Alzheimer's disease — TREM2

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

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

Blocking TREM2 would repolarise tumour-associated macrophages and restore T-cell infiltration in PDAC allografts.

Macrophage phenotype shifted on flow cytometry but tumour growth curves showed no separation from isotype control.

Why it matched: shares TREM2 · shared focus: TREM2

Long-term voluntary running would reduce insoluble amyloid, neuroinflammation and non-cognitive behavioural problems in the 5xFAD mouse model of Alzheimer's disease.

After 24 weeks of wheel running started before heavy plaque formation (female mice, n = 30), microglia, cytokines and insoluble amyloid-beta were unchanged. Runners actually developed hindlimb clasping earlier (p = 0.009) and showed more anxiety-like and exploratory behaviour.

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

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 · mechanism: Proteostasis