Developing Topics.

Abstract

Alzheimer's disease (AD) is a multifactorial disease including pre-clinical, prodromal and clinical phases. CSF "A/T/N" (Ab42, pTau181, tTau) biomarkers help characterize the biological state of AD. The primary aim was to assess contributions of eight CSF markers for predicting changes in cognition. CSF from 237 participants (CN: 176[74.3%], MCI: 33[13.9%], AD: 28[11.8%]) of the Australian Imaging, Biomarkers and Lifestyle (AIBL) study of ageing was used to measure Ab42 (GenII assay), pTau181, and tTau (Elecsys®) along with neurogranin, neurofilament light (NFL), α-synuclein, glial fibrillary acidic protein (GFAP), chitinase-3-like protein 1 (YKL-40), soluble triggering receptor expressed on myeloid cells-2 (sTREM2), s100 calcium-binding protein B (s100B), and interleukin-6 (IL-6) from the NeuroToolKit (NTK) panel of exploratory prototype assays (all Roche Diagnostics International Ltd). NTK biomarker concentrations were measured amongst each of four ATN groups at baseline; 1) A-/T-/N- (reference group), 2) A+/T±/N± (amyloid+), 3) A-/T±/N± (amyloid-), and 4) A+/T+/N+. Change in cognition was assessed using the pre-clinical Alzheimer's cognitive composite (PACC) and the clinical dementia rating sum of boxes (CDR-SB) scores, in all four ATN groups, stratified by low/high NTK biomarker over a minimum of 36 months. The primary outcome was defined as change in cognition in amyloid+ participants modulated by the addition of NTK markers to ATN groups. A+/T+/N+ participants had faster cognitive decline on both PACC and CDR-SB over time compared to all other groups (Figure 1A, PACC; Figure 1B, CDR-SB). Within the amyloid+ group, participants with high sTREM2 (K+) had a faster rate of decline in PACC compared to those with low sTREM2 (K-, p = 0.04; Figure 1C), whilst participants with high α-synuclein had a faster increase in CDR-SB compared with those with low α-synuclein (p = 0.005; Figure 1D). Amongst participants who were A+/T+/N+, those with high YKL40 had a significantly faster rate of decline in PACC (p = 0.017; Figure 1E), and a faster increase in CDR-SB, (p = 0.017; Figure 1F) compared with those who with low YKL40. Biomarkers of microglial activation (sTREM2), synaptic function and synuclein metabolism (α-synuclein), and astrocytic activation (YKL-40) may be appropriate to discern rates of cognitive change within amyloid+ participants. Findings are being validated in a separate population.