Cerebrospinal fluid proteomic profiling of individuals with prodromal Alzheimer's disease classified using two different neurodegenerative biomarkers (N) in A/T/N classification

EMIF-AD MBD Study Group

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BACKGROUND: The amyloid/tau/neurodegeneration (A/T/N) framework is a recent biomarker classification system. Several markers have been suggested for use as neuronal injury marker (N-component) and these may identify different subtypes. Here we investigated whether N-markers neurofilament light (NFL) and hippocampal volume (HCV) are associated with different pathophysiological processes as assessed by CSF proteomics in individuals with mild cognitive impairment and typical AD (MCI-AD, A+T+). METHOD: We included 176 individuals from the European EMIF-AD MBD study and Maastricht BB-ACL study. Based on CSF Aβ1-42 (A) and p-tau (T), individuals were classified as cognitively normal A-T- (CN, n=108, 58% women, mean age 63years). Based on CSF Aβ1-42 (A), p-tau (T) and NFL or HCV (N), individuals with MCI were classified as MCI A+T+N- or MCI A+T+N- (n=68, 56% women, mean age 71years). To define abnormality, center-specific cut-offs were used for Aβ1-42 and p-tau, and the Youden index (CN vs AD dementia) was used for NFL and HCV. We centrally generated CSF proteomic data using tandem tag mass spectrometry. We compared protein concentrations between A/T/N groups using ANOVA adjusted for age and sex (1/3observations per group minimum). We performed Gene Ontology enrichment analyses to uncover the biological pathways related to the dysregulated proteins in each group. RESULT: The distribution of A/T/N subgroups among MCI-AD individuals is presented in Figure 1. The majority of MCI-AD individuals had both impairments in NFL and HCV. The profile in MCI A+T+N(NFL)+ and MCI A+T+N(HCV)+ relative to CN were very similar with respectively 172 and 178 increased proteins and 39 and 28 decreased proteins. The increased proteins were enriched for cytoskeleton, synapses and neurons, energy metabolism, oxidative stress and immune system. The decreased proteins were related to other immune processes. Relative to MCI A+T+N(NFL)-, MCI A+T+N(NFL)+ showed 114 decreased proteins and 14 increased proteins. These decreased proteins were enriched for extracellular matrix, neurons and synapses, angiogenesis, immune system and lysosomes. The 14 increased proteins were related to cytoskeleton. MCI A+T+N(HCV)+ and MCI A+T+N(HCV)- showed a similar proteomic profile. CONCLUSION: Our results show that, in typical MCI-AD, NFL-based grouping identifies different AD subtypes while HCV-based grouping results in similar groups.
Original languageEnglish
Pages (from-to)e053030
JournalAlzheimer's & dementia : the journal of the Alzheimer's Association
Publication statusPublished - 1 Dec 2021

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