1. Introduction
Loneliness is defined as a distressing feeling associated with discrepancies between an individual’s actual and desired social relationships [
1]. Accumulating evidence has suggested that loneliness has a detrimental effect on cognitive health in late life, specifically on various domains of cognitive function, including episodic memory and executive function [
1,
2,
3,
4]. A longitudinal study found that higher degrees of loneliness are associated with double the risk of developing Alzheimer’s disease (AD) at follow up [
5].
Although a consistent body of literature has identified the association between loneliness and cognitive function, several important questions remain unanswered. First, the neural mechanism by which loneliness detrimentally influences cognition is elusive. Understanding the neural mechanism is crucial, as it may clarify the potential intervention that could prevent or delay the onset of loneliness-induced cognitive impairment. Therefore, we were interested in investigating whether brain pathological and anatomical markers of cognitive decline play a specific role in the loneliness-related cognitive deterioration.
A longitudinal study found that increases in loneliness were correlated with a greater volume of white matter hyperintensities among non-demented older adults [
6,
7,
8]. White matter hyperintensities, a marker of small-vessel cerebrovascular disease observed on T2-weighted magnetic resonance imaging in older adults, are a valid predictor of episodic memory. Moreover, it has been known that WMHs confer additive risk for AD and predict the progression of AD-related neurodegeneration [
9,
10,
11]. Given these findings, we chose white matter hyperintensities as a candidate mechanism underlying loneliness-related memory function. Moreover, lonely older adults had lower gray matter and hippocampus volumes, which are among the strongest radiological predictors of memory deficits, compared with those who were not lonely [
7,
12]. Accordingly, we also examined whether whole gray matter and hippocampus volume play a specialized role in the relationship between loneliness and memory performance as a mediator.
One important factor to consider when examining the link between loneliness and cognition is gender. Numerous studies highlighted gender differences in physiological responses to social stress [
13,
14]. Specifically, men with low social integration were at a higher risk of mortality than women and the feeling of loneliness was associated with elevated inflammation only in men [
13,
15,
16,
17]. Considering that lonely men are more vulnerable to disease and death than lonely women, the same level of loneliness might also be expected to induce more adverse cognitive outcomes in men than women. However, few studies to date have focused on gender differences in the association between loneliness and cognitive functions. Therefore, the current study explored whether loneliness-related memory functions through neurological factors differ by gender.
Lastly, it is crucial to distinguish between subjective and objective features of social isolation. Because loneliness is a subjective experience related to unfulfilled social needs, it is conceptually distinct from objective social isolation, such as a small social network size and infrequent social interaction. Despite the distinction, most existing studies have used the inconsistent terminology of indicators of social isolation and loneliness [
18,
19,
20]. As such, inconsistent conceptual terminology can interrupt communication between researchers and limit knowledge about the comparative effects of different social relationship dimensions. Therefore, we separately assessed two distinct aspects of social isolation, and the influences of loneliness were examined after controlling the effects of objective features of social isolation in all analyses.
Therefore, this study aimed to identify neural mechanisms underlying the association between loneliness and memory functioning and examine the moderating role of gender in this relationship. We hypothesized that white matter hyperintensities and hippocampal and whole gray matter volumes would mediate the relationship between loneliness and memory performance as a candidate mechanism. We also hypothesized that the indirect mediating effects of loneliness on memory function through neurological factors would be stronger in men than women.
Figure 1 presents a hypothetical model.
4. Discussion
The current study investigated the neural mechanisms underlying loneliness-related memory deficits and examined whether these mediating effects vary by gender. Our findings showed that loneliness negatively affected memory performance through white matter hyperintensities (WMHs). Moreover, the study identified gender differences in these mediation effects, specifically the mediating effect of WMHs on the association between loneliness and recall memory function was significant in men, but not in women. These findings indicate that loneliness is more strongly associated with memory function through WMHs among men than among women.
