Based on world trends, the prevalence of dementia is estimated to increase dramatically by 2050 (1). Cognitive impairment, including mild cognitive impairment and dementia, can cause serious mental damage to patients and a huge financial burden on society. Given that there is no effective drug treatment for dementia, cognitive impairment is a huge economic burden on an aging society.

Cognitive impairment is a multifactorial disease with a variety of genetic and environmental etiologies, such as obesity, cerebral infarction, hypertension, and systemic illnesses (2). Most risk factors, including apolipoprotein E genotype, biological hormones, cardiovascular disease, and depression responsible for cognitive impairment, are evident in both sexes, but to date, many of these approaches have overlooked the role of sex difference when examining this association (3). Estrogens could chemically modulate homocysteine levels leading to a discrepancy in plasma total homocysteine (tHcy) levels between women and men (4, 5). The mechanisms are yet unclear, but the conjugation of estrogens could increase the formation of estrogen homocysteine conjugates, which results in lower levels of toxic homocysteine (4). Moreover, estrogens influence homocysteine metabolism including abnormities of anabolic and catabolic status, vitamin status, and the remethylation pathway (6).

Homocysteine is a sulfur-containing amino acid that is an important intermediate product in the metabolism of methionine and cysteine (7). Higher plasma tHcy concentrations have been frequently associated with cognitive impairment and dementia (8). Accumulating evidence suggests that hyperhomocysteinemia (HHcy) could deteriorate cognitive function among healthy older adults (9, 10). Compared to the healthy population, patients with Alzheimer's disease have increased plasma tHcy concentrations (11). Moreover, evidence from experimental studies has revealed that HHcy could cause platelet activation, endothelial dysfunction, oxidative stress, and chronic inflammation, contributing to the pathogenesis of dementia (12). Higher tHcy levels are associated with cerebral atrophy, a major pathological process in dementia (8).

In China, 245 million patients have hypertension, with a prevalence of 23.2% (13). Several research studies have suggested that elevated blood pressure, especially in elderly populations, is associated with cognitive impairment (14). However, no published studies to date have explored the effect of plasma tHcy concentrations on cognitive function among hypertensive patients. Considering that China bears a heavy burden of hypertension and that HHcy could worsen cognitive function, we investigated the association between plasma tHcy levels and cognitive function using the Mini-Mental State Examination (MMSE) test among hypertensive patients in China.

This study showed a threshold effect of plasma tHcy levels on MMSE scores among hypertensive patients in China and the inflection point of tHcy was 27.1 μmol/L. There was an enhanced inverse relationship between tHcy levels and MMSE scores in female patients with tHcy concentrations of less than 26.9 μmol/L compared to male patients with tHcy concentrations <32.0 μmol/L.

A lot of evidence from experimental and clinical studies has revealed that elevated tHcy could cause cognitive decline, white matter damage, brain atrophy, neurofibrillary tangles, and dementia (8–12, 20–23). The Northern Manhattan study included 2871 stroke-free subjects and showed that elevated tHcy concentrations were independently associated with cognitive impairment (9). The odds of cognitive impairment were 2.8-fold higher in participants with HHcy than in those with plasma tHcy levels <10 μmol/L (20). In a cohort study consisting of healthy elderly people, cross-sectional analyses showed that increased tHcy levels were significantly associated with poorer performance on all neuropsychological tests and this result was further validated in a longitudinal study (21). Additionally, HHcy increased the risk of cognitive impairment and affects executive functioning, complex attention, cognitive flexibility, and memory in postmenopausal women (22). The study found modest inverse relationships between homocysteine levels and some indicators of cognitive function, including the global MMSE evaluation and the picture-association, verbal attention-span, and pattern-recognition tests (24).

Several possible mechanisms might contribute to the harmful effects of HHcy on cognitive decline. HHcy could increase S-adenosylhomocysteine (SAH) in the prefrontal cortex of Alzheimer's patients, which inhibits methyltransferases and is associated with cognitive impairment (25). Oxidative damage could result from interactions between highly reactive transition metals, such as copper, and oxidizing molecules, such as homocysteine in the brain (26). Increased copper or homocysteine levels in the elderly could promote significant oxidative damage to neurons and contribute to the development of Alzheimer's disease or related neurodegenerative conditions (26). HHcy and vascular contributed to cognitive impairment and dementia through myocyte proliferation, vessel wall fibrosis, impaired nitric oxide signaling, superoxide generation, and pro-coagulant actions (27).

