Table 1.

All reviewed studies investigating the effects of DR in AD. N/A: relevant data not reported; n/s: relevant data not significant; Aβ: amyloid beta; BHB: beta-hydroxybutyrate; GFAP: glial fibrillary acidic protein; PRCs: protein restriction cycles; IGFBP-1/3: insulin growth factor binding protein- 1/3; IGF-1: insulin growth factor-1; GSK-3β: Glycogen synthase kinase-3 beta; PKA: protein kinase A; NOX2: NADPH oxidase 2; MCI: mild cognitive impairment; aMCI: amnestic mild cognitive impairment.

1 Alzheimer’s Disease Animal Studies
Model Organism	Age & Sex	Dietary Interventions	Cognitive Function & Neurogenesis	Brain Pathology	Biomarkers	Reference
PS1 mutant knock-in mice	6-weeks male	ADF for 3 months	N/A	↓ neuronal damage	↓ lipid peroxidation product (4-hydroxynonenal)	Zhu et al. 1999 [73]
Tg2576 mice	3 months female	30% CR for 9 months	N/A	↓ Aβ plaques; ↓ Aβ levels	N/A	Wang et al. 2005 [65]
(1) APP (J20) and (2) APP + PS1 mice	(1) 14–15-weeks and (2) 9-weeks male	(1) 40% CR for 2 weeks (2) 40% CR for 15 weeks	N/A	↓ Aβ plaques	n/s	Patel et al. 2005 [74]
APP/V717I mice	3 months female	KD for 43 days	N/A	↓ Aβ levels	↑BHB	Auwera et al. 2005 [83]
3xTgAD mice	3 months male & female	40% CR or ADF for 14 months	↑cognition (40% CR = ADF)	↓ Aβ plaques; ↓ tau phosphorylation (40% CR)	N/A	Halagappa et al. 2007 [79]
PS1 and PS2 double knockout (cDKO) mice	4 months male & female	30% CR for 4 months	↑cognition; ↓brain atrophy	↓ tau phosphorylation	↓ GFAP; ↓ cleaved caspase-3	Wu et al. 2008 [77]
APP and PS1 (dtg APP/PS1)	13–14 months male	40% CR for 14 weeks	N/A	↓ Aβ volume	N/A	Mouton et al. 2009 [75]
3xTg-AD mice	8–9 months male	PRCs for 18–19 weeks	↑ cognition	↓ Tau phosphorylation; ns Aβ plaques	↑ IGFBP-1; ↓ IGF-1; ↓ IGFBP-3; n/s CD11b	Parrella et al. 2013 [84]
Tg4510 mice	18-weeks male & female	CR for 3 months (reduction of body weight to less than 35–40%)	↑ cognition; n/s brain atrophy	N/A	N/A	Brownlow et al. 2014 [78]
Tg2576 mice	2.5 months male & female	30% CR for 2.8 or 12.5 months	N/A	↓ Aβ plaques; ↓ Aβ levels; ↓ gamma secretase complex	N/A	Schafer et al. 2015 [68]
APP/PS1 (B6C3-Tg (APPswe, PS1dE) 85Dbo/J) mice	5 months male & female	ADF for 5 months	↑ cognition	↓ Aβ plaques	N/A	Zhang et al. 2017 [76]
AppNL-G-F knock in mice	12 months male	ADF for either 1, 4 or 12 months.	↑ cognition; ↑ synaptic plasticity	N/A	N/A	Liu et al. 2019 [69]
5XFAD mice	2 months female	ADF for 4 months	↓ synaptic plasticity	↑ neuronal injury; n/s Aβ accumulation	↑IBA-1; ↑GFAP; ↑pro-inflammatory cytokines	Lazic et al. 2020 [85]
3xTg-AD	6 months male	ADF for 3 months	↑ cognition; ↑ neuronal differentiation; ↑ GSK-3β	N/A	↑ AMPK, ↑ BDNF, ↓ PKA, ↓insulin	Li et al. 2020 [82]
(1) E4FAD and (2) 3xTg-AD mice	(1) 3 months female E4FAD (2) 3.5 months (long-term) and 6.5 months (short-term) male and female 3xTgAD	(1) FMD for 4.5 months 2) FMD or 4% PR for 15 months (long-term); FMD for 2 months (short-term)	(1) ↑cognition, ↑neurogenesis (2) ↑cognition, ↑neurogenesis (FMD > 4% PR) (long-term); ↑ cognition (short-term)	(1) ↓ Aβ plaques, ↓ Aβ levels (2) ↓ Aβ plaques, ↓tau hyperphosphoryation (FMD > 4% PR) (long-term); ↓ Aβ plaques, ↓ tau hyperphosphoryation (short-term)	(1) ↓pro-inflammatory cytokines, ↓ NOX2 levels (2) ↓ CD11b (FMD > 4% PR) (long-term); ↓ NOX2 levels, ↓ IBA-1, ↓ pro-inflammatory cytokines (short-term)	Rangan et al. 2022 [86]
2 Alzheimer ’s Disease Human Studies
Patient Population	Age & Sex	Dietary Interventions		Clinical Findings		Reference
Obese adults with MCI	60+ (mean: 68) male & female	CR counseling with nutritionists (n = 38) or brief lifestyle counseling (n = 37) for 12 months		↑ global cognition, ↑ memory, ↑ semantic fluency		Horie et al. 2016 [87]
Adults with very mild to moderate AD	(mean: 78) male & female	KD for 3 months followed by 1 month of regular diet		↑ cognition		Taylor et al. 2017 [88]
Adults with aMCI or mild AD	55–80 (mean: 71) male & female	placebo (n = 16) and FMD (1 cycle every 2 months) (n = 12)		N/A		Rangan et al. 2022 [86]