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Lower practice effects as a marker of cognitive performance and dementia risk: A literature review

Abstract Background Practice effects (PEs) are improvements in performance after repeated exposure to test materials, and typically viewed as a source of bias in repeated cognitive assessments. We aimed to determine whether characterizing PEs could also provide a useful marker of early cognitive decline. Methods We conducted a systematic review of the literature, searching PsycInfo (Ebsco) and PubMed databases for articles studying PEs in aging and dementia populations. Articles published between 1920 and 2019 were included. Result We identified 259 articles, of which 27 studied PEs as markers of cognitive performance. These studies consistently showed that smaller, less‐robust PEs were associated with current diagnostic status and/or future cognitive decline. In addition, lower PEs were associated with Alzheimer's disease risk factors and neurodegeneration biomarkers. Conclusion PEs provide a potentially useful marker of cognitive decline, and could prove valuable as part of a cost‐effective strategy to select individuals who are at‐risk for dementia for future interventions.


BACKGROUND
Practice effects (PEs) are expected improvements in cognitive performance seen on repeated exposure to test material in the absence of intervention. 1 PEs, also referred to as retest or learning effects, are typically viewed as a source of bias or error when analyzing data from repeated cognitive assessments, 2,3 particularly in the study of Alzheimer's disease (AD) and other neurodegenerative disorders leading to dementia where cognitive decline is a key marker of clinical change. 4,5 PEs can hinder our understanding of the disease course of AD and other neurodegenerative diseases, as well as improve the evaluation of interventions that aim to slow or halt cognitive decline. 6 That is, by masking cognitive decline due to an underlying neurodegenerative process or by inflating cognitive gain in the absence of treatment induced brain changes, PEs may lead to underestimating the severity of disease progression or overestimating the efficacy of treatment effects. 7 The absence of PEs may also provide useful information in the context of AD and dementia. More specifically, one might expect attenuated PEs in disorders such as mild cognitive impairment (MCI) and AD, in which learning is compromised. This was, for example, supported by Duff et al., 8 who showed that lower PEs were predictive of cognitive decline 1 year later in individuals with MCI. Another study found that cognitively healthy older adults who later progressed to AD dementia had substantially lower PEs on episodic memory tasks compared to those who remained cognitively healthy. 9 Together, these findings suggest that lower PEs may indicate a subtle cognitive impairment preceding overt reduction in cognitive performance, and may serve as an early marker to differentiate neurodegeneration from healthy cognitive aging. This would be of particular relevance in pre-dementia disease stages such as MCI or subjective cognitive decline, when objective cognitive decline is modest or not easily captured by traditional cognitive assessments. 10,11 Therefore, the aim of the current review was to examine the role of PEs as a potential marker for cognitive decline in the study of cognitive aging.

Screening and review process
We selected articles using the following steps:

Data extraction
The following data were extracted from each included article: study population (ie, normal cognition, MCI, and/or dementia), mean age, retest interval, cognitive domains, cognitive task, biomarkers (if TA B L E 1 Theme definitions and related hypotheses of articles from Category C

Theme 1 Practice Effect Variability Defines Cases
Hypothesis: Lower practice effects in mild cognitive impairment and Alzheimer's disease/dementia could serve as additional evidence for presence of prodromal or clinical dementia conditions.

Theme 2 Practice Effect Variability Predicts Outcomes
Hypothesis: Lower practice effects may be an important early indicator of longitudinal outcomes such as cognitive decline, change in cognitive test scores, change in diagnostic status, or incidence of MCI or dementia.  Figure 1 shows the results from the screening and review processes.

RESULTS
The search identified 259 articles published between October 1920 and December 2019. We determined that 107 of these investigated either PEs on cognitive tests in aging samples or methods on modeling PEs, and underwent full-text evaluation by research team members. Of those, 27 met eligibility for Category C and were included in the current study. We assigned six of the 27 articles to primary Theme 1 (22%), 10 to primary Theme 2 (37%), and 11 to primary Theme 3 (41%). We assigned secondary themes for five of the articles (three to Theme 3 and two to Theme 1).

Theme 1: PE variability defines cases
Studies assigned to Theme 1 addressed the hypothesis that individuals with MCI or AD had lower PEs than individuals with normal cognitive functioning. 15 those who improved and subsequently appeared intact ("MCI-normal," classified as MCI at baseline but as intact at 1 week follow-up), the latter showed significant PEs, whereas the former did not. 22

Theme 2: PE variability predicts future cognitive decline
All Theme 2 articles addressed the hypothesis that lower PEs observed over time may be an important early indicator of future cognitive decline. This was evidenced by associations between smaller or less robust PEs and (1) subsequent decline in cognitive test scores 8,20,21,35 ; (2) risk of progression to AD 9 ; (3) incidence of MCI or dementia 14,32,34 ; and (4) terminal decline. 18 Most studies showed that findings varied by cognitive domain, with abundant evidence that lower PEs on episodic memory measures predicted future cognitive decline, 9,18,21,32,34 whereas others found that the predictive value of PEs was largely consistent across different cognitive domains. 20 Furthermore, it should be noted that studies varied highly in terms of retest intervals, which ranged from single-time retesting at the same day, 23 to multiple repeated assessments over several years 32 ( Figure 2).

