In this nationwide population-based study of 579,710 66-year-old adults, subjects with SCD were more likely to develop subsequent dementia than those without SCD over an average follow-up period of 6.68 years. The association between SCD and subsequent dementia was robust across sex, subtype of dementia (AD or other than AD), history of psychiatric disorders or neurological diseases, and presence of depressive symptoms. The severity of subjective memory impairment was also associated with risk of subsequent dementia. Furthermore, regardless of the presence of depressive symptoms, SCD was significantly associated with subsequent dementia, with an increased association in the presence of depressive symptoms.
The positive association between SCD and subsequent dementia found in our study is generally consistent with previous studies. A recent population-based study (n = 2,710) reported an aHR in SCD similar to that of our study (aHR = 1.18, 95% CI 1.03 to 1.33) [19]. The prevalence of SCD in our study was 38.3% (222,056 in 579,710), which is comparable to prevalence estimates of previous community-based studies, which ranged from 22.1% to 56.0% [5]. However, the rate of incident dementia and risk of subsequent dementia in the SCD group compared to the non-SCD group in our study was lower than in previous research. In a recent multicentre cohort study of 4,369 participants, the incidence rate of dementia in SCD cases was reported to be 17.7 per 1,000 person-years [10], which is higher than our result of 8.6 per 1,000 person-years. Discrepancies between our results and those of previous SCD studies may be due to the heterogeneity of the study populations [10, 12]. Reports have indicated that, when compared to community populations, patients who visited memory clinics had a higher progression rate from normal cognition to MCI [28], from SCD to AD [10], and from MCI to AD [29].
The higher progression rate observed in memory clinic samples has been attributed to the subjects’ greater likelihood of experiencing the early signs of neurodegenerative disease and of spontaneously reporting memory complaints [9, 10, 14, 28, 29]. More importantly, decreased functional abilities were found in memory clinic attendees at baseline, which significantly indicates a risk for dementia [28, 29]. In contrast to previous studies, our study consisted of subjects obtained from a population-based setting, and thus better illustrates the robust association between SCD and subsequent dementia in the general population. In accordance with a previous study [19], our analyses revealed equivalent incidence rates of dementia associated with SCD (8.6 per 1,000 person-years) and other risk factors including current smoking (7.24/1,000 person-years), heavy alcohol drinking (7.44/1,000 person-years), no exercise (7.54/1,000 person-years), diabetes mellitus (8.91/1,000 person-years), cerebrovascular disease (11.34/1,000 person-years), and depression (12.46/1,000 person-years). This result suggests that SCD has a similar magnitude of risk for subsequent dementia as other lifestyle and vascular risk factors in a community population.
Our analysis showed a higher incidence of dementia in women with SCD than in men with SCD (9.57 vs. 7.20/1,000 person-years) but the risk of dementia associated with SCD was comparable in both sexes after adjusting for various factors (aHR = 1.38, 95% CI 1.33 to 1.42 for women; aHR = 1.38, 95% CI 1.32 to 1.44 for men; Table 2 and Table S3 in the online supplement). Some studies reported women to be more susceptible than men to progression from SCD to dementia [30, 31], whereas others found no significant sex difference [8, 10, 19]. Some have reported a tendency for women to report SCD worries with a higher sensitivity to subtle cognitive symptoms relating to dementia progression when compared to men [32]. Women are also known to be susceptible to dementia, possibly due to their longevity and sex-specific biological factors [33]. However, in our study with the largest sample size, before and after adjusting for various clinical factors and sociodemographic variables, the risk of dementia associated with SCD was comparable in both sexes.
Our results also highlight the positive linear association between the severity of subjective memory impairment and subsequent dementia (Figure 2). This finding suggests that the more severe the subjective memory complaints, the greater the risk of subsequent dementia. KDSQ-P, a validated pre-screening tool for dementia [22], includes items measuring subjective memory using multiple response types. In recent studies, many authors have evaluated SCD with multiple items [34, 35] and some have administered face-to-face interviews [8, 30, 34, 36]. Moreover, many of them asked about specific memory (70.7%) and functional decline (41.6%) to assess SCD [34]. The single question defining SCD in this study lacked information on concerns, non-memory domains, and impairment. However, the use of a general question to identify the presence of SCD and a variety of additional questions regarding specific subjective memory impairment may also clarify the effect of well-defined features of SCD on subsequent dementia.
