ≥ 85% and limiting the intermediate zone. We included 217 subjects (158 NDG, 59 non-NDG). Serum and CSF NfL levels were significantly higher in NDG. Age strongly increased NfL levels, particularly in serum where diagnostic separation declined beyond age 70. The SVM-based model applied to CSF NfL defined continuous, age-adjusted, two-threshold cutoffs, identifying low-risk, high-risk, and intermediate zones. The proposed framework for CSF NfL provides a clinically oriented decision-support tool to stratify the likelihood of underlying neurodegeneration and guide diagnostic workup in cognitive neurology settings, pending external validation.
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Registered trials
Read under generation 80e0d062 · epoch 390. Bibliography from PubMed, PubMed Central and OpenAlex; grants from NIH RePORTER; trial links from ClinicalTrials.gov; estimates, votes and beliefs from the OpenQuestion graph.