The ketogenic diet as a potential prevention or therapeutic strategy for AD

Abstract

AbstractBackgroundDiet is a powerful modulator of brain health. The ketogenic diet (KD), a very low carbohydrate diet, is remarkably effective in treating refractory epilepsy; 50‐70% of patients have >50% seizure reduction and 30% have >90% seizure reduction. Although the mechanisms underlying its effectiveness are not definitively known, reduction of neuronal hyperexcitability and neuroprotective effects of ketones have been demonstrated, as has reduction in AD pathology in rodent models. We tested the effect of a 6‐week Modified Mediterranean‐like KD (MMKD) compared with a low‐fat American Heart Association Diet (AHAD) on AD biomarkers and memory.MethodThe study used a randomized crossover design in which participants consumed either a MMKD (5‐10% of total daily calories obtained from carbohydrates) or the control AHAD (∼15% of calories obtained from fat per day) for 6 weeks, followed by a 6‐week washout period during which participants were instructed to resume their pre‐study diet, after which the second diet was consumed for 6 weeks. Diets were equicaloric with participants’ normal diet. Compliance was verified by measuring blood ketone levels. CSF collection, pseudocontinuous arterial spin label (pcASL) MRI, 11C‐AcAc/18F FDG Positron Emission Tomography (PET), and memory testing (Z score composite constructed from Story Recall and Free and Cued Selective Reminding Test) were performed at baseline and at the end of each intervention.ResultA total of 20 participants completed both diets, with 3 participants discontinuing the study early. Mean compliance rates for completers were 90% for the MMKD and 95% for AHAD. The MMKD was associated with increased CSF Aβ42 and decreased tau. Cerebral perfusion increased after the MMKD in AD regions of interest, and whole‐brain ketone uptake increased on 11C‐AcAc PET. No changes in these outcomes were observed following the AHAD. Memory performance improved after both diets.ConclusionThe MKKD intervention favorably influenced CSF AD biomarkers, cerebral perfusion, and memory. These results provide the basis for an ongoing Phase II study using a longer intervention in a larger sample of adults with MCI.