In this study, the SCD group with depressive symptoms had a greater risk for subsequent dementia than the group without depressive symptoms, with a significant interaction effect (Figure 3). Although depressive symptoms are regarded as a crucial factor for subsequent dementia due to their association with cognitive disorders [7, 13, 16, 37], previous studies have found a minimal effect of mood scores on the association between SCD and further cognitive decline [8, 19, 38]. This is possibly attributable to the limited size of the studies. Our results imply that SCD and depressive symptoms not only act independently as risk factors for dementia but also contribute to its development through their interaction.
We observed that SCD was likely to be an incipient symptom of both AD and non-AD related dementias (see Table S5 in the online supplement). Studies have suggested that SCD is related to AD pathology. It has been demonstrated that AD biomarkers such as cerebrospinal fluid β-amyloid [39, 40], plasma β-amyloid [41], hippocampal atrophy [41], and amyloid retention in positron emission tomography [42] are associated with SCD. Although the prevalence of AD pathology in SCD may differ between memory centres due to their varied study designs [43], SCD might be an early symptom in the preclinical stage of AD. Previous studies have reported inconsistent results regarding the association between SCD and non-AD dementia, such as vascular dementia, Lewy body dementia, and frontotemporal lobar degeneration [8, 10]. Although the typical symptoms of dementia differ according to case, memory dysfunction could represent an early symptom in all forms of dementia [44]. Importantly, memory dysfunction can have diverse manifestations including difficulties with episodic and semantic memory and encoding, retrieval, and recognition types of memory. Our results suggest that SCD can broadly be used as a risk indicator for a myriad of cognitive disorders such as AD and non-AD.
The major strength of our study is that we have used the largest nationwide representative cohort data to date relating SCD to subsequent dementia. We analysed 579,710 eligible subjects, extracted from over 50 million entries in the NHIS database. Clinical cohorts in SCD research have relatively small to modest numbers of selective participants, ranging from 42 to 4,500 [10, 34]. In addition, studies that have assessed the risks associated with subjective memory complaints have used diverse and inconsistent characteristics, including the number of participants (17 to 2,901), the age of participants (18 to 87), the follow-up periods (1 to 15 years), the operational criteria for defining SCD, and methods of assessing dementia [6, 12, 34]. Consequently, when these studies are combined for meta-analysis, the significant heterogeneity between studies may add significant noise towards estimating the association between SCD and dementia. As an additional strength, our results are based on the mandatory national healthcare screening service, which is more reflective of the general population, and might be more robust and generalisable than studies conducted through memory clinics. In this study, measuring SCD in a large homogeneous community population with comprehensive information enabled us to investigate SCD and risk for both AD and non-AD dementia with a wide range of clinical covariates, extended time frame, consideration of depressive disorder and subclinical symptoms, and comparison with peers of the same age without SCD.
This study also has several limitations. Firstly, the main weakness is the lack of objective cognition test results. Normal performance on standardized cognitive tests is one of the research criteria for SCD [14]. To reduce bias related to this limitation, we excluded subjects with pre-existing cognitive decline from the analysis, namely subjects with impaired ADLs, a documented history of dementia, MCI, or with a prescription for dementia medication. Secondly, although we comprehensively adjusted for various confounds, we did not consider the years of education, occupational attainment, family history, imaging biomarkers, or other potentially relevant confounds. However, we adjusted for covariates such as comprehensive disease diagnosis, income level, and healthcare visit frequency that can only be obtained from the national data. Thirdly, the operational definition of AD may be susceptible to misdiagnosis or underdiagnosis, although the incidence rate of AD in our study population was similar to the rates reported in epidemiological studies conducted in South Korea [45]. Fourthly, the age of 66 years of this cohort is relatively young, and thus the findings may not represent the entire elderly group. Finally, because the study population included individuals from only a single country, our findings may not be generalisable to people of other backgrounds.