Table 1.

Human, in vitro and animal studies on the association between ketogenic intervention and AD biomarkers.

Human studies
Ketogenic Intervention	Dose, duration	Subjects	AD biomarker	Outcomes	Reference
MMKD (<10% carbohydrate, 60–65% fat, and 30–35% protein)	Daily MMKD for 6 weeks	11 MCI participants, (Age: 64.6 ± 6.4 yr)	CSF Aβ42, Aβ40, tau, and p-tau181	Aβ42, Aβ-42/40, total tau, p-tau181	Nagpal et al. (2019)
MMKD (5–10% carbohydrate, 60–65% fat, and 30% protein)	Daily MMKD for 6 weeks	20 participants; MCI (n = 11) and SMC (n = 9), (Age: 64.6 ± 6.4 yr)	CSF Aβ42, Aβ40, t-tau, p-tau181, NFL	Aβ42, t-tau (only MCI), NFL, no changes in p-tau 181, Aβ40 or Aβ42/40	Neth et al. (2020)
kMCT (60% caprylic acid, 40% capric acid)	30 g/day kMCT for 6 months	MCI (n = 19), Aged ≥55 yr	IL-8, IL-6, IL-10, IL-17	Circulating IL-8, No changes in IL-6, IL-10, IL-17	Myette-Côté et al. (2021)

In vitro studies
Ketogenic Intervention	Dose, duration	AD biomarker	Outcomes	Reference
VCO	2 g of VCO for 24-48 h	Aβ40, Aβ42	Aβ neurotoxicity, Neural survival	Nafar and Mearow (2014)
AcAc & βHB	Combination of 20 mM AcAc/20 mM βHB for 48 h	Aβ40	Aβ peptide efflux	Versele et al. (2020)

Animal studies
Ketogenic intervention	Dose, duration	Pathology stage and age	Type of animal model	AD biomarker	Outcomes	References
βHB and AcAc	βHB: 600 mg/kg/day, AcAc: 150 mg/kg/day for 2 months	Early stage of AD at 4 months old	APP mouse model (n = 12–14)	Aβ42, Aβ40 and Aβ38	Accumulation of intracellular Aβ42. No changes in Aβ40 and Aβ38	Yin et al. (2016)
βHB	1.5 mmol/kg/d βHB for 28 days	Mid-stage of AD with cognitive deficit at 3.5 months old	APP/PS1 mice	Aβ oligomer, APP, IL-1β, TNF-α, and IL-6	Aβ42 accumulation, Senile plaques, APP expression, IL-1β, TNF-α, IL-6	Wu et al. (2019)
βHB	1.5 mmol/kg/day of βHB for 4 weeks	_	ApoE− C57BL/6 J mice	Aβ, Tau	tau tangles, Aβ plaques	Krishnan et al. (2020)
KET (D-β-hydroxybutyrate and (R)-1,3-butanediol)	152 mg/dL for 300 days	Advanced stage of AD at 8.5 months old	3xTgAD mouse model	Aβ, pTau	Aβ aggregation, tau phosphorylation	Kashiwaya et al. (2013)
MCT diet (84% kcal fat, 13% kcal protein and 2% kcal carbohydrates)	MCT diet for 8 weeks.	High fat diet-induced cognitive impairment from 8 weeks old	Male C57BL/6 mice (n = 16)	NF-κB, TNF-α, APP and p-tau	pTau/Tau ratio, APP expression, TNF-α, NF-κB,	Lin et al. (2022)
Ketogenic TD.96355 containing 90.5% fat, 0.3% carbohydrate, and 9.2% protein	KD for 30 days	TBI-induced neuronal loss at 6–7 weeks old	Male ICR mice (n = 26)	GFAP	GFAP in dentate gyrus, Reactive astrocytes.	Har-Even et al. (2021)
3-hydroxybutyl-3-hydroxybutyrate	0.5 mL/kg/day KE for 30 days	TBI-induced morphological and functional deficits at 8 weeks old	Male Sprague Dawley rats (n = 32)	GFAP	GFAP, Brain astrogliosis, Neuroinflammation	Almeida-Suhett et al. (2022)
Ketogenic TD 96355	Daily for 30 days	Kainic acid-induced-hippocampal neuroinflammation	Male ICR mice (n = 30)	TNF-α, NF-κB, PPARγ	TNF-α levels, NF-κB, PPARγ	Jeong et al. (2011)
βHB	1.5 mmol/kg/d for 8 weeks	Chronic cerebral hypoperfusion-induced-neuroinflammation with cognitive impairment in adult rats	Male Sprague–Dawley rats (n = 25)	NF-κB, TNF-α, IL-1β	NF-κB, IL-1β, TNF-α	Wang et al. (2023)

MMKD, Modified Mediterranean Ketogenic Diet; MCI, Mild Cognitive Impairment; CSF, Cerebrospinal Fluid; Aβ, Amyloid Beta; p-tau, phosphorylated tau; SMC, Subjective memory complaints; NFL, Neurofilament Light; kMCT, ketogenic Medium Chain Triglycerides; IL, Interleukin; VCO, Virgin coconut oil; AcAc, Acetoacetate; βHB, βeta Hydroxybutyrate; APP, amyloid precursor protein; TNFα, Tumor Necrosis Factor alpha; ApoE, Apolipoprotein E; KET, Ketone esters; NF-κB, Nuclear factor kappa B; GFAP, Glial fibrillary acidic protein; PPARy, Peroxisome Proliferator-Activated Receptor y; PS1, Presenilin 1; TBI, Traumatic Brain Injury.