CSF proteomics in autosomal dominant Alzheimer’s disease highlights parallels with sporadic disease

Abstract

Autosomal dominant Alzheimer’s disease (ADAD) offers a unique opportunity to study pathophysiological changes in a relatively young population with few comorbidities. A comprehensive investigation of proteome changes occurring in ADAD could provide valuable insights into AD-related biological mechanisms and uncover novel biomarkers and therapeutic targets. Furthermore, ADAD might serve as a model for sporadic AD, but in-depth proteome comparisons are lacking. We aimed to identify dysregulated CSF proteins in ADAD and determine the degree of overlap with sporadic AD. We measured 1472 proteins in CSF of PSEN1 or APP mutation carriers (n = 22) and age- and sex-matched controls (n = 20) from the Amsterdam Dementia Cohort using proximity extension-based immunoassays (PEA) by Olink. We compared protein abundance between groups with two-sided t-tests and identified enriched biological pathways. Using the same protein panels in paired plasma samples, we investigated correlations between CSF proteins and their plasma counterparts. Finally, we compared our results with recently published PEA data from an international cohort of sporadic AD (n = 230) and non-AD dementias (n = 301). All statistical analyses were false discovery rate-corrected. We detected 66 differentially abundant CSF proteins (65 increased, one decreased) in ADAD compared to controls (q < 0.05). The most strongly upregulated proteins (fold change >1.8) were related to immunity (CHIT1, ITGB2, SMOC2), cytoskeletal structure (MAPT, NEFL) and tissue remodeling (TMSB10, MMP-10). Significant CSF-plasma correlations were found for the upregulated proteins SMOC2 and LILR1B. 36 of the 66 differentially expressed proteins had been previously measured in the sporadic dementias cohort, 34 of which (94%) were also significantly upregulated in sporadic AD, with a strong correlation between the fold changes of these proteins in both cohorts (rs = 0.730, p < 0.001). 29 of these 36 proteins (81%) were also upregulated among non-AD patients with suspected AD co-pathology. This CSF proteomics study demonstrates substantial biochemical similarities between ADAD and sporadic AD, suggesting involvement of the same biological processes. Besides known AD-related proteins, we identified several relatively novel proteins, such as TMSB10, MMP-10 and SMOC2, which have potential as novel biomarkers. With shared pathophysiological CSF changes, ADAD study findings might be translatable to sporadic AD, which could greatly expedite therapy development.

CSF biomarkers of immune activation and Alzheimer’s disease for predicting cognitive impairment risk in the elderly

“…REG4 was recognized as the top-ranked CSF immune activation marker predicting CDR conversion independently of other factors in cognitively unimpaired elderly. However, there were no apparent differences in CSF REG4 levels between control and MCI/AD subjects in other cohorts ( 55 , 56 ). CSF REG4 was up-regulated in AD compared to non-AD dementia cases including dementia with Lewy bodies and frontotemporal dementia ( 55 ).…”

“…Among the 85 immune activation markers associated with CDR conversion in our cohort with P values < 0.05 in unadjusted analysis, CSF levels of WNT9A, IL-6, and CXCL6 were altered in MCI cases with amyloid pathology compared to control groups ( 55 ). While higher CSF levels of MMP10, TNFSF13, ANGPTL4, LTBR, WNT9A, CD4, FLT3LG, CD84, MICB_MICA, and CCL23 were detected in AD cases than control groups in the 85 immune activation markers ( 55 ), another study also found the increases of MMP10, TNFSF13, and CD4 in CSF from autosomal dominant AD ( 56 ).These observations indicate that some CSF immune activation markers start changing even at presymptomatic early stages of cognitive impairment. REG4 was recognized as the top-ranked CSF immune activation marker predicting CDR conversion independently of other factors in cognitively unimpaired elderly.…”

“…Numerous studies have investigated CSF proteome profiling using the Olink proximity extension assay in MCI and AD cases ( 55 , 56 ). Among the 85 immune activation markers associated with CDR conversion in our cohort with P values < 0.05 in unadjusted analysis, CSF levels of WNT9A, IL-6, and CXCL6 were altered in MCI cases with amyloid pathology compared to control groups ( 55 ).…”

Proteostasis as a fundamental principle of Tau immunotherapy

“…This will be facilitated by an increased exploitation of fluid markers including plasma and cerebrospinal fluid for both diagnosis and therapeutic validation. 49–52…”

Global analysis of the heparin-enriched plasma proteome captures matrisome-associated proteins in Alzheimer’s disease

“…These studies revealed pathophysiological mechanisms such as synapse loss and neuroinflammation linked to immune, vascular, metabolic and extracellular matrix (ECM) dysfunction. Furthermore, integrated analyses across brain and biofluids demonstrated a significant overlap between brain network changes and the CSF proteome in AD, enabling early disease prediction even in the preclinical phase of AD 12, 14-16 . For example, CSF proteomic measurements in autosomal dominant AD (ADAD) that overlap with brain protein co-expression modules were recently used to define the evolution of AD pathology over a timescale spanning six decades 17 .…”