TABLE 2.
Clinical evidence of compounds targeting brain energy metabolism in neurodegenerative diseases.
| Treatment | Indication | Study design | Results | References |
| Insulin | ||||
| Intranasal insulin | Healthy | Intranasal insulin (4 × 40 IU/d) vs. placebo; 8 weeks; 38 subjects | ↑ Declarative memory (delayed recall of words) and mood; No changes in blood glucose and plasma insulin | Benedict et al., 2004 |
| Intranasal insulin or ASP-I | Healthy | Acute/8 weeks intranasal insulin or ASP-I (rapid acting insulin analog) (4 × 40IU/day) vs. placebo; 36 male subjects | ↑ Declarative memory (word lists) after long-term administration (ASP-I > insulin); No change in blood glucose and plasma insulin | Benedict et al., 2007 |
| Intranasal insulin | MCI or AD | Acute intranasal insulin (10, 20, 40 or 60 IU) vs. placebo; 33 patients | ↑ Verbal memory in APOE4 (–) patients (max at 20 IU) ↓ Verbal memory in APOE4 (+) patients (n.s.); No change in blood insulin and glucose levels | Reger et al., 2008a |
| Intranasal insulin | Early AD | Intranasal insulin (20 IU BID) vs. placebo; 21 days; 24 patients | ↑ Verbal information retention after delay, attention, functional status; ↑ Aβ40/42 ratio; No change in blood insulin and glucose levels | Reger et al., 2008b |
| Intranasal insulin | MCI or mild to moderate AD | Intranasal insulin (20, 40 IU) vs. placebo; 4 months; 104 patients | ↑ Memory (delayed story) (ADAS-Cog and ADCS-ADL in younger participants); ↓ Dementia Severity Rating Scale; ↓ CMRGlc decline (FDG PET in precuneus, frontal and occipital cortices) | Craft et al., 2012 |
| Intranasal insulin | MCI or AD | Intranasal insulin (20, 40 IU) vs. placebo; 4 months; 104 subjects | ↑ Memory (delayed story; dose and sex-dependent); No change in memory in APOE4 (+) subjects | Claxton et al., 2013 |
| Intranasal insulin or detemir | MCI or mild to moderate AD | Intranasal insulin, insulin analog detemir or placebo; 4 months; 36 patients | ↑ Memory composite (delayed list and story recall) and preserved brain volume after insulin (not detemir); ↓ CSF Tau-P181/Aβ42 after insulin (not detemir); No change in daily functioning (insulin or detemir) | Craft et al., 2017 |
| Intranasal insulin | PD | Intranasal insulin (40 IU) vs. placebo; 4 weeks; 16 patients | ↑ Cognition (verbal fluency) and motor function | Novak et al., 2019 |
| Intranasal insulin | MCI or AD | Intranasal insulin (40 IU) vs. placebo; 12 months (followed by 6 months open label extension); 289 patients | No change in memory (ADAS-Cog-12) (differences between groups depending on the injection device used); No change in CSF AD biomarkers, CSF insulin or blood glucose | Craft et al., 2020 |
| Intranasal glulisine | MCI or mild AD | Intranasal Glulisine (rapid-acting insulin analog) (20 IU BID) vs. placebo; 6 months; 35 patients | No change in cognition (ADAS-Cog13), CDR global score, FAQ or mood. No change in blood glucose or insulin levels | Rosenbloom et al., 2021 |
| GLP1-R agonists | ||||
| Liraglutide | AD | Liraglutide vs. placebo; 6 months; 38 patients | ↓ CMRGlc decline (FDG PET in precuneus, cerebellum, temporal and occipital cortices); No change in cognition or Aβ (global and regional brain areas) | Egefjord et al., 2012; Gejl et al., 2016 |
| Liraglutide | MCI | Liraglutide vs. placebo; 12 weeks; 41 patients | ↑ Connectivity in the DMN (fMRI); No change in cognition | Watson et al., 2019 |
| Liraglutide | Mild AD | Liraglutide vs. placebo; 1 year; 204 patients (without T2D) | ↑ Memory (composite z-score); ↑ Temporal lobe and total gray matter volumes; No change in CMRGlc (FDG PET) | Femminella et al., 2019 |
