Bioactive peptides (BPs) are a natural, safe, and cost-effective alternative to synthetic small-molecule and antibody-based drugs and may be especially useful in preventing or treating neurodegenerative disorders (NDs) (Singh et al., 2024). Their potent interaction with biological targets, minimal toxicity, and high specificity facilitate their development into pharmaceuticals (Majura et al., 2022; Wang et al., 2022a). Typically, these molecules are short-chain amino acids (usually 2 to 20), have a molecular mass of less than 10 kDa (Bizzotto et al., 2024), and usually are inactive within the sequence of the precursor protein (Nollet and Ötleş, 2022). They can modulate physiological functions in humans when activated through enzymatic hydrolysis or other release methods (Sarmadi and Ismail, 2010; Zaky et al., 2022). Dietary proteins are excellent sources of BPs and hydrolysates, which have been found to exhibit a variety of physiological activities based on the type, quantity, sequence, and amino acid characteristics (Agyei et al., 2016; Daliri et al., 2017). These activities include antioxidant, anticancer, antithrombotic, antihypertensive, anti-obesity, anti-inflammatory, opioid, mineral binding, immunomodulatory, antiaging, and antimicrobial properties (Akbarian et al., 2022; Zaky et al., 2022). Specifically, the antioxidant and anti-inflammatory actions are intricately connected to cellular regeneration which seems vital as a neuroprotective effect against NDs (Baig et al., 2018; Wang et al., 2022b). This field has been growing substantially due to the increasing knowledge about the sources and availability of peptides, their mechanism of action, and the higher acceptance of health-promoting bioactive compounds. The global market for BPs has grown considerably with peptide-based drugs accounting for a remarkable proportion of the pharmaceutical market revenue, with North America, Europe, and the Asia Pacific being the central markets (Majura et al., 2022).

Science and technology have undoubtedly contributed to a significant increase in human life expectancy, but this has not necessarily led to a proportional increase in quality of life. Greater longevity is associated with a higher prevalence of age-related neurodegenerative diseases, including Alzheimer's disease (AD), Parkinson's disease, Huntington's disease, and amyotrophic lateral sclerosis (Gorman, 2008; Ross and Poirier, 2004; Skovronsky et al., 2006; Teleanu et al., 2022). Other factors that influence the development of NDs include lifestyle, genetic variations, and environmental factors (Armstrong, 2019; Choi and Tanzi, 2020; Kocahan and Doǧan, 2017; Llewellyn et al., 2019; Siddappaji and Gopal, 2021). Worldwide more than 44 million people are affected by AD and other dementias and this number is expected to reach 152 million people by 2050 (“2023 Alzheimer's Disease Facts and Figures,”, 2023; Li et al., 2022). Regarding its economic impact, in 2020, the World Alzheimer's Report estimated that the worldwide total cost of dementia was 1 trillion US$ and that would increase to 2 trillion US$ by 2030 (Sarmadi and Ismail, 2010). These numbers highlight the economic burden of the high prevalence of NDs (Holtzman et al., 2011).

AD is the most common ND, mainly characterised by progressive loss of memory, leading to a decrease in mobility, cognition, and ultimately to death (Fan et al., 2020; Lambert et al., 2013). Even though there is a lack of evidence about the molecular causes of AD, its main pathophysiological features are the loss of medium and large pyramidal neurons from hippocampal regions (Gorman, 2008; West et al., 1994), the extracellular amyloid plaques formed by Aβ and the intracellular neurofibrillary tangles composed of hyperphosphorylated tau protein (Fan et al., 2020; Gorman, 2008; Holtzman et al., 2011; Ross and Poirier, 2004; Si et al., 2023).

Until now, the Food and Drug Administration has approved four small-molecule drugs and three antibodies to alleviate or stabilize AD symptoms, namely three acetylcholinesterase inhibitors, including: Razadyne (galantamine), Exelon (rivastigmine), and Aricept (donepezil); one N-methyl d-aspartate (NMDA) antagonist, namely Namenda (memantine) (Alzheimer and Association, 2024; Chen et al., 2021; Choi and Tanzi, 2020; Fan et al., 2020; Liu et al., 2019b).; and aducanumab, lecanemab, and donanemab as promising antibodies in elucidating the role of Aβ in AD pathogenesis. However, despite their efficacy in reducing Aβ brain accumulation, the clinical relevance of these treatments remains to be fully established (Farlow and Cummings, 2007; Mullard, 2024). They all have side effects like nausea, vomiting, diarrhoea, cramps, fatigue, confusion, headaches, and none are certain to treat the cognitive deficits associated with AD (Colovic et al., 2013; Deshpande et al., 2019; Fan et al., 2020). Therefore, there is an urgent need for alternative treatment approaches, such as exploring the therapeutic potential of natural, “smart” formulations, for safer and inexpensive therapeutics, which can provide a better solution for managing AD (Deshpande et al., 2019).

Here, we review strategies for obtaining BPs from different dietary protein sources and unraveling the therapeutic potential of peptide-rich extracts, presenting some in vitro, cell-based, and in vivo studies that assess the health benefits of these bioactive compounds. Focus will be given to neuroprotective BPs that have an impact on NDs, namely on AD.