The Missing Link in Antiamyloid Therapy

Alzheimer's disease (AD) impacts millions of elderly adults worldwide causing cognitive decline and severe deterioration of activities of daily life. The popular causal hypotheses for several decades include beta-amyloid (Aβ) deposition and tau hyperphosphorylation. AD research and more than 34% of clinical trials in AD are based on these two hypotheses. A phase-III clinical trial of lecanemab in early AD and mild cognitive impaired (MCI) patients reported a delay in cognitive decline of 27% over an 18-month treatment schedule. This multicenter trial found high specificity of lecanemab toward toxic protofibrils and subsequent clearance of beta-amyloid. There were, however, adverse events, which included cerebral edema and intracerebral hemorrhages in 23.1% of patients compared to 9.3% for those who received a placebo. Suboptimal clinical outcomes, brain volume loss, and adverse events in lecanemab treatment prompted a search for an alternative etiopathogenic explanation. Our research and others have focused on the oxidative stress (OS) hypothesis in AD. Autopsy studies have found significant depletion of the master antioxidant glutathione (GSH) in the hippocampal region, and is believed to be an early event in AD progression. Hippocampal GSH depletion is positively correlated with memory impairment. We have confirmed non-invasively with magnetic resonance spectroscopy (MRS) the depletion of GSH in patients with MCI and AD. We therefore propose a combinational therapy involving oral supplementation of gamma-glutamylcysteine (GGC), an early precursor of glutathione, to replenish brain GSH in addition to lecanemab, potentially to maximize desirable outcomes from combined therapeutic approach.