HAI Book 2025 - Flipbook - Page 187
Baillet, Marion
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Transcutaneous auricular vagus nerve stimulation improves learning
and sleep-wake quality in older APOE-ε4 carriers
Marion Baillet1,2, Maxime Van Egroo1,2,3, Nina Engels-Domínguez1,3, Jill Grube1, Haley Fenlon1,
Emma E. Wiklund1, Lukas Heinrich1,3, Joost M. Riphagen1,2, Kathryn V. Papp2,4,5, Ronald G.
Garcia1,2,6, Roberta Sclocco1,2,7,8, Vitaly Napadow1,2,7,8, Heidi I. L. Jacobs1,2,3
1
Athinoula A. Martinos Center for Biomedical Imaging, Department of Radiology, Massachusetts General Hospital,
Boston, MA, US
2
Harvard Medical School, Boston, MA, US
3
Faculty of Health, Medicine and Life Sciences, Mental Health and Neuroscience Research Institute, Alzheimer
Centre Limburg, Maastricht University, Maastricht, NL
4
Center for Alzheimer Research and Treatment, Department of Neurology, Brigham and Women’s Hospital, Boston,
MA, US
5
Department of Neurology, Massachusetts General Hospital, Boston, MA, US
6
Department of Psychiatry, Massachusetts General Hospital, Boston, MA, US
7
Department of Radiology, Logan University, Chesterfield, MO, US
8
Department of Physical Medicine and Rehabilitation, Spaulding Rehabilitation Hospital, Boston, MA, US
Background: The locus coeruleus (LC) constitutes a critical site of initial tau accumulation, and modulates
cognitive processes and sleep, which are affected early on in Alzheimer9s disease. Here, we investigated the
potential of transcutaneous auricular vagus nerve stimulation (taVNS), a neuromodulatory technique presumed to
indirectly target LC activity, to improve learning and sleep-wake quality in asymptomatic older individuals.
Methods: Fifty-nine participants from WALLe, an ongoing single-site randomized intervention study comparing
repeated sham vs. stimulation, were included (Fig.1). Participants were invited for 10 separate visits over the
course of two weeks during which they received either sham or stimulation and completed the same version of a
Face-Name Associative Memory Exam (FNAME) to assess daily learning. A subset of participants had APOE
genotype (n=51) and objective measures of sleep-wake quality (n=50) derived from actigraphy recordings before
and during/after the intervention. Nonlinear mixed-effects models and paired t-tests were used to investigate
intervention-related changes in learning and in sleep-wake quality, respectively.
Results: While we did not observe an effect of taVNS on FNAME metrics (time*condition, all p>0.05), we found
that APOE-ε4 carriers receiving the stimulation exhibited greater practice effects on response times in recalling
the first letter of names compared to APOE-ε4 carriers in the sham condition, while no difference was observed
for non-carriers (time*condition*APOE, p=0.0002, Fig.2). Regarding sleep-wake quality, participants receiving the
stimulation displayed a decrease in the number of nocturnal awakenings compared to the sham condition
(p=0.032), and this effect was stronger among APOE-ε4 carriers (p=0.014, Fig.3).
Conclusions: Our findings indicate that repeated taVNS is beneficial for APOE-ε4 carriers by improving learning
and sleep-wake quality, suggesting taVNS may be an effective non-invasive intervention approach to modulate
cognition and sleep in at-risk individuals. Considering that this study is still ongoing, these preliminary results will
be reassessed in a larger sample.
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