Subtypes of Alzheimer’s disease and the ATN biomarker scheme

Abstract

AbstractBackgroundUnderstanding the association between two popular classification schemes: AD subtypes (based on patterns of brain atrophy) and the ATN (based on dichotomous categories of amyloid‐beta deposition (A), tauopathy (T) and neurodegeneration (N)) might increase our current understanding of the neurobiological heterogeneity within AD. We aimed to evaluate the association between the AD subtypes based on brain atrophy patterns and the ATN scheme, in the context of other relevant disease measures such as a marker of small vessel disease (white matter changes, WMC) and the source of the patients: ADNI vs. a memory clinic (KIDS).MethodsAD patients from two large cohorts were investigated: Alzheimer’s Disease Neuroimaging Initiative (ADNI) and Karolinska Imaging Dementia Study (KIDS). The ATN categories were entirely based on cerebrospinal fluid (CSF) biomarkers, and the subtypes on atrophy patterns were based on visual ratings from magnetic resonance imaging. Clustering analysis was used to further investigate associations with demographic and clinical factors.ResultsThe clustering analysis showed different distributions of ATN profiles and brain atrophy patterns in ADNI as compared with KIDS. Typical AD was the most frequent AD subtype in both cohorts, while limbic‐predominant and minimal atrophy AD were more frequent in KIDS than in ADNI. The A+T+N‐ profile was more frequent in ADNI, while A+T‐N+ and A+T‐N‐ profiles were more frequent in KIDS. The distribution of AD subtypes was associated with age in ADNI while in KIDS, it was also associated with MMSE as a measure of global cognition.ConclusionsThe distribution of and association between AD subtypes and ATN profiles depends on the source of the patients, aligning with different demographic and clinical characteristics depending on whether the cohort is more selective (ADNI) or more naturalistic and heterogeneous (KIDS). In ADNI we found a distribution of ATN profiles that seems to mainly reflect AD staging (i.e. A+T‐N‐, A+T+N‐, and A+T+N+). In KIDS, which is a heterogeneous memory clinic cohort, the ATN distribution seem to be determined by very early disease stages, either more “pure” (i.e. A+T‐N‐) or also including comorbidities contributing to unspecific neurodegeneration in the absence of a T+ biomarker (i.e. A+T‐N+).