Cerebrospinal fluid proteomics and biological heterogeneity in Alzheimer’s disease: A literature review

Abstract

Alzheimer’s disease (AD) is the most common cause of dementia and is characterized by aggregation of amyloid and tau proteins in the brain. Results from genetic studies suggest that the pathophysiology underlying AD is complex, but studying this complexity in patients remains difficult. The cerebrospinal fluid (CSF) proteome contains a large number of proteins that can reflect ongoing biological processes. Proteomics techniques can be used to measure many proteins simultaneously in individual patients and may therefore provide an opportunity to study AD disease mechanisms. Here, we review the CSF proteomics literature to identify proteins consistently associated with AD, and perform pathway analyses on these proteins to study which biological processes may be involved in the disease. We performed a literature search of studies that investigated CSF proteomic alterations related to AD. We included original research articles when they measured at least 10 proteins in (antemortem) CSF in at least 10 individuals with AD, mild cognitive impairment (MCI) or controls. We examined if proteins were consistently related to AD, defined as consistent increase or decrease in AD vs. controls across studies. Next, we used the proteins identified as input to pathway analyses using Reactome to investigate which biological processes were enriched. In total, 29 studies were included that investigated AD-related changes to the CSF proteome, including a total of 1434 individuals with AD (of whom 47.1% had a CSF biomarker profile and 9.6% a postmortem examination consistent with AD) and 1380 controls. The studies reported 1 to 138 proteins associated with AD, of which 97 proteins were reported by two or more studies. Among proteins that were measured in more than one study, 27 (27.8%) showed consistent increases, 15 (15.5%) consistent decreases and 55 (56.7%) had contrasting results. Pathway analyses showed that AD-related proteins were enriched for hemostasis, lipoprotein and extracellular matrix pathways. These results indicate that proteomic alterations in CSF associated with AD reflect involvement of various biological pathways. The frequent occurrence of inconsistent protein level changes reported by different studies suggests that additional biological and/or (pre)analytical factors may influence the CSF proteome in AD, which should be further investigated in order to improve understanding of the biological complexity underlying AD.