No clear associations between subjective memory concerns and subsequent change in cognitive function: the PATH through life study

In recent years, there has been substantial interest in the potential for subjective perception of cognitive decline, particularly, subjective concerns about memory, as a prognostic indicator for increased risk of Mild Cognitive Impairment (MCI) or dementia, see recent reviews (Wang et al. 2020; Wion et al. 2021). This follows on from the 2014 publication of a conceptual framework for research in subjective cognitive decline (SCD) in Alzheimer’s Disease (AD) (Jessen et al. 2014), and it is supported by imaging outputs that have highlighted a potential preferential vulnerability of AD relevant regions in SCD (Wang et al. 2020), including associations between hippocampal atrophy and subjective memory decline specifically (Cherbuin et al. 2015).

However, despite the growth of the literature in this area, estimates of prevalence and progression rates (conversion to MCI or dementia) are inconsistent. This lack of consistency may be driven in part by different sample characteristics, (e.g. a recent study reported sex differences (Jones et al. 2019)), or by variation in the experience of subjective decline itself as a remitting or stable condition (Si et al. 2020). For example, sustained SCD has been associated with a doubling in the risk of developing AD, a finding not seen for non-sustained SCD (Wolfsgruber et al. 2016). A greater understanding of the relationship between subjective and objective cognitive decline over time is needed before we can understand whether, how, and in whom we can classify subjective impairment as a reliable indicator for objective decline.

Our aim was to examine the relationship between stable and remitting subjective memory concerns (SMC) and contemporaneous and subsequent objective cognitive decline. We hypothesized that stable SMC would show the strongest association with objective measures of decline.

Figure S1 shows how the analytic sample was achieved. There were 1236 participants (aged 62.4 ± 1.5 years, 53% male) included in the analytic sample with a mean age at baseline of 62.4 (Standard Deviation (SD) 1.5), 53% of whom were male (Table S1). This represented 75% of the 1645 participants who were followed up at wave 4. Baseline characteristics of those with “no”, “remitting”, “new-onset” and “sustained” SMC are presented in Table 1. Of the 1236 analysed participants, 1013 (82%) were categorized as having “no”, 77 (6%) “remitting” (SMC reported only at wave 1), 77 (6%) “new-onset” (reported only at wave 2), and 69 (6%) “sustained” SMC (at both waves). Baseline characteristics of participants who were included in the current analyses and those who were lost to follow-up or excluded are shown in Table S1.

In this population study of older adults in the Canberra region of Australia, around a third of reported SMC could be classified as “sustained”, that is, present at baseline and wave 2 assessment four years later. Compared to those with “no” SMC, neither presence of self-reported “remitting” nor “sustained” SMC was associated subsequent decline in cognition. However, there were some associations seen for contemporaneous assessment of cognition. Overall, our hypothesis was only partially supported with “sustained” SMC showing the strongest associations with poorer contemporaneous performance on the SDMT and Purdue pegboard (non-dominant hand) performance but without similar findings for the other neuropsychological tests. Our results imply that participants were self-identifying some level of contemporaneous cognitive impairment but that this did not predict subsequent decline. Although the evidence base in this area is mixed our results are not inconsistent with prior studies, for example the proportion of our study population (11.8% at wave 1 and 11.8% at wave 2) who reported SMC, is comparable to the 12.6% seen in a 2007 study of 2389 participants in Germany aged 75 to 89 years, where SMC was assessed by a question, “Do you feel like your memory is becoming worse?”, with answers of “yes, this worries me” (versus “yes, but this does not worry me” or “no”) (Jessen et al. 2007), and congruent with a European study which used two measures of cognition taken 6 years apart (Mol et al. 2006), and found no relationship between baseline SMC and subsequent cognitive decline.

The focus of our analyses was the consistency of SMC reported in two initial waves (4 years apart). Other than consistency, we note that further complexities around the perception of SMC should also be considered in future studies. For example, while SMC without worry was independently associated with an increased risk of developing dementia compared to those without SMC, SMC with worry roughly doubled that risk (Jessen 2010). Although anxiety and depressive symptoms should always be considered as a confounder, our results suggest that the association between SMC and cognitive deficit or dementia cannot be wholly explained by these symptoms (Jessen et al. 2007; Jonker et al. 2000), evidenced by similar findings in those who had no anxiety or depression symptoms at baseline.

Our analyses add to the growing literature on the relationship between SMC and objective measures of cognitive function. When using a neuropsychological battery in the current study, the small change between waves in raw scores or time meant stable performance in our sample. Despite the 4-year intervals between waves, potential practice effects may still exist. Consistently, the slopes in the linear mixed models were mostly less than 0.2 SD or 3%, meaning that the differences in decline between SMC groups might be too subtle to be attested. Further work is required to confirm the utility of SMC as a robust indicator of future decline. Nevertheless, for people in their 60 s, SMC may be a useful indicator of an acute or contemporaneous drop in cognitive function.

Strengths and limitations. The population: The current study used data from a large population-based sample broadly representative of the Australian population (Anstey et al. 2012) with participants from a narrow age range and 12 years of follow-up and the opportunity to evaluate “sustained” and “remitting” SMC in addition to the more usual single time point assessment. Nevertheless, the selection of a population sample aged just 60–64, requirement for participation in follow-up visits, relatively short follow-up in the context of cognitive decline (3 waves over 8 years), may mean we were unable to detect patterns that may be visible in higher risk sections of the population or over longer time periods. It may also be that cognitive concerns expressed in early late-life are less likely to reflect actual, measurable decline than in a later life population (Jonker et al. 2000). Finally it may also be that attrition meant we missed the participants for whom this was most relevant, although our IPW analyses would suggest that this was not the case.

The assessment: The lack of structural and functional imaging and blood or cerebrospinal fluid based biomarkers for all participants to allow a biological contextualisation of our results inevitably limit our findings, as does use of a limited tool to assess SMC rather than a more complex assessment of SCD including nonmemory domains (Jessen et al. 2014; Molinuevo et al. 2017; Rabin et al. 2015; Smart et al. 2014). SMC may be sensitive but not specific in an early-late life population such as ours (Jessen 2010). Furthermore, the questions used to assess SMC in this study may have been open to varied interpretation by the participants. Specifically, participants might have interpreted the instruction to consider a time "earlier in life" as their teenage or early adulthood years or may have used a shorter time frame (e.g. 5 years ago). This may influence our results as those who answered “yes” to the first question did not proceed to the next two questions. Further, we categorized those who answered “don`t know” to the question on whether memory problems interfere with day-to-day life as experiencing SMC. Though there is no evidence against this approach, only a non-medical study in 1990s (Gilljam and Granberg 1993) supported it. It should be noted that 60 participants indicated “don`t know” at wave 1 and/or wave 2, including seven also reported that they had seen doctor about their memory.

Despite the fact that people with SMC in their 60 s had poorer contemporaneous memory scores and impaired processing speed, there was no strong association between SMC, sustained or otherwise, and faster decline over follow up. Overall this implies that people may be able to perceive poorer performance but, whilst this may represent a decline from expected performance levels it does not necessarily indicate an at risk population for future decline. Further work is required to evaluate the fluctuating nature of SMC and its relationship with cognitive trajectories over longer periods of the life-course.