NIA-AA staging of preclinical Alzheimer disease: discordance and concordance of CSF and imaging biomarkers

Abstract

The National Institute of Aging and Alzheimer’s Association (NIA-AA) criteria for Alzheimer disease (AD) treat neuroimaging and cerebrospinal fluid (CSF) markers of AD pathology as if they would be interchangeable. We tested this assumption in 212 cognitively normal participants who have both neuroimaging and CSF measures of β-amyloid (CSF Aβ1-42 and PET imaging with Pittsburgh Compound B) and neuronal injury (CSF t-tau and p-tau and structural MRI) with longitudinal clinical follow-up. Participants were classified in preclinical AD Stage 1 (β-amyloidosis) or preclinical AD Stage 2+ (β-amyloidosis and neuronal injury) using the NIA-AA criteria, or in the normal or suspected non-Alzheimer pathophysiology group (SNAP; neuronal injury without β-amyloidosis). At baseline, 21% of participants had preclinical AD based on CSF and 28% based upon neuroimaging. Between modalities, staging was concordant in only 47% of participants. Disagreement resulted from low concordance between biomarkers of neuronal injury. Still, individuals in Stage 2+ using either criterion had an increased risk for clinical decline. This highlights the heterogeneity of the definition of neuronal injury, and has important implications for clinical trials utilizing biomarkers for enrollment or as surrogate endpoint measures.

Detectable Neuropsychological Differences in Early Preclinical Alzheimer’s Disease: A Meta-Analysis

“…Because of the low number of studies, results from this analysis are presented with caution. One study (Vos et al, 2016), presented data separately for amyloid determined via CSF and PET, so this study was considered as two separate studies for this analysis, yielding a total of 10 studies. Demographic data per dataset is presented in Table 3.…”

Longitudinal β-Amyloid Deposition and Hippocampal Volume in Preclinical Alzheimer Disease and Suspected Non–Alzheimer Disease Pathophysiology

“…19,35,48 This heterogeneity suggests that multiple pathways could lead to abnormal markers of neuronal injury and ND. Individuals who are initially classified as SNAP but go onto demonstrate Aβ + would technically then fall into preclinical stage 2.…”

“…Owing to potential incongruences in markers of ND, 35 participants were classified into NIA-AA stages at baseline in 2 ways. For the first set of analyses, baseline ND+ was defined using only HCV z .…”

Amyloidosis and neurodegeneration result in distinct structural connectivity patterns in mild cognitive impairment

“…In accordance with this hypothesis of heterogeneity of MCI A-N+ etiologies, we found that among all MCI A-N+, only 20% were positive by both biomarkers, whereas they were 47% in the MCI A+N+ (supplementary Table S4). However, it has been also proposed that MCI A-N+ may reflect a proportion of AD individuals with subthreshold Aß SUVr (Vos et al, 2016(Vos et al, , 2015. We SUVr in MCI A-N+ classified using CSF Aβ 42 as amyloid biomarker (Wisse et al, 2015).…”