Amyloid Depletion in Alzheimer's Disease

Amyloid depletion is becoming a clinical reality for disease modification in the therapy of Alzheimer’s disease. Aducanumab is one of three antibodies with biological activities to deplete amyloid efficiently to minimal non-pathogenic levels within 6 to 18 months.

Amyloid, a brain protein, accumulates in Alzheimer’s disease during decades before initial signs of dementia appear in patients.

Amyloid can damage the brain’s nerve cells resulting in memory problems, difficulties with orientation in space and time, language, thoughtful planning and learning new things.

Brain nerve cells damaged by amyloid suffer from communication loss, broken transport systems and the formation of neurofibrillary tangles. These consist of pathologic tau proteins. Besides amyloid deletion, reversing tau pathology is a therapeutic objective for the treatment of Alzheimer’s disease.

Aducanumab, approved by the U.S. FDA in 2021, is the first of a class of amyloid depleting drugs currently in late-stage development. These seek to slow the progression of Alzheimer’s disease by reversing amyloid and tau pathologies.

Aducanumab is a human monoclonal antibody discovered by Neurimmune’s RTM technology. Its biological activity of amyloid depletion involves microglia cells in brains. Aducanumab’s engagement with amyloid enables microglia cells to remove amyloid by degrading it.

Together, Neurimmune's and Biogen's scientists described in the journal Nature that 12 monthly infusions of aducanumab depleted brain amyloid in Alzheimer’s disease patients (Sevigny J. et al., 2016).

Phase 3 clinical trials confirmed aducanumab’s amyloid-depleting activity down to 25 centiloids from 85 centiloid at baseline. The remaining 25 centiloids are below the 30 centiloid benchmark indicating only minimal residual amyloid (Budd Haeberlein et al., 2022).

Surprisingly, amyloid depletion reduced tau pathology: Tau-PET imaging, plasma and cerebrospinal fluid levels of tau as well as histologic brain tissue examinations consistently established that amyloid depletion is accompanied by reduced tau pathology. The data showed a statistically significant correlation between plasma p-tau reduction and less cognitive and functional decline in patients with Alzheimer’s disease (O. Hansson, CTAD2021).

Results from phase 3 clinical trials with amyloid depleting antibodies aducanumab, lecanemab, donanemab and gantenerumab suggested that amyloid depletion below 25 centiloids translates into statistically significant and clinically relevant slowing of decline in cognitive abilities, activities of daily living and behavioral functions. Results from three clinical trials have consistently established this clinical efficacy (EMERGE, CLARITY AD, TRAILBLAZER-ALZ). Three additional phase 3 clinical trials with higher residual amyloid levels of 34-51 centiloids failed to show slowing of disease progression (GRADUATE I, GRADUATE II, ENGAGE).

Together the results of the phase 3 clinical trials indicate that amyloid depletion to very low levels is required for clinical efficacy. This can be achieved by either high antibody doses or prolonged treatment time intervals or by a combination of both.

Currently, amyloid depleting antibodies are administered by intravenous infusion. Future developments focus on subcutaneous applications with autoinjector self-administration.

Budd Haeberlein et al., 2022; Plowey et al., 2022; van Dyck et al., 2022; Mintun et al., 2022; Sevigny et al., 2016