Abstract: Formation and deposition of amyloid-beta (Aβ) are considered one of the main drivers of Alzheimer’s disease (AD). For more than 30 years, Aβ has challenged researchers through its complex physicochemical properties and multiple peptide processing steps that involve several proteases (Andreasson et al., 2007), ultimately creating many Aβ variants that trigger various physiological effects in neurons, glia, and peripheral immune cells (Busch et al., 2022a). Recent research identified various additional naturally occurring Aβ species with different lengths and chemical modifications. Their impact on AD pathology is currently not well understood, although some of them occur at much higher abundance than Aβ1–42 and Aβ1–40. Here, we highlight new findings that challenge traditional views and summarize recent findings that argue for a significant contribution of previously neglected Aβ variants to the development and progression of AD. Next, we provide an overview on the technical challenges and open questions associated with their study and highlight how different Aβ variants such as Aβ11–40 and Aβ17–40 may use formyl peptide receptor signaling to trigger distinct cellular effects in neurons, glia, and immune cells.