Efficacy and Safety of Photobiomodulation Therapy in Patients With Mild Cognitive Impairment and Mild Alzheimer's Disease

Alzheimer's disease and its prodromal stage, mild cognitive impairment, are characterized by progressive neurodegeneration for which disease-modifying options remain limited. Photobiomodulation therapy (PBMT) delivers non-ionizing red and near-infrared light to neural tissue, where it is absorbed by cytochrome c oxidase in the mitochondrial respiratory chain. This is hypothesized to enhance ATP production, modulate reactive oxygen species and intracellular signaling, increase regional cerebral blood flow, and support neuroprotective and anti-inflammatory processes, providing the biological basis for evaluating PBMT as a non-invasive intervention in early Alzheimer's disease.

This is a single-center, prospective, randomized, double-blind, sham-controlled trial conducted at the Department of Cognitive Disorders, Beijing Tiantan Hospital, Capital Medical University. Eligible participants are randomly allocated in a 1:1 ratio to the active PBMT arm or the sham-control arm using a computer-generated randomization sequence. To preserve double blinding, the active and sham devices are identical in appearance and operation; the sham device emits visible light at a wavelength without established photobiomodulatory effect, so that neither participants nor outcome assessors can distinguish between arms. Treatment is self-administered at home according to a fixed schedule over the 6-month intervention period, with adherence monitored through device usage records and scheduled study visits.

Assessments are performed at baseline, Month 3, and Month 6 by trained raters blinded to group allocation. Beyond the clinical and neuropsychological battery, structural and functional MRI is used to examine treatment-associated changes in cortical and hippocampal volume, white matter integrity, and cerebral blood flow perfusion, supporting exploratory analysis of the candidate mechanisms above. Safety is monitored throughout via adverse-event reporting, device-related event tracking, and review of skin and nasal tolerability. Efficacy analyses compare between- and within-group change from baseline across the cognitive, neuropsychiatric, sleep, daily-function, and caregiver-burden domains, with imaging and tolerability data used to characterize the safety profile and explore possible mechanisms of action of PBMT in AD-derived MCI and mild AD.

1、Inclusion Criteria：

• Age 50-85 years
• Meet the 2011 NIA-AA diagnostic criteria for "MCI due to AD" or "probable AD dementia," or meet the 2018 NIA-AA "ATN" diagnostic framework for AD；
• 0.5 ≤ CDR ≤ 2; for illiterate: MMSE ≤ 13; for primary school education: MMSE ≤ 19; for junior high school or above: MMSE ≤ 24; for MCI: ADL-20 ≤ 22; for mild AD: ADL-20 > 22；
• Able to understand instructions and cooperate with serological tests, scale assessments, and brain MRI；
• Have a study partner who can participate throughout the study。

2、Exclusion Criteria：

• Inability to complete serological tests, scale assessments, or brain MRI due to severe visual/auditory impairment, severe neuropsychiatric symptoms, contraindications to MRI, etc.
• History of other central nervous system injuries causing cognitive decline (e.g., severe traumatic brain injury, severe CNS infection, carbon monoxide poisoning, alcohol abuse, primary CNS tumors)
• Unstable or severe heart, lung, liver, kidney, or hematopoietic diseases, poor general health
• Short life expectancy due to major diseases (e.g., end-stage metastatic cancer cachexia)
• Large skin lesions or scars on the scalp, or poor heat dissipation that cannot tolerate PBMT
• Patients with photosensitivity disorders
• Abnormal nasal structure (deviated septum or large polyps); bacterial or viral infection; nasal dryness/bleeding; nasopharyngeal carcinoma unsuitable for intranasal device insertion.