TABLE 1.

Summary of study characteristics from included studies

Study	Population	N	Age,1 y	Study location	Design	Intervention and dose	Study duration	Primary outcome	Results
Bock, M., et al. 2018 (52)	MS	60	42.3 ± 12.5	Germany	Randomized, controlled, 3-armed parallel, clinical pilot trial	Dietary; AKD, CR	6 mo	MSQoL-54; eicosanoid gene expression	MSQoL-54 was inversely correlated with the expression of ALOX5 and COX1. Expression of ALOX5 in combined AKD/CR (KA) group was significantly reduced compared to control. Within-group comparison of KA group demonstrated the expression of COX1 and COX2 were also significantly impaired after the intervention
Brandt, J., et al. 2019 (51)	MCI - early AD	14	71.3 ± 6.1	USA	Randomized, parallel group controlled clinical trial	Dietary; MAD, NIAD	12 wk	Cognition	Participants in the MAD group experienced improved Memory Composite Scores, although they were not statistically significant. Participants in the MAD group who were not adherent to the dietary protocol experienced a decline in memory
Choi, IY., et al. 2016 (50)	MS	60	44.8 ± 11.1	Germany	Randomized, 3-armed parallel, clinical pilot trial	Dietary; FMD, KD, control	6 mo	Safety and feasibility; HRQoL	Administration of the FMD and KD in people with MS was safe and well tolerated. Positive effects of FMD or KD treatment were observed in RRMS participants in self-reported HRQoL measures including pain
Fortier, M., et al. 2019 (49)	MCI	52	74.6 ± 6.4	Canada	Randomized, placebo-controlled trial	MCT (liquid emulsion; 30 g in 250 mL lactose-free skim milk daily)	6 mo	Brain ketone and glucose metabolism	Brain ketone metabolism, quantified with FDG-PET, increased by 230% for subjects in MCT group. Secondary measures of cognition improved within the MCT group at endpoint versus baseline. Language was the only cognitive domain that differed significantly between groups
Henderson, S., et al. 2009, 2011 (46, 47)	AD	152	76.9 ± 8.3	USA	Randomized, double-blind, placebo-controlled, parallel-group, multicenter trial	MCT (AC-1202; 30 g powdered sachet, equiv. to 10 g active AC-1202 daily)	12 wk	Cognition	APOE-ε4(+) participants did not differ from placebo in the ADAS-Cog at any time point. APOE-ε4(–) participants performed significantly better than placebo in ADAS-Cog at day 45 and day 90. APOE-ε4 status appears to be a primary modulator of ketosis, as APOE-ε4(–) subjects had better response to treatment than APOE-ε4(+)
Henderson, S., et al. 2020 (48)	AD	413	76.7 ± 6.5	USA	Randomized, double-blind, placebo-controlled, parallel-group, multicenter trial	MCT (AC-1204); 40 g, equiv. to 20 g caprylic triglyceride daily)	26 wk	Cognition	No significant effects were observed between groups in the ADAS-Cog or ADCS-CGIC scores at week 26 across treatment groups. A significant negative change was observed in the MMSE score from baseline; AC-1204 group performed worse than placebo. AC-1204 group reported significant improvements in QoL compared to placebo
Krikorian, R., et al. 2012 (61)	MCI	23	69.4 ± 6	USA	Randomized, controlled trial	Dietary; HC, LC	6 wk	Cognition	LC diet improved secondary memory performance and paired associate learning task. Serum ketone body concentrations were associated with improved memory performance
Krikorian, R., et al. 2019 (60)	PD-MCI	14	65.7 ± 5.8	USA	Randomized, controlled, parallel-group trial	Dietary; HC, KD	8 wk	Cognition	Nutritional ketosis enhanced cognitive performance in people with PD-MCI. A strong inverse association was observed between intervention-related weight reduction and memory enhancement in the KD group
Lee, J., et al. 2020 (59)	MS	14	51.9 ± 10.1	USA	Randomized, controlled parallel-group trial	Dietary; MPD, MKD, control	12 wk	Feasibility, fatigue, QoL, cognition, physical function	Mean MFIS scores significantly decreased for the MPD group at endpoint. No differences in EDSS scores were observed within or between intervention groups. No changes observed between groups in the cognitive component of the PASAT, although the MPD group had significantly higher scores at endpoint compared to controls. The MKD group achieved maximal mean BHB concentrations of 1.48 ± 1.10 mmol/L, though these numbers declined by the 12-wk mark. Participants on the MKD experienced a decline in fasting glucose and insulin, suggesting improvements in glucose metabolism
Nagpal, R., et al. 2019 (58)	MCI	17	64.6 ± 6.4	USA	Randomized, double-blind, crossover, single-center pilot study	Dietary; MMKD, AHAD	6 wk	AD biomarkers	Concentrations of Proteobacteria correlated positively with Aβ-42 and Aβ-40, whereas fecal propionate and butyrate correlated negatively with Aβ-42 in subjects with MCI. MMKD slightly reduced fecal lactate and acetate while increasing propionate and butyrate. AHAD increased acetate and propionate while reducing butyrate
Neth, B., et al. 2020 (57)	SCI-MCI	20	64.2 ± 6.3	USA	Randomized crossover design	Dietary; MMKD, AHAD	6 wk	AD CSF biomarkers, cognition, cerebral blood flow, cerebral ketone uptake, metabolic parameters	Following MMKD, all participants saw an improvement in metabolic parameters (↓ HbA1c, glucose, insulin, triglycerides, and VLDL), an increase in cerebral perfusion and cerebral ketone body uptake along with improved memory performance assessed by FCSRT was also observed. An increase in CSF Aβ42 and decreased CSF tau was associated with MMKD. Following AHAD, no changes in metabolic parameters was noted, however, a reduction in CSF tau was observed
Phillips, M., et al. 2018 (56)	PD	47	62.9 ± 7	New Zealand	Randomized, controlled, parallel group, pilot trial	Dietary; KD, LFD	8 wk	Motor and nonmotor function	MDS-UPDRS scores significantly decreased across groups. KD group scores decreased further in Part 1 (−4.58 ± 2.17 points, 41% improvement from BL scores) compared to LFD group (−0.99 ± 3.63 points, representing an 11% improvement). Largest between-group reductions were observed for urinary problems, pain, fatigue, daytime sleepiness, and cognitive impairment
Rebello, C., et al. 2015 (55)	MCI	4	58–78 y	USA	Randomized, double-blind, placebo-controlled, parallel trial	MCT (Nestle™; 56 g daily, added to 6 ounces of Yoplait™ 99% fat-free fruit yogurt)	24 wk	Cognition	MCT group (n = 1) increased ADAS-Cog score by 5 points. Second participant declined by 4 points. No effect on TMT or DST was observed. No statistical analysis performed due to small sample
Saadatnia, M., et al. 2009 (54)	MS	80	29.9 ± 8.1	USA	Prospective, parallel group, controlled trial	Fasting, control	4 wk	Disease relapse	There were no significant changes in median number of MS attacks or in the EDSS in fasting group compared to controls 6 mo after intervention
Torosyan, N., et al. 2018 (44)	AD	16	79.9 ± 9.2	USA	Randomized, double-blind, placebo-controlled trial	MCT (caprylidene; 40 g daily)	45 d	Regional cerebral blood flow	APOE-ε4(–) participants had significantly elevated rCBF in the left superior lateral temporal cortex by sVOI analysis after adopting a caprylidene diet for 45 d. Generally, greater increases in rCBF were observed with caprylidene therapy inAPOE-ε4(–) participants compared to APOE-ε4(+) counterparts
Xu, Q., et al. 2019 (53)	AD	53	75.1 ± 7.5	China	Randomized, double-blind, placebo-controlled trial	MCT (dosed TID; total daily dose 17.3 g)	30 d	Cognition	Significant reductions in the ADAS-Cog-C (mean change –2.62 points from baseline) were observed in APOE-ε4(–) participants who received MCT treatment. All ADAS-Cog domains were significantly reduced after the intervention. After 30 d, concentrations of serum BHB and AcAc increased by 129% and 87%, respectively, in the MCT group. No significant changes were observed in ADL scores. Metabolomics revealed top 3 pathways implicated in MCT treatment were fatty acid biosynthesis, linoleic acid metabolism, and steroid hormone biosynthesis. A total of 15.2% of participants were considered “complete responders”; defined by a 7-point improvement on ADAS-Cog

