Researchers have been testing the amyloid hypothesis for more than 30 years, often with disappointing results. When will it be time to throw in the towel? If the results of the trials listed below are negative, the amyloid cascade hypothesis will be in "serious, serious trouble," as one expert recently told MedPage Today.
Spearheaded by , of Harvard, the trial seeks to enroll 1,000 cognitively normal patients who have amyloid buildup confirmed by a brain scan -- what's been dubbed "preclinical" Alzheimer's disease, although the exact progression isn't yet clear. They'll be randomized to solanezumab or placebo for three years, followed by a two-year extension phase.
Bottom Line: The trial will be able to show the effects of an anti-amyloid drug on a specific group of patients -- those with amyloid accumulation but no symptoms -- who are selected for inclusion in the trial.
From the trials unit of the established , DIAN-TU will study the effects of solanezumab or gantenerumab compared with placebo in 160 patients who harbor mutations in the APP or PSEN1/2 genes that put them at extremely high risk of Alzheimer's disease. DIAN has been run at Washington University in St. Louis since 2008 by ; and , there is in charge of DIAN-TU.
Bottom Line: The trial will be able to show whether anti-amyloid drugs can help people whose Alzheimer's disease is driven by gene mutations that affect amyloid pathways. However, it won't be possible to generalize the findings from this study to sporadic forms of the disease.
The API, run by Banner Alzheimer's Institute in Arizona under the leadership of , involves two studies: one in familial Alzheimer's caused by mutations in the PSEN1 gene, another in patients with the APOE4 gene variant that increases Alzheimer's risk but isn't as deterministic as APP or PSEN1/2.
The PSEN1 trial enrolls some 300 patients from one family in Colombia to see whether crenezumab can stave off the Alzheimer's that develops by age 45, on average, in these patients.
The APOE4 trial will test either an active immunotherapy against amyloid or a beta-secretase1 inhibitor to prevent disease in those with this genetic sensitivity.
Bottom Line: These trials could only show that amyloid might have a role in familial and genetically susceptible forms of Alzheimer's -- still no applicable findings for patients without any of these markers.
General Amyloid Antibody Studies
After failing in studies of patients with mild-to-moderate disease, drug developers are turning their attention to earlier stages of Alzheimer's. Many of these -- solanezumab, gantenerumab, and aducanumab -- are being looked at in prodromal and early-stage disease.
Bottom Line: If these findings don't pan out, pharma may be forced to give up on anti-amyloid drugs in sporadic Alzheimer's.