Ketogenic Diet to Reduce Osteoarthritis Pain in MCI

OA and dementia are two leading contributors to disability worldwide. Although traditionally studied separately, accumulating evidence indicates substantial overlap in their underlying inflammatory, metabolic, and neuroimmune pathways. Chronic OA pain is associated with systemic inflammatory mediators, increased peripheral nociceptor sensitization, impaired descending inhibition, and central neuroinflammation driven by microglia and astrocyte activation. These same mechanisms contribute to cognitive decline, reduced synaptic plasticity, hippocampal vulnerability, and progression from MCI to ADRD.

In aging adults, chronic pain accelerates cognitive decline and increases risk for dementia, and cognitive impairment exacerbates pain-related disability. Neuroinflammation-particularly microglial activation and NLRP3 inflammasome signaling-is a shared mechanistic link between the two conditions. Identifying interventions that target this shared biology is crucial for improving outcomes for older adults with comorbid pain and cognitive decline.

The ketogenic diet has demonstrated therapeutic effects in multiple neurological, metabolic, and inflammatory conditions. Mechanisms include suppression of the NLRP3 inflammasome, improved mitochondrial efficiency, enhanced lipid metabolism via TREM2-associated pathways, reduced oxidative stress, reduced systemic inflammation, glycemic control, and modulation of gut microbiota.

Preclinical data show that ketone bodies improve cognitive function and reduce neuroinflammation in models of AD. Human studies demonstrate the feasibility and potential cognitive benefit of WFKD in ADRD populations and post-concussion syndrome. Additionally, this study team recently investigated the impact of an 8-week WFKD on modifiable risk factors associated with metabolic syndrome, on gut microbiota structure, and RNASeq in healthy, middle-aged adults. However, the application of a WFKD to individuals with OA and early cognitive impairment is unexplored. Our team has conducted two previous clinical trials and is currently analyzing outcomes of an NIA-funded clinical trial using the WFKD. Participants from these trials have successfully adopted the WFKD, evidenced by objective and reported ketone body production and macronutrient profile of dietary intake. The WFKD used in these trials improved micronutrient intake and intake of non-starchy vegetables, and suggests that the WFKD may benefit cognition in patients with AD and symptoms in patients with post-concussion syndrome.

This population is particularly relevant given the aging US population, the high prevalence of OA-associated chronic pain, the presence of early neuroinflammation and neurodegeneration, poor diet quality contributing to systemic inflammation, and heightened vulnerability to cognitive decline, reduced quality of life, and hospitalization/institutionalization.

Understanding how a WFKD influences pain, neuroinflammation, central sensitization, cognitive performance, and biologic indicators from the gut and peripheral nerves will provide critical insight into mechanistic targets for future clinical trials.

Inclusion criteria

• English speaking
• Diagnosis of major joint osteoarthritis
• Diagnosis of mild cognitive impairment

Exclusion criteria

• Diabetes that requires insulin
• Cancer requiring chemo- or radiation therapy in the last 2 years
• Cardiac event within 1 year
• Recent history of renal stones
• Diagnosis of fibromyalgia
• Already following a ketogenic diet
• Following a dietary pattern that does not allow for a ketogenic approach
• Unable to control one's diet