¹Values are mean ± SD unless otherwise specified. AD, Alzheimer's disease; ADAS-Cog, Alzheimer's Disease Assessment Scale-cognitive Subscale; ADCS-CGIC, Alzheimer's Disease Cooperative Study-Clinical Global Impression of Change; ADL, activities of daily living; AHAD, American Heart Association Diet; AKD, adapted ketogenic diet; ALOX-5, arachidonate 5-lipoxygenase; APOE-ε4, apolipoprotein E allele ε4; BHB, β-hydroxybutyrate; BL, baseline; COX1, cyclooxygenase 1; COX2, cyclooxygenase 2; CR, calorie restriction; CSF, cerebrospinal fluid; DST, Digital Symbol Test; EDSS, Expanded Disability Status Scale; FCSRT, Free and Cued Selective Reminding Test; FDG-PET, Fluorodeoxyglucose Positron Emission Tomography; FMD, fasting mimicking diet; HbA1c, hemoglobin A1c; HC, high-carbohydrate; HRQoL, health-related quality of life; KA, ketogenic approach; KD, ketogenic diet; LC, low-carboydrate; LFD, low-fat diet; MAD, modified Atkin's diet; MCI, mild cognitive impairment; MCT, medium-chain triglycerides; MDS-UPDRS, Movement Disorders Society-Unified Parkinson Disease Rating Scale; MFIS, modified Fatigue Impact Scale; MKD, modified ketogenic diet; MMKD, modified Mediterranean ketogenic diet; MMSE, Mini-Mental State Examination; MPD, modified Paleolithic diet; MS, multiple sclerosis; MSQoL-54, Multiple Sclerosis Quality of Life-54 questionnaire; NDD, neurodegenerative disease; NIAD, National Institute on Aging Diet; PD, Parkinson's disease; PD-MCI, mild cognitive impairment due to Parkinson's disease; PASAT, Paced Auditory Serial Addition Test; QoL, quality of life; SCI, subjective cognitive impairment; rCBF, regional cerebral blood flow; RRMS, relapse-remitting multiple sclerosis; sVOI, standardized volumes of interest; TID, three times per day; TMT, Trail Making Test; VLDL, very-low-density lipoprotein; V-PAL, Verbal Paired Association Learning Test.