Biomarkers.

Background: Extracellular vesicles (EVs) are lipid bilayer nanoparticles (30-10,000 nm) released from all cells that facilitate cell-to-cell communication. Cell type-specific EVs can be enriched using cell-specific surface markers. Neuronal-enriched EVs (NEVs) contain measurable neurotrophins, pro- and mature brain-derived neurotrophic factor (BDNF), that have opposing action in neuronal plasticity. Exercise shifts the proBDNF/BDNF ratio toward BDNF, potentially enhancing brain health. This study investigates the relationship between NEV proBDNF/BDNF, Default Mode Network (DMN), and a BDNF polymorphism (Val66Met) in the context of the NIH-funded "Risk Reduction for Alzheimer's Disease" (rrAD) trial (NCT02913664).

Method: rrAD is a phase-II randomized controlled trial with banked plasma and neuroimaging from 512 cognitively normal subjects (ages 60-85, 34% aged 65-85) with a family history of Alzheimer's Disease (AD) and/or memory complaints. The 372 subjects that provided DNA consent were genotyped for Val66Met (Rs6265). EVs were isolated using ExoQuick followed by anti-NCAM-L1 immunoprecipitation and analyzed for size/concentration with a Zetaview NTA. Levels of proBDNF/BDNF protein were quantified by ELISA in baseline, 12, and 24-month plasma samples. MRI was performed on 3T scanners. Resting state functional (rs-f) MRI data was pre-processed using AFNI and ICA-based strategy was used for noise reduction.

Result: Of 372 consenting rrAD participants, 68% were Val/Val and 32% Met-carriers (Val/Met and Met/Met). Of Met carriers, 56% were male (sex vs. Met-carrier, P=0.33). A preliminary blinded cohort of EV isolation in n=21 subjects showed a substantial impact of BDNF Val66Met polymorphism on the proBDNF/BDNF ratio at baseline and 12 months. Higher BDNF in NEVs coincided with significantly stronger rs-fMRI connectivity in the ventral and dorsal DMN (P =0.02). However, the precise nature of this relationship and how it relates to rrAD intervention responses remains to be fully understood.

Conclusion: The study highlights the potential of BDNF polymorphisms in affecting the proBDNF/BDNF ratio and DMN activity, offering a valuable tool for disease prognosis and therapeutic effectiveness. It also suggests that AD trials need to account for BDNF polymorphisms to determine whether interventions aimed at slowing/preventing dementia are influenced by genetic factors and/or sex.