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Alzheimer's Disease Research and Treatments / Dementia and Cognitive Impairment Research · Journal article
Journal of Alzheimer S Disease · August 12, 2026
Early or partial results. Treat as a signal, not a conclusion.
This retrospective cohort study of 130 patients with amyloid-negative, tau-positive cerebrospinal fluid biomarkers found higher total tau associated with mortality (HR 1.003 per unit, p=0.006) and faster progression (r=0.22, p=0.011), but tau associations reversed direction when both total and phosphorylated tau were modeled together. The authors acknowledge the joint-model findings as hypothesis-generating and urge caution in interpretation.
Retrospective cohort study. 130 patients with amyloid-negative cerebrospinal fluid pattern (normal Aβ42, elevated phosphorylated tau and total tau) evaluated at a tertiary neurology center. Mean age 68.8 ± 10.1 years; 45.4% female. Diagnoses: mild cognitive impairment 30%, frontotemporal dementia 30%, and other neurological c…. Intervention: Cerebrospinal fluid tau biomarkers (total tau and phosphorylated tau levels measured; values reported as elevated versus normal).. Compared with: Null (observational cohort with stratification by biomarker level and diagnosis); no active intervention or control arm.. n = 130. Single tertiary neurology center; location not specified..
Survival differed across diagnostic groups (log-rank p = 0.037), with more favorable outcomes in mild cognitive impairment Male sex more frequent among non-survivors (88.9% versus 45.6%, p < 0.001) Higher CSF total tau associated with mortality in joint Cox model (HR 1.003, 95% CI 1.001–1.006, p = 0.006)
Higher CSF total tau associated with mortality in joint Cox model (HR 1.003, 95% CI 1.001–1.006, p = 0.006) Neither total tau nor phosphorylated tau independently associated with mortality; both significant in opposite directions in joint model
This study suggests that cerebrospinal fluid total tau may carry prognostic information in the rare amyloid-negative, tau-positive biomarker profile, but the conflicting joint-model findings and retrospective design limit immediate clinical application. Clinicians should treat these associations as preliminary pending prospective validation and clarification of tau biomarker interactions.
Retrospective cohort study of modest size with exploratory biomarker associations in a rare subgroup; joint-model findings acknowledged by authors as hypothesis-generating and requiring caution.
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This study suggests that cerebrospinal fluid total tau may carry prognostic information in the rare amyloid-negative, tau-positive biomarker profile, but the conflicting joint-model findings and retrospective design limit immediate clinical application. Clinicians should treat these associations as preliminary pending prospective validation and clarification of tau biomarker interactions.
Graded across the dimensions that decide whether you should act, each from what the source actually supports. There is no single score, and where a dimension was not assessed it says so.
Background Amyloid-negative tau-related neurodegeneration represents a non-Alzheimer biomarker-defined profile; however, its clinical heterogeneity and prognostic relevance remain unclear within Alzheimer's disease-related frameworks. Objective To characterize the clinical spectrum and identify predictors of mortality in patients with this profile. Methods In this retrospective cohort study, 1280 patients evaluated at a tertiary neurology center were screened, and 130 with an amyloid-negative cerebrospinal fluid (CSF) pattern [amyloid-β (Aβ) 42 normal, phosphorylated tau (pTau), and total tau (tTau) elevated] were included. Survival was assessed using Kaplan–Meier analysis, and predictors of mortality were evaluated using Cox models. Results The cohort (mean age 68.8 ± 10.1 years; 45.4% female) showed heterogeneous diagnoses, mainly mild cognitive impairment and frontotemporal dementia (each 30%). Survival differed across diagnostic groups (log-rank p = 0.037), with more favorable outcomes in mild cognitive impairment. Male sex was more frequent among non-survivors (88.9% versus 45.6%, p < 0.001). Higher CSF tTau levels were associated with mortality in the joint Cox model (HR 1.003, 95% CI 1.001–1.006, p = 0.006) and faster clinical progression (r = 0.22, p = 0.011). When modeled separately, neither tTau nor pTau was independently associated with mortality; however, both became significant in opposite directions when included jointly. Conclusions The amyloid-negative A−T + N + profile represents a clinically heterogeneous subgroup with prognostic relevance. CSF tTau was associated with mortality and faster clinical progression, but the joint-model findings involving tTau and pTau should be interpreted cautiously as hypothesis-generating. Further studies are needed to clarify the prognostic value of tau-related biomarkers in this population.
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