The intertwined network among multiple pathological factors, such as free radicals, acetylcholinesterase (AChE), metal-free amyloid-b (Ab), and metal-bound Ab (metal-Ab) (Fig. and), has given the difficulty in combating Alzheimer's disease (AD). Oxidative stress characterized by dysregulated free radicals can damage lipids, nucleic acids, and proteins, which leads to organelle dysfunction and apoptosis. As illustrated in the cholinergic hypothesis, AChE is associated with the development of AD. The synaptic concentration of the neurotransmitter acetylcholine (ACh) is adjusted by the catalytic activity of AChE; however, the abnormally reduced level of ACh can be driven by the increased amount of AChE. In addition, highly concentrated AChE within senile plaques (SPs) can colocalize and interact with Ab species, resulting in the AChE-Ab complexation and the acceleration of amyloid aggregation. Ab peptides tend to aggregate into oligomers and fibrils. In particular, metastable and structured Ab oligomers are known to cause toxicity in cellular systems by triggering membrane disruptions, abnormal cellular signaling, and organelle dysfunction. High concentrations of metal ions [e.g., Cu(I/II) and Zn(II)] are also found in the SPs of AD patients, and they can affect the conformation and aggregation behaviors of Ab by their coordination to Ab. Moreover, redox-active Cu(I/II)bound Ab species can produce reactive oxygen species via Fenton-like reactions and, consequently, aggravate oxidative stress. Several pharmacological trials employing antioxidants (e.g., vitamin E), AChE inhibitors (e.g., donepezil, galantamine, rivastigmine), and anti-Ab drugs (e.g., aducanumab) have been attempted to prevent the progression of AD. Such single target-based therapeutics can temporarily relieve symptoms, and their efficacies are still questionable, however. 9,26 Thus, significant endeavors in designing chemical reagents capable of targeting and modulating two or more pathogenic elements have been made to elucidate the complex pathology of AD and discover effective therapeutic candidates. Herein, we illustrate rational approaches for developing flavonoids that can target multiple pathogenic factors, including free radicals, AChE, metal-free Ab, and metal-Ab, as depicted in Fig. , and modulate their reactivities. We identified key structural features shown in flavonoids that are responsible for versatile reactivities against desired pathological targets through structure-activity relationship studies. Moreover, the most promising flavonoid with multiple functions was developed based on our structure-activity relationship analyses, with the determination of molecular-level mechanistic details. Our overall work demonstrates the development of flavonoids as small molecule-based chemical reagents capable of controlling multiple pathological components associated with neurodegenerative disorders, such as AD.