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. 2026 Apr 26;28(1):177–187. doi: 10.1080/19585969.2026.2658530

Therapeutic effects of 40 Hz light stimulation on clinical and pathological features of Alzheimer’s disease

Ping-Song Chou a,b,c,d, Ching‑Fang Chien a,b,c,d, Ling‑Chun Huang a,b,d,e, Yuan‑Han Yang a,b,d,e,✉
PMCID: PMC13112872  PMID: 42035365

Abstract

Background

Current pharmacological treatments offer only limited benefits in altering the course of Alzheimer’s disease (AD). Given these limitations, nonpharmacological interventions have emerged as potential therapeutic strategies. This study investigates the therapeutic effects of 40 Hz light stimulation in AD and analyzes blood biomarkers to explore its potential disease-modifying effects.

Methods

This longitudinal study examined the effects of 40 Hz light stimulation on clinical symptoms and blood biomarkers in AD patients. Fourteen individuals were enrolled, with 11 completing the 3-month light stimulation, and 6 continuing to 6 months for the final blood biomarker analysis, including amyloid beta (Aβ) oligomers, Aβ-40, Aβ-42, tau phosphorylated at threonine 181 (p-tau181) and 217 (p-tau217), and neurofilament light chain.

Results

At 3 months, cognitive function remained stable or improved in 63.6% of participants, depressive symptoms improved in 54.5%, caregiver burden decreased in 72.7%, and sleep quality improved in 90.9% (p = .014). At 6 months, cognitive function and neuropsychiatric symptoms remained stable or improved in 33.3% and 66.7% of participants, respectively. Biomarker analysis showed decreased Aβ oligomers, increased Aβ-42 and reduced p-tau, suggesting potential disease-modifying effects.

Conclusions

40 Hz light stimulation demonstrated short-term benefits in cognitive stability, caregiver burden relief, and sleep improvement, with biomarker findings indicating possible neuroprotective effects.

Keywords: Amyloid-beta, biomarkers, visual gamma entrainment, tau protein

Introduction

Alzheimer’s disease (AD) is a major global health challenge, affecting millions of individuals worldwide. According to the World Health Organisation, more than 55 million people have dementia, with AD accounting for 60% to 80% of cases (2024 Alzheimer’s disease facts and figures 2024). AD is characterised by pathological changes in the brain, including amyloid-beta (Aβ) deposition, tau hyperphosphorylation, and neurodegeneration (Bloom 2014). Although amyloid plaques, composed of insoluble fibrillar Aβ, represent a classical pathological hallmark, growing evidence indicates that soluble Aβ oligomers are the more neurotoxic species. These oligomers disrupt synaptic function and initiate a cascade of events leading to downstream neurodegeneration (Hampel et al. 2021). Blood-based biomarkers have become valuable tools for diagnosing diseases early, monitoring their progression, and evaluating therapeutic interventions. Among these biomarkers, Aβ oligomers, Aβ-40, Aβ-42, and tau phosphorylated at threonine 181 (p-tau181) and 217 (p-tau217) are key indicators of amyloid and tau pathology (Hansson et al. 2023; Youn et al. 2020). Neurofilament light chain (NfL), a marker of axonal injury, is also a biomarker for neurodegeneration in AD, and an increased NfL level is associated with disease progression and cognitive decline (de Wolf et al. 2020). Assessing these biomarkers could be a non-invasive and accessible approach to determining the effectiveness of interventions for AD.

Cognitive impairment and the behavioural and psychological symptoms of dementia (BPSD) substantially affect both patients with AD and their caregivers (Isik et al. 2019). Sleep disturbances are also highly prevalent in patients with AD and are considered both a consequence of and a contributing factor to disease progression (Chen et al. 2024). These challenges not only adversely affect patients’ quality of life but also place a substantial burden on caregivers. Addressing cognitive impairment, behavioural symptoms, and sleep disturbances requires comprehensive management strategies tailored to the needs of both patients and caregivers.

Although advancements have been made in research, effective treatments for AD remain limited, highlighting an urgent need for novel therapeutic strategies. Pharmacological treatments for AD, such as cholinesterase inhibitors (e.g. donepezil and rivastigmine) and N-methyl-D-aspartate receptor antagonists (e.g. memantine), provide symptomatic relief but have limited efficacy in slowing disease progression (Briggs et al. 2016). Although advances in disease-modifying therapies, such as antiamyloid monoclonal antibodies, offer potential benefits, their use remains constrained by high costs, limited accessibility, and risks of adverse effects, including amyloid-related imaging abnormalities (van Dyck et al. 2023). Because of these limitations, nonpharmacological interventions have gained attention in academia for their safety, accessibility, and potential to improve cognition and quality of life. Approaches such as cognitive stimulation, physical exercise, dietary interventions, and sensory-based therapies (e.g. light therapy and music therapy) have demonstrated promise in improving cognitive function, mood, sleep quality, and overall well-being (Wang et al. 2020).

