The implications of different approaches to define AT(N) in Alzheimer disease

Abstract

Objective: To compare different β-amyloid (Aβ), tau, and neurodegeneration (AT[N]) variants within the Swedish BioFINDER studies.

Methods: A total of 490 participants were classified into AT(N) groups. These include 53 cognitively unimpaired (CU) and 48 cognitively impaired (CI) participants (14 mild cognitive impairment [MCI] and 34 Alzheimer disease [AD] dementia) from BioFINDER-1 and 389 participants from BioFINDER-2 (245 CU and 144 CI [138 MCI and 6 AD dementia]). Biomarkers for A were CSF Aβ₄₂ and amyloid-PET ([¹⁸F]flutemetamol); for T, CSF phosphorylated tau (p-tau) and tau PET ([¹⁸F]flortaucipir); and for (N), hippocampal volume, temporal cortical thickness, and CSF neurofilament light (NfL). Binarization of biomarkers was achieved using cutoffs defined in other cohorts. The relationship between different AT(N) combinations and cognitive trajectories (longitudinal Mini-Mental State Examination scores) was examined using linear mixed modeling and coefficient of variation.

Results: Among CU participants, A-T-(N)- or A+T-(N)- variants were most common. However, more T+ cases were seen using p-tau than tau PET. Among CI participants, A+T+(N)+ was more common; however, more (N)+ cases were seen for MRI measures relative to CSF NfL. Tau PET best predicted longitudinal cognitive decline in CI and p-tau in CU participants. Among CI participants, continuous T (especially tau PET) and (N) measures improved the prediction of cognitive decline compared to binary measures.

Conclusions: Our findings show that different AT(N) variants are not interchangeable, and that optimal variants differ by clinical stage. In some cases, dichotomizing biomarkers may result in loss of important prognostic information.

Figure 1. Pairwise scatterplots for A, T, and (N) variables in BioFINDER-1

Scatterplots show the association between continuous measures for amyloid (A), tau (B–D), and (N) (E–G) biomarkers. Dashed lines indicate cutoff points. Spearman correlations (ρ) with p values, Cohen kappa statistic (κ), and concordance (percentage showing both biomarkers positive or negative) are shown at the top of each panel. For A and T comparisons, the upper right and lower left quadrants indicate concordance positive (+/+) and negative (−/−), respectively. For the comparisons (N)1 vs (N)2, the lower left and upper right quadrants indicate concordance positive and negative, respectively. For the 2 remaining (N) comparisons, concordant positive is in the lower right quadrant while concordant negative is in the upper left. Percentage figures across quadrants indicate distribution (percentage-wise) of participants. Aβ = β-amyloid; AT(N) = β-amyloid, tau, and neurodegeneration classification system; CI = cognitively impaired; CU = cognitively unimpaired; ITC = inferior temporal cortex; NfL = neurofilament light; p-tau = tau phosphorylated at Thr181; ROI = region of interest; SUVR = standardized uptake value ratio.

Figure 2. Prevalence of different AT(N) categories in different AT(N) variants among cognitively unimpaired (CU) and cognitively impaired (CI) participants in BioFINDER-1

Prevalence is reported without (A,C) and with (B, D) consideration for the (N) component. CSF Aβ₄₂ (A1); amyloid PET neocortical standardized uptake value ratio (SUVR) (A2); CSF tau phosphorylated at Thr181 (T1); tau PET inferior temporal cortex SUVR (T2); tau PET Braak V/VI SUVR (T3); hippocampal volume, adjusted for intracranial volume ([N]1); cortical thickness with a temporal meta–region of interest ([N]2); CSF neurofilament light ([N]3). AT(N) = β-amyloid, tau, and neurodegeneration classification system.

Figure 3. Prevalence of T and (N) positivity across cognitively unimpaired (CU) and cognitively impaired (CI) participants in BioFINDER-1 and BioFINDER-2

Prevalence estimates for CU participants are shown in (A) (BioFINDER, n = 101: 53 CU and 48 CI participants) and (B) (BioFINDER-2, n = 389: 245 CU and 144 CI participants) and for CI participants in (C) (BioFINDER-1) and (D) (BioFINDER-2). AT(N) = β-amyloid, tau, and neurodegeneration classification system.

Figure 4. AT(N) variants and longitudinal cognition

(A, D) R² for different AT(N) variants to predict longitudinal Mini-Mental State Examination (MMSE) for cognitively unimpaired (CU) and cognitively impaired (CI) participants, respectively (divided by A biomarkers). The selected models in (B,C) and (E, F) are the top 2 best for CU and CI participants, respectively; 25 and 75 refer to 25th and 75th quartiles, where higher indicates a more abnormal biomarker. All CI participants were positive using CSF Aβ₄₂ in ratio with Aβ_40. AT(N) = β-amyloid, tau, and neurodegeneration classification system. ITC = inferior temporal cortex; p-tau = phosphorylated at Thr181; ROI = region of interest.