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.

A comprehensive systematic review of CSF proteins and peptides that define Alzheimer’s disease

“…However, these 5 proteins appear both as increased and decreased in different proteomic studies. Although the number of studies included in Wesenhagen analysis was lower than ours, these findings are in agreement with their study [13], and prompts us to suggest that they cannot be considered as reliable CSF biomarkers of AD. While it is likely that heterogeneity in response direction may reflect irrelevant physiological or environmental factors, it is also interesting to speculate that this heterogeneity reflects unknown endophenotypes in AD.…”

“…Both can be considered high quality CSF biomarkers, as they represent abundant proteins which consistently change in the same direction in 14 and 6 AD proteomics studies, respectively. VGF is a member of the granin family of proteins [19] previously proposed as a good marker for AD [10,13], and a decrease in VGF-derived peptides in AD has been confirmed using other experimental approaches [14,20,21]. Interestingly, the 9 peptides that appear as reliable markers for the VGF down-regulation in AD correspond to both N-and C-terminal sequences, suggesting that the synthesis of the precursor protein itself is repressed in AD and not a specific derived peptide.…”

“…Among those that stand out due to their consistency within the various studies (bolditalic proteins in Table 3) we found Complement C3 (CO3, 6 studies), Alpha-2-macroglobulin (A2MG, 4 studies), FIBB (3 studies), Pyruvate kinase (KPYM, 3 studies) and Spondin-1 (SPON1, 3 studies). This set of proteins has previously been reported to increase in AD CSF [13]. However, our analysis, which includes only significant data, permits the identification of proteins with consistently increased levels in AD CSF whose potential as reliable AD biomarkers was previously overlooked.…”

“…Subsequently, Bastos et al compiled data from 18 proteomic studies to obtain 309 proteins expressed differentially in CSF obtained from AD patients vs. controls [12]. The most recent CSF proteomic analysis, which appeared while we were finishing our study, included 29 studies, of which 25 specifically investigated differences between AD and controls, and reported that 478 proteins exhibited different levels in AD compared to controls [13]. This analysis includes most of the proteins that have been shown to differ between AD and controls.…”

Association of CSF Proteins With Tau and Amyloid β Levels in Asymptomatic 70-year-olds 

“…CHL1 is processed and cleaved by BACE1 (46), the major beta secretase giving rise to amyloid-β peptides in AD through cleavage of the amyloid precursor protein (APP). It has been found at lower levels in CSF from MCI patients as well as patients with AD (47). Furthermore, NRCAM has been shown to be cleaved by ADAM10, which acts as an alpha-secretase for APP (48).…”