Breaking the vicious cycle: bitter compounds targeting metabolic defects and inflammation in Alzheimer's disease

Alzheimer's disease (AD), a neurodegenerative disorder characterized by progressive cognitive decline, poses an increasing global health burden among aging populations. Despite decades of research, its pathogenesis remains incompletely understood, and effective therapies are urgently needed. Growing evidence links AD progression to inflammation and type 2 diabetes mellitus (T2DM), with hyperglycemia, insulin resistance, and chronic inflammation synergistically driving neuronal dysfunction. These factors perpetuate a pathogenic "metabolic-inflammatory cycle": inflammatory cytokines disrupt insulin signaling, exacerbating insulin resistance, which further amplifies neuroinflammation. Whereas anti-inflammatory and antidiabetic drugs show limited clinical efficacy in AD, bitter compounds, natural and synthetic agents with pleiotropic bioactivities, offer a novel therapeutic avenue. Notably, bitter compounds such as the alkaloid berberine, the flavonoid naringenin, and synthetic bitter compounds such as denatonium benzoate and metformin exhibit dual anti-inflammatory and metabolic regulatory effects. Preclinical studies have demonstrated their ability to suppress neuroinflammation, restore insulin sensitivity, and mitigate amyloid/tau pathology, potentially disrupting the metabolic-inflammatory cycle. Emerging insights also highlight their modulation of the gut-brain axis, linking intestinal homeostasis to neuroprotection. This mini-review synthesizes current evidence on the interplay of T2DM and inflammation in AD, emphasizing how bitter compounds target immunometabolic cross talk. This review also briefly discusses the metabolic and anti-inflammatory properties of bitter compounds via the gut-brain axis, alongside their potential for combination with current anti-AD drugs, suggesting multidisciplinary collaboration. Further mechanistic studies and clinical validation are warranted to translate bitter compound-based therapies into practice, addressing unmet needs in AD management.