Prognostic significance of cerebrospinal fluid tau biomarkers in amyloid-negative A−T + N + neurodegeneration: A retrospective cohort study
Aslı Aksoy Gündoğdu, Bedia Samancı, Merve Alaylıoğlu, Erdi Şahin, Çağrı Ulukan, İbrahim Hakan Gürvit, Erdinç Dursun, Haşmet Ayhan Hanağası, Duygu Gezen-Ak, Başar BilgiçBackground
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.