Theme 3: PE variability associate with AD risk factors and biomarkers
The majority of articles we assigned to Theme 3 demonstrated that lower PEs were associated with AD risk factors and biomarkers indicative of neurodegeneration (Table 3). For example, several studies showed that lower PEs were associated with greater presence of AD risk factors such as apolipoprotein E gene (APOE) ε4 alleles or a positive family history of dementia. 14,32,33 In addition, attenuated PEs have been found to be more common in groups with specific neuroimaging markers that are indicative of dementia, such as lower cerebral blood flow, 27 brain hypometabolism, 13 smaller hippocampal volumes, 19 and higher levels of amyloid. 24,25,29 More specifically, Machulda et al.
showed that lower PEs were associated with lower hippocampal volume and brain hypometabolism regardless of amyloidosis, suggesting that PEs were more closely related to neurodegeneration than amyloid status. 31   who showed greater PEs would be at lower risk of future negative cognitive/clinical outcomes than those who had lower PEs. Overall, we found consistent evidence from a modest-sized published literature that smaller, less robust PEs on repeated cognitive testing may be an important early indicator of current diagnostic status and future cognitive decline. In addition, lower PEs were associated with risk factors and markers indicative for dementia, such as APOE genotype and biological markers of neurodegeneration.
Our review identified 27 articles evaluating evidence that characterized PEs in older adults can provide a marker for (future) cognitive performance and risk of dementia. Overall, 25 of those articles provided support for one or more of our defined hypotheses (Figure 3).
These studies supported the hypotheses that the magnitude of PEs is associated with (1) current cognitive performance or clinical status (Theme 1) and/or (2) future cognitive decline and risk of progression to AD dementia (Theme 2). Most of these studies were cross-sectional or longitudinal comparisons between cognitively healthy older adults and those with MCI or AD. 8,[15][16][17] However, one study suggested that characterizing PEs in cognitively healthy individuals at baseline could aid in the prediction of who would develop AD in the future. 9 Lower PEs were also found to be more common in groups with specific biological markers (Theme 3), including brain metabolism, hippocampal volume, and amyloid load. 13,29,31 Together with Theme 2 findings, these results suggest that the assessment of PEs, in combination with biomarkers, could be used to detect preclinical AD. This would be of particular relevance in the context of current AD research and clinical trials, which are increasingly focusing on earlier, preclinical populations. 11,47 F I G U R E 3 Overview of the 25 articles providing evidence for one or more of the a priori defined hypotheses (Theme 1, 2, and/or 3) Although we identified accumulating evidence of the clinical value of PEs in the study of AD, it should be noted that some findings remain inconclusive. For instance, it is yet unclear whether PEs can predict future cognitive decline beyond baseline cognitive performance. 37 In addition, some studies showed consistent results for PEs across multiple cognitive domains, 20 whereas other studies indicated that the predictive value of PEs was domain-specific. 31 It is difficult to determine whether differences across studies reflected disparate assessment protocols or the selection of only statistically significant findings to present in publications. Findings regarding APOE ε4 status were also contradictory; whereas three studies found that APOE ε4 carriers had lower PEs for memory, 14 three other studies found no such association between APOE ε4 alleles and PEs. 9,30,32 Unfortunately, it was difficult to formally compare studies with contrasting findings, as the studies reported varied highly with respect to retest intervals, diagnostic groups, cognitive domains, biomarkers, and methods used to calculate and model PEs (see Table 2). Particularly the latter should be taken into account when integrating the various findings. For example, an empirical change score between the first-and second-time testing It should also be considered that, as our primary focus was on PEs as a potential marker for cognitive decline, we included only articles that were assigned to Category C. Therefore, we excluded several articles that focused on understanding mechanisms underlying PEs, for example, by determining whether PEs can be attributed to repeated content rather than context effects, 50 or by investigating different aspects of memory (eg, encoding vs. retrieval) as underlying mechanisms of PEs. 51 We note that those and other articles were not overlooked in the review process, but rather fell outside the scope of the current review. On the other hand, novel, potentially eligible, Category C articles may have been published while the current article was in preparation (eg 52,53 ), but were not included as they were not available online before our final search date (January 2020). Although these two articles were not included in this review, they provide further support for the hypothesis that the absence of PEs is a potential marker of cogni- The idea that an absence of PEs could indicate (subtle) cognitive impairment, implies that researchers should consider characterizing PEs as a marker or risk factor of cognitive decline in studies of cognitive aging and AD. For example, identifying individuals with lower than expected PEs could potentially serve as a cost-effective strategy to enrich enrollment in longitudinal studies, and predict who might be at higher risk for developing AD. Furthermore, identifying high-risk individuals may be an effective strategy to enroll high-risk individuals in randomized-controlled trials of disease-modifying therapeutics.
To develop evidence-based recommendations for enrollment in clinical trials, additional research is needed to determine the possible role of lower PEs for estimating AD risk, and potentially in combination with other approaches such as AD biomarkers. We did not find any evaluations of PEs with respect to longitudinal imaging or fluid biomarker data, so it will be important to relate the magnitude of PEs to longitudinal neuroimaging and biomarker data in future research. Furthermore, methods for calculating PEs also warrant consideration in future work, as we found that those methods varied widely, which may have accounted, in part, for contrasting findings across studies. Using more sophisticated characterization of PEs across specific cognitive domains and applying modern psychometric techniques to develop reliable estimates of learning and practice could improve identification of early stage AD. This, in turn, will help to clarify whether individuals with lower PEs are at higher risk for conversion to AD.
In conclusion, we found accumulating evidence that a lack of PEs may represent an early indicator of future cognitive decline and that lower PEs are associated with specific AD biomarkers. The combination of PEs and these biomarkers may yield an optimal approach to estimate AD risk. Future research could then focus on identifying high-risk cohorts from a combination of cognitive and clinical features, and lower than expected PEs. This cost-effective strategy may be able to enrich samples in clinical trials and provide a valuable cognitive marker for subtle pharmacological or treatment responses.