ATN classification and clinical progression in subjective cognitive decline: The SCIENCe project

Abstract

Objective: To investigate the relationship between the ATN classification system (amyloid, tau, neurodegeneration) and risk of dementia and cognitive decline in individuals with subjective cognitive decline (SCD).

Methods: We classified 693 participants with SCD (60 ± 9 years, 41% women, Mini-Mental State Examination score 28 ± 2) from the Amsterdam Dementia Cohort and Subjective Cognitive Impairment Cohort (SCIENCe) project according to the ATN model, as determined by amyloid PET or CSF β-amyloid (A), CSF p-tau (T), and MRI-based medial temporal lobe atrophy (N). All underwent extensive neuropsychological assessment. For 342 participants, follow-up was available (3 ± 2 years). As a control population, we included 124 participants without SCD.

Results: Fifty-six (n = 385) participants had normal Alzheimer disease (AD) biomarkers (A-T-N-), 27% (n = 186) had non-AD pathologic change (A-T-N+, A-T+N-, A-T+N+), 18% (n = 122) fell within the Alzheimer continuum (A+T-N-, A+T-N+, A+T+N-, A+T+N+). ATN profiles were unevenly distributed, with A-T+N+, A+T-N+, and A+T+N+ containing very few participants. Cox regression showed that compared to A-T-N-, participants in A+ profiles had a higher risk of dementia with a dose-response pattern for number of biomarkers affected. Linear mixed models showed participants in A+ profiles showed a steeper decline on tests addressing memory, attention, language, and executive functions. In the control group, there was no association between ATN and cognition.

Conclusions: Among individuals presenting with SCD at a memory clinic, those with a biomarker profile A-T+N+, A+T-N-, A+T+N-, and A+T+N+ were at increased risk of dementia, and showed steeper cognitive decline compared to A-T-N- individuals. These results suggest a future where biomarker results could be used for individualized risk profiling in cognitively normal individuals presenting at a memory clinic.

Figure 1. Distribution of the ATN biomarker profiles in subjective cognitive decline

Pie chart illustrates the distribution of the 8-profile and 3-category ATN classification. AD = Alzheimer disease.

Figure 2. Kaplan-Meier curves illustrating clinical progression in subjective cognitive decline

Kaplan-Meier curves illustrate clinical progression to dementia (A) and to mild cognitive impairment or dementia (B). Separate lines represent the 8 ATN biomarker profiles. The numbers at risk for time points 0, 1, 2, 3, 4, and 5 years are depicted below the figure.

Figure 3. Spaghetti plots illustrating raw neuropsychological test performance over time in subjective cognitive decline

Spaghetti plots show individual neuropsychological trajectories on 6 neuropsychological tests: (A) Visual Association Test version A (VAT-A); (B) Rey Auditory Verbal Learning Test (RAVLT) delayed recall; (C) animal fluency; (D) Trail-Making Test, part A (TMT-A); (E) Stroop I; (F) Stroop III. Separate lines represent the unadjusted mean trajectory of the 8 ATN profiles with 95% confidence intervals. Figures represent raw test scores.