Mild Cognitive Impairment (MCI) is one of the common neurocognitive disorders and a significant public health issue, with its prevalence increasing with age. Its prevalence increases with age, the prevalence is 6.7% in individuals aged 60-64 years and 25.2% in those aged 80-84 years (1). MCI due to AD is considered to be associated with an increased risk of developing dementia, particularly Alzheimer’s dementia (1). Therefore, it is essential to identify and intervene early in cases of MCI (1). A nationwide cross-sectional study in China showed that the prevalence of mild cognitive impairment (MCI) is 15.5%, with approximately 38.77 million people affected by this condition (2). Early intervention can help delay the progression of the disease and ensure better outcomes.

Brain-Derived Neurotrophic Factor (BDNF) is a member of the neurotrophin family that plays an important role in promoting the growth, differentiation, and survival of neurons. It is crucial for neuroplasticity and cognitive function (3). Some studies suggest that BDNF levels are linked to the occurrence of neurodegenerative disorders such as Alzheimer’s Disease (AD), Frontotemporal Dementia (FTD), Lewy Body Dementia (LBD), and Vascular Dementia (VAD). However, studies on peripheral BDNF levels in patients with AD and MCI have yielded inconsistent results. On one hand, some studies have found significantly lower serum BDNF levels in AD and MCI patients compared to healthy controls (4–8). On the other hand, other studies have reported increased peripheral levels of BDNF in AD and MCI patients compared to healthy individuals (9–11). Furthermore, there are discrepancies in the trends of BDNF level changes: some studies show a decrease in peripheral BDNF levels during the MCI stage and an increase during the AD stage (12), while others indicate an increase during the MCI stage followed by a decrease during the AD stage (13). These conflicting results may be related to sample differences (population, medication use, etc.), methodological differences (cognitive assessment tools, sample handling, etc.), and environmental factors (lifestyle, etc.).

BDNF gene polymorphism is associated with neurodegenerative diseases, with the rs6265 (Val66Met) polymorphism linked to the risk of Alzheimer’s Disease (AD) (14, 15) and related to cognitive function (6, 16–21). Moreover, the secretion of BDNF is affected by BDNF rs6265 polymorphism (22, 23), indicating that BDNF gene polymorphism may impact the expression and activity of the protein, thereby influencing individual neuroplasticity and cognitive function. A meta-analysis indicated that individuals carrying the Met/Met genotype not only have poorer cognitive abilities but also lower serum BDNF levels (19). Studies show that BDNF gene polymorphism is significantly associated with memory function (24), while other studies find no significant link between gene polymorphism and cognitive function (25). These conflicting results may be due to the complex interactions between multiple genes affecting cognitive function and insufficient consideration of gene-environment interactions (26, 27). Although previous research has focused on the relationship between BDNF gene polymorphisms and cognitive functions, the majority of studies have concentrated on rs6265. There is less research on other polymorphic segments, particularly concerning interactions with environmental factors such as lifestyle.

The impact of genetics and environment on Alzheimer’s Disease (AD) is not independent; the interplay between immutable risk factors such as genetics and modifiable factors like environment and physical activity can influence the onset of AD (28). Besides the impact of BDNF gene polymorphism on cognition, social activity, as a significant lifestyle factor, has been shown to positively affect cognition in the elderly adults (29, 30). Active participation in social activities not only provides cognitive stimulation but may also indirectly affect BDNF levels and function by reducing stress and enhancing social support (31). Engaging more in social activities could help prevent or delay cognitive decline in elderly adults patients with Mild Cognitive Impairment (MCI) (32). A longitudinal study showed that in elderly individuals without cognitive impairment potentially modifiable factor such as social isolation may contribure to a condition of biopsychosocial frailty, which may increase the risk of dementia (33). Therefore, exploring the interactions between BDNF gene polymorphism, BDNF levels, and social engagement is crucial for understanding the complex etiology of MCI and its prevention strategies.

This study aims to explore the relationship between BDNF gene polymorphism and susceptibility to MCI, as well as the connection between BDNF levels and cognitive function in MCI patients. Additionally, the study will examine the impact of the interaction between social activities and BDNF polymorphism on the risk of MCI. Due to the lack of obvious symptoms, elderly individuals with mild cognitive impairment (MCI) may not receive timely diagnosis and medical treatment, leading them to often reside in the community rather than in hospitals. Therefore, early identification of MCI among community-dwelling elderly individuals is crucial. This study focuses on the elderly community population, aiming to provide a theoretical basis for the early diagnosis and personalized intervention of MCI.

