WMH and biomarker heterogeneity of individuals on the amyloid pathway

Abstract

AbstractBackgroundResearch studies of Alzheimer’s disease (AD) are increasingly using biomarker‐based criteria to define disease. One useful definition is amyloid positivity since it identifies those on a pathological pathway that likely results in AD. However, within amyloid positive individuals, there is substantial heterogeneity in terms of when biomarkers that measure different aspects of the disease become abnormal. Here we examine this heterogeneity amongst biomarkers that reflect various aspects of the disease process.MethodCSF Amyloid positive individuals’ data from Alzheimer’s Disease Neuroimaging Initiative (ADNIGO/2/3) were used (n = 376). Demographics were compared across diagnostic group using linear regression and Fisher’s exact tests where appropriate, table 1. CSF phosphorylated tau (ptau), whole‐brain and hippocampal volume, Logical memory (LM) and Trails A and B, and white matter hyperintensity (WMH) volumes were used to derive data‐driven subtypes using the z‐score version of the SuStaIn algorithm. The algorithm produced subtypes with differing patterns of biomarker orderings. SuStaIn calculated z‐scores using 86 CSF amyloid negative, APOE e4 non‐carrier healthy controls, selected from ADNIGO/2/3. Proportions of APOE e4 carriers, and clinical diagnosis were compared between subtypes using Fisher’s exact test.Result359 individuals were grouped into three subtypes (figure 1); determined using cross‐validation. Subtype one (n = 136) had an initial event of WMH, followed by LM, trails A and B, and whole‐brain volume (hippocampal sparing). Subtype two (n = 115) had initial events of ptau, followed by LM and hippocampal volume (tau‐led). Subtype three (n = 108) had initial events of LM total, followed by ptau and hippocampal volume (tau‐late). 17 individuals were not subtyped, as their biomarker data showed no significant abnormalities and would suggest that they are not on an AD pathway.There was a trend towards a higher proportion APOE e4 carriers in subtype one and three (p = .06). There was a significant difference in clinical diagnosis between subtypes (p < .001), with subtype one having a lower proportion of CNs and a higher proportion of MCIs than subtypes two and three (figure 1).ConclusionWe found considerable heterogeneity in biomarker progression sequences in individuals with elevated amyloid.