Suspected limited efficacy of γ-secretase modulators.

Mild cognitive impairment and Alzheimer's disease (AD) are associated with changes in γ-secretase activity in the brain, producing an amyloid β-protein-42-lowering γ-modulator-like effect. We show here that this modulation occurs at the stage of amyloid deposition, presumably decades earlier than the onset of AD. In addition, γ-secretase modulator-1, a γ-modulator, altered γ-secretase activity in the AD brain but to a lesser extent than in the normal brain. These findings suggest that γ-modulators have limited efficacy against amyloid deposition and AD.