Alzheimer's disease (AD) is a neurodegenerative disorder primarily affecting the cerebral cortex, temporal lobe, hippocampus, amygdala, entorhinal cortex (EC), and parahippocampal region. Its hallmark is impaired memory and cognitive deficits, accompanied by behavioral changes like agitation, dysphoria, and apathy, strongly correlated with cognitive dysfunction. AD is the most common cause of dementia globally. Current treatments focus on symptom management and slowing progression, but a continuous search for preventive and curative agents is underway. This review investigates the therapeutic potential of honey, a natural product rich in flavonoids and phenolic acids, as a promising nutraceutical agent in AD. While allopathic medications have shown promise, they can cause severe side effects; conversely, honey's adverse effects are rare and mild. The review aims to consolidate current understanding of honey's effects on various aspects of AD pathology, specifically focusing on its impact on memory, cognition, and behavior.

The pathogenesis of AD is complex and remains incompletely understood. The amyloid cascade hypothesis posits that extracellular amyloid-beta (Aβ) plaque accumulation initiates the process, leading to oxidative damage and inflammation. However, the tau hypothesis suggests that tau pathology precedes Aβ aggregation. A third viewpoint suggests multiple concurrent pathways, emphasizing the correlation between dementia and serum amyloid protein content in Aβ plaques, rather than plaque or tangle burden alone. Genetically, AD involves abnormalities in the expression of APOE, APP, BACE1, PSEN-1, and PSEN-2. APOE ε4 allele is associated with sporadic AD, while the other four genes are implicated in familial AD. At the macroscopic level, AD causes reduced brain tissue and enlarged ventricles; microscopically, it involves synapse loss, pyramidal neuron damage, neurodegeneration, and impaired long-term potentiation (LTP) in certain pathways. Oxidative stress, caused by an imbalance between antioxidants and oxidants, and neuroinflammation, marked by an imbalance in pro- and anti-inflammatory cytokines, are also crucial features of AD. The current research focuses on the potential of honey, rich in polyphenols, as a means to mitigate these issues. The review focuses on flavonoids and phenolic acids, the two classes of polyphenols primarily responsible for the antioxidant, anti-inflammatory, and neuroprotective actions in honey.

This review article uses a systematic approach to examine existing literature on the effects of honey on Alzheimer's disease. Studies focusing on honey's components (particularly flavonoids and phenolic acids), their impact on the central nervous system (CNS), and the effects of honey intake on memory, cognition, and behavior in various animal models are analyzed. The review is not based on the generation or analysis of new data but rather on a comprehensive synthesis of published research findings from various sources including journals and databases. Specific search terms used, inclusion criteria, and the selection process for studies are not explicitly stated but can be inferred from the extensive list of citations. Tables 1 and 2 summarize the therapeutic potential of flavonoids and phenolic acids found in honey; Tables 3 and 4 showcase the impacts of honey consumption on memory and cognition in animal models and humans, respectively. Data from these tables and the discussion of the various studies provide the evidence base for the review's conclusions. Figures 1, 2, and 3 depict the interaction of honey components with different aspects of the central nervous system, highlighting the possible effects of flavonoids and phenolic acids on improving memory and reducing AD symptoms.

The review highlights the abundance of flavonoids and phenolic acids in honey, attributing its neuroprotective effects to its phenolic content. Several studies using AD models (summarized in Tables 1 and 2) show the antioxidant, anti-inflammatory, and neuroprotective properties of these compounds, notably in reducing amyloid deposition and tau hyperphosphorylation. Ellagic acid, for example, improved memory, reduced lipid peroxidation, increased antioxidant enzyme levels, and improved neuronal morphology. Honey's effects on memory and cognition are supported by studies in both rodents (Table 3) and humans (Table 4). In rodents, honey improved learning, spatial memory, reduced anxiety, and decreased depressive-like symptoms. In humans, honey consumption demonstrated a decrease in dementia development and improved learning and memory scores, showcasing honey's potential for both prevention and treatment. Furthermore, honey's impact extends to the dopaminergic system, crucial for learning and memory, by potentially preventing the degeneration of dopaminergic neurons and increasing dopamine levels. While the precise mechanisms remain to be fully elucidated, the review suggests that honey's neuroprotective effects are mediated by its ability to attenuate oxidative stress and neuroinflammation. The review also points out conflicting results regarding the expression of antioxidant enzymes after polyphenol treatment. More research focusing on primates and clinical trials in humans is needed to validate the observed effects.

This review supports the hypothesis that honey, due to its polyphenol content, acts as a nootropic agent, offering potential benefits in preventing and treating AD. The findings address the research question by demonstrating honey's multifaceted actions on the CNS, impacting oxidative stress, neuroinflammation, the cholinergic and dopaminergic systems, and ultimately, memory and cognition. The significance of these results lies in identifying honey as a potential natural therapeutic option. While many studies have examined the effects of individual polyphenols, honey provides a readily available source of multiple beneficial compounds simultaneously. The review’s findings are relevant to the field by suggesting an alternative approach to AD treatment, potentially mitigating side effects associated with current pharmacological interventions. Future research focusing on standardized honey preparations and carefully designed clinical trials in humans is crucial to further establish the efficacy and dosage of honey in AD management.

Honey, rich in flavonoids and phenolic acids, exhibits promising potential as a nootropic agent for AD. Its antioxidant, anti-inflammatory, and neuroprotective properties, as demonstrated in animal models and some human studies, suggest its use in preventing AD progression and ameliorating existing damage. Future research should focus on establishing optimal honey types, dosages, and treatment durations, as well as conducting large-scale human clinical trials to confirm its efficacy and safety in preventing and treating AD. Investigating honey's effects on the dopaminergic system and exploring synergistic combinations with other nutraceuticals are further avenues for research.

The review relies heavily on studies conducted in animal models, primarily rodents. The extrapolation of findings to humans requires caution, as there may be species-specific differences in the metabolism and effects of honey components. The lack of large-scale, well-controlled human clinical trials limits the definitive conclusions about honey's efficacy in AD treatment. The variability in honey composition based on geographic location, floral source, and processing methods necessitates further research to standardize honey preparations for therapeutic use. The contrasting findings regarding the expression of antioxidant enzymes necessitate further investigation to clarify the specific effects and mechanisms of action.