Investigators on the Anti-Amyloid Treatment in Asymptomatic Alzheimer's Disease (A4) Study -- testing the beta-amyloid scavenging drug solanezumab in clinically healthy people at elevated risk for Alzheimer's disease -- now have an extra $8 million to examine additional aspects of the disease.
The funds will support additional evaluations in a subset of A4 participants and also a complementary study of 500 individuals volunteering for the drug trial but not enrolled.
Most noteworthy will be brain PET scans aimed at measuring participants' burdens of tau protein deposits.
Co-principal investigator Reisa Sperling, MD, of Brigham and Women's Hospital in Boston, told 鶹ý that these scans would use the still-investigational AV1451 tracer to image tau tangles.
"We're pretty excited about it," she said in an email. She explained that the scans would be performed at baseline and after 18 and 36 months in the study.
One goal is to determine if the anti-amyloid antibody treatment also affects tau burdens, Sperling said, as well as allowing for an examination of risk factors associated with degrees of baseline tau burden.
"Our natural history data in normals from the Harvard Aging Brain Study suggest that amyloid is strongly correlated with tau, particularly tau spreading outside of the medial temporal lobe into the cortex, and that spreading of tau is the strongest predictor of memory problems," she explained.
"But this is exactly why we are excited about this study -- as we do not really yet understand the link between amyloid and tau -- and this trial will help us know whether changing amyloid can actually slow tau spreading."
The two main pathologies of Alzheimer's disease are beta-amyloid plaques and neurofibrillary tangles made up of hyperphosphorylated tau protein. Their relationship and relative contributions to the clinical symptoms of Alzheimer's disease remain active areas for research and debate.
Several PET tracer agents have been developed for imaging beta-amyloid plaques in living patients, but similar compounds for tau have lagged behind. The new clinical studies attached to the A4 trial will be among the largest to date.
The is putting up the additional $8 million. The A4 trial, which is to start later this year, is supported by Eli Lilly (which owns solanezumab and AV1451), the National Institutes of Health, and nonprofit organizations. Projected enrollment is about 1,000, with participants selected via brain amyloid PET scans to identify those 65 to 85 years old with high plaque burdens but without symptoms of cognitive decline.
A4 investigators plan to screen some 3,000 individuals for enrollment in A4; 500 of those considered ineligible will be matched as closely as possible to A4 participants and enrolled in the complementary study, dubbed the Longitudinal Evaluation of Amyloid Risk and Neurodegeneration (LEARN). It will serve as a natural history observational cohort in parallel with A4.
The tau scans will be performed in 100 A4 participants and 50 in the LEARN cohort.
A4 is widely considered a make-or-break trial for anti-amyloid therapies in Alzheimer's disease. All previous phase III trials of such agents have ended in failure, including a trial of solanezumab in diagnosed patients. But a subgroup analysis in that study found that those with the mildest impairment had a noticeable slowing in the rate of cognitive decline, compared with the placebo group.
On the other hand, a large trial of another anti-amyloid drug developed by Roche, in December.
Lilly is also conducting another trial on its own with solanezumab in patients with mild symptoms.