Photobiomodulation (PBM) is a therapeutic technique that uses light to stimulate cellular activity, promote tissue repair, and reduce inflammation. In AD, PBM has emerged as a non-invasive and promising approach to address underlying pathological mechanisms. These include enhancing mitochondrial function, reducing oxidative stress, modulating neuroinflammation, promoting neurogenesis and synaptogenesis, and potentially mitigating the characteristic pathological features of AD (Ramanishankar et al. 2024; Stepanov et al. 2022).

Two primary modalities of PBM—continuous wave (CW) and pulsed wave (PW), particularly at a frequency of 40 Hz—exhibit distinct mechanisms and therapeutic effects in AD. Although both aim to deliver clinical benefits, their underlying actions and consequent effects on the brain may differ substantially.

CW PBM delivers a steady, uninterrupted stream of red and near-infrared light, and its primary mechanism is thought to enhance mitochondrial function by increasing cytochrome c oxidase activity, thereby promoting adenosine triphosphate (ATP) production (Cardoso et al. 2022). In addition, CW PBM has been shown to reduce oxidative stress by enhancing the activity of antioxidant enzymes, and to attenuate inflammation by modulating inflammatory pathways and suppressing the production of pro-inflammatory cytokines (Ramanishankar et al. 2024). Evidence also suggests that CW PBM enhances microglia-mediated phagocytosis of Aβ, thereby promoting its clearance from the central nervous system (Stepanov et al. 2022). Furthermore, CW PBM may restore synaptic plasticity in degenerating neurons and reduce Aβ burden by modulating cholesterol dysregulation (Golovynska et al. 2025). It has also been reported to decrease Aβ production and plaque formation by shifting amyloid precursor protein processing towards the non-amyloidogenic pathway, ultimately improving memory and cognitive performance in AD mouse models (Zhang et al. 2020). Clinically, CW PBM treatment has been associated with improved cognitive function and activities of daily living, and appears to be safe and potentially beneficial for patients with AD (Chen et al. 2023).

In contrast, PW PBM at 40 Hz offers a more targeted approach that leverages the brain’s natural neuronal oscillatory rhythms, and has shown promise in AD research. Gamma oscillations at 40 Hz are closely linked to cognitive function, neural synchronisation, and memory consolidation (Deng et al. 2024). In AD, gamma activity is often impaired, contributing to neurodegeneration and cognitive decline (Traikapi and Konstantinou 2021). The core principle of 40 Hz PBM is a phenomenon known as neural entrainment, whereby flickering light at 40 Hz is used to restore disrupted neural oscillations. The therapeutic benefits of 40 Hz light stimulation in AD may be attributed to its ability to attenuate disease-associated pathology, including modulation of microglial phagocytic activity, promotion of amyloid clearance, reduction of plaque formation (Iaccarino et al. 2016), and preservation of synaptic plasticity and mitochondrial function (Barzegar Behrooz et al. 2024).

Although both CW PBM and PW PBM have been shown to reduce Aβ peptide aggregation and improve cognitive performance in AD mouse models (Xu et al. 2024), the pulsed 40 Hz approach offers a distinct advantage by specifically targeting and restoring the brain’s critical gamma rhythms. This unique mechanism not only confers general neuroprotection but also directly addresses core pathological processes of AD, positioning it as a potentially disease-modifying strategy. Consequently, 40 Hz light stimulation may represent an innovative and effective therapeutic modality for AD.

Human trials have indicated that this non-invasive approach may provide cognitive benefits, positioning it as a potential adjunctive therapy for AD management. Studies have reported that 40 Hz light stimulation could slow global functional decline, preserve cognitive function, improve neuropsychiatric symptoms, and reduce caregiver burden in patients with AD (Chan et al. 2022; Li et al. 2024). However, evidence on the impact of 40 Hz light stimulation on AD biomarkers remains limited. A short-duration 40 Hz light therapy regimen did not reduce cortical amyloid load in patients with early AD (Ismail et al. 2018). Further studies are warranted to determine whether extended treatment durations might yield therapeutic benefits.

In the present study, we examined the effects of 40 Hz light stimulation on cognition, BPSD, caregiver burden, and sleep disturbances in patients with AD. As a novel aspect, we also analysed blood biomarkers to assess the impact of 40 Hz light stimulation on amyloid, tau, and other neurodegenerative processes. The findings provide new insights into the mechanisms underlying the therapeutic effects of 40 Hz light stimulation and support its potential as a non-invasive intervention for neurodegenerative diseases.

Method

Participants

This study enrolled individuals who received a clinical diagnosis of AD from a neurologist or psychiatrist in accordance with the guidelines of the National Institute on Aging–Alzheimer’s Association (McKhann et al. 2011) or the Diagnostic and Statistical Manual of Mental Disorders, Fifth Edition. Individuals were considered eligible if they were aged between 50 and 100 years. Because light stimulation was administered as an adjuvant non-pharmacological therapy, all participants continued to receive acetylcholinesterase inhibitors (donepezil or rivastigmine) as part of their standard AD treatment.

