CSF proteomic analysis across the Alzheimer's disease continuum

Introduction

Alzheimer"s disease (AD) can be viewed as a continuum, starting with a preclinical phase that begins many years before onset of symptoms during which amyloid plaques start to accumulate in the brain, progressing to the clinical stage characterized by mild cognitive impairment, and finally on to Alzheimer"s disease dementia. Measuring proteomic changes in the cerebrospinal fluid (CSF) across the AD continuum can reveal at which point in the disease progression different pathological changes occur, identify staging biomarkers that can be used to monitor disease progression and the effect of treatments, and determine new therapeutic targets.

Methods

We performed a cross-sectional TMT proteomic study of CSF from the Translational Biomarkers in Aging and Dementia (TRIAD) cohort (n = 214); a highly profiled cohort with clinical and neuropsychological assessments as well as quantitative amyloid and tau positron emission tomography (PET) data that includes participants within the entire Alzheimer"s disease spectrum, as well as patients with frontotemporal dementia, other dementias, and healthy elderly and young individuals. Peptide correlation network analysis was performed to identify peptide clusters, and linear models were used to assess their changes across the disease stages. Many of the findings were validated using data from two previous CSF proteomics studies.

Results

Early proteomic changes were detected for proteins linked to endo-lysosomal dysfunction and APOE-related pathways (e.g. CTSD, SIAE, RELN, AGT) that increased in the beginning of the disease and returned to normal in the later stages. Many of these proteins correlated specifically with CSF Amyloid-beta 1-42, suggesting a link to amyloid pathology.

Several proteins known to be associated with neurodegenerative processes (e.g. NEFL, YWHAG, ALDOA) showed a gradual increase with disease progression and correlated strongly with tau PET SUVR, as well as with many phospho-tau forms (e.g., pTau217, pTau181, pTau231). Protein C4A/C4B also showed an increase across the AD continuum but correlated more strongly with pTau205.

Proteomic changes in the late disease stages involved proteins that reflect diverse neurodegenerative processes and an increase in blood-derived proteins (e.g., ALB, PLG) indicative of blood-brain barrier dysfunction, as well as a decrease in synaptic proteins that may reflect synaptic loss.

Conclusions

The concentration of many CSF proteins involved in diverse cellular and pathological processes change across the AD continuum, following different trajectories throughout the course of the disease. Some of these proteins may therefore be better for early diagnosis while others are more suitable to monitor disease progression and treatment effects. Our results also highlight the usefulness of correlating proteome changes to imaging and fluid biomarker data in addition to clinical assessments.