Discordance between CSF and PET biomarkers of amyloid pathology are associated with distinct pathophysiologic process in early stages of Alzheimer’s disease
Year: 2024
Type: article
Abstract: Background Alzheimer’s disease (AD) pathophysiology is complex. Decrease in CSF soluble Aβ42/40 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 Aβ42, amyloid PET, and CSF p‐tau into four groups (controls [Aβ42‐/ PET‐], Stage 1a [Aβ42+/ PET‐], Stage 1b [Aβ42‐/ PET+], Stage 2 [Aβ42+/ PET+]). Of note, Abnormal CSF Aβ42(+) was defined as < 976.6 pg/mL and normal (‐) as ≥ 976.6 pg/mL; abnormal brain amyloid by PET (+) was defined as 18F‐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 (Aβ42‐/PET‐) and Stage 1b (Aβ42‐/ PET+), or between Stage 1a (Aβ42+/ PET‐) and Stage 2 (Aβ42+/ PET+), after Benjamini‐Hochberg adjustment. We found 1462 proteins differentially expressed between controls (Aβ42‐/PET‐) and Stage 1a (Aβ42+/PET‐) related to abnormality in CSF soluble Aβ42. This number was much higher than 62 proteins differed between Stage 1b (Aβ42‐/ PET+) and Stage 1a (Aβ42+/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 Aβ42. Conclusion Our results reveal distinct pathophysiologic process associated with decrease in CSF soluble Aβ42 and increase in amyloid plaques measure by amyloid PET. Decrease in CSF Aβ42 appears to be more neurotoxic and are associated with more pathophysiological changes than increase in amyloid plaques at the early stages of AD.
Source: Alzheimer s & Dementia
DOI: 10.1002/alz.089461
Institution: University of Minnesota
Language: English
Subfield: Psychiatry and Mental health
Field: Medicine
Domain: Health Sciences
Open Access status: hybrid
Estimated APC paid: $4,000
OpenAlex ID: W4406210339