We excluded patients residing in nursing homes, those with a history of epilepsy or febrile seizures, and those with severe uncorrected visual impairments. Patients with substantial cognitive or sensory deficits that would prevent reliable neuropsychological assessment, including severe hearing impairment despite the use of hearing aids or severe aphasia, were also excluded. Moreover, individuals who were bedridden and unable to move independently were excluded.

This study was approved by the Institutional Review Board of Kaohsiung Medical University Hospital (KMUHIRB-SV(I)-20230011). Written informed consent was obtained from all participants and their relatives before enrolment.

Intervention

Participants were assigned to receive daily exposure to a commercially available light fixture (Delta M + BrainCare Light, Delta Electronics, Taipei, Taiwan). The device utilises patented multi-frequency lighting technology that renders the 40 Hz flicker imperceptible to the human eye. It features an inner white light-emitting diode (LED) that generates the 40 Hz visual flicker, alongside an outer non-flickering general light within the same luminaire. The Delta M + BrainCare Light has a colour temperature of 4000 K and delivers an intensity of 400 lx at a distance of 100 cm. Its smooth, continuous white light is suitable for normal daily activities. Previous studies have demonstrated that the Delta M + BrainCare Light can reduce tau pathology, inhibit Aβ-42 secretion and aggregation, and enhance microglial phagocytosiss (Chang et al. 2024). In addition, it offers a feasible and practical intervention model for patients with AD in day-care settings (Li et al. 2024).

In this home-based study, the Delta M + BrainCare Light was incorporated into a desk lamp and placed in the area of the home most frequently used by each participant, allowing the device to fit naturally into their daily routines. As it was intended for home use, there were no specific requirements regarding irradiation distance or targeted body areas. Participants were instructed to use the lamp for at least 1 h per day, 5 to 7 days per week. The duration of daily light exposure was recorded by either the participants or their caregivers.

After the initial 3-month period, the participants underwent their first follow-up clinical and neuropsychological assessments. Those who chose to continue light stimulation completed a second follow-up assessment, including biomarker measurements, at 6 months.

Clinical and neuropsychological assessments

Baseline demographic data, including age, sex, education level, occupation, medical history, and family history of dementia, were collected. Participants underwent a comprehensive battery of neuropsychological assessments at baseline and at 3- and 6-month intervals. These assessments included the Cognitive Abilities Screening Instrument (CASI), the Clinical Dementia Rating (CDR) scale, the CDR-Sum of Boxes (CDR-SB), the Neuropsychiatric Inventory Questionnaire (NPI-Q), and the Geriatric Depression Scale (GDS). The CASI-estimated Mini-Mental State Examination (MMSE) score (MMSE-CE) was also calculated because some CASI items could be converted to match the MMSE scoring system (Teng et al. 1994). The Zarit Burden Interview (ZBI) was used to assess caregiver burden. In addition, sleep quality and daytime sleepiness were evaluated using the Pittsburgh Sleep Quality Index (PSQI) and the Epworth Sleepiness Scale (ESS), respectively.

Biomarker measurement

To investigate the potential effects of 40 Hz light stimulation on amyloid, tau, and neurodegenerative processes in AD, blood biomarkers were analysed. Blood samples were collected from the antecubital vein by using EDTA tubes, with approximately 10 mL of blood drawn per participant. Plasma and genetic analyses were performed, including apolipoprotein E (ApoE) genotyping and protein measurements for Aβ oligomers, Aβ-40, Aβ-42, p-tau181, p-tau217, and NfL. Blood biomarkers were measured at baseline and after 6 months of light stimulation.

Quantification of Aβ oligomers, Aβ-40, Aβ-42, p-tau181, p-tau217, and NfL in plasma was performed using specific enzyme-linked immunosorbent assay kits: oligomeric amyloid-β ELISA kit (FitFocus, Shanghai, CHN, code ABOELAL); the human amyloid β (1-40) assay kit (Invitrogen, Waltham, MA, USA, code KHB3481); the human amyloid β (1-42) assay kit (Invitrogen, code KHB3441); the human tau (pT181) assay kit (Invitrogen, code KHO06310); the human phospho tau (217 P) ELISA kit (Immuno-Biological Laboratories Co., Gunma, Japan, code 27904); and the human neurofilament protein L (NF-L) ELISA kit (CUSABIO, Houston, TX, USA, catalogue CSB-E16094h). All assays were performed in accordance with the manufacturer’s instructions. Reagents were prepared at room temperature (20 °C to 25 °C) approximately 30 min before use.

