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Medical News & Perspectives
November 13, 2018

Is There a Seasonal Influence on Cognition and Dementia?

JAMA. 2018;320(18):1848-1849. doi:10.1001/jama.2018.16286

Cognitive performance may peak in late summer and early fall and decline in late winter and early spring—at least in the Northern hemisphere—according to a recent study involving more than 3000 older people both with and without Alzheimer disease. The findings, published in PLOS Medicine in September, point to potentially exploitable fluctuations in cognition even in patients with dementia.

Limited research has previously linked the seasons to cognition in younger people. Most recently, European investigators found annual rhythms of brain activity in healthy young participants performing tasks of sustained attention and working memory.

In the new study, neurologist Andrew Lim, MD, of Sunnybrook Health Sciences Centre at the University of Toronto, led an analysis of cognition and its biological correlates in people in their 60s, 70s, and 80s enrolled in 5 ongoing cohort studies in the United States, Canada, and France. Changes in cognition were robustly associated with season across the groups.

The researchers believe this seasonal variation, if borne out in future studies, could one day be harnessed to improve thinking and memory in people with cognitive impairments.

Finding Patterns

Lim and his collaborators were inspired by the well-known influence of the 24-hour circadian cycle on cognition. Cognitive performance varies with circadian rhythmicity, generally peaking in the late evening. “Knowing that to be the case, I wondered whether there might be a seasonal impact as well, especially in a place like Toronto, where there are dramatic changes from season to season,” Lim said.

In an article published in Nature Communications last year, he reported widespread daily and seasonal rhythms of gene expression and epigenetic modifications in the human neocortex. The results were based on postmortem autopsies of brain tissue samples from 757 participants in 2 ongoing US studies of older persons: the Rush Memory and Aging Project (MAP) and the Religious Orders Study (ROS).

The new study involved the MAP and ROS cohorts, as well as the Chicago-based Minority Aging Research Study (MARS), the Toronto-based Sunnybrook Dementia Study (SDS), and the Paris-based Centre de Neurologie Cognitive (CNC) study. Participants in the MAP, ROS, and MARS studies were free of known dementia or cognitive impairment at enrollment, while the SDS participants were diagnosed with Alzheimer disease and the CNC participants were diagnosed with cognitive disorders including Alzheimer disease, frontotemporal dementia, nondegenerative dementia, Lewy body disease, and Parkinson disease.

By tapping into an array of cohorts, the researchers were able to identify seasonal patterns of cognition across a range of measures and markers.

They started by looking at the performance of participants without cognitive impairment on first evaluation. Among these 2761 people, those tested in the late summer and early fall scored the highest, while those evaluated in the late winter and early spring fared worst, with a cognitive gap equivalent to a 4.8-year age difference.

Of this group, 813 participants were later diagnosed with mild cognitive impairment or Alzheimer disease. The timing of their diagnoses showed a similar pattern: Those evaluated in winter or spring were 30% more likely to meet the criteria for impairment or disease than those tested in summer or fall. According to Lim, this finding could help explain why a fraction of individuals diagnosed with mild cognitive impairment can later exhibit normal cognition.

Next, the researchers analyzed the most recent cognitive evaluations from those participants without cognitive impairment at enrollment who died during their study. The seasonal associations remained, even in participants with an Alzheimer diagnosis confirmed by a postmortem neuropathological evaluation. This finding was replicated in baseline data from the Canadian cohort with Alzheimer disease. In this group, Dementia Rating Scale scores were highest in the fall and lowest in the spring, with higher scores indicating better cognition.

The researchers then measured cerebral spinal fluid (CSF) amyloid levels in the French cohort with a range of cognitive disorders at enrollment. Amyloid levels in CSF are a biomarker associated with Alzheimer disease. In general, Lim explained, “the higher the levels of CSF amyloid [42], the lower the levels of brain amyloid.” Again, his team found a similar seasonal correlation, with levels of β-amyloid (Aβ) 42 peaking in late June.

However, this seasonal rhythmicity was not observed in participants diagnosed with Alzheimer disease. According to Lim, these patients may continue to have seasonal variation in Aβ biology, but it may not be appreciable in CSF. It’s also possible that seasonal variations in Aβ biology, while important in earlier stages of disease, are not the main driving factor associated with seasonal rhythms in cognition in later disease.

The finding that patients with established Alzheimer disease pathology retain some degree of cognitive plasticity is cause for hope, Lim said. “There is something that still happens even in folks whose brains have a ton of plaques and tangles that allows them to improve in cognition from the late winter to the late summer,” he said. “This is important, because if we can understand what these mechanisms are—what the source of the plasticity is—then there’s a possibility that we’re going to be able to leverage that.”

Open Questions

Follow-up studies are needed to address the study’s major limitation: the lack of repeated cognitive measures in individual participants. “Basically, we’re using each person as one data point to assess the overall level of cognitive performance in the population over the course of the year,” said Philip De Jager, MD, PhD, a neurologist at Columbia University Medical Center in New York City and senior author of the study. Person-specific data collected every few months would more firmly demonstrate that cognition fluctuates in individuals with the seasons.

Replication studies should also include more racially diverse cohorts—only white and black people were represented in the study—and geographic variation beyond the Northern hemisphere and temperