CSF Proteomic Signatures are Associated With Cognitive Decline in the Alzheimer’s Disease Continuum

Abstract

AbstractBackgroundIndividuals with Alzheimer’s disease (AD) show variability in cognitive decline. Little is known about the underlying biological processes. Using an untargeted CSF proteomics approach, we explored the biological processes associated with cognitive decline throughout the AD continuum.MethodWe included 280 AD individuals from the Amsterdam Dementia Cohort (median age 66 (IQR:60‐70) years, 124 (44%) female, n = 34 preclinical AD, n = 77 MCI due to AD, n = 169 AD‐dementia, all abnormal CSF amyloid, Table 1). The CSF proteome was quantified at baseline using LC‐MS/MS in an untargeted manner based on TMT labelingWe included n = 2318 proteins measured in ≥50% individuals. We used the MMSE score as a proxy for global cognition, and created summary scores for cognitive domains (i.e., episodic memory, executive functioning, attention and language) using neuropsychological test scores. We applied linear mixed models to test the association between each protein and cognitive decline over time, with age, sex and education as covariates, a random intercept for patient ID, and a random slope for time; stratified for syndrome diagnosis. We performed pathway enrichment analysis on proteins associated with cognitive decline.ResultIndividuals with preclinical AD showed most decline on episodic memory compared to other domains. In preclinical AD, 150 proteins, enriched for cell death and cell adhesion, were associated with memory decline. Individuals with MCI showed most decline on episodic memory and executive functioning. Proteins associated with decline on memory (n = 188, Figure 1) and executive functioning (n = 213) were enriched for complement and coagulation cascade and innate immune processes. Proteins associated with memory decline were also enriched for synaptic plasticity. Individuals with AD‐dementia showed more decline on attention and language compared to other AD‐stages. In AD‐dementia, 69 proteins, enriched for innate immune processes, were associated with decline on the MMSE and 127 proteins, enriched for synaptic plasticity, were associated with decline on language.ConclusionProteins involved in innate immune processes, synaptic plasticity and cell death were associated with cognitive decline in AD, with different processes involved in different stages. These results provide insight into the pathophysiology of cognitive decline and hint towards potential therapeutic targets for prevention of cognitive decline in AD.