Statistical analysis

Statistical analyses were performed using SPSS (version 19.0; SPSS Statistics, Chicago, IL, USA). Categorical variables are presented as numbers and proportions, and continuous variables are expressed as means and standard deviations or medians and interquartile ranges (IQRs). Within-subject changes in clinical and neuropsychological assessments and biomarker data over time were analysed using the Wilcoxon signed-rank test after the 40 Hz light stimulation at 3- and 6-month intervals. A 2-tailed P value of <.05 was considered significant.

Results

A total of 14 patients with AD were enrolled. However, 2 participants withdrew for personal reasons, leaving 12 individuals who completed the initial assessment and began 40 Hz light stimulation. Of these, 11 completed the 3-month follow-up clinical and neuropsychological assessments.

Among the participants, 8 continued and completed 6 months of 40 Hz light stimulation, and all of them underwent follow-up clinical and neuropsychological assessments. Blood biomarker analysis was also conducted at the 6-month mark. However, one participant was excluded because of sample quality problems, and another was excluded because of poor adherence to 40 Hz light stimulation. Thus, 6 participants were included in the final biomarker analysis. The use of the M + BrainCare Light was well tolerated, with no participants reporting discomfort and no dropouts attributable to adverse effects.

Baseline characteristics

Of the 12 participants who completed the initial assessment, 5 were men and 7 were women, with a mean age of 81.0 ± 4.2 years (range: 73 to 87 years) and an average education level of 9.8 ± 5.8 years (range: 0 to 18 years). Dementia severity, as assessed using the CDR scale, was distributed as follows: 1 participant had a CDR score of 0, 2 had a score of 0.5, 8 had a score of 1.0, and 1 had a score of 2.0 (Table 1).

Table 1.

Baseline demographic data and clinical characteristics of all participants.

N = 12  
Age (years)1 81 ± 4.2
Sex (male)2 5 (41.7%)
Education level (years)1 9.8 ± 5.8
MMSE-CE3 22 (11.75, 24.25)
CASI3 68 (39, 79.5)
CDR-SB3 6.5 (4.25, 8.75)
CDR2  
 0 1 (8.3%)
 0.5 2 (16.7%)
 1.0 8 (66.7%)
 2.0 1 (8.3%)
NPI-Q3 5 (2.25, 8.5)
GDS3 1 (0, 3.25)
ZBI3 35.5 (22.5, 45.25)
PSQI3 4.5 (2.25, 10.25)
ESS3 3 (0, 11)
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CASI: Cognitive Abilities Screening Instrument; CDR: Clinical Dementia Rating; CDR-SB: CDR-Sum of Box; ESS: Epworth Sleepiness Scale; GDS: Geriatric Depression Scale; MMSE-CE: CASI-Estimated Mini-Mental State Examination; NPI-Q: Neuropsychiatric Inventory Questionnaire; PSQI: Pittsburgh Sleep Quality Index; ZBI: Zarit Burden Interview.

1

Mean ± standard deviation (SD); 2N (%); 3median (interquartile range, IQR).

At baseline, the participants exhibited varying degrees of cognitive impairment and behavioural symptoms. The median MMSE-CE score was 22 (IQR: 11.75 to 24.25), and the CASI had a median score of 68 (IQR: 39 to 79.5), indicating mild to moderate cognitive dysfunction. Dementia severity, measured using the CDR-SB, had a median score of 6.5 (IQR: 4.25 to 8.75). For BPSD, the NPI-Q had a median score of 5 (IQR: 2.25 to 8.5), and the GDS had a median score of 1 (IQR: 0 to 3.25), indicating mild neuropsychiatric disturbances. Caregiver burden, assessed using the ZBI, had a median score of 35.5 (IQR: 22.5 to 45.25). Sleep disturbances were also evaluated, with the PSQI yielding a median score of 4.5 (IQR: 2.25 to 10.25), whereas daytime sleepiness, measured using the ESS, had a median score of 3 (IQR: 0 to 11) (Table 1).

Light stimulation outcomes

Eleven participants completed 3 months of 40 Hz light stimulation, with an average total exposure of 201.1 ± 120.9 hours (range: 44.0 to 483.5 hours). After 3 months, the MMSE-CE, CASI, CDR-SB, and CDR scores remained stable or improved in 36.4%, 63.6%, 63.6%, and 63.6% of participants, respectively. In terms of BPSD, the NPI-Q and GDS scores remained stable or improved in 54.5% of participants. Caregiver burden decreased in 72.7% of caregivers. Sleep quality improved or remained stable in 90.9% of participants (p = .014), whereas 63.6% reported improved or stable daytime sleepiness. These findings indicated the short-term benefits of 40 Hz light stimulation in terms of cognition, BPSD, caregiver burden, and sleep quality in patients with AD (Table 2; Supplement Figure 1).

Table 2.

Clinical response after 3-month 40 Hz light stimulation.

