This study utilized a large sample of cognitively normal older persons and a longitudinal study design, to investigate the relationships among depression, SCD, and incident NCD. Both depression and SCD were independently associated with the risk of MCI and dementia, with HR of 1.4 and 2.0, respectively. The results were robust to several sensitivity analyses. Co-occurring depression and SCD had the highest risk of developing NCD (HR 2.8), with half of the participants in this group developing NCD within 7.2 years of follow-up (compared to 12.2 years in participants without depression or SCD).
The findings may have implications to health services which are involved in the care of older persons. SCD often co-occurs with depression [1, 5, 7, 8] and is not uncommonly the primary presentation of older persons with depression to many health services [8]. Until recently, the evidence has been uncertain on the unique role of SCD on NCD, in the context of depression [1, 5, 7, 8]. This has translated into the prevailing practice where SCD in depression is viewed primarily as a mood-related symptom [7], with minimal emphasis to follow-up on the patients’ cognitive function or monitor for the onset of NCD (apart from the initial cognitive screening to rule out NCD as the primary diagnosis). The findings from the current study allow us to draw a more definite conclusion on the independent role of SCD in depression and may potentially change our approach in the management of SCD among older persons with depression. In older patients with depression, the presence of SCD can indicate a very high risk of NCD. While the focus on managing depression remains pertinent to improve the quality of life of the patients, there may be an equally relevant need to closely monitor these patients for incident NCD. Potentially, the newer biomarkers of NCD (such as those related to amyloid protein, tau protein, and neuronal injury) [6] may be useful in these patients to identify those at very early stages of NCD for timely preventive interventions, especially when the biomarkers become more accessible to general clinicians in the foreseeable future. In future preventive trials, the identification of co-occurring depressive symptoms and SCD may also be a useful recruitment strategy to select cognitively normal individuals who are at high risk of developing NCD [19], given that these individuals are more likely to develop NCD within a shorter time frame, and hence, the efficiency of clinical trials may be improved by reducing the duration of follow-up to the outcome of interest.
The findings may potentially also have implications to our understanding of NCD. Depression and SCD have been shown to correlate strongly with each other in prior studies [1, 5, 7, 8] and, hence traditionally, have often been understood as arising from the same construct along the continuum of depressive symptoms [7, 8]. The findings from this study suggest that depression and SCD are plausibly two distinct constructs that may independently lead to NCD, which then raises further question, on whether the two may also have distinct neurobiological pathways that lead to NCD. Prior studies have already implicated different sets of neurobiology for depression and SCD. For example, in studies of neurotransmitters, the monoaminergic system in the brain stem have been associated with depression [20], while the cholinergic system in the basal forebrain has been linked to SCD [21]. In studies of neuroanatomical regions, changes in entorhinal, anterior cingulate, and left middle frontal cortices have been associated with depression in patients with prodromal NCD [22], while white matter lesions, smaller left hippocampal volumes, and temporal lobe atrophy have been linked to SCD [23]. However, it remains uncertain whether the reported neurobiological evidences are still shared between depression and SCD, which indicates that depression and SCD are merely two presentations of a common NCD pathology, or whether depression and SCD may involve two distinct neurobiological pathways that converge to lead to NCD. Further research is needed to clarify on this uncertainty—if the latter hypothesis may plausibly be true, the delineation of differing pathways may potentially improve our understanding on the pathogenesis of NCD as well as identify new drug targets which may inform future development of disease-modifying drugs for NCD.
Several limitations should be considered. First, the participants in the study involved those who volunteered at the Alzheimer’s Disease Centers. They may be more representative of patients who voluntarily present to healthcare settings than those in the community. Second, depression in this study was defined based on established cut-off scores on GDS. Although GDS does not produce a definitive diagnosis of clinical depression, this depression scale has been shown in a recent diagnostic meta-analysis [11] to have excellent sensitivity and specificity, especially at its optimal cut-off score of GDS ≥ 4, in detecting major depression. Moreover, the results remained consistent in the sensitivity analyses, even with alternative cut-off scores of GDS (that is, GDS ≥ 5 and GDS ≥ 6), which lend some credence to the validity of the findings. Third, the SCD measure in this study was based on a single question and focused on the memory domain. While this may not be an uncommon practice in the current literature on SCD [24, 25], such SCD measure may not have captured the full range of memory concerns or other non-memory domains. Fourth, the diagnoses of MCI and dementia were made by single clinicians in 25.9% of the participants. They may not necessarily be as accurate as those made via consensus conference.
