Honey and Alzheimer's Disease-Current Understanding and Future Prospects

Alzheimer's disease (AD) is a neurodegenerative disorder affecting the cerebral cortex, temporal lobe, hippocampus, amygdala, entorhinal cortex, and parahippocampal regions, and is characterized by impaired memory, cognitive deficits, and behavioral changes. It accounts for 60–70% of global dementia cases. Proposed therapeutic strategies target reduction of amyloid deposition, oxidative stress, neuroinflammation, and improvement of cognitive function via drugs (e.g., NMDA antagonists, cholinergic agents, anti-amyloid/tau therapies) and antioxidant/neuroprotective agents (e.g., idebenone, α-tocopherol, estrogen analogues, and honey). Given adverse effects of many pharmacologic agents, interest has grown in nutraceuticals. Honey, rich in phenolic compounds (flavonoids and phenolic acids), exhibits antioxidant, anti-inflammatory, and neuroprotective properties, suggesting potential for preventing and treating AD-related CNS pathology and improving memory and cognition.

Pathophysiology of AD includes extracellular amyloid-β (Aβ) plaque accumulation and intracellular neurofibrillary tangles (NFTs) of hyperphosphorylated tau (amyloid cascade and tau hypotheses), with evidence of multiple co-occurring pathological pathways. Genetic risk factors include APOE (ε4 increases risk) for sporadic AD and APP, BACE1, PSEN-1, PSEN-2 for familial AD. AD brains show macroscopic atrophy and ventricular enlargement and microscopic synaptic loss, pyramidal neuron damage, oxidative stress (reduced SOD, GSH, catalase; increased MDA, 3-nitrotyrosine, 8-oxo markers) and chronic neuroinflammation (elevated IL-1, TNFα, NFκB; reduced IL-4, IL-10). Honey composition varies by geography and floral sources, affecting phenolic profiles and antioxidant capacity; stingless bee and Tualang honeys often show higher phenolics and TAC. Phenolic compounds (flavonoids and phenolic acids) in honey are associated with antioxidant, anti-inflammatory, anti-amyloid, anti-tau, and neuroprotective effects in AD models. Individual compounds reviewed (e.g., myricetin, luteolin, naringenin/naringin, quercetin; chlorogenic, ellagic, ferulic, gallic, caffeic, p-coumaric acids) commonly reduce oxidative damage markers (MDA, NO/nitrite), modulate antioxidant enzymes (SOD, catalase, GSH), down-regulate pro-inflammatory mediators (NFκB, TLR4, COX-2, TNFα, IL-1β/6), upregulate Nrf2, reduce Aβ deposition (via α-secretase increase and BACE1/γ-secretase modulation), attenuate tau hyperphosphorylation, and preserve synapses and LTP. Polyphenols can modulate gene expression (APP, BACE1, PSEN-1, GPx1). Evidence from animal models and limited human studies indicates honey and its polyphenols improve memory and cognition, possibly via cholinesterase inhibition (lower AChE/BChE), neuroprotection in hippocampus and prefrontal/piriform cortices, and preservation of cortico-hippocampal circuitry. Emerging literature suggests dopaminergic system involvement in AD memory deficits; polyphenols may protect dopaminergic neurons, implying an additional mechanism by which honey could benefit cognition.