N = 11 Pre-40 Hz Post-40 Hz Stable or improving p Value2
MMSE-CE1 22 (11, 25) 21 (11, 23) 36.4% 0.241
CASI1 66 (35, 80) 72 (33, 79) 63.6% 0.624
CDR-SB1 7 (5, 9) 6.5 (4, 10) 63.6% 0.610
CDR1 1.0 (1.0, 1.0) 1.0 (0.5, 2.0) 63.6% 0.098
NPI-Q1 5 (2, 7) 6 (2, 9) 54.5% 0.200
GDS1 1 (0, 4) 1 (1, 4) 54.5% 0.201
ZBI1 35 (21, 46) 36 (22, 46) 72.7% 0.789
PSQI1 5 (2, 11) 4 (1, 9) 90.9% 0.014*
ESS1 4 (0, 12) 3 (0, 10) 63.6% 0.943
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CASI: Cognitive Abilities Screening Instrument; CDR: Clinical Dementia Rating; CDR-SB: CDR-Sum of Box; ESS: Epworth Sleepiness Scale; GDS: Geriatric Depression Scale; MMSE-CE: CASI-Estimated Mini-Mental State Examination; NPI-Q: Neuropsychiatric Inventory Questionnaire; PSQI: Pittsburgh Sleep Quality Index; ZBI: Zarit Burden Interview.

1

Median (interquartile range, IQR); 2Wilcoxon signed-rank test.

*

p < .05.

Six participants completed 6 months of 40 Hz light stimulation, with an average total exposure of 296.5 ± 137.9 hours (range: 160.2 to 526.3 hours). After 6 months, the MMSE-CE, CASI, CDR-SB, and CDR scores remained stable or improved in 33.3%, 16.7%, 16.7%, and 50.0% of participants, respectively. Cognitive status did not significantly differ before and after 40 Hz light stimulation, indicating that 40 Hz light stimulation helped maintain cognitive function in patients with AD over 6 months (Table 3).

Table 3.

Clinical response and changes in biomarkers after 6-month 40 Hz light stimulation.

N = 6        
Clinical response Pre-40 Hz Post-40 Hz Stable or improving p Value3
MMSE-CE1 22 (13.25, 25.25) 20 (12.5, 22) 33.3% 0.131
CASI1 74.5 (46.25, 81.25) 73.5 (40.75, 76.5) 16.7% 0.074
CDR-SB1 6 (3.625, 8.250) 8.5 (4.5, 12.75) 16.7% 0.058
CDR1 1.0 (0.5, 1.0) 1.0 (0.88, 2.0) 50.0% 0.102
NPI-Q1 7 (4.5, 10.5) 4.5 (2, 16.5) 66.7% 0.916
GDS1 1 (0.75, 5.25) 1 (0, 3.5) 83.3% 0.257
ZBI1 32.5 (18.75, 39.5) 35.5 (14.75, 52.75) 50% 0.400
PSQI1 4.5 (1.5, 10.5) 4 (2, 9.25) 66.7% 0.599
ESS1 3 (0.75, 6.75) 0 (0, 6.25) 83.3% 0.104
Biomarkers Pre-40 Hz Post-40 Hz Interval decrease P value3
Aβ oligomers (pg/mL)2 133.4 ± 26.5 127.7 ± 29.7 66.7% 0.600
Aβ-40 (pg/mL)2 21.2 ± 19.6 20.1 ± 17.7 66.7% 0.753
Aβ-42 (pg/mL)2 16.4 ± 4.9 19.0 ± 10.5 16.7% 0.173
p-tau181 (pg/mL)2 6.3 ± 1.3 5.8 ± 0.7 66.7% 0.293
p-tau217 (pg/mL)2 0.8 ± 0.6 0.6 ± 0.4 83.3% 0.249
NfL (pg/mL)2 15.9 ± 6.8 18.4 ± 10.5 33.3% 0.463
Aβ-42/Aβ-402 1.3 ± 0.9 1.6 ± 1.1 33.3% 0.249
Aβ-42/p-tau1812 2.6 ± 0.7 3.3 ± 1.6 33.3% 0.249
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Aβ: amyloid-beta; CASI: Cognitive Abilities Screening Instrument; CDR: Clinical Dementia Rating; CDR-SB: CDR-Sum of Box; ESS: Epworth Sleepiness Scale; GDS: Geriatric Depression Scale; MMSE-CE: CASI-estimated Mini-Mental State Examination; NfL: Neurofilament light chain; NPI-Q: Neuropsychiatric Inventory Questionnaire; PSQI: Pittsburgh Sleep Quality Index; p-tau181: tau phosphorylated at threonine 181; p-tau217: tau phosphorylated at threonine 217; ZBI, Zarit Burden Interview.

1

Median (interquartile range, IQR); 2Mean ± standard deviation; 3Wilcoxon signed-rank test.

The proportion of participants with stable or improved NPI-Q and GDS scores increased to 66.7% and 83.3%, respectively. Caregiver burden remained low in 50% of caregivers. Sleep quality remained improved or stable in 66.7% of participants, and 83.3% reported improved or stable daytime sleepiness. These findings indicated that 40 Hz light stimulation provided sustained benefits in reducing BPSD, alleviating caregiver burden, and improving sleep quality in patients with AD (Table 3; Figure 1). No correlation was observed between the duration of light stimulation and the changes in the above measurements.

