Alzheimer’s disease (AD) is the most prevalent neurodegenerative disorder, with its incidence continually rising. However, despite significant efforts over nearly a century of research, clinicians have not discovered effective disease-modifying treatments for disease, thereby making AD one of the largest health concerns today.
Pathological characteristics in AD appear a long time before clinical symptoms, therefore, leading to significant interest in understanding the alterations in the brain and systemic changes observed in individuals who were at risk for AD to prevent progressive decline in neurological abilities.
The traditional ketogenic diet (KD) was first introduced at the Mayo Clinic in 1921 for treating epilepsy and it remains a crucial part of clinical care for patients. The KD is a low-carbohydrate, high-fat diet that shifts the body’s primary fuel source from glucose to fats and ketones, including ketosis and the production of ketone bodies. The diet proved to be remarkably effective in controlling seizures, leading to its continued use in clinical practice. A modified version of the KD with the gradual carbohydrate elevation showed a similar degree of efficacy for seizure control while facilitating better long-term tolerance.
Inclusion criteria include those who were at risk for AD due to baseline cognitive dysfunction (MCI) diagnosed according to National Institutes of Health-Alzheimer’s Association (NIH-AA) or Alzheimer’s Disease Neuroimaging Initiative (ADNI) criteria, or due to subjective memory complaints. All participants had prediabetes, defined by HbA1c levels between 5.7% and 6.4%, according to ADA guidelines. The exclusion criteria included prior neurological or neurodegenerative diagnoses (except MCI), major psychiatric disorders (except well-controlled depression), prior stroke, or use of medications affecting the CNS, diabetes, or lipid levels. The study explored links between insulin resistance, AD risk, and targeted interventions.
The study, approved by the Wake Forest Institutional Review Board (ClinicalTrials.gov Identifier: NCT02984540), was conducted under strict ethical oversight and sought to investigate the interaction between insulin resistance and AD risk and the effect of dietary interventions. A randomized crossover trial was conducted, in which the subjects were on either a Modified Mediterranean-Ketogenic Diet (MMKD) or the American Heart Association Diet (AHAD) for six weeks, separated by a washout period. The MMKD thus focused on very low carbohydrate content (5-10% of total calories), moderate protein intake (30%), and high fat intake (60-65%), and was based on the Modified Atkins Diet. Participants consumed less than 20 grams of carbohydrates daily, from whole foods including green leafy vegetables, berries, nuts, and lean protein supplemented by extra virgin olive oil.
The plasma lipidome underwent significant alterations due to the modified Mediterranean ketogenic diet (MMKD). The MMKD significantly altered 18 of 47 lipid classes at FDR-corrected p-values < 0.05, whereas the American Heart Association Diet (AHAD) showed no significant associations.
The key changes included increases in acylcarnitines (1.41-fold, p = 4.83 × 10−3), hydroxylated acylcarnitines (1.58-fold, p = 2.15 × 10−3), and free fatty acids (1.80-fold, p = 2.20 × 10−3), which suggested increased lipid lipolysis. Triglycerides decreased to 0.75-fold, with a p-value of 1.20 × 10−2. Ethanolamine ether lipids have experienced critical increases (PE(O) 1.63-fold, p = 2.15 × 10−3; PE(P) 1.62-fold, p = 2.15 × 10−3), and deoxyceramides were decreased (0.69-fold, p = 4.83 × 10−3). Specific lipid species responses, including acylcarnitines, AC (16:0)-OH (1.63-fold, p = 5.84 × 10−4), and free fatty acids, FA (22:5) (1.84-fold, p = 1.33 × 10−4), further highlighted the dietary impact.
The crossover model, advanced lipidomic analysis, and well-defined participant data of the study design allowed for a more accurate assessment of the effects of the ketogenic diet on lipid metabolism in AD. This approach controlled for individual differences, making it more likely to detect diet-related changes. The study shows that the advantage of a ketogenic diet may extend further than ketosis itself and would support the integrated diet, directed toward ketosis, rather than supplementing with ketone bodies or medium-chain triglycerides.
Although the mechanism for these changes is not clear, the results are encouraging. MCI subjects were more sensitive to the MMKD, despite receiving the same diet and menu as the other groups. Future research will investigate these mechanisms and test whether the lipid changes caused by the MMKD are associated with improvements in brain health, as measured by novel blood-based biomarkers for Alzheimer’s.
In conclusion, this study is the first clinical trial assessing the impact of this modified ketogenic diet on lipid profile in at-risk adult individuals. The results confirm that the modified ketogenic diet induces substantial alterations in the plasma lipidome with the most beneficial changes observed in patients with cognitive impairment. Significantly, the MMKD-related lipid alterations were opposite to the known AD lipid profile that has been defined. These results indicate that a mild ketogenic diet might be used as an intervention to reverse pathologic AD lipid alterations but further research is necessary. The lower relative cost and risks associated with an MMKD improve the utilization of this approach for prevention or add-on to other therapies for early symptomatic AD.
Reference: Neth BJ, Huynh K, Giles C, et al. Consuming a modified Mediterranean ketogenic diet reverses the peripheral lipid signature of Alzheimer’s disease in humans. Commun Med. 2025;5:11. doi:10.1038/s43856-024-00682-w