Gene-environment interactions play a crucial role in complex diseases such as neurodegenerative disorders (38). We found a significant interaction between BDNF rs7103411 polymorphism and social activity. Among carriers of the T allele, those who engaged in social activities had a significantly lower risk of developing MCI compared to those who did not participate. Social activities, as a key lifestyle factor, have profound impacts on cognitive function and psychological health in the elderly adults. Especially in elderly populations, promoting social engagement and reducing feelings of loneliness may help maintain and enhance cognitive functions (31, 39, 40). Cognitive reserve might be a potential mechanism by which social isolation affects cognitive function (40), where having extensive social connections and engaging in challenging, complex social interactions can provide mental stimulation and thus build cognitive reserve (41). Ward et al.’s study revealed that the Val66Met polymorphism of the BDNF gene might indirectly influence cognitive function by regulating an individual’s use of cognitive reserves, particularly in executive functions (42). Additionally, elderly adults with depression or anxiety might experience more negative social interactions, which could exacerbate feelings of loneliness and isolation. Evans et al. highlighted the relationship between social isolation and symptoms of depression and anxiety, as well as their interaction with cognitive function in the elderly adults (43). A study has been shown that patients with early-onset AD who carry the ApoE4 allele in relatively early stages might develop a greater impairment on episodic verbal memory task, as compared to ApoE4 non-carriers (44). Furthermore, studies have revealed the interaction between BDNF and feelings of loneliness impacting cognitive decline, particularly manifesting as more pronounced semantic memory deterioration and increased feelings of loneliness among participants with lower BDNF expression levels (45). This finding further supports the protective mechanism of BDNF on cognitive functions.These findings, together with our study, emphasize the complexity of interactions among social engagement, gene polymorphism, and cognitive reserve, providing insights into the etiology and prevention strategies for MCI.

BDNF gene polymorphisms are a focal point in research on Alzheimer’s disease (AD) and Mild Cognitive Impairment (MCI), revealing their significant role as prognostic markers in memory decline and hippocampal atrophy in MCI patients, and their close association with the progression of MCI (15). In healthy adults with high levels of Aβ accumulation in the brain, carriers of the Met allele exhibit greater declines in cognitive function and hippocampal volume (20), further underscoring the potential role of the BDNF gene in regulating cognitive processes. This study found that BDNF rs7103411 polymorphism is associated with MCI risk. In a study of an elderly adults German cohort, rs7103411 polymorphism was significantly related to memory performance, with carriers of the C allele showing an increased risk of cognitive decline (including memory and perceptual speed) (22). However, in our research, individuals carrying the C allele were found to have a reduced risk of MCI compared to TT individuals. This could be due to differences in genetic background, gender stratification, and differences in cognitive function tests. A study in an English community of elderly adults did not find an association between rs7103411 and cognitive function, which might primarily be due to the use of a haplotype analysis method (25). Additionally, we observed lower serum BDNF levels in rs7103411 T allele carriers compared to CC individuals among MCI patients, further suggesting that BDNF gene polymorphism might affect cognitive functions and their decline by modulating BDNF expression levels. Moreover, cognitive function and susceptibility to MCI may be influenced by complex interactions among multiple genes (26). The effects of a single gene polymorphism may be offset or enhanced by the actions of other genes, making it difficult to consistently observe the impacts of individual polymorphisms across all studies (46).

This study did not find an association between polymorphisms rs6265, rs11030104, rs11030100, and rs988748 with susceptibility to Mild Cognitive Impairment (MCI). Beyond the limitations of sample size and study type, the cohort selected from community-dwelling elderly adults with MCI had relatively short disease duration and milder disease severity, which may have hindered the observation of correlations between cognitive abilities and both BDNF levels and genetic polymorphisms. Similarly, previous research has shown that rs6265 polymorphism is not significantly associated with the age of onset, severity, or rate of cognitive decline in Alzheimer’s disease (AD) (47, 48). No significant association was found between rs11030104 and cognitive decline in AD patients either (49). Currently, the understanding of the specific roles of the BDNF gene in cognitive function and the development of MCI is still limited. The biological effects of polymorphisms may involve complex molecular pathways and networks that are not yet fully understood and should be further explored in future research. For example, genetic variants affecting amyloid precursor protein (APP), tau binding proteins, immunity, and lipid metabolism play a critical role in AD, as shown by a largely cited study (50), with underwent an Author correction (51). Differences in definitions of MCI or cognitive decline and variations in studies across different subtypes may lead to contradictory conclusions (1, 52). Additionally, due to the limitations of the survey content, the impact of gene-environment interactions may not have been fully considered, which can also contribute to divergent study results (27, 53, 54).