Figure 1.

Three side-by-side line graphs display individual patient trajectories for Clinical Dementia Rating, Geriatric Depression Scale, and Epworth Sleepiness Scale assessments before and after 40 Hz light stimulation. Colored lines connect the baseline and post-treatment scores for six participants, visually illustrating the maintenance of global function, a reduction in depressive symptoms, and an improvement in daytime sleepiness.

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Changes in CDR, GDS, and ESS scores after 6-month 40 Hz light stimulation. After six months of 40 Hz light stimulation, 50.0% of participants demonstrated stable CDR scores. Additionally, 83.3% of participants showed either stable or improved scores on the GDS and ESS. These findings suggest that 40 Hz light stimulation may help preserve cognitive function, alleviate depressive symptoms, and enhance daytime alertness in patients with Alzheimer’s disease over a six-month period. *Two participants’ CDR scores increased from 1.0 to 2.0, while two participants maintained a CDR of 1.0. In Figure 1, overlapping lines for these participants resulted in only four visible curves in CDR, even though six participants were included in the analysis. *Two participants’ GDS scores decreased from 1 to 0. In Figure 1, overlapping lines for these participants resulted in only five visible curves in GDS, even though six participants were included in the analysis. CDR: Clinical Dementia Rating; ESS: Epworth Sleepiness Scale; GDS: Geriatric Depression Scale.

Biomarker analysis

At baseline, blood biomarker analysis revealed varying levels of amyloid, tau, and neurodegeneration markers. The mean Aβ oligomers, Aβ-40 and Aβ-42 levels were 133.4 ± 26.5, 21.2 ± 19.6 and 16.4 ± 4.9 pg/mL, respectively. Phosphorylated tau markers, including p-tau181 and p-tau217, had mean levels of 6.3 ± 1.3 and 0.8 ± 0.6 pg/mL, respectively. NfL, a marker of axonal injury and neurodegeneration, had a mean level of 15.9 ± 6.8 pg/mL. The mean Aβ-42/Aβ-40 ratio, which reflects amyloid plaque burden, was 1.3 ± 0.9. The Aβ-42/p-tau181 ratio, which predicts both Aβ deposition status and cognitive decline in AD, was 2.6 ± 0.7.

After 6 months of 40 Hz light stimulation, the Aβ oligomers level decreased in 66.7%, and the Aβ-42 level increased in 83.3% of participants. P-tau181 and p-tau217 levels decreased in 66.7% and 83.3% of participants, respectively. The NfL level decreased in 33.3% of participants. The Aβ-42/Aβ-40 and Aβ-42/p-tau181 ratios increased in 66.7% of participants. These biomarker changes indicated that 40 Hz light stimulation reduced Aβ and tau pathology in patients with AD (Table 3; Figure 2). No correlation was observed between the duration of light stimulation and changes in the aforementioned biomarkers.

Figure 2.

A two-by-two grid of four line graphs displays individual patient biomarker trajectories. The four panels show measurements for amyloid-beta oligomers, the ratio of amyloid-beta 42 to amyloid-beta 40 (Aβ-42/Aβ-40), tau phosphorylated at threonine 217 (p-tau217), and the ratio of Aβ-42 to tau phosphorylated at threonine 181 (p-tau181). In each panel, six colored lines connect the pre-40 Hz and post-40 Hz data points, illustrating that 40 Hz light stimulation reduced amyloid beta and tau pathology in patients with Alzheimer’s disease.

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Changes in Aβ oligomers, Aβ-42/Aβ-40, p-tau217, and Aβ-42/p-tau181 after 6-month 40 Hz light stimulation. After six months of 40 Hz light stimulation, 66.7% of participants showed a decreased in the Aβ oligomers and an increase in the Aβ-42/Aβ-40 ratio, while 83.3% exhibited a reduction in plasma p-tau217 levels. Additionally, the Aβ-42/p-tau181 ratio increased in 66.7% of participants. These biomarker changes suggest that 40 Hz light stimulation may mitigate amyloid-β and tau pathology in patients with Alzheimer’s disease. Aβ, amyloid-beta; p-tau181, tau phosphorylated at threonine 181; p-tau217, tau phosphorylated at threonine 217.

