Background:

Cholesterol andlipid-transport dysfunction contribute to Alzheimer’s disease (AD) pathophysiology. It has beenobserved that CSF APOA1 was lower in AD and associated with both MMSE and CSF pTau181¹. Preclinical evidence suggests thatincreasing APOA1 expression may improve cognition, reduce neuroinflammation, and support synaptic and myelin integrity^2-4. We describe the effect of investigational Spectris™ treatment on CSF lipid transport proteins.

Methods:

We conducted CSF proteomics in amyloid-positive MCI participants (n=10) enrolled in the FLICKER trial (NCT03543878)⁵. Participants used the investigational Spectris sensory stimulation device daily for 1 hour for 4 (N=5) or 8 (N=5) weeks (delayed startdesign). CSF was collected at baseline, 4 weeks, and 8 weeks; proteins were measured using unbiased tandem mass tag massspectrometry⁶. Changes in protein abundance were compared between participants who received 8 weeks treatment (n=5) andparticipants (n=5) who did not receive stimulation; proteins were mapped to published brain protein co-expression modules⁷ viaGo Elite (version 1.2.5) to assess the impact of Spectris treatment on AD-related pathophysiological pathways⁸. 

Results:

Spectris treatment induced consistent up-regulation of CSF lipid transport proteins, including APOA1, APOA2, and APOL1—key components of HDL-like lipid transport or metabolism (Figure 1). GO Elite pathway analysis demonstrated that 13/29 upregulated pathways involve lipid transport or metabolism (Figure 2).

Conclusion:

Spectris treatment increased CSF levels of lipid transport proteins in the treatment group. Enhanced CSF lipid-transportprotein levels may support myelin maintenance, synaptic repair, and immune regulation. These preliminary biomarker findingssuggest that modulation of HDL-like lipid transport proteins supports further investigation of lipid transport modulation as apotential brain resilience pathway and as a potential biomarker in future AD clinical trials.