Table 4.
Small molecules enhancing Aβ clearance
| Name (alternative name) | Mechanism of action | Clinical phase (current status) |
Pathological biomarker | Cognition | Ref |
|---|---|---|---|---|---|
| RAGE antagonists | |||||
| Azeliragon (TPP488) | RAGE antagonist | Phase 3 (STEADFAST, terminated for futility) | No data available | No benefit overall; *HbA1c ≥6.5% ↑ (ADAS-Cog11) | [118] |
| ApoE lipidation enhancers | |||||
| Bexarotene | RXR agonist | Phase 2 (completed) | Amyloid PET: No benefit overall; *APOE4 noncarrier ↓ (regional amyloid) *Serum Aβ42 ↑ (correlated with decreased cortical amyloid in treated APOE4 noncarrier) |
No benefit overall *APOE4 noncarrier ↓ (MMSE) |
[113, 126] |
| CS6253 | ABCA1 modulator | Phase 1 (completed) | No data available | No data available | [127] |
| Microglia modulators | |||||
| GV-971 | Gut-brain axis immunomodulator | Phase 3 (China, completed→ conditional approval in China) Phase 3 (GREEN MEMORY, suspended for COVID-19) |
No data available | *↑ (ADAS-Cog12); *MMSE 11-14 ↑ (CIBIC+) | [129] |
| VG-3927 | TREM2 agonist | Phase 1 (completed) | No data available | No data available | [133, 134] |
| IDE enhancers | |||||
| Nasal Insulin | IDE-mediated Aβ clearance65 | Phase 2/3 (SNIFF, completed) | CSF Aβ42/Aβ40 and Aβ42/total tau ratios: No benefit overall; *Device 1 subgroup ↑ | No benefit overall; *Device 1 subgroup ↑ (ADAS-Cog12, ADL-MCI) | [139] |
*Asterisks indicate statistically significant differences. Arrows indicate the direction of change: for cognitive outcomes, ↑ and ↓ represent improvement or worsening, respectively; for pathological biomarkers, ↑ and ↓ indicate numerical increase or decrease. (-) indicates no change.