Alzheimer Drug Trials: Combination of Safe and Efficacious Biologicals to Break the Amyloidosis-Neuroinflammation Vicious Cycle

Abstract

Late-onset Alzheimer's disease (LOAD) is a long-enduring neurodegenerative disease that progresses for decades before the symptoms of cognitive decline and loss of executive function are measurable. Amyloid deposits among other pathological changes, tau hyperphosphorylation, synapse loss, microglia and astroglia activation, and hippocampal atrophy are among the pathological hallmarks of the disease. These are present in the brain before memory complaints are reported and an AD diagnosis is made. The attempt to postpone or prevent the disease is becoming a more and more plausible goal because new early electrophysiological, cognitive, blood-based, and imaging-based diagnostics are being brought forward at the same time as the first anti-amyloid antibody is about to be approved. In view of known contributions of neuroinflammation to the pathology of LOAD, we should not focus solely on anti-amyloid therapies and ignore the interactive neuroinflammatory component of AD. Our belief is that it would be more rewarding to start clinical trials using combination therapies that are based on approved, safe, and efficacious anti-neuroinflammatory agents such as anti-interleukin-1 signaling agents in combination with the anti-amyloid antibodies that have been shown to be safe in multiyear trials. The proposal is that we should administer these two classes of safe biologicals to symptom-free individuals in midlife who are identified as having a high-riskfor-Alzheimer's-disease using "precision medicine."

A broad cathepsin inhibitor blocks crystal-stimulated inflammasome-dependent and -independent inflammation, and gout arthritis

“…Based on this a clinical trial treating patients with advanced atherosclerotic disease with Canakinumab was performed and showed benefit in reducing recurrent cardiac events and lowering C-reactive protein levels (45). Yet another disease that may be linked to the particle-stimulated inflammatory response is Alzheimer's disease, where the particle is thought to be beta-amyloid aggregates (46,47). Since cathepsin inhibitors can block such crystal/particle-stimulated inflammation, our findings raise the possibility that these agents might be useful in treating these diseases.…”

Dementia Appraisal: Overview of Good Clinical Practices, Barriers, and Gaps for Integrated Care

“…With the growing knowledge of the contribution of neuroinflammation to late-onset AD, there has been increased interest in clinical trials using anti-inflammatory agents in combination with anti-amyloid therapies [164].…”

Therapeutic plasma exchange with albumin: a new approach to treat Alzheimer’s disease

“…Microglial activation and neuroinflammatory processes are locked in a vicious cycle with amyloidosis [31]. TPE could potentially have a beneficial effect to break up both arms of this cycle by removing excess Aβ and proinflammatory mediators.…”

“…In this regard, the amyloidosisneuroinflammation feedback loop can be a relevant therapeutic target in AD. There is a need to design clinical trials that use combination therapies based on approved, safe, and efficacious anti-neuroinflammatory agents such as anti-IL-1 signaling agents in combination with anti-Aβ antibodies that have demonstrated to be safe in multiyear trials [31]. Importantly, as a possible new approach to treating AD, TPE exerts both effects simultaneously as it eliminates both the pathological deposit of Aβ, and the proinflammatory elements involved in AD pathogenesis.…”