br Methods br Results br Discussion In this investigation

Methods

Results

Discussion
In this investigation, we examined whether variation in CR or BDNF Val66Met, either independently or through CR-gene interaction, affected 36-month cognitive change in healthy older participants of the Tasmanian Healthy Brain Project. Although no longitudinal differences were identified in any cognitive domain between BDNF Val homozygotes and Met carriers, we found that baseline CR had a positive association with change in working memory performance that was stronger in the THBP control group. We also found that the BDNF Val66Met polymorphism interacted with baseline CR to affect 36-month change in executive function performance, in that CR-related differences in function decreased across the follow-up ginsenoside rh2 in BDNF Val homozygotes, but became more pronounced in BDNF Met carriers. This suggests that CR may affect the higher order cognitive processing of aging individuals differently based on variation in BDNF Val66Met, which is noteworthy given that associations of CR and cognitive change are typically only observed in conjunction with the presence of significant neuropathology [34].
Higher CR is reliably associated with higher cognitive function in middle and older age, independent of any potential protective effect on age-related decline or dementia risk [35]. The results of our previous cross-sectional analysis support this, where we found positive relationships between CR and function in multiple cognitive domains [21]. In the present study, we found that CR exerted an effect on the rate of change in working memory performance, with higher CR associated ginsenoside rh2 with a greater improvement in performance across the 36-month follow-up period. However, this modulation of working memory performance by CR was identified solely in the subgroup of control participants of the THBP (N = 93), and may simply be a result of differences in demographic and cognitive variables. Should this effect represent more than a sampling bias, it may reflect a buffering of negative aging-related memory changes by CR, although reports are mixed regarding a role of CR in cognitive aging [36]. This result may also be due to the use of better cognitive strategies to achieve greater improvements in functioning over time in individuals with higher CR, as improved cognitive strategy selection is hypothesized to underpin part of the cognitive benefits of CR [37].
Our most significant finding was an interaction between BDNF Val66Met and CR in predicting change in executive function performance. Here, results indicated that BDNF Val66Met status determined whether CR-related differences in performance decreased or increased across the 36-month follow-up period. This effect has been identified in a previous baseline analysis of this data set [21], which identified a stronger association of CR and executive function in BDNF Val homozygotes than in BDNF Met carriers. Overall, this set of results suggests that the expected positive association of lifetime exposure to cognitively stimulating activities and cognitive performance is weaker in BDNF Met carriers and that this may culminate in the amplification of CR-related differences in aging-related cognitive trajectories. Despite this, the present results also indicated that the influence of any of the included predictors on 36-month cognitive change did not vary by the BDNF Val66Met polymorphism in the other assessed cognitive domains (i.e., episodic memory, working memory, language processing), with negligible or very small effect sizes identified. Similarities between CR and executive function may explain why this CR effect was observed solely in the executive function domain [38], and both constructs share commonalities in relation to cognitive flexibility [8,39] and a reliance on frontal lobe activity [40,41].
Interpretation of the present results should be undertaken with consideration of the following limitations: (1) at baseline, our sample consisted of high-functioning older adults who were well educated and likely had higher CR than average (mean IQ = 112.86, mean years of education completed = 13.98). Therefore, our results may not be applicable to wider populations; (2) APOE has been shown to interact with BDNF Val66Met in healthy, preclinical, and AD individuals [5,42,43] but we were not able to include an APOE × BDNF Val66Met interaction term due to the small number of cases in the APOE ε4/BDNF Met group; (3) patterns of aging-related cognitive decline were not observable in the sample, overall. This may be partly accounted for by practice effects [44], and similar patterns of cognitive change in healthy older adults have been reported in other cohorts, even in the absence of intervention [45]; (4) the THBP intervention may have had an influence on the cognitive trajectories described in our study. However, our analyses included THBP group interaction terms to adjust for any potential effect of the intervention, and experimental/control group membership was evenly distributed across BDNF groups at baseline.