Association between ATN profiles and mortality in a clinical cohort of patients with cognitive disorders

Alzheimer's disease (AD) is the 5th leading cause of death in people 65 years and older. The ATN classification reflects a biological definition of AD pathology with markers of Aβ deposition (A), pathologic tau (T), and neurodegeneration (N). Little is known about the relationship between ATN status and the risk of mortality, leading us to examine this association in a relatively large population of patients seen at a memory clinic for cognitive disorders.

Data were drawn from the BioCogBank Study, including patients seen for cognitive disorders in Lariboisiere Hospital (Paris, France), followed up to 15 years. All participants underwent a lumbar puncture for an assessment of the levels of CSF tau (tau), phosphorylated tau (p-tau181), and β-amyloid 42 peptide (Aβ42). Vital status on July 1, 2020, was recorded for each participant using the national mortality register. Individuals were categorized according to their ATN profiles based on CSF Aβ42 or Aβ42/40 ratio, p-tau181, and tau. Kaplan-Meier and multivariate Cox analyses were performed with A-T-N - participants as the reference using a short (5 years) and long follow-up (15 years).

Of the 1353 patients in the study (mean age: 68 years old, 53% of women, mean MMSE score: 22.6), 262 died during the follow-up. At 5 years of follow-up, A-T-N + individuals had the highest risk of mortality in Kaplan-Meier and adjusted Cox analyses [HR (95% CI) = 2.93 (1.31-6.56)]. At 15 years of follow-up, patients in the AD spectrum had a higher mortality risk with a gradient effect for biomarker positivity: A-T + [HR = 1.63 (1.04-2.55)], A + T - [HR = 2.17 (1.44-3.26)], and A + T + individuals [HR = 2.38 (1.66-3.39)], compared to A-T-N - patients. Adjustments on potential confounders had little impact on these associations.

This study shows ATN profiles to be associated with mortality in a relatively large patient cohort based on a memory clinic. Patients with isolated evidence of neurodegeneration had a higher mortality rate in the short follow-up, and patients with the AD profile had the highest mortality rate in the long follow-up.