Alzheimer's disease — Voluntary wheel running in 5xFAD mice

Early clearance of amyloid plaques via monoclonal antibody would slow cognitive decline in prodromal patients.

Plaque burden dropped on PET imaging but ADAS-Cog scores showed no separation from placebo at 18 months.

Why it matched: shares APP/amyloid-beta · same research area · mechanism: Proteostasis · mechanism: Synaptic & neuronal function

Activating LXR or RXR receptors, which raise APOE and are reported to help clear amyloid beta, would lower amyloid beta 40 in the brain and spinal fluid of rats.

Treating normal rats for 3 or 7 days with the LXR agonist T0901317 or the RXR agonist bexarotene did not significantly change amyloid beta 40 in the brain or spinal fluid.

Why it matched: shares APP/amyloid-beta · same research area · mechanism: Proteostasis · failed the same way: Held in the model species, not beyond it

Removing aggregated amyloid beta with aducanumab would slow decline on the Clinical Dementia Rating Sum of Boxes in early Alzheimer's disease.

Both phase 3 trials were halted for futility on pooled interim data. In the fuller analyses, EMERGE met the primary endpoint (−0.39 for high dose vs placebo, P = .012) but ENGAGE did not (+0.03, P = .833), with 3,285 patients across 348 sites.

Why it matched: shares APP/amyloid-beta · same research area · mechanism: Proteostasis

A TREM2 agonist antibody would boost microglial plaque clearance and slow decline in early Alzheimer's.

Microglial activation markers rose and soluble TREM2 in CSF dropped, but CDR-SB scores were unchanged at 12 months.

Why it matched: same research area · mechanism: Proteostasis · mechanism: Inflammation & innate immunity

GSK-3 beta inhibition would reduce tau hyperphosphorylation and slow decline in mild-to-moderate Alzheimer's.

CSF p-tau181 dropped by 28% but ADAS-Cog showed no difference from placebo; the high-dose arm was halted for safety.

Why it matched: same research area · mechanism: Proteostasis