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-risk-for-Alzheimer’s-disease using “precision medicine.”

Keywords: dementia and neurological disorders; inflammation; microglia; neurodegenerative diseases; neuroinflammatory disorders; pharmacology.

Figure 1.

“Two Hit” Synergy to Break the Vicious Cycle: Anti-IL-1 Strategy Backed Up by Simultaneous Aβ Reduction. Amyloid oligomers and plaque increase IL-1 and NLRP3 and activate microglia. Anti-Aβ antibody reduces oligomer and plaque burden, relieving proinflammatory signaling. Anti-IL-1 biologicals, such as anakinra, canakinumab, or rilonacept, block IL-1 signaling, relieving proinflammatory activation of amyloidosis and tau phosphorylation (see text for details). IL = interleukin.