APOE4, AGE & SEX REGULATE RESPIRATORY PLASTICITY ELICITED BY ACUTE INTERMITTENT HYPERCAPNIC-HYPOXIA

bioRxiv preprint, 2023 · DOI: https://doi.org/10.1101/2023.01.06.522840 · Published: January 7, 2023

Simple Explanation

Acute intermittent hypoxia (AIH) is a novel rehabilitation strategy to induce functional recovery of respiratory and non-respiratory motor systems in people with chronic spinal cord injury and/or neurodegenerative diseases. Since most AIH trials report considerable inter-individual variability in AIH outcomes, we investigated factors that potentially undermine the response to an optimized AIH protocol, acute intermittent hypercapnic-hypoxia (AIHH), in healthy humans. We demonstrate that genetics (particularly the lipid transporter, APOE), age and sex are important biological determinants of AIHH-induced respiratory motor plasticity.

Study Duration

Not specified

Participants

17 healthy individuals (age=27±5 years)

Evidence Level

Not specified

Key Findings

1
AIHH-induced changes in diaphragm MEP amplitudes were lower in individuals heterozygous for APOE4 (i.e., APOE3/4) allele versus other APOE genotypes (p=0.048).
2
Males exhibited a greater diaphragm MEP enhancement versus females, regardless of age (p=0.004).
3
Age was inversely related with change in P0.1 within the limited age range studied (p=0.007).

Research Summary

We investigated the role of genetics, age and sex on AIHH-induced respiratory motor plasticity of both cortical (presumably volitional) diaphragm MEPs and brainstem automatic (P0.1) neural pathways in healthy adults. We report increased diaphragm MEP amplitudes following AIHH are diminished in people heterozygous for the APOE4 allele and unaffected in BDNFval/met heterozygotes. Experiments using humanized APOE4 knock-in rats support a causal relationship between APOE4 and impaired AIHH-induced respiratory motor plasticity.

Practical Implications

Personalized Rehabilitation Strategies

Age, sex, and APOE4 allele status should be considered when designing AIHH-based rehabilitation protocols.

Targeted Therapies

Future studies should explore therapeutic targets to mitigate the dysfunctional effects of the APOE4 genotype to unlock AIHH-induced neuroplasticity in APOE4 carriers.

Clinical Trial Stratification

Stratifying participants based on genetic risk factors like APOE4 may improve the success of AIH/AIHH clinical trials.

Study Limitations

1
Limited number of genes and SNPs investigated
2
Adequate correction for multiple comparisons will remain a challenge.
3
Need to increase the age range studied beyond 40 years and extend investigations to people living with disease or injury.

Your Feedback

Was this summary helpful?

Back to Physiology