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

Abstract

Under the ATN framework, CSF 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 CSF levels across amnestic and non-amnestic variants or due to co-occurring pathologies might lead to misdiagnoses. We assess the diagnostic accuracy of CSF 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 CSF concentrations of amyloid-β1-42 peptide, 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 cut-offs for positivity. Amyloid-β1-42 did not differ between amnestic and non-amnestic Alzheimer's disease, and receiver operating characteristic curve analyses indicated that amyloid-β1-42 was equally effective in discriminating both groups from frontotemporal lobar degeneration. However, CSF concentrations of phosphorylated tau, total tau, and the ratio of phosphorylated tau to amyloid-β1-42 were 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-β1-42 maintains 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-β1-42 ratio. In contrast, T and N status biomarkers differed between amnestic and non-amnestic Alzheimer's disease; standard cut-offs for phosphorylated tau and total tau may thus result in misclassifications for non-amnestic Alzheimer's disease patients. Consideration of clinical syndrome may help improve the accuracy of ATN designations for identifying true non-amnestic Alzheimer's disease.

Keywords: ATN; cerebrospinal fluid; frontotemporal degeneration; non-amnestic Alzheimer’s disease.

Figure 1

CSF Aβ_1–42 concentrations according to phenotype (amnestic, non-amnestic) and post-mortem ratings of amyloid-β pathology. Left: Plots for patients with primary Alzheimer’s disease (AD) pathology. Right: Plots for patients with primary FTLD pathology. Horizontal line indicates CSF Aβ_1–42 = 192 pg/ml, with patients below the line designated as A+. CSF levels above the line are considered normal. Colour indicates modified Thal staging of amyloid-β pathology on a 0–3 scale (white indicates cases with no available Thal staging). Shape indicates presence or absence of copathology.

Figure 2

CSF p-tau concentrations according to phenotype (amnestic, non-amnestic) and post-mortem ratings of tau neurofibrillary tangle pathology. Left: Plots for patients with primary Alzheimer’s disease (AD) pathology. Right: Plots for patients with primary FTLD pathology. Horizontal line indicates CSF p-tau = 23 pg/ml, with patients at or above the line designated as positive for pathological tau (T+). CSF levels below the line are considered normal. Colour indicates post-mortem Braak staging of tau tangles (white indicates cases with no available Braak staging). Shape indicates presence or absence of copathology.

Figure 3

CSF t-tau concentrations according to phenotype (amnestic, non-amnestic) and post-mortem ratings of brain atrophy. Left: Plots for patients with primary Alzheimer’s disease (AD) pathology. Right: Plots for patients with primary FTLD pathology. Horizontal line indicates CSF t-tau = 93 pg/ml, with patients at or above the line designated as positive for neurodegeneration (N+). CSF levels below the line are considered normal. Colour indicates severity of gross brain atrophy (white indicates cases with no available atrophy). Shape indicates presence/absence of copathology.

Figure 4

CSF p-tau/Aβ_1–42 according to phenotype (amnestic, non-amnestic) and post-mortem ratings of Alzheimer’s disease likelihood. Left: Plots for patients with primary Alzheimer’s disease (AD) pathology. Right: Plots for patients with primary FTLD pathology. Horizontal line indicates CSF p-tau/Aβ_1–42 = 0.10, with patients at or above the line designated as positive for Alzheimer’s disease pathology. Ratios below the line are considered negative for Alzheimer’s disease. Colour indicates level of Alzheimer’s disease pathological change given by ABC score (white indicates cases with no available ABC score). Shape indicates presence/absence of co-pathology.