Alzheimer’s Disease & Neuronal Dysfunction: Brain Stimulation as a Possible Substitute or Supplement for Medication?

As the world’s population ages, the global prevalence of Alzheimer’s disease (AD) rises, with about 50 million people currently diagnosed. By 2050, the global prevalence of AD dementia will triple from 50 to 150 million, with the majority of afflicted individuals residing in low- and middle-income nations. Today, the total healthcare spending for those with AD and related dementia is around $600 billion, constituting a significant socioeconomic burden. With the increasing projections of cases, this raises a major concern about the global economic impact if the cost of care ends up tripling or continues to exceed these costs. Despite a century of extensive research since Alois Alzheimer coined the disease in 1906, only symptomatic treatments are generally available. Unfortunately, symptomatic treatments serve primarily as symptom relievers rather than slowing disease progression. Two recently approved medications, Aducanumab and Lecanemab, that are currently only accessible to American residents offer some optimism. Still, with prohibitive annual price tags between $26,500 and $56,000 per patient, it will be challenging to reach the whole world’s population. The core aim of this thesis is to explore whether a new type of light-based brain stimulation can be used as a possible substitute or supplement to medication for the symptomatic or disease-modifying treatment of AD. The new type of light-based brain stimulation is based on the idea of substantially imperceptible flickering light, coined invisible spectral flicker. This treatment approach builds on studies in animal models showing a potential to target a new type of disease process — designated as neuronal dysfunction for the purposes of this thesis. Particularly, interneurons, a specific fast-spiking type, are dysfunctional in their capacity to control neuronal hyperactivation via their intrinsic inhibitory nature on the hyperactivity of pyramidal neurons. The treatment approach is thought to target the vicious cycle of β-amyloid peptide (Aβ)-dependent neuronal hyperactivation through enhanced inhibitory capacity. Enhanced inhibitory capacity is thought to be important for the brain to function properly. In this thesis, it is hypothesized that AD is tightly linked to the dysfunctional capability of interneuronal inhibition. Measuring the direct effects of interneurons in the human brain is difficult. However, this thesis examined the light characteristics of invisible spectral flicker and its effects on both healthy and Alzheimer’s diseased brains over the course of ten sequential studies presented in this thesis. In Study I, the procedure for a novel color mixing technique is provided. This facilitates the creation of various types of invisible spectral flickering light sources. Ultimately, this will enable investigators to conduct multiple studies connecting the light characteristics with physiological measures such as electroencephalography. In Study II, an innovative approach towards 40 Hz entrainment using invisible spectral flicker is presented. Due to substantially imperceptible flicker, it is also possible for future randomized, placebo-controlled clinical trials to be conducted with adequate double blinding. Additionally, it is anticipated that these interventions will significantly reduce levels of discomfort when compared to those involving stroboscopic flicker. In Study III, a possible advantage of determining the critical flicker fusion frequency by employing the staircase technique with a forced choice between two alternatives is demonstrated. In particular, the study demonstrates a portable experimental setup that may be employed in a straightforward manner to possibly improve the efficacy of light treatment for patients in the AD continuum. In Study IV, it is shown that changing the exposure angle from normal incidence to oblique incidence of 30 degrees will result in a small decrease in gamma entrainment. Furthermore, the study reveals no significant effect of brightness, confirms the highest entrainment with strobe, yet large entrainment and the highest comfort with invisible spectral flicker. In Study V, the importance of the red component within the composition of heterochromatic flickering light to secure a large gamma entrainment is demonstrated. Therefore, hinting at the significance of red in the invisible spectral flickering light. Furthermore, the study observes that heterochromatic flicker with amber/red and lime/red provides the largest influence on gamma entrainment. This result indicates that heterochromatic flicker between red and a wide spectrum source (such as lime and amber) might be the most optimal light source for administrating gamma entrainment with heterochromatic light sources. In Study VI, it is demonstrated that invisible spectral flicker has the capacity to elicit steady-state visually evoked potentials at a number of frequencies in the low gamma region, which ranges from 36 to 44 Hz. Additionally, the study detected no preference or tendency for any particular gamma stimulation frequency among the participants, and this held throughout the whole tested range. Without further analysis, there is currently no reason to re-evaluate the choice of 40 Hz for light-based brain stimulation based on the preliminary results of this experiment. In Study VII, the preliminary findings in the first clinical trial with a healthy elderly cohort established that 40 Hz stimulation with invisible spectral flicker appears safe to use with considerably high feasibility regarding user adherence. Thus, this motivated our research collaboration to continue to our subsequent second clinical trial to treat patients with mild-to-moderate Alzheimer’s disease. In Study VIII, the reported results in the second clinical trial indicate that the intervention with 40 Hz invisible spectral flicker seems safe for patients with mild to moderate AD. Feasibility and compliance with the usage of the intervention is substantially greater than in photobiomodulation studies, bright light therapy studies, and traditional pharmacological trials using medication. In terms of preliminary efficacy, the study indicates probable tendencies toward improvements in cognition, brain volume, and the capacity to temporarily and perhaps chronically modulate brain oscillations. Consequently, the results support the move to extensive Phase 2/3 randomized controlled trials for evaluating the efficacy and potential superiority of 40 Hz invisible spectral flicker compared to standard-of-care for the treatment of patients with mild-to-moderate AD. In Study IX, it is demonstrated that the research team is able to conduct a largescale clinical trial in 62 patients for the treatment of mild-to-moderate Alzheimer’s disease. Currently, the study has eight patients enrolled and is actively recruiting. Results from the trials are expected to be analyzed in Q1 of 2025. In Study X, it is demonstrated that it is possible to carry the research forward into a different indication, i.e., treatment of major depressive disorder, which is deeply tied to electrophysiological dysfunction and is considered a prodromal and potential preclinical stage of AD. This could open up the avenue for other disease-modifying light-based brain stimulation interventions throughout the Alzheimer’s disease continuum by including all preclinical, prodromal, and dementia stages of AD. In summary, the ten internal studies and new external research studies using lightbased brain stimulation have the potential to improve cognition, gamma activity, activities of daily living, sleep quality, and brain volume in mild-to-moderate Alzheimer’s disease patients. Owing to the complexity of substantial precedents from previous pharmaceutical Phase3̇ studies and the rapidly changing regulatory landscape, a larger Phase 3 study validating our Phase 1, and Phase 2 outcomes is needed before approval and patient access is possible. Further research is required prior to substituting pharmaceutical medication. Yet in terms of supplementation, the safety and feasibility evidence seems encouraging, and the question of which type of achievable efficacy can be provided is more pressing.