In the mediation analysis, we found that increases in loneliness were associated with increased volume of WMHs, and those who have larger WMHs performed worse on the long-term memory recall and recognition tests. These results are consistent with a previous study that showed loneliness to be associated with the progression of WMHs [
6,
8]. Since lonely individuals have an increased sensitivity to social threats, they are more likely to experience negative thoughts and daily events as stressful [
2,
34]. Chronic experience of social stress may activate biological responses, such as the dysregulation of HPA functioning, hypercortisolism, and impaired immune functioning [
12,
35], and WMHs are one of the negative outcomes of prolonged HPA axis activation and abnormally elevated inflammatory response [
36]. In addition, an aging study with neuroimaging reported that negative health outcomes of loneliness, such as cardiovascular risk factors and established cardiovascular disease, were strongly associated with the presence and progression of WMHs [
37]. These previous studies support our findings that the volume of WMHs is a neural mechanism linking the association between loneliness and memory function.
The study found that gender moderates the mediating effect of WMHs on the association between loneliness and LTM recall index. The results showed that higher levels of loneliness were associated with a greater volume of WMHs and more severe memory deficits in men, but not in women. These findings extend existing knowledge on gender differences in the detrimental effects of loneliness on health in late life. While previous studies have only found gender differences in the relationship between loneliness and physical health, this study is the first to show that gender differences may also be present in the relationship between loneliness and late-life cognitive function. The moderated mediation results in the current study may be due to different patterns of social relationships across the gender. Previous research has shown that low levels of education and living alone are associated with a higher risk of social isolation and poor health in later life [
38,
39]. As shown in
Table 1, women in this study are more likely to live alone and have lower levels of education than men. Although these statistics suggest that women are more likely to be socially isolated and to have poorer physical health than men, men had higher levels of WMH than women, and there was no significant difference in memory test scores between the genders. In other words, despite the differences in education and living alone, there were no significant differences in neuropathological burden and cognitive function across genders. These findings can be explained by stress buffering theory, which suggests that social support from intimate relationships can buffer the harmful effects of social challenges on health and promote psychological and physical well-being [
40]. Evidence suggests that women tend to maintain more intimate partners and larger support networks, while men typically rely on their spouses for support in late life [
41,
42,
43,
44,
45]. Abundant social support is known to be a protective factor, buffering the effects of neuropathological burden and delaying the onset of cognitive decline [
43,
46,
47]. Therefore, older women may be less likely to experience loneliness-related white matter lesions leading to memory deficits compared to older men. The findings have important implications for the development of gender-specific interventions to mitigate the negative effects of loneliness on cognitive health.
The study found that gender differences were observed in the association between WMHs and memory function but not in the association between WMHs and loneliness. These findings suggest that other external variables related to WMHs, in addition to loneliness and WMHs, might have influenced the results. For example, men have a higher risk of cerebrovascular disease and hypertension than women, which are strongly associated with the development of WMHs [
48,
49,
50]. In addition, men have higher rates of smoking and alcohol consumption compared to women, both of which are strongly associated with WMHs and cognitive decline [
51,
52]. These additional external variables may have interacted synergistically with WMHs to affect memory function, potentially explaining the observed gender differences in mediating effects.
The current study had several limitations. First, since it was conceptualized via a cross-sectional design, the causality cannot be inferred. For example, our findings do not rule out the possibility that loneliness may appear as the behavioral manifestation of cognitive dysfunction [
1]. To minimize this possibility, the study excluded older adults with mild or significant cognitive impairment through screening procedures. According to other longitudinal study findings, loneliness could be a predictor of greater cognitive decline, but low cognition at baseline did not predict changes in loneliness over time [
53]. A future replication study using longitudinal design is required to validate the causality between loneliness and memory deficits. Second, considering that participants in the study are older adults in a rural township, the findings could not be generalized to the overall population. Thus, the findings in this study should be interpreted carefully, and further research is needed for Korean older adults in urban area to obtain robust results.
In summary, the study found that white matter hyperintensities, a key risk factor for cognitive decline, to be a mechanism underlying the association between loneliness and memory function in older men. In other words, men who feel lonely are more likely to have a greater volume of white matter lesions and also to experience progression of long-term recall memory dysfunction compared to women in late life. These findings may have significant implications for public health, as understanding how loneliness affects memory performance may lead to the development of therapeutic and preventive interventions to address the loneliness-related memory deficits. Furthermore, gender differences in mediating effects can be used to develop gender-specific interventions for lonely older adults in the community.