Alzheimer's disease — GSK-3 beta

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 MAPT/tau · similar wording · same research area · mechanism: Proteostasis · failed the same way: Target engaged, outcome unchanged

GSK-3 beta inhibition would restore hepatic insulin sensitivity in diet-induced obese models.

Robust glucose lowering in mouse models did not replicate in a non-human primate crossover study.

Why it matched: shares GSK3B · shared focus: GSK-3 beta · similar wording

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 · similar wording · mechanism: Proteostasis · failed the same way: Target engaged, outcome unchanged

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: same research area · similar wording · mechanism: Proteostasis

High levels of LRRK2, especially the G2019S mutant that causes inherited Parkinson's disease, would cause or worsen alpha-synuclein disease in mouse brain neurons.

High LRRK2 left alpha-synuclein and Tau levels unchanged and did not worsen alpha-synuclein disease in mice that also made high alpha-synuclein. In some lines, high LRRK2 improved motor skills.

Why it matched: shares MAPT/tau · mechanism: Proteostasis