Alzheimer's disease (AD) is the most common neurodegenerative disorder and the leading cause of dementia worldwide, accounting for 60–80% of cases. Its prevalence is substantial, particularly in China, where over 16.99 million individuals were affected by AD or other dementias in 2021, representing nearly 30% of the global burden (Zhi et al., 2025). It is a progressive condition characterized by cognitive decline, memory loss, and behavioral disturbances. Neuropathologically, AD is defined by the accumulation of extracellular amyloid-beta (Aβ) plaques and intracellular neurofibrillary tangles (NFTs) composed of hyperphosphorylated tau protein, which lead to synaptic dysfunction and neuronal loss (Long and Holtzman, 2019; Zhou et al., 2024). Although recent anti-Aβ antibodies show plaque-clearing potential, their clinical benefits remain debated, underscoring the necessity for multi-target therapeutic strategies (Karran and De Strooper, 2022). Neuroinflammation is now recognized as a central driver of AD progression. Chronic activation of microglia—the brain's resident immune cells—triggers sustained release of pro-inflammatory cytokines such as interleukin 1β (IL-1β) and tumor necrosis factor-α (TNF-α), which not only fail to clear pathological proteins but also promote further tau phosphorylation and neuronal damage, creating a vicious cycle that accelerates disease (Leng and Edison, 2021).

The risk of AD arises from a complex interplay between genetic and modifiable environmental factors (Bellou et al., 2017; Scheltens et al., 2021). Significant modifiable risk factors include hypertension, diabetes, obesity, low education, physical inactivity, and social isolation (Rosenau et al., 2024). Among modifiable risk factors, hyperhomocysteinemia (HHcy)—elevated plasma homocysteine (Hcy) levels—has emerged as a strong independent risk factor for AD (Zhou and Chen, 2019), correlating with increased disease severity and brain atrophy (Gao et al., 2024; Song et al., 2023). HHcy is hypothesized to contribute to AD through several pathways, including oxidative stress, endoplasmic reticulum stress, endothelial dysfunction, and enhanced neuroinflammation (Jakubowski and Witucki, 2025; Kaur et al., 2023; Kim et al., 2008; Zaric et al., 2019). Notably, evidence suggests that Hcy may exert a pronounced effect on both tau pathology (Di Meco et al., 2019; Shirafuji et al., 2018) and Aβ deposition (Chung et al., 2016; Sade Yazdi et al., 2021). This potential association is therapeutically significant, as it could redirect focus toward tau-centric mechanisms in AD patients with vascular comorbidities.

This study aims to address key gaps by investigating the differential impact of diet-induced HHcy on Aβ and tau pathologies in the 3 × Tg-AD mouse model, and to evaluate whether neutralizing peripheral IL-1β can mitigate HHcy-accelerated neurodegeneration and cognitive deficits. Results demonstrate that HHcy preferentially exacerbates tauopathy—inducing oligomerization, hyperphosphorylation, and NFT formation—with a dissociated effect on Aβ pathology characterized by a specific increase in insoluble Aβ1–40. Peripheral anti-IL-1β monoclonal antibody treatment significantly ameliorated tau pathology, improved cognitive function, and inactivated hippocampal glycogen synthase kinase 3 beta (GSK3β). These findings underscore the role of IL-1β-mediated neuroinflammation in linking HHcy to tau pathology and highlight the potential of immunomodulatory strategies for AD, particularly in individuals with elevated Hcy.