ATN status in amnestic and non-amnestic Alzheimer’s disease and frontotemporal lobar degeneration

AbstractUnder the ATN framework, cerebrospinal fluid analytes provide evidence of the presence or absence of Alzheimer’s disease pathological hallmarks: amyloid plaques (A), phosphorylated tau (T), and accompanying neurodegeneration (N). Still, differences in cerebrospinal fluid levels across amnestic and non-amnestic variants or due to co-occurring pathologies might lead to misdiagnoses. We assess the diagnostic accuracy of cerebrospinal fluid markers for amyloid, tau, and neurodegeneration in an autopsy cohort of 118 Alzheimer’s disease patients (98 amnestic; 20 non-amnestic) and 64 frontotemporal lobar degeneration patients (five amnestic; 59 non-amnestic). We calculated between-group differences in cerebrospinal fluid concentrations of amyloid-β1–42peptide, tau protein phosphorylated at threonine 181, total tau, and the ratio of phosphorylated tau to amyloid-β1–42. Results show that non-amnestic Alzheimer’s disease patients were less likely to be correctly classified under the ATN framework using independent, published biomarker cutoffs for positivity. Amyloid-β1–42did not differ between amnestic and non-amnestic Alzheimer’s disease, and receiver operating characteristic curve analyses indicated that amyloid-β1–42was equally effective in discriminating both groups from frontotemporal lobar degeneration. However, cerebrospinal fluid concentrations of phosphorylated tau, total tau, and the ratio of phosphorylated tau to amyloid-β1–42were significantly lower in non-amnestic compared to amnestic Alzheimer’s disease patients. Receiver operating characteristic curve analyses for these markers showed reduced area under the curve when discriminating non-amnestic Alzheimer’s disease from frontotemporal lobar degeneration, compared to discrimination of amnestic Alzheimer’s disease from frontotemporal lobar degeneration. In addition, the ATN framework was relatively insensitive to frontotemporal lobar degeneration, and these patients were likely to be classified as having normal biomarkers or biomarkers suggestive of primary Alzheimer’s disease pathology. We conclude that amyloid-β1–42maintains high sensitivity to A status, although with lower specificity, and this single biomarker provides better sensitivity to non-amnestic Alzheimer’s disease than either the ATN framework or the phosphorylated-tau/amyloid-β1–42ratio. In contrast, T and N status biomarkers differed between amnestic and non-amnestic Alzheimer’s disease; standard cutoffs for phosphorylated tau and total tau may thus result in misclassifications for non-amnestic Alzheimer’s patients. Consideration of clinical syndrome may help improve the accuracy of ATN designations for identifying true non-amnestic Alzheimer’s disease.Abbreviated SummaryCousins et al. assess the 2018 ATN framework and find that non-amnestic patients with Alzheimer’s disease (AD) have lower cerebrospinal fluid (CSF) phosphorylated tau and total tau than amnestic AD, while CSF amyloid-β accurately stratifies both non-amnestic and amnestic AD from frontotemporal lobar degeneration.