TABLE 3.

Intervention particularities, outcomes, and findings of the included randomized controlled trials assessing the effects of ketogenic therapy on patients with mild cognitive impairment and/or AD¹

First author	Brandt (45)	Craft (46)	Fortier (47)	Henderson (48)	Henderson (49)	Krikorian (50)	Ota (51)2	Rebello (52)	Reger (53)	Torosyan (54)
Intervention	MAD with ≤20 g net CHO (total CHO minus fiber), large amounts of fat to satiety, moderate protein, ample hydration and unrestricted energy intake.	MMKD (<15 g CHO/d)	kMCT drink: emulsion with 12% Captex 355 [60% caprylic acid (8:0), 40% capric acid; Abitec Corp.] in lactose-free skim milk. The drink provided 30 g kMCT in 250 mL  (Nalgene).	Powder sachets with 10 g AC1202 (MCT composed of glycerin and caprylic acid, known as tricaprylin/ trioctanoin), mixed with a meal replacement drink (Ensure, Abbott Lab Inc.), taken at breakfast for 7 d, and a double dose thereafter (2 × 10 g AC1202)	2 × powder sachets per day with 10 g AC1202 each (MCT, >95% of the fatty acids being caprylic acid). Product luted in water or other liquids, forming a drink.	Dietary education and counseling for adherence to a KD (5%–10% of calories from protein, <20 g CHO/d), with fruit restriction and a CHO intake based on small portions of vegetables. MUFA was the preferred fat source.	Meal: 50 g ketogenic formula (Ketonformula) containing 20 g of MCTs.	56 g MCTs (MCT oil, Nestlé) added to 6 oz Yoplait 99% fat-free fruit yogurt.	MCTs (40 mL) (Neo-Bee 895, Stepan Inc.), blended with 152 mL heavy whipping cream to form a 690-kcal drink.	40 g caprylidene (MCT) Axona® in capsules (Accera, Inc.).
Comparator	NIA diet: high intake of fruit, whole-gains, fat-free/low-fat dairy, seafood, lean meat, eggs, poultry, oils, beans, peas, vegetable, nuts/seeds. Low intake of sodium, solid fats, refined gains, sugar.	Equicaloric AHAD (<10 g fat/d).	Placebo drink: refined, bleached, winterized, deodorized, high-oleic-acid sunflower oil, as the non-ketogenic lipid.	Powder sachets with 10 g placebo, mixed with a meal replacement drink (Ensure, Abbott Lab, Inc.), taken at breakfast for 7 d, and a double dose thereafter (2 × 10 g placebo).	2 × powder sachets per day, each with 10 g placebo (isocaloric to the active powder, consisting of 51% gum acacia, 37% dextrose, 10% safflower oil, and 2% syloid).	Healthy diet with ≥50% of calories from CHO, high fruit and vegetable intake. MUFA as the preferred fat source.	Meal: isocaloric placebo formula without MCTs.	Placebo (canola oil, color matched) added to 177.4 mL Yoplait 99% fat-free fruit yogurt.	Placebo drink with heavy whipping cream alone (232 mL, 690 kcal).	Placebo capsule.
Intervention duration	12 wk	6 wk	6 mo	90 d	90 d	6 wk	1 meal (single intake), consumed 120 min before tests	24 wk	1 meal consumed 90 min before tests	45 d
Acute intervention	No	No	No	NR3	NR3	No	✓	✓	✓	✓
Long-term intervention	✓	✓	✓	✓	✓	✓	No2	✓	No	✓
Washout duration	N/A	6 wk	N/A	2 wk post-intervention	2 wk post-intervention	N/A	1 visit (NOD)	N/A	1 visit	N/A
Compliance assessment	Urinary ketone levels (intervention) and HEI ≥85 (controls)	Plasma ketone levels	Bottle count, blind blood analyses	Consumption log >80% of intended dose	NR	Diet records evaluated by a dietitian and urinary ketones	N/A (acute intervention only)	By a registered dietitian via daily diet diaries	N/A (acute intervention only)	NR
APOE ε4 status	✓	No	✓	✓	✓	No	No	✓	✓	✓
Adverse events	Minor GI issues and 1 vasovagal episode	NR	Nausea, therapy intolerance, headache, GI issues (diarrhea, reflux, bloating, constipation)	GI adverse events	NR	NR	Diarrhea	GI issues	NR	NR
Primary outcomes	MCS	Δ in CSF levels of Aβ42 and t-tau (INNO-BIA-Alzbio3)	Δ in CMRAcAc and CMRKetones by PET imaging (Patlak method)	Improvements in cognition (Δ in the ADAS-Cog and ADCS-CGIC)	ADAS-Cog	TMT, V-PAL, GDS	Acute WAIS-III, WMS-R, Stroop, TMT, all at 120 min post-meal	ADAS-Cog, TMT, and Digit Symbol tests	ADAS-Cog, MMSE, Stroop	rCBF (15O-water PET scans) analyzed with sVOI and voxel-based spm
Secondary outcomes	MMSE, MDS-HC, POMS-Bi	Δ in memory composite score, insulin sensitivity, [11C] AcAc PET uptake	CMRGlu, plasma medium-chain fatty acidsCognition: RL/RI-16, MMSE, MoCA, VF, BVMT-R, BNT, TMT, Stroop	MMSE, serum BHB	Serum BHB	Urinary ketone levels, fasting plasma insulin, anthropometry, FPG	Plasma ketone bodies (AcAc and BHB) concentrations	Plasma Glu, insulin, and pre-/post-prandial BHB	BHB	rCBF by sVOI and voxel-based spm
Time points	Baseline, at 3, 6, 9, and 12 wk	Baseline, at 6, 12, and 18 wk	Baseline, end (last wk of mo 6)	Baseline, days 45 and 90	Baseline, days 45, 90, and 104	Baseline and end of intervention (post-6 wk)	Baseline, at 120 min post–meal ingestion	Baseline, weeks 4, 8, 12, 16, and 20	Baseline, 90 min	Baseline (before, after first pill) and on day 45 (before, after final pill)
Results	MCS of the MAD group increased slightly over the trial, whereas in the NIA group it declined slightly (not significantly). MCS and MMSE scores of compliant patients did not differ from baseline. Mood of MAD subjects improved at wk 6.	Global [11C] AcAc uptake increased after the KD intervention. CSF t-tau increased with the KD, with a similar trend noted for Aβ42. Global [11C] AcAc uptake decreased after the low-fat diet. No changes were observed after adoption of the low-fat diet regime.	Brain ketone metabolism increased (230%) in the kMCT group, whereas brain Glu uptake remained unchanged. Episodic memory, language, executive function, and processing speed improved on the kMCT vs. baseline. Increased brain ketone uptake was related to several cognitive scales.	AC-1202 elevated serum ketone bodies and improved ADAS-Cog scores compared with the placebo. Effects were most notable in APOE ε4(−) subjects. A significant pharmacologic response was observed between serum BHB levels and change in the ADAS-Cog scores in APOE ε4(−) subjects, at day 90.	Among APOE genotypes, homozygous carriers of the ε3 on AC-1202 had improved cognition relative to placebo. Improved cognition was noted among APOE ε4(−) subjects on AC-1202 relative to placebo. Specific genotype combinations of IDE and APOE ε4(−), and IL1B and APOE ε4(−) produced more improvements.	The intervention improved secondary memory performance and reduced energy intake and anthropometric parameters. No effect was recorded on the depressive symptoms and the TMT. Ketone levels were positively correlated with memory performance.	The ketogenic formula increased plasma ketone bodies. No differences were noted between scores after taking the ketogenic or the placebo formula, in any cognitive test after correction for multiple testing.	MCT oil intake increased serum ketone bodies and improved memory in the APOE ε4(−) participant, whereas intake of placebo did not improve any cognitive measure. In the APOE ε4(+) patient an increase in post-prandial serum BHB was noted.	MCT treatment improved ADAS-Cog performance for APOE ε4(−) subjects, but not for the (+) ones. Higher ketone levels were associated with greater improvement in paragraph recall among those on MCT treatment.	APOE ε4(−) patients had elevated rCBF in the left superior lateral temporal cortex after 45 d of following adopting a caprylidene diet. APOE ε4(+) patients did not display changes in rCBF.

