ATN profiles among cognitively normal individuals and longitudinal cognitive outcomes

Abstract

Objective: To examine the long-term cognitive trajectories of individuals with normal cognition at baseline and distinct amyloid/tau/neurodegeneration (ATN) profiles.

Methods: Pooling data across 4 cohort studies, 814 cognitively normal participants (mean baseline age = 59.6 years) were classified into 8 ATN groups using baseline CSF levels of β-amyloid 1-42 as a measure of amyloid (A), phosphorylated tau 181 as a measure of tau (T), and total tau as a measure of neurodegeneration (N). Cognitive performance was measured using a previously validated global factor score and with the Mini-Mental State Examination. We compared the cognitive trajectories across groups using growth curve models (mean follow-up time = 7 years).

Results: Using different model formulations and cut points for determining biomarker abnormality, only the group with abnormal levels of amyloid, tau, and neurodegeneration (A+T+N+) showed consistently greater cognitive decline than the group with normal levels of all biomarkers (A-T-N-). Replicating prior findings using the 2011 National Institute on Aging-Alzheimer's Association/suspected non-Alzheimer disease pathophysiology schema, only individuals with abnormal levels of both amyloid and phosphorylated tau 181 or total tau (stage 2) showed greater cognitive decline than those with normal biomarker levels (stage 0).

Conclusion: The results are consistent with the hypothesis that both elevated brain amyloid and neurofibrillary tangles are necessary to observe accelerated neurodegeneration, which in turn leads to cognitive decline.

Figure 1. Estimates of longitudinal change in cognition for the 4 National Institute on Aging–Alzheimer’s Association/SNAP groups

Estimates from linear growth curve models predicting cognitive factor scores (A and B) and MMSE scores (C and D) over time among individuals classified into the 3 preclinical AD groups (stages 0, 1, 2) and SNAP using baseline CSF Aβ_1–42 and t-tau (A and C) or Aβ_1–42 and p-tau₁₈₁ (B and D) for classification. The estimates are adjusted for baseline age, sex, education, and the age × time interaction and the timescale was years since baseline. The stage 2 group (solid green line) showed the greatest rate of decline among the 4 groups. Aβ_1–42 = β-amyloid 1–42; MMSE = Mini-Mental State Examination; p-tau₁₈₁ = phosphorylated tau 181; SNAP = suspected non–Alzheimer disease pathophysiology; t-tau = total tau.

Figure 2. Estimates of longitudinal change in cognition for the 8 ATN profile groups

Estimates from linear growth curve models predicting cognitive factor scores (A and B) and MMSE scores (C and D) over time among individuals classified into the 8 ATN profile groups using baseline CSF β-amyloid 1–42 as a measure of amyloid, CSF phosphorylated tau 181 as a measure of tau, and CSF total tau as a measure of neurodegeneration. The estimates are adjusted for baseline age, sex, education, and the age × time interaction, and the timescale was years since baseline (A and C) or chronological age (B and D). Only the A+T+N+ group (solid black line) consistently showed greater decline than the biomarker-negative (A−T−N−) group (solid orange line). ATN = amyloid/tau/neurodegeneration; MMSE = Mini-Mental State Examination.