Abstract Background: Post-COVID-19 cognitive impairment (PCCI), characterized by deficits in attention, memory, and executive functioning, remains a major challenge among patients with long COVID. Oxidative stress is a key contributor to this condition. Cysteine-rich whey protein isolate (CRWPI), such as Immunocal®, enhances intracellular glutathione production and may offer neuroprotective benefits.

Objective: To evaluate the efficacy of Immunocal® supplementation on cognitive function, particularly attention and memory, and functional performance in individuals with ICCP.

Methods: A randomized, controlled, parallel-group trial was conducted in Cali, Colombia, with 120 adults recovering from COVID-19 with mild to moderate cognitive impairment. Participants were randomly assigned to three groups: (1) immune® supplementation (CRWPI) (20 g/day), (2) neuropsychological rehabilitation, or (3) no intervention (control), for 12 weeks. Cognitive outcomes were assessed using the Montreal Cognitive Assessment (MoCA) and the NEUROPSI attention and memory test. Physical endurance was measured using the 30-second foot test (STST). Clinical symptoms evaluated through a medical assessment form, before and after the intervention, were also taken into account. Results: Both the Immunocal® and neurorehabilitation groups showed statistically significant improvements in all attention subdomains and memory types compared to the control. Immunocal® produced greater gains in divided attention and working memory, suggesting a specific advantage in cognitive domains sensitive to oxidative stress. STST performance was also significantly improved in the Immunocal® group. No significant improvements were seen in the control group.

Conclusion: Immunocal® supplementation significantly improves cognitive performance, comparable to structured neurorehabilitation, in individuals with ICCP. It also shows potential to improve physical endurance, clinical symptoms, and reduce fatigue. These findings support the integration of Immunocal® as a non-pharmacological intervention for cognitive dysfunction related to long COVID.

Study Design and Participants This randomized, controlled, parallel-group trial included subjects at least 18 years of age in Cali, Colombia, who recovered from COVID-19 infection and presented with mild to moderate cognitive impairment and no history of Immunocal administration. Subjects with a history of cerebrovascular or cardiovascular disease and current or previous use of Immunocal were excluded from screening. Ethical approval was obtained from the IRB of the Universidad Libre and informed consent was obtained.

Sampling and protocol A consecutive non-probabilistic sampling was performed. For this study, a target sample of 120 subjects was selected to achieve a 95% confidence level. A double-blind randomization process was used to divide subjects into three groups of 40 participants as follows: 1. CRWPI (Immunocal®) supplementation; 2. Structured neuropsychological rehabilitation (Neurorehabilitation), and no intervention (control).

A group of neuropsychologists with experience in the application of cognitive tools and neuropsychological rehabilitation were responsible for the evaluation and management of the neuropsychological phase of the study. Neuropsychological rehabilitation consisted of 45-minute face-to-face group sessions that were conducted three times a week over a 12-week period. After 12 weeks, a neuropsychological evaluation was completed on each subject.

CRWPI Immunocal® (Immunotec ™) was administered at a dose of 20 grams (2 sachets once daily) for 12 consecutive weeks. The research team delivered the Immunocal directly to the subjects and instructed them how to mix and self-administer it.

Pre-test cognitive functioning was assessed using NEUROPSI attention and memory, while only NEUROPSI attention and memory were used to assess the same cognitive domains at 12 weeks.

The main objective of NEUROPSI Attention and Memory is to assess a broad spectrum of cognitive functions, including spatial, temporal and personal orientation; attention and concentration; working memory; verbal and visual memory, and executive and motor functions. The NEUROPSI Attention and Memory test considers age and schooling for the acquisition of quantitative and qualitative data and classifies amnesic and attentional alterations into four different categories.

The 30-second sit-stand (STST) test is a widely used assessment designed to assess lower-body strength and functional endurance.19 It measures how many complete stops a person can complete from a seated position in 30 seconds, without using their arms for support. This test provides valuable information about muscle strength and balance, making it a practical tool for monitoring physical performance and the effectiveness of interventions such as exercise programs or nutritional supplements. STST is often used to assess fatigue in the muscles of the lower extremities and trunk. This test was performed on all available participants after the intervention period was completed.

The participants were also evaluated before and after the intervention by the doctors of the research group, through a medical assessment form where all clinical symptoms due to the virus were recorded.

Inclusion:

• Adults ≥18 years with confirmed prior COVID-19
• with persistent cognitive symptoms
• able to complete testing
• and willing to consent.

Exclusion:

• Pre-existing dementia or major psychiatric illness
• whey protein allergy - participation in another cognitive trial
• severe hepatic/renal/metabolic disease, pregnancy
• or any condition interfering with participation.

This is an open-label study. No masking will be applied. All participants, care providers, and investigators will be aware of the treatment being administered. Outcome assessors will also be unblinded.