Research Article: Seasonal plasticity of cognition and related biological measures in adults with and without Alzheimer disease: Analysis of multiple cohorts

Date Published: September 4, 2018

Publisher: Public Library of Science

Author(s): Andrew S. P. Lim, Chris Gaiteri, Lei Yu, Shahmir Sohail, Walter Swardfager, Shinya Tasaki, Julie A. Schneider, Claire Paquet, Donald T. Stuss, Mario Masellis, Sandra E. Black, Jacques Hugon, Aron S. Buchman, Lisa L. Barnes, David A. Bennett, Philip L. De Jager, Michelle M Mielke

Abstract: BackgroundThere are few data concerning the association between season and cognition and its neurobiological correlates in older persons—effects with important translational and therapeutic implications for the diagnosis and treatment of Alzheimer disease (AD). We aimed to measure these effects.Methods and findingsWe analyzed data from 3,353 participants from 3 observational community-based cohort studies of older persons (the Rush Memory and Aging Project [MAP], the Religious Orders Study [ROS], and the Minority Aging Research Study [MARS]) and 2 observational memory-clinic-based cohort studies (Centre de Neurologie Cognitive [CNC] study at Lariboisière Hospital and the Sunnybrook Dementia Study [SDS]). We performed neuropsychological testing and, in subsets of participants, evaluated cerebrospinal fluid AD biomarkers, standardized structured autopsy measures, and/or prefrontal cortex gene expression by RNA sequencing. We examined the association between season and these variables using nested multiple linear and logistic regression models. There was a robust association between season and cognition that was replicated in multiple cohorts (amplitude = 0.14 SD [a measure of the magnitude of seasonal variation relative to overall variability; 95% CI 0.07–0.23], p = 0.007, in the combined MAP, ROS, and MARS cohorts; amplitude = 0.50 SD [95% CI 0.07–0.66], p = 0.017, in the SDS cohort). Average composite global cognitive function was higher in the summer and fall compared to winter and spring, with the difference equivalent in cognitive effect to 4.8 years’ difference in age (95% CI 2.1–8.4, p = 0.002). Further, the odds of meeting criteria for mild cognitive impairment or dementia were higher in the winter and spring (odds ratio 1.31 [95% CI 1.10–1.57], p = 0.003). These results were robust against multiple potential confounders including depressive symptoms, sleep, physical activity, and thyroid status and persisted in cases with AD pathology. Moreover, season had a marked effect on cerebrospinal fluid Aβ 42 level (amplitude 0.30 SD [95% CI 0.10–0.64], p = 0.003), which peaked in the summer, and on the brain expression of 4 cognition-associated modules of co-expressed genes (m6: amplitude = 0.44 SD [95% CI 0.21–0.65], p = 0.0021; m13: amplitude = 0.46 SD [95% CI 0.27–0.76], p = 0.0009; m109: amplitude = 0.43 SD [95% CI 0.24–0.67], p = 0.0021; and m122: amplitude 0.46 SD [95% CI 0.20–0.71], p = 0.0012), which were in phase or anti-phase to the rhythms of cognition and which were in turn associated with binding sites for several seasonally rhythmic transcription factors including BCL11A, CTCF, EGR1, MEF2C, and THAP1. Limitations include the evaluation of each participant or sample once per annual cycle, reliance on self-report for measurement of environmental and behavioral factors, and potentially limited generalizability to individuals in equatorial regions or in the southern hemisphere.ConclusionsSeason has a clinically significant association with cognition and its neurobiological correlates in older adults with and without AD pathology. There may be value in increasing dementia-related clinical resources in the winter and early spring, when symptoms are likely to be most pronounced. Moreover, the persistence of robust seasonal plasticity in cognition and its neurobiological correlates, even in the context of concomitant AD pathology, suggests that targeting environmental or behavioral drivers of seasonal cognitive plasticity, or the key transcription factors and genes identified in this study as potentially mediating these effects, may allow us to substantially improve cognition in adults with and without AD.

Partial Text: Seasonal rhythms modulate several aspects of human behavior and physiology including brain functions such as mood in seasonal affective disorder [1], symptom onset in schizophrenia [2], and functional MRI (fMRI) brain responses to cognitive tasks [3]. Several studies suggest that season may modulate cognition in younger adults [4,5], although this is not a universal finding [3,6,7], and data from older adults are lacking.

In this study of 3,353 older adults across multiple countries, cohorts, and races, there was a significant and reproducible association between season and cognition, with peak cognition near the fall equinox and a seasonal effect equivalent to a roughly 4-year difference in age. This association was independent of mood, sleep, physical activity, and thyroid status; it was clinically significant, as reflected in a nearly 30% higher odds of meeting criteria for MCI or dementia in winter and spring compared to summer and fall; and it persisted in cases with pathologically confirmed AD. Moreover, season was also associated with CSF Aβ levels and the brain expression of cognition-associated gene modules that were associated with identifiable transcription factor binding sites. Additional dementia care resources may be needed in the winter and spring, when cognition is likely to be worse. Moreover, these findings suggest substantial seasonal plasticity of cognition, amyloid biology, and cognition-related transcriptional programs, even in the presence of pathological AD. Seasonal factors may thus be important modifiers of the association of cognition with AD pathology, an effect potentially mediated by BCL11A, EGR1, THAP1, CTCF, MEF2C, and other key transcription factors, some of which are themselves seasonally rhythmic. Further work to understand the mechanisms underlying this plasticity may lead to novel environmental, behavioral, or pharmacological interventions to improve cognition in AD by enhancing the normal summer and fall peak in cognition, and/or extending it into other seasons.



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