| Liraglutide | T2D | Liraglutide vs. placebo; 3 weeks; 40 patients (obesity with pre-diabetes or early-stage T2D) | ↑ Memory (composite z-score: attention, memory, executive control) | Vadini et al., 2020 |
| Semaglutide | MCI or mild AD | Semaglutide vs. placebo; 2 years; 2 studies of 1840 patients | Estimated study completion date: 2025 | Clinical trials NCT04777396 and NCT04777409 |
| Metformin | ||||
| Metformin | AD | Long-term use of Metformin on 7’686 patients aged 65+ | ↑ Risk of developing AD with long-term use of Metformin (presumably through Vit B12 deficiency) | Imfeld et al., 2012 |
| Metformin | MCI | Metformin vs. placebo; 1 year; 80 patients (overweight and non-diabetic) | ↑ Memory on SRT; No change in ADAS-Cog, glucose uptake or plasma Aβ | Luchsinger et al., 2016 |
| Metformin | MCI or AD | Metformin vs. placebo; 8 weeks; 20 patients (non-diabetic) | ↑ Executive functions; ↑ Learning and memory (n.s.); No change in AD biomarkers | Koenig et al., 2017 |
| Metformin | AD | Meta analyses | ↓ Dementia incidence in diabetic patients treated with Metformin | Campbell et al., 2018; Chin-Hsiao, 2019; Samaras et al., 2020; Sluggett et al., 2020 |
| Metformin | MCI | Metformin vs. placebo; 2 years; 370 patients (overweight/obese w/o T2D) | Estimated study completion: 2025 | Clinical trial NCT04098666 |
| Ketogenic Diet | ||||
| MCT | Mild to moderate AD | MCT (Ketasyn/AC-1202) vs. placebo; 12 weeks; 152 patients | ↑ Memory (ADAS-Cog) in APOE4(–), but not in APOE4(+) subjects | Henderson et al., 2009; Henderson and Poirier, 2011 |
| KD | MCI | Low carbohydrates (5–10% cal.) vs. high carbohydrate (50% cal.) diet; 6 weeks; 23 patients | ↑ Memory, positively correlated with ketone levels | Krikorian et al., 2012 |
| MAD | MCI or early-stage AD | MAD vs. recommended diet; 12 weeks; 27 patients | ↑ Episodic memory (n.s.); Low adherence | Brandt et al., 2019 |
| KD | MCI in PD | KD vs. recommended diet; 8 weeks; 14 patients | ↑ Memory, positively correlated with body weight loss; No effect on motor function | Krikorian et al., 2019 |
| MCT | MCI | MCT (kMCT drink) vs. placebo drink; 6 months; 52 patients | ↑ Cognitive functions | Fortier et al., 2019 |
| MCT | Mild to moderate AD APOE4(–) | MCT (jelly) vs. placebo; 30 days; 46 patients | ↑ Memory (ADAS-Cog) | Xu et al., 2020 |
| MCT | Mild to moderate AD APOE4 (–) | MCT (Tricaprilin/AC-1204) vs. placebo; 26 weeks; 413 patients | No effect on memory (ADAS-Cog11) | Henderson et al., 2020 |
| MCT | MCI | MCT (kMCT drink) vs. placebo drink; 6 months; 122 patients | ↑ Cognitive functions | Fortier et al., 2021 |
| MCT | Mild to moderate AD APOE4 (–) | MCT (AC-SD-03/CER-0001) vs. placebo; 26 weeks; 300 patients with decreased FDG PET signal | Estimated study completion: 2024 | Clinical trial NCT04187547 |
ADAS-Cog, The Alzheimer’s Disease Assessment Scale–Cognitive Subscale; AD, Alzheimer’s disease; ADCS-ADL, Alzheimer’s disease cooperative study – Activity of daily living; ALS, Amyotrophic lateral sclerosis; APOE4, apolipoprotein 4; BID, twice a day; CMRGlc, cerebral metabolic rate of glucose; CDR, clinical dementia rating; CSF, cerebrospinal fluid; DMN, default mode network; FAQ, Functional Activities Questionnaire; FDG-PET, fluorodeoxyglucose-positron emission tomography; IU, international units; KD, ketogenic diet; MAD, Modified Atkins Diet; MCI, mild cognitive impairment; MCT, Medium Chain Triglyceride; n.s., not significant; PD, Parkinson’s disease; SRT, Selective Remining Test; T2D, Type 2 Diabetes.