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 a follow-up period of up to eight 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, the significant association between SCD and dementia was independent of 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) [18]. Moreover, 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 that ranged from 22.1–56.0% [4]. However, the rate of incident dementia and risk of subsequent dementia in the SCD group compared to the non-SCD group in our study were lower than in previous studies. In a recent multi-center cohort study of 4,369 participants, the incidence rate of dementia in patients with SCD was reported to be 17.7 per 1,000 person-years [9], 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 [9, 11]. Reports have indicated that, when compared to community populations, patients who visited memory clinics had a higher conversion rate from normal cognition to MCI [22], from SCD to AD [9], and from MCI to AD [23]. The higher conversion 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 [8, 9, 13, 22, 23]. More importantly, decreased functional abilities were found in memory clinic attendees at the baseline, which indicates a significant risk for dementia [22, 23]. 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. Additionally, in accordance with the suggested features of SCD, including onset at 60 years or older and only lasting a few years [13], the homogeneity of age in our study subjects represents the strength for observing the association between SCD and subsequent dementia.
Our analysis showed a higher rate of conversion from SCD to dementia in women than men (6.5% vs. 4.8%) but no sex difference in the aHR (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). Some studies reported women to be more susceptible than men to conversion from SCD to dementia [24, 25], whereas others found no significant sex difference [7, 9, 18]. 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 [26]. However, in our study, after adjusting for various clinical factors and sociodemographic variables, it appears that 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 (Fig. 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 [21], includes items measuring subjective memory and instrumental ADLs using multiple response types. In a recent review of self-report measures used in the SCD working group, most measures included multiple items (mean = 18.8 items) [27]. Moreover, many of them ask about specific memory (70.7%) and functional decline (41.6%) to assess SCD [27]. 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 (Fig. 3). Although depressive symptoms are regarded as a crucial factor for subsequent dementia due to their association with cognitive disorders [6, 12, 15, 28], previous studies have found a minimal effect of mood scores on the association between SCD and further cognitive decline [7, 18, 29]. This is possibly attributable to the limited size of the studies. Our results imply that SCD and depressive symptoms not only act as independent 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 S3 in the online supplement). 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 [7, 9]. Although the typical symptoms of dementia differ according to the case, memory dysfunctions may represent an early symptom in all forms of dementia [30]. Importantly, memory dysfunctions can have diverse manifestations including difficulties with episodic and semantic memory and encoding, retrieval, and recognition. 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 dementias.
The major strength of our study was the use of the largest nationwide representative cohort dataset to date that relates SCD to subsequent dementia. We analyzed 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 [9, 27]. In addition, studies which have assessed the risks associated with subjective memory complaints have used diverse and inconsistent characteristics, including the number of participants (17 to 2,901), age (18 to 87), follow-up periods (1 to 15 years), operational criteria for defining SCD, and methods of assessing dementia [5, 11, 27]. Consequently, when these studies are combined for meta-analysis, the significant heterogeneity between studies may add considerable 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 generalizable 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. First, 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 [13]. 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. Second, 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. Third, the operational definition of AD may be susceptible to misdiagnosis or underdiagnosis, although the rate of AD in our study population was similar to the rates reported in epidemiological studies conducted in South Korea [31]. Finally, because the study population included individuals from only a single country, our findings may not be generalizable to people of other backgrounds.