A recent Danish memory clinic cohort study sheds light on the enigmatic A–T+ biomarker profile – defined by elevated CSF p-tau181 in the absence of amyloid pathology. This commentary explores the clinical and conceptual implications of A–T+, arguing that it reflects a heterogeneous, non-Alzheimer group and highlighting the need to rethink A–T+ within a broader neurobiological framework. A–T+ is not diagnostic noise, but a call to investigate diverse pathways of neurodegeneration beyond amyloid-tau paradigms.
JackCRJrBennettDABlennowK, et al.A/T/N: an unbiased descriptive classification scheme for Alzheimer disease biomarkers. Neurology2016; 87: 539–547.
2.
VosSJBDelvenneAJackCRJr, et al.The clinical importance of suspected non-Alzheimer disease pathophysiology. Nat Rev Neurol2024; 20: 337–346.
3.
AndersenLSNSimonsenAHVogelA, et al.Isolated elevation of 181p-tau in the cerebrospinal fluid is associated with distinct clinical features: findings from a Danish memory clinic cohort. J Alzheimers Dis2025; 106: 111–119.
4.
JackCRJrAndrewsJSBeachTG, et al.Revised criteria for diagnosis and staging of Alzheimer's disease: Alzheimer's association workgroup. Alzheimers Dement2024; 20: 5143–5169.
5.
TondelliMSalemmeSVincetiG, et al.Predictive value of phospho-tau/total-tau ratio in amyloid-negative mild cognitive impairment. Neurosci Lett2022; 787: 136811.
6.
Costoya-SánchezAMoscosoASilva-RodríguezJ, et al.Increased medial temporal tau positron emission tomography uptake in the absence of amyloid-β positivity. JAMA Neurol2023; 80: 1051–1061.
7.
EricksonPSimrénJBrumWS, et al.Prevalence and clinical implications of a β-amyloid-negative, tau-positive cerebrospinal fluid biomarker profile in Alzheimer disease. JAMA Neurol2023; 80: 969–979.