This study indicates that multiple single nucleotide polymorphisms (SNPs) within the BDNF gene, including rs6265, rs11030104, rs7103411, and rs988748, are associated with serum BDNF levels in patients with Mild Cognitive Impairment (MCI). Reduced BDNF levels and signaling are linked to neurodegenerative diseases such as MCI, Alzheimer’s Disease (AD), and Parkinson’s Disease (PD) (3). Notably, the rs6265 polymorphism, consistent with findings from numerous studies, has been shown to correlate with BDNF levels and is closely associated with key neurophysiological processes involved in cognition (23, 55, 56). Specifically, rs6265 is linked to changes in hippocampal volume, cortical thickness, and abnormalities in synaptic connections, which are critical indicators of cognitive function (55, 56). Further research has also highlighted the role of rs6265 in learning, memory retention, executive functions, and the decline in perceptual speed among the elderly adults (57, 58). The evidence from this study further supports the significant role of the rs6265 polymorphism in cognitive dysfunction. Polymorphisms rs11030104, rs7103411, and rs988748 show differences in BDNF expression levels within haplotypes (59). Higher BDNF expression levels may be associated with poorer cognitive performance, including overall cognition, episodic memory, executive functions, visuospatial abilities, and semantic processing (60). Although our study identified differences in serum BDNF levels across multiple BDNF SNPs, aside from rs7103411, no other polymorphisms were found to be associated with MCI. This analysis might be influenced by the study’s sample originating from community-dwelling elderly adults individuals selected without self-perceived symptoms, whose symptoms may not be readily noticeable. Secondly, changes in serum BDNF levels as early biomarkers for MCI or AD might occur before the observable progression of the disease.

Current research on the peripheral BDNF levels in patients with AD and MCI shows inconsistent results. Some studies suggest that BDNF levels are elevated in MCI patients, possibly reflecting a compensatory neurorestorative mechanism at the early stages of AD (11, 13, 61). However, in AD patients, extensive neuronal damage and depleted cognitive reserves lead to a significant decrease in BDNF levels (4, 13). In rat models, homozygous rats for rs6265 show a notable reduction in BDNF release compared to heterozygous rats, yet they exhibit significantly enhanced synaptic growth capabilities (62). Some researchers hypothesize that a decrease in serum BDNF levels is a late event in the progression of AD hence changes in BDNF levels during the MCI stage might not be pronounced (4). Concurrently, our study observed a negative correlation between BDNF levels and scores on MMSE and orientation tasks in MCI patients. These findings further support the hypothesis that BDNF serves as a compensatory and protective mechanism in patients with MCI or early-stage AD. The role of BDNF in neuroprotection and neuroregeneration has been extensively studied, and our results did not find a significant correlation between serum BDNF levels and MCI status. This may be due to the influence of various biological, methodological, and environmental factors on serum BDNF levels.

Our study has certain limitations, including a small sample size, a cross-sectional study design, and potential confounding factors. Future research should employ larger sample sizes and longitudinal study designs, and consider a wider range of genetic and environmental factors to delve deeper into the mechanisms of BDNF in the development of MCI. Additionally, exploring the interactions between BDNF and other biomarkers will be an important direction for future studies. Previous research has primarily focused on the Val66Met polymorphism, with the relatively limited investigation into other polymorphic sites within the BDNF gene. This finding suggests that polymorphic sites other than Val66Met may also play roles in cognitive decline and susceptibility to MCI, which warrants further verification in future studies. Considering BDNF’s critical role in neuroprotection and neuroplasticity, our findings underscore the need for future research to thoroughly explore the complex biological mechanisms between BDNF and MCI, as well as the potential long-term effects on cognitive function in the elderly adults.