Introduction

The increase in life expectancy in recent decades has led to a rise of age-related diseases (Guo et al., 2022), including dementias. AD is the most common form and its prevalence is around 40% in people over 85 years of age (Alzheimer’s disease facts and figures, 2023). In the early stage of disease development, patients experience a decline in cognitive function and difficulty remembering recent events (short-term memory loss) (Reiss et al., 2022). During the progression of the disease, patients encounter difficulties in speech and cognitive thinking, accompanied by long-term memory loss. There is a strong relationship between cognitive decline and the depletion of the neurotransmitter acetylcholine in the brain of AD patients (Zuin et al., 2022).

Reason why cholinergic hypothesis has been central to the development of anti-Alzheimer's drugs (Zuin et al., 2022). The advances in the pathophysiological understanding of AD have elucidated the links between cholinergic hypothesis and other pathological mechanisms, including the formation and accumulation of Aβ, hyperphosphorylation of tau protein and neuroinflammation (Monteiro et al., 2023, Hampel et al., 2021). Current treatments for Alzheimer's disease primarily target its symptoms rather than the disease itself. Cognitive function can be temporarily improved by medications such as memantine, galantamine, rivastigmine, and donepezil. Immunotherapies like Aducanumab, Lecanemab and Donanemab have recently demonstrated the ability to slow the progression of the disease somewhat by reducing amyloid plaques, but their use remains limited due to adverse effects and access issues. Current research focuses on identifying anti-Alzheimer's agents (disease-modifying therapies) capable of preventing mild cognitive decline and slowing its progression. This is particularly crucial given the promising initial results of research focused on early diagnosis of the disease (Hajjo et al., 2022).

Polypharmacology is an approach more suited to the pathological complexity of AD, hoping to overcome the limitations of current treatments. This is why up to 03 agents described as multi-targeted have entered clinical trials in January 2025 in the AD drug development pipeline (Cummings et al., 2025). Recent advances in life sciences have highlighted the growing importance of network pharmacology in modern research. Furthermore, it integrates the principles of systems biology to explore biological networks and identify key signalling nodes that may serve as potential therapeutic targets with diverse modes of action. Coupled with molecular docking approaches, these models can predict the mode of action of candidates on specific targets (Jabalia et al., 2021). Experimental validation is an essential step in the translation of hypotheses using a bioinformatics approach, particularly in the context of complex diseases requiring a multitarget and multifactorial approach such as AD. Since the discovery of AD, several animal models have emerged, but the pharmacological model using scopolamine makes it possible to better mimic the cholinergic dysfunction associated with AD (Tang, 2019).

Bioactive compounds from plants are increasingly sought after for their anti-Alzheimer properties (Chen et al., 2021). Among these, terpenoids and tannins are being increasingly exploited in the search for anti-Alzheimer's ingredients due to their synergistic and complementary effects on cholinergic dysfunction (Yoo and Park, 2012; Hussain et al., 2019). In this context, several natural products such as green tea extract and rosemary extract, which are rich in terpenoids and tannins, have demonstrated neuroprotective effects in the preclinical phase (Malar et al., 2020; Oresanya and Orhan, 2024).

Recently, we showed that Terminalia macroptera tannin-rich extracts (TeMac™) and glycosyl terpenoid-rich fractions (GT-TeMac™), each prevent hippocampal alterations and cholinergic dysfunction in scopolamine-treated rats (Ambamba et al., 2025a, Ambamba et al., 2025b). Adey et al. (2021) showed that the ethyl acetate fraction of Terminalia macroptera combines tannins and terpenoids. In addition, a study by Ior et al. (2021) showed that this fraction administered at a dose of 100 mg/kg body weight, attenuated psychotic symptoms in mice. The objective of this work is to study the effect of the combined tannin-terpenoid fraction (TT-TeMac™) on the prevention of scopolamine-induced cholinergic dysfunctions and neuronal alterations. This by integrating phytochemical approaches to identify bioactive compounds, network pharmacology to predict potential targets involved in cholinergic dysfunction and identified compounds, molecular docking to assess compound-target interactions, and an in vivo model for experimental validation.