Synonyms: Gamma entrainment using sensory stimuli
Therapy Type: Procedural Intervention
Target Type: Amyloid-Related (timeline), Inflammation (timeline), Other (timeline)
Condition(s): Alzheimer's Disease
U.S. FDA Status: Alzheimer's Disease (Phase 1)
Company: Cognito Therapeutics, Inc.
GENUS refers to a non-invasive procedure being developed by Cognito Therapeutics. The company developed a device called GammaSense Stimulation, which delivers sensory stimuli at gamma band frequency in order to entrain gamma oscillations in the brain. An LED light flashing at 40 Hz for one hour boosts gamma power in visual (V1), prefrontal, and somatosensory cortices, and hippocampal CA1. It also increases synchronization between V1 and the other regions. A second paradigm combines light and sound at 40 Hz to strengthen gamma oscillations throughout auditory cortex, hippocampus, and medial prefrontal cortex.
In 5XFAD, APPPS1, and wild-type mice, one hour of light-based GENUS reportedly halved Aβ levels, and one week of GENUS in 6-month-old 5XFAD mice cut amyloid plaque load by two-thirds. In TauP301S, this regimen cut phosphorylated tau by 40 percent (Iccarino et al., 2016).
Neuron numbers were maintained in TauP301S mice for three weeks with GENUS starting at 7.5 months of age, when neurodegeneration begins in this model. In the inducible p25 neurodegeneration mouse model, six weeks of GENUS preserved neuron number and cortical thickness. In both models, GENUS maintained neuronal expression of genes affecting synaptic transmission and vesicle trafficking, protected DNA, increased the density of mushroom spines, and improved performance in the Morris water maze. In all models tested, GENUS lowered microgliosis and inflammatory gene expression, while increasing internalization of Aβ (Adaikkan et al., 2019). The combination of light and sound at 40 Hz in 6-month-old 5XFAD mice had similar effects to light alone, but reached more brain areas (Martorell et al., 2019).
A separate study linked acoustic stimulation to lowered amyloid plaques and increased microglial numbers in the hippocampi of 5XFAD mice (Lee et al., 2018). For a review on gamma band neural stimulation, see McDermott et al., 2018).
In a brief, independent pilot study conducted without Cognito Therapeutics, 10 days of 40 Hz light therapy did not affect amyloid load, as measured by PiB PET, in 10 AD patients (Ismail et al., 2018).
In April, 2018, Cognito Therapeutics began a Phase 1 trial called Overture to evaluate combined auditory and visual GENUS in 60 people with AD or mild cognitive impairment due to AD. Participants receive one hour of GENUS, or sham treatment, daily for six months, with a follow-up visit one month later to assess safety. The primary outcome is ADAS-Cog score, with amyloid imaging as a secondary outcome. The trial takes place at six sites in the U.S.
In May 2019, a second Phase 1 study called Etude began comparing dosing paradigms for auditory and visual GENUS in 20 people with AD or mild cognitive impairment due to AD. These include one hour once per day, one hour twice per day, one hour every other day, and 30 or 120 minutes twice per day. The primary outcomes are amyloid PET and safety; secondary, ADAS-Cog.
In November 2018, a third study called Flicker started evaluating the tolerability of a combined audio-visual stimulation for one hour per day on 10 people with AD. Five participants will receive eight weeks of GENUS; five will receive four weeks of no intervention followed by four weeks of intervention. These three trials are set to end in the fall of 2019.
For all trials of GENUS, see clinicaltrials.gov
Last Updated: 17 Jun 2019
Research Models Citations
- Ismail R, Hansen AK, Parbo P, Brændgaard H, Gottrup H, Brooks DJ, Borghammer P. The Effect of 40-Hz Light Therapy on Amyloid Load in Patients with Prodromal and Clinical Alzheimer's Disease. Int J Alzheimers Dis. 2018;2018:6852303. Epub 2018 Jul 30 PubMed.
- Iaccarino HF, Singer AC, Martorell AJ, Rudenko A, Gao F, Gillingham TZ, Mathys H, Seo J, Kritskiy O, Abdurrob F, Adaikkan C, Canter RG, Rueda R, Brown EN, Boyden ES, Tsai LH. Gamma frequency entrainment attenuates amyloid load and modifies microglia. Nature. 2016 Dec 7;540(7632):230-235. PubMed.
- Adaikkan C, Middleton SJ, Marco A, Pao PC, Mathys H, Kim DN, Gao F, Young JZ, Suk HJ, Boyden ES, McHugh TJ, Tsai LH. Gamma Entrainment Binds Higher-Order Brain Regions and Offers Neuroprotection. Neuron. 2019 Jun 5;102(5):929-943.e8. Epub 2019 May 7 PubMed.
- Martorell AJ, Paulson AL, Suk HJ, Abdurrob F, Drummond GT, Guan W, Young JZ, Kim DN, Kritskiy O, Barker SJ, Mangena V, Prince SM, Brown EN, Chung K, Boyden ES, Singer AC, Tsai LH. Multi-sensory Gamma Stimulation Ameliorates Alzheimer's-Associated Pathology and Improves Cognition. Cell. 2019 Apr 4;177(2):256-271.e22. Epub 2019 Mar 14 PubMed.
- Lee J, Ryu S, Kim HJ, Jung J, Lee B, Kim T. 40 Hz acoustic stimulation decreases amyloid beta and modulates brain rhythms in a mouse model of Alzheimers disease. BioRχiv. August 20, 2018.
- McDermott B, Porter E, Hughes D, McGinley B, Lang M, O'Halloran M, Jones M. Gamma Band Neural Stimulation in Humans and the Promise of a New Modality to Prevent and Treat Alzheimer's Disease. J Alzheimers Dis. 2018;65(2):363-392. PubMed.
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