CSF proteomics reveals changes in myelin and synaptic biology after Spectris treatment
Authors: Hajós Mihály , Pandey Kiran , Singer Annabelle C. , Duong Duc , Bitarafan Sara , Shpokayte Monika , Malchano Zach , Kern Ralph , Lah James J. , Levey Allan I. , Seyfried Nicholas T. 
Published: February 2025

INTRODUCTION

Brain steady‐state gamma oscillations evoked using a non‐invasive medical device (Spectris) have shown potential clinical benefits in patients with mild–moderate Alzheimer's disease (AD), including reduced functional and cognitive decline, reduced brain volume and myelin loss, and increased brain functional connectivity. We analyzed changes in cerebrospinal fluid (CSF) proteins after Spectris treatment in mild cognitive impairment (MCI) and their relationship to established biological pathways implicated in AD.

METHODS

Unbiased proteomic analysis of CSF samples from participants with amyloid‐positive MCI (n = 10) was conducted from the FLICKER (NCT03543878) clinical trial. Participants used the Cognito Therapeutics medical device (Spectris), confirmed to evoke steady‐state gamma oscillations. Participants were instructed to use the device daily for 1 hour each day during the trial. CSF was collected prior to the start of stimulation and after 4 and 8 weeks of treatment. The proteome was analyzed using tandem mass tag mass spectrometry.

RESULTS

Differential expression analysis of proteins at baseline and after 8 weeks of treatment (N = 5) revealed that 110 out of 2951 proteins met the significance threshold (analysis of variance, P < 0.05, no false discovery rate). Sixty proteins were upregulated, and 50 proteins were downregulated after treatment. Changes in protein expression were mapped to the consensus human AD protein network, representing co‐expressed and functionally linked modules linked to cell type and biochemical pathways. Treatment altered CSF proteins linked to AD‐related brain proteome modules, including those involved in myelination (proteolipid protein 1, ecotropic viral integration site 2A), synaptic and neuroimmune functions, and regulation of cellular lipid transportation. Biological pathway analysis revealed that most impacted pathways were associated with lipoproteins, cholesterol, phospholipids processing, and phosphatidylcholine biosynthesis.

DISCUSSION

The CSF proteomic changes observed in this study suggest pleiotropic effects on multiple pathways involved in AD, including myelination, synaptic and neuroimmune function, and lipid transport. These findings are also consistent with observations of white matter and myelin preservation after Spectris treatment of AD.

Highlights

We analyzed changes in cerebrospinal fluid (CSF) proteins in response to sensory‐evoked gamma oscillations in individuals with mild cognitive impairment.

Sensory evoked steady‐state gamma oscillations were evoked by Spectris medical device.

Changes in CSF proteins were observed after 8 weeks of daily 1 hour treatment.

Affected proteins were related to myelination, synaptic and neuroimmune functions, and regulation of cellular lipid transportation.

Proteomic changes support clinical outcomes and myelin preservation of Spectris treatment.