Discussion

Novelty of this study

The present study provides new insights into the therapeutic effects of 40 Hz light stimulation on decreasing amyloid pathology and tau phosphorylation burden in patients with AD. The findings of the current study are in agreement with those of previous studies indicating that 40 Hz light stimulation may slow global functional decline, preserve cognitive function, improve BPSD, and reduce caregiver burden in patients with AD. In contrast to previous studies that have primarily focused on cognitive and neurophysiological changes, the present study performed blood biomarker analysis to longitudinally track changes in amyloid pathology, tau phosphorylation, and neuronal injury, providing a more comprehensive evaluation of the biological effects of 40 Hz light stimulation in AD. This study is among the first to demonstrate an association between 40 Hz light stimulation and a reduction in Aβ oligomers, Aβ-40 and tau pathology (p-tau181 and p-tau217), an increase in Aβ-42, and an improved Aβ-42/Aβ-40 ratio, collectively suggesting its potential as a disease-modifying intervention for AD.

Furthermore, most previous research has tested experimental light stimulation devices in highly controlled environments, with limited applicability to daily life. In contrast, our study implemented the intervention at home during participants’ regular routines, which enhances the external validity and real-world feasibility of this approach. Finally, we confirmed that daily 40 Hz light stimulation was safe and well tolerated, supporting its potential for broader application as a non-invasive and practical therapeutic strategy.

Blood biomarkers as indicators of 40 Hz light stimulation efficacy

Our findings indicate that after 6 months of 40 Hz light stimulation, the Aβ oligomers level decreased in 66.7% of participant, indicating reduced amyloid burden and oligomers production after therapy. In addition, Aβ-40 level decreased, whereas the Aβ-42 level increased, leading to an elevated Aβ-42/Aβ-40 ratio in 66.7% of participants. The Aβ-42/Aβ-40 ratio reflects amyloid plaque deposition in the brain, with higher ratios indicating decreased amyloid burden (Doecke et al. 2020; Schindler et al. 2019). In this study, these biomarkers were used to monitor potential amyloid-related changes after 40 Hz light stimulation, suggesting that this intervention may modulate amyloid processing.

Elevated levels of phosphorylated tau, particularly p-tau181 and p-tau217, are associated with both Aβ plaques and neurofibrillary tangle formation, a core pathological feature of AD (Thijssen et al. 2021). P-tau181 helps differentiate AD from other dementias, is correlated with tau and amyloid pathology, and reflects clinical severity (Mielke et al. 2018). P-tau217 is a highly sensitive marker for AD pathology and disease progression, with some studies indicating that it outperforms p-tau181 (Ashton et al. 2024; Palmqvist et al. 2020). Longitudinal changes in plasma phosphorylated tau levels are associated with cognitive decline in patients with AD, and p-tau217 is the strongest predictor of this decline (Mattsson-Carlgren et al. 2023). In the present study, p-tau181 and p-tau217 levels decreased in 66.7% and 83.3% of participants, respectively, indicating that 40 Hz light stimulation reduces tau-related neurodegeneration and amyloid burden. In addition, the plasma Aβ-42/p-tau181 ratio is a prognostic biomarker for Aβ burden and cognitive decline (Fowler et al. 2022). In the current study, the Aβ-42/p-tau181 ratio was increased in most participants, suggesting a reduction in AD pathology. Taken together, these findings indicate that 40 Hz light stimulation may modulate the interaction between amyloid and tau pathologies, leading to a reduction in tau pathology and amyloid accumulation, ultimately supporting cognitive stability.

The therapeutic effects of 40 Hz light stimulation in AD are hypothesised to be driven by several biological mechanisms. Exposure to 40 Hz flickering light induces gamma oscillations, which can preserve neuronal and synaptic density and enhance cognitive performance (Adaikkan et al. 2019). Studies have reported that gamma entrainment activates microglia and astrocytes, facilitating the clearance of Aβ and hyperphosphorylated tau from the brain (Iaccarino et al. 2016; Martorell et al. 2019). Consistent with these mechanisms, our biomarker findings demonstrated a decrease in Aβ oligomers level, an increase in the Aβ-42/Aβ-40 ratio and a decrease in the phosphorylated tau level after stimulation.

NfL, a structural protein found in neurons, is released into the bloodstream in response to neuronal damage, and elevated plasma NfL levels is a biomarker for diagnosing AD and predicting disease progression (Jin et al. 2019; Preische et al. 2019). In the present study, NfL was used to determine the potential neuroprotective effects of 40 Hz light stimulation. A decrease in the NfL level was observed in 33.3% of participants, suggesting a protective effect against neurodegeneration.

The findings of the present study reinforce the potential of 40 Hz light stimulation as a non-invasive, safe, and cost-effective intervention for AD. Given the promising biomarker changes observed in this study, integrating 40 Hz light stimulation with existing pharmacological treatments may enhance therapeutic efficacy. In addition, improvements observed in BPSD and caregiver burden suggest broader benefits beyond cognition, supporting the feasibility of 40 Hz light stimulation as a home-based adjunct therapy to improve the overall quality of life for patients with AD and their caregivers.

