Subjective cognitive decline and subsequent dementia: a nationwide cohort study of 579,710 people aged 66 years in South Korea

Dementia represents one of the most prevalent neurodegenerative disorders worldwide and is present in approximately 10% of people aged 65 years and older [1]. Moreover, the public health burden of dementia is growing more rapidly than any other disease [2]. It has been reported that almost 80% of people worry about developing dementia [3] and identify dementia as their most feared illness, over cancer, heart disease, stroke, and diabetes [4]. Aging is concomitant with increased episodes of forgetfulness, and memory complaints are prevalent in approximately 25 to 50% of older adults [5]. Previous studies have found that memory complaints may relate to subclinical psychiatric symptoms [5‐7], but they can also represent an early indicator of dementia, including Alzheimer’s disease (AD) [8‐12]. Considering the growing number of patients with dementia and the associated medical and societal burden, it is important to characterize at-risk groups or preclinical states of dementia in order to facilitate early interventions to reduce cognitive impairment in the future.

As part of this effort, considerable progress has been made investigating the prospective dementia risk associated with subjective cognitive decline (SCD) [13, 14]. SCD refers to a subjective experience of cognitive decline without objective cognitive deficits [14]. Research indicates that SCD may represent an early symptom of AD signifying the preclinical stage [9‐12], which can progress to mild cognitive impairment (MCI) and dementia in the AD continuum [12‐15]. However, SCD is also associated with poor physical health and with psychiatric disorders such as depression, which confounds the association with dementia [16, 17]. For example, depression is a major risk factor for dementia, and previous work has indicated that SCD could be linked with subsyndromal depressive symptoms rather than with subsequent dementia [18]. The considerable heterogeneity present across numerous small studies has contributed to conflicting results and has prevented consensus in the field [16‐18].

Regarding the recruitment setting, it has been observed that SCD in memory clinic cases increased the risk of dementia [10], whereas SCD in community populations showed less significant or non-significant associations [10, 19]. Given that the concerns and health-seeking behaviors of community-recruited older adults may differ from those of memory clinic patients [10], investigations using a large community sample would improve the accuracy for estimating the SCD-associated risk for incident dementia in the general population.

This study analyzed a nationwide population-based cohort that includes 51.8% of the 66-year-old adult population in South Korea. We aimed (1) to determine whether the risk of subsequent dementia increases in subjects with SCD compared to those without SCD, (2) to evaluate whether the severity of subjective memory impairment is associated with subsequent dementia, and (3) to examine whether depressive symptoms affect the association between SCD and subsequent dementia.

During the period from 2009 to 2011, a total of 650,861 individuals participated in the NSPTA and had KDSQ-P information available. Of these, we excluded 21,458 individuals who reported impaired ADL function; 12,658 individuals with dementia, MCI, or with a documented history of cognitive-enhancing medication; 18,760 individuals with missing or duplicate data; 14,315 individuals with outlier data; 2632 individuals with a psychotic disorder; and 1328 individuals who died or were lost to follow-up between their NSPTA participation date and the index date. In total, 579,710 subjects were included in the final study population for analysis, of which 222,056 (38.3%) experienced SCD (see the flowchart of study participants in Figure S1 in the online supplement). They were followed for an average of 6.68 ± 1.33 years per person and a total of 3,870,293 person-years.

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 the 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 = 2710) 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 the 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 multicenter cohort study of 4369 participants, the incidence rate of dementia in SCD cases was reported to be 17.7 per 1000 person-years [10], which is higher than our result of 8.6 per 1000 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 diseases 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 1000 person-years) and other risk factors including current smoking (7.24/1000 person-years), heavy alcohol drinking (7.44/1000 person-years), no exercise (7.54/1000 person-years), diabetes mellitus (8.91/1000 person-years), cerebrovascular disease (11.34/1000 person-years), and depression (12.46/1000 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. 7.20/1000 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 (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 [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 (Fig. 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 centers 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 the 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 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 4500 [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 2901), the age of participants (18 to 87), the follow-up periods (1 to 15 years), the operational criteria for defining SCD, and the 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 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. 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 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 generalizable to people of other backgrounds.

Our study, in a population-based cohort, is the largest to date and demonstrates the importance of SCD as an early, independent risk factor for dementia. These findings thus provide strong evidence for the role of SCD in characterizing the initial high-risk stage of dementia. As a growing public health issue, SCD should be further investigated as a risk factor for dementia. Giving additional attention to SCD as a risk factor for dementia could facilitate more focused surveillance from the public and healthcare professionals. However, it may not be appropriate for the public to view SCD as a disease state that should be actively treated. Instead, an approach focused on prevention for people with SCD, including lifestyle modifications or providing education on dementia, could be promising. Future studies should further explore the clinical and neurobiological nature of SCD as an early sign of dementia.