¹AcAc, acetoacetate; AD, Alzheimer disease; ADAS-Cog, Alzheimer's Disease Assessment Scale-Cognitive subscale (58); ADCS-CGIC, AD Cooperative Study—Clinical Global Impression of Change (76); AHAD, American Heart Association diet; APOE (ε4), apoε4 allele; Aβ42, amyloid β 42; BHB, serum β-hydroxybutyrate; BNT, Boston Naming Test (65); BVMT-R, Brief Visuospatial Memory Test-Revised (62); CHO, carbohydrates; CMR, cerebral metabolic rate; CSF, cerebrospinal fluid; FPG, fasting plasma glucose; GDS, Geriatric Depression Scale (73); GI, gastrointestinal; Glu, glucose; HEI, Healthy Eating Index (57); IDE, insulin-degrading enzyme; IL1B, interleukin 1β; KD, ketogenic diet; kMCT, commercially available drink; MAD, modified Atkins diet; MCS, Memory Composite Score (Hopkins Verbal Learning Test-Revised and BVMT-R); MCT, medium-chain triglyceride; MDS-HC, Minimum Data Set for Home Care (75); MMKD, Modified Mediterranean Ketogenic diet; MMSE, Mini-Mental State Exam (59); MoCA, Montreal Cognitive Assessment (60, 64); N/A, not applicable; NIA, National Institute of Aging; NOD, not other defined; NR, not reported; PET, positron emission tomography; POMS-Bi, Profile of Mood States Bipolar Scale (74); rCBF, regional cerebral blood flow; RL/RI-16, Rappel Libre/Rappel Indicé (64); spm, statistical parametric mapping; Stroop, Stroop Color Word Interference (66); sVOI, standardized volumes of interest; TMT, Trail Making Test (68); t-tau, total tau; VF, Verbal Fluency (67); V-PAL, Verbal Paired Associate Learning Test (63); WAIS-III, Wechsler Adult Intelligence Scale-3^rd (77); WMS-R, Wechsler Memory Scale-Revised (78).

²The study had a double design: a RCT (presented herein) and a longitudinal clinical trial without a comparator (omitted for not fulfilling the inclusion criteria).

³Some outcomes were also measured after the first intervention.