Carotenoids as Multifunctional Nutritional Modulators in Alzheimer’s Disease: A Mini‑Review of Parallel Effects on Oxidative Stress, Connexin 43, and Amyloid‑β Aggregation

Abstract

Alzheimer’s disease (AD) is characterized by the accumulation of amyloid‑beta (Aβ) plaques and associated oxidative and inflammatory neurotoxicity. Carotenoids are being investigated as promising nutritional candidates that may attenuate Aβ‑induced damage through multiple parallel mechanisms, including reducing oxidative stress, modulating gap junction intercellular communication (GJIC), and interfering with Aβ aggregation. Microglial activation and subsequent release of reactive oxygen species (ROS) and cytokine together alter astrocytic connexin 43 (Cx43) function, disrupt GJIC, and drive excitotoxic signaling that further increases Aβ production. Carotenoids exhibit antioxidant activity through free radical scavenging and support of mitochondrial function and have been associated with modulation of Cx43 expression and astrocytic coupling under conditions of oxidative and inflammatory stress, potentially helping to maintain neuronal energy balance and ion homeostasis. These effects may also influence redox‑ and cytokine‑dependent pathways implicated in pathological hemichannel activity. In addition, certain carotenoids can directly interact with Aβ in experimental models, inhibiting fibril formation and attenuating Aβ‑associated inflammatory responses. Overall, the current evidence base is dominated by in vitro, animal, and observational studies. Notably, while clinical evidence remains limited, a preliminary interventional study in AD patients reported that a combination of lutein, zeaxanthin, meso‑zeaxanthin, and omega‑3 fatty acids was associated with slower functional decline and improvements in certain behavioral and clinical measures, whereas carotenoids alone had a smaller impact. A subsequent randomized clinical trial using a similar carotenoid–omega‑3 formulation plus vitamin E showed modest benefits on selected memory and clinical outcomes. In contrast, omega‑3 fatty acids or vitamin E, administered without concomitant carotenoids in other trials, have not consistently shown clear benefits for AD progression. In addition, a randomized trial of lutein/zeaxanthin supplementation in community‑dwelling older adults with self‑reported cognitive complaints suggested modest, domain‑specific improvements, particularly in visual memory and learning. This mini‑review summarizes current experimental and clinical evidence for these antioxidant, gap‑junction‑modulating, and anti‑aggregatory actions in the context of Aβ‑driven neurodegeneration and highlights the potential role of these carotenoids as multifunctional agents in nutritional strategies against AD.