To our knowledge, this is the first report on the threshold effect of plasma tHcy levels on MMSE scores in hypertensive populations, which might be attributed to geographic regional differences and higher levels of plasma tHcy in this crowd (28–30). A hypertensive population with higher tHcy levels was relatively common in China (28). The mean concentration of plasma tHcy was 17.9 μmol/L in our study, much higher than the mean tHcy was 9.8 μmol/L in a previous study (24).

According to the study results (Table 3), the inverse association of tHcy levels with MMSE was significant up to a specific threshold but disappeared above that in both sexes. However, the threshold is different according to sex [lower in females than males (26.9 vs. 32 μmol/L)], probably due to lower tHcy levels in females. In line with previous studies, homocysteine levels were significantly lower in females than in males patients (31). The differences may be related to estrogen, but since the average age of the study was in the post-menopausal range, any influence of estrogen would be diminished. Compared with female subjects, male patients had more risk factors such as smoking, drinking, and lower eGFR levels. Moreover, differences in B12, folate, and renal and possibly thyroid function may explain why the threshold was different according to sex. A limitation of this study was that major determinants of homocysteine levels were not controlled. These included B12 and folate status and thyroid function. Further research is needed to examine the relationship between sex, tHcy levels, and MMSE scores.

This study had several other limitations. First, the MMSE tests, as a screening test for the diagnosis of clinical cognitive impairment, are considered less sensitive and specific for mild cognitive impairment than other tests. Our study participants were more likely to be from a less educated rural population. Previous studies have shown that MMSE was a reliable tool for evaluating the cognitive function of people who are less educated (18, 19). Further studies combining MMSE and other tests, such as the Cognitive Capacity Screening Examination or Mini-Cog test, are needed to confirm this result. Second, this study was conducted on hypertensive Chinese patients; thus, we did not know whether this applies to other populations. Third, as with all observational studies, although we adjusted for multiple potential confounders, we cannot exclude the possibility of residual confounding factors including uncontrolled folate and vitamin B12 status. Finally, this study was a cross-sectional analysis and thus did not determine the causal relationship between plasma tHcy levels and cognitive decline. Intervention and prevention should be promoted to ameliorate cognitive symptoms in the elderly who are at risk of dementia, and more trials are required to investigate the preventive and therapeutic effects of homocysteine-lowering strategies on cognitive decline and to explore the underlying pathophysiological mechanisms.

Our study suggests that there was a threshold effect of plasma tHcy levels on MMSE scores among hypertensive patients in China. Increased plasma tHcy levels were independently associated with a cognitive decline only among hypertensive patients with tHcy concentrations of <27.1 μmol/L. Moreover, this showed that the threshold differed according to sex, with female patients having a lower threshold than male patients. Further studies are needed to explore the underlying pathophysiological mechanisms on the threshold effect of plasma tHcy levels on the MMSE scores.

The original contributions presented in the study are included in the article/Supplementary material, further inquiries can be directed to the corresponding author/s.

The studies involving human participants were reviewed and approved by the Second Affiliated Hospital of Nanchang University. The patients/participants provided their written informed consent to participate in this study.

LW and JC participated in literature search, data analysis, and data interpretation. LW wrote the manuscript. FH, JL, YX, XZ, SS, WZ, LZ, TW, and JT extracted and collected data, conceived the study, and participated in its design and coordination. HB and XC participated in the study design and provided critical revision. All authors read and approved the final manuscript.

This work was supported by the Jiangxi Science and Technology Innovation Platform Project (20165BCD41005), the Jiangxi Provincial Natural Science Foundation (20212ACB206019), the Jiangxi Science and Technology Innovation Base Construction Project (20221ZDG02010), the Jiangxi Provincial Health Commission Science and Technology Project (202210495), and the Fund project of the Second Affiliated Hospital of Nanchang University (2016YNQN12034, 2019YNLZ12010, 2021efyA01, and 2021YNFY2024).

The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.

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