- Honey contains diverse phenolic acids and flavonoids that mediate antioxidant, anti-inflammatory, neuroprotective, anti-amyloid, and anti-tau effects in AD models. Many compounds (e.g., luteolin, quercetin, ferulic, ellagic, gallic, caffeic acids) reduced oxidative markers (e.g., MDA), increased antioxidant defenses (SOD, GSH, catalase), downregulated inflammatory mediators (NFκB, TNFα, IL-1β/6), and improved synaptic plasticity (LTP). - Anti-amyloid/tau: Several polyphenols decreased Aβ deposition (often via increased α-secretase and reduced BACE1 activity/expression) and reduced tau phosphorylation (e.g., ellagic acid via AKT/GSK3β signaling). Some exceptions (kaempferol, chlorogenic acid) showed less consistent anti-amyloid effects. - Cholinergic modulation: Polyphenols and honey reduced AChE and BChE activities; honey intake lowered BChE and AChE, contributing to improved cognition and memory in animal and human studies. - Dopaminergic system: Literature indicates AD involves dopaminergic neuron/synapse dysfunction; polyphenols can protect dopaminergic neurons and increase dopamine, suggesting honey might also benefit memory via dopaminergic pathways. - Animal studies of honey: Multiple rodent studies (Tualang, stingless bee, honeydew honeys) reported improved learning and memory, reduced anxiety/depression-like behavior, increased hippocampal pyramidal cell counts, reduced oxidative stress and neuroinflammation, and improved cholinesterase profiles, with doses ranging from ~0.1–2.0 g/kg/d or included as dietary components over weeks to months. - Human studies: In a 5-year randomized, placebo-controlled trial in older adults, ~28% of placebo versus <7% of honey group developed dementia; postmenopausal women consuming 20 g/day Tualang honey for 16 weeks showed improved learning and memory; combination formulations including honey (e.g., with sedge and saffron) improved attention, memory, and cognition in patients with mild-to-moderate major neurocognitive disorder. - Safety: Honey’s notable adverse effect is rare allergy/anaphylaxis due to pollen/bee proteins; otherwise fewer contraindications compared to many pharmacologic agents. - Variability: Antioxidant capacity and phenolic profiles vary significantly by honey type, floral source, geography, and storage; direct in vivo comparisons across honey types are lacking.

The review synthesizes evidence that honey and its phenolic constituents target multiple AD-relevant pathways—oxidative stress, neuroinflammation, amyloidogenesis, tau pathology, synaptic dysfunction, and cholinergic deficits—thereby addressing the need for multi-target therapies in AD. Animal and limited human data support benefits of honey on memory and cognition, consistent with observed biochemical and histological neuroprotection (e.g., preserved hippocampal neurons, improved LTP). Cholinesterase inhibition (notably BChE) and modulation of the ACh system provide a plausible mechanism for cognitive improvement, although paradoxical CSF/brain AChE differences suggest neuroprotective mechanisms beyond simple AChE inhibition. Evidence linking dopaminergic dysfunction to AD cognitive deficits and the dopaminergic neuroprotection afforded by polyphenols suggest an additional pathway through which honey may exert nootropic effects. Nonetheless, heterogeneity in honey composition, paucity of standardized dosing regimens, and limited clinical trials constrain definitive conclusions. The review posits honey as a promising preventive and adjunctive therapeutic candidate, especially if combined with other nutraceuticals, while emphasizing the need for rigorous clinical validation and mechanistic studies focused on honey-derived polyphenols.

Honey, rich in flavonoids and phenolic acids, exhibits broad antioxidant, anti-inflammatory, anti-amyloid, anti-tau, and neuroprotective actions that translate into improved cognition and memory in preclinical models and suggest benefit in humans. Polyphenols can modulate key AD pathways (APP processing/BACE1, tau phosphorylation, Nrf2 signaling, inflammatory cascades) and neurotransmitter systems (cholinergic, potentially dopaminergic). Given variability in phenolic profiles among honey types and potential context-dependent pro-oxidant effects of some polyphenols, future research should focus on: (1) standardizing and characterizing honey types and doses; (2) head-to-head in vivo comparisons of different honeys; (3) controlled clinical trials in MCI and AD populations; (4) mechanistic studies on dopaminergic and cholinergic modulation by honey; (5) evaluation of synergistic nutraceutical combinations with honey; and (6) translational studies in primate models of sporadic AD. Honey represents a promising, accessible nootropic candidate for AD prevention and adjunctive management, pending further clinical validation.

- Narrative review with no original data; no formal systematic search or meta-analysis described. - Limited human evidence; most findings are from rodent models or in vitro studies. - Significant variability in honey composition by floral/geographic source; lack of standardized preparations and dosing regimens. - Few or no in vivo comparative studies across honey types; scarce primate data for sporadic AD models. - Potential pro-oxidant effects of polyphenols contextually; safety and long-term effects in AD populations require further study. - Some human studies used combination formulations (honey plus other agents), complicating attribution of effects to honey alone. - Optimal dose, duration, and timing (prevention vs treatment) remain undetermined.