Discordance between CSF and PET biomarkers of amyloid pathology are associated with distinct pathophysiologic process in early stages of Alzheimer’s disease

Abstract Background Alzheimer’s disease (AD) pathophysiology is complex. Decrease in CSF soluble Aβ 42/40 and accumulation of amyloid plaques (by amyloid PET) are two distinct biomarkers of amyloid pathology. However, the pathophysiologic process associated with each biomarker is not clear. To this end, we examined CSF protein difference across biological stages defined by biomarkers, with emphasize on early stages of AD where CSF and amyloid PET evaluations are discordant. Method 392 nondemented participants from the Alzheimer’s Disease Neuroimaging Initiative (ADNI) were biologically defined based on CSF Aβ 42 , amyloid PET, and CSF p‐tau into four groups (controls [Aβ 42 ‐/ PET‐], Stage 1a [Aβ 42 +/ PET‐], Stage 1b [Aβ 42 ‐/ PET+], Stage 2 [Aβ 42 +/ PET+]). Of note, Abnormal CSF Aβ 42 (+) was defined as < 976.6 pg/mL and normal (‐) as ≥ 976.6 pg/mL; abnormal brain amyloid by PET (+) was defined as 18 F‐florbetapir > 1.11 SUVR and normal (‐) as ≤ 1.11 SUVR. All 4 groups had normal CSF p‐tau (defined as ≤ 26.47 ng/mL). SomaScan was used to measure over 7000 proteins in CSF proteome. Result There was no significant protein difference between controls (Aβ 42 ‐/PET‐) and Stage 1b (Aβ 42 ‐/ PET+), or between Stage 1a (Aβ 42 +/ PET‐) and Stage 2 (Aβ 42 +/ PET+), after Benjamini‐Hochberg adjustment. We found 1462 proteins differentially expressed between controls (Aβ 42 ‐/PET‐) and Stage 1a (Aβ 42 +/PET‐) related to abnormality in CSF soluble Aβ 42 . This number was much higher than 62 proteins differed between Stage 1b (Aβ 42 ‐/ PET+) and Stage 1a (Aβ 42 +/PET‐) related to abnormality in amyloid PET. GO enrichment analysis of biological pathways and cellular components suggested neuropeptide signaling pathway and extracellular process are the most significant pathway and cellular components related to amyloid PET; whereas numerous pathways in neuron, synapse, axon were enriched and represented by protein differences related to CSF soluble Aβ 42. Conclusion Our results reveal distinct pathophysiologic process associated with decrease in CSF soluble Aβ 42 and increase in amyloid plaques measure by amyloid PET. Decrease in CSF Aβ 42 appears to be more neurotoxic and are associated with more pathophysiological changes than increase in amyloid plaques at the early stages of AD.