Associations of meal timing and sleep timing with premenstrual syndrome and dysmenorrhea in Japanese women: a cross-sectional study.

Alzheimer’s disease (AD), the leading cause of dementia, has emerged as a major global health challenge. Currently, approximately 55 million individuals are affected worldwide, and this number is projected to rise to nearly 152 million by 2050 (). The onset of AD is influenced by both genetic and environmental factors. Among genetic determinants, the ε4 genotype is recognized as the strongest genetic risk factor, conferring a 2- to 6-fold increased risk of AD, whereas the ε2 genotype exerts a protective effect (). Beyond genetic predisposition, modifiable environmental exposures also play a crucial role in AD pathogenesis. As a major cardiovascular risk factor, hypertension (HTN) has been identified as an important and potentially modifiable environmental contributor to AD (, , , ), although its precise mechanisms remain incompletely understood. In recent years, increasing attention has been directed toward the interplay between genetic and environmental factors in AD development. Such interactions can manifest as additive or multiplicative effects wherein different risk factors exert cumulative or synergistic impacts on disease risk (, , , ). A comprehensive understanding of these interactive patterns is crucial for improving AD prediction, prevention, and precision intervention strategies. Although both HTN and the ε4 genotype are strongly associated with AD risk, it remains uncertain whether HTN interacts with the genotypes to influence AD susceptibility. Kivipelto () reported that the coexistence of HTN, the ε4 genotype, and hypercholesterolemia synergistically increases AD risk. Peila () found that HTN was significantly associated with increased AD risk only among non- ε4 carriers. The overall evidence base is still weak and limited by variations in population characteristics, sample size, and statistical modeling. In addition, the underlying peripheral mechanisms by which HTN and its interplay with ε4 were linked to AD occurrence remain largely unclear. Although AD has long been regarded as a disease confined to the brain, emerging evidence indicates that peripheral factors, such as immune and metabolic dysfunctions, play pivotal roles in its onset and progression. The peripheral blood proteomics offer a promising avenue for uncovering these mechanisms. Studies have shown that peripheral immune responses, oxidative stress, and metabolic disturbances can impact brain health and exacerbate neurodegenerative processes (,). Therefore, investigating the peripheral blood proteome may help identify candidate peripheral biological correlates and hypothesis-generating pathways related to the complex association among HTN, genotype, and AD.