Benefits of 40 Hz light for sleep problems in AD

Sleep disturbances are common in AD and are associated with increased Aβ accumulation, tau pathology, and cognitive decline (Ju et al. 2014; Lucey 2020). Disruptions in the sleep–wake cycle, including fragmented sleep, increased nocturnal wakefulness, and excessive daytime sleepiness, exacerbate disease progression and impose a substantial burden on both patients and caregivers (Peter-Derex et al. 2015). The findings of the present study indicate that 40 Hz light stimulation improved sleep quality and significantly reduced daytime sleepiness. The mechanisms underlying these benefits may involve the entrainment of gamma oscillations, which regulate circadian rhythms in AD (Yao et al. 2020). By enhancing sleep quality, 40 Hz light stimulation may help mitigate cognitive decline because poor sleep accelerates Aβ and tau accumulation (Mander et al. 2016; Holth et al. 2017). These findings suggest that 40 Hz light stimulation is a promising nonpharmacological approach to managing sleep disturbances in AD, offering potential benefits for both patients and their caregivers.

Limitations of this study

This study has several limitations that should be acknowledged. First, the sample size was small, including only 14 participants, with an even smaller number completing the 6-month follow-up. Due to the small sample size, we were unable to perform subgroup analyses comparing participants treated with donepezil versus rivastigmine, and thus potential differences between these pharmacological treatments in response to 40 Hz light stimulation remain to be explored in future studies. A larger cohort is needed to validate these preliminary findings. Second, because the intervention was intended for naturalistic, home-based use, there were no strict requirements regarding irradiation distance, beam geometry, or specific body targets. Consequently, we could not measure individual-level parameters such as exact power density delivered to the brain, as the mechanism of stimulation relied on visual entrainment via the retina rather than direct transcranial penetration through the scalp and skull. Variability in total hours of light exposure may have influenced the results; however, no dose-dependent effects were observed on clinical outcomes or biomarkers, suggesting that the duration of use may have had a limited impact on the overall effects. Third, this study did not include a control group. The absence of a placebo or sham light condition inevitably limits the ability to attribute the observed outcomes exclusively to 40 Hz light stimulation. To mitigate this limitation, we employed intra-individual comparisons, evaluating changes within each participant relative to their own baseline. This approach not only reduces the impact of inter-individual variability and potential confounding factors but also mirrors real-world clinical practice, where therapeutic responses are typically assessed relative to patients’ prior status. In addition, the follow-up period was limited to 6 months. While this duration provided meaningful insights, longer-term follow-up will be necessary to determine whether the observed biomarker changes translate into sustained cognitive benefits. To address these limitations and establish the clinical relevance of 40 Hz light stimulation, large-scale randomised controlled trials investigating the long-term effects of 40 Hz light stimulation should be conducted. Such studies will be essential in confirming the therapeutic potential of 40 Hz light stimulation and elucidating its role in reducing Aβ and tau pathology in patients with AD.

In conclusion, this study provides preliminary evidence that 40 Hz light stimulation may confer cognitive, behavioural, and neurophysiological benefits in AD when used at home during daily routines, as reflected by both clinical assessments and biomarker changes. Observed reductions in blood Aβ oligomers, phosphorylated tau (p-tau181 and p-tau217), and NfL, along with increases in Aβ-42, the Aβ-42/Aβ-40 ratio, and amyloid/tau ratios, underscore the potential of non-invasive neuromodulation as a novel therapeutic strategy. The findings further highlight the feasibility and real-world applicability of daily 40 Hz multi-luminaire light exposure, demonstrating both high patient adherence and excellent tolerability in a home-based setting. While further studies are needed, 40 Hz light stimulation appears to be a promising, accessible, and safe approach for slowing AD progression and improving patient outcomes.

Supplementary Material

Supplemental Material
TDCN_A_2658530_SM3521.tif (6.3MB, tif)

Funding Statement

This study was supported by the National Health Research Institutes Grant [NHRI-11A1-CG-CO-06-2225-1, NHRI-12A1-CG-CO-06-2225-1, NHRI-13A1-CG-CO-06-2225-1, NHRI-14A1-CG-CO-06-2225-1], and Kaohsiung Medical University Research Centre [KMU-TC113B02].

Author contributions

Ping-Song Chou (Software; Formal analysis; Data Curation; Writing - Original Draft; Visualization); Ching‑Fang Chien (Methodology; Validation; Investigation); Ling‑Chun Huang (Conceptualization; Methodology; Validation; Investigation); Yuan‑Han Yang (Conceptualization; Methodology; Validation; Investigation; Resources; Data Curation; Writing - Review & Editing; Supervision; Project administration; Funding acquisition).

Declaration of generative AI and AI-assisted technologies in the writing process

During the preparation of this manuscript, the authors used ChatGPT (GPT-4-turbo) to enhance readability and language clarity, accounting for approximately 20% of the writing process. After utilising this tool, the authors carefully reviewed and edited the content to ensure accuracy and integrity, taking full responsibility for the final manuscript.

Disclosure statement

No potential conflict of interest was reported by the author(s).

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Supplemental Material
TDCN_A_2658530_SM3521.tif (6.3MB, tif)

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