Background
Alzheimer’s Disease (AD) is a debilitating disease that leads to severe cognitive impairment and functional decline.NRF-2 has been identified in modulating the effects of inflammation and oxidative stress in AD. Activation of NRF-2 leads to an increased production of antioxidant enzymes, including heme oxygenase, which has been shown to have protective effects in neurodegenerative disorders such as AD. Dimethyl fumarate and diroximel fumarate (DMF) have been approved for the use in relapsing–remitting multiple sclerosis. Research indicates that they can modulate the effects of neuroinflammation and oxidative stress through the NRF-2 pathway, and as such, could serve as a potential therapeutic option in AD.
Methods
- A search was conducted to evaluate the role of dimethyl fumarate (DMF), and by extension diroximel fumarate (DRF), on cognition overall and, more specifically, regarding AD pathophysiology.
- This search was completed utilizing the PubMed database ranging in dates from 1995 to 2023.
- Selected papers were reviewed by the authors to determine the relevance to the aim of the review and proposed clinical trial design.
Results
- A phase I trial designwould include randomizing patients to the standard dose of DMF used for MS vs placebo.
- Dosing for the medication arm would include 120 mg twice a day for 7 days followed by 240 mg twice a day for dimethyl fumarate, or 231 mg twice a day for 7 days followed by 462 mg twice a day for diroximel fumarate.
- The primary outcome measure would focus on safety and would require careful monitoring of lymphocyte counts and monitoring of neurological function.
- Inclusion criteria would include early AD/aMCI (e.g., Mini Mental Status Exam (MMSE) ≥ 20).
- Exclusion criteria include the presence of other neurological disease, psychiatric disease, chronic infection, frequent recurrent infections or history of malignancy, excluding non-melanoma skin cancer.
- In phase II trial design, the primary outcome measure would be efficacy, measured by a comparison of functional scales at set time points (baseline, 1 year, and 3 years).
- Inclusion criteria would include (a) the diagnosis of early AD with evidence of brain amyloid by cerebrospinal fluid (CSF)(b) an MMSE score ≥ 22 points or Clinical Dementia Rating (CDR).
- Exclusion criteria would include (a) dementia due to a condition other than AD(b) other neurological disease or psychiatric disease.
Conclusion
There is sufficient evidence to suggest that activation of the NRF-2 pathway can potentially counteract the neurodegeneration seen in AD by attenuating these effects. A clinical trial investigating DMF as a treatment for patients with AD could offer another option for patients and families to improve quality of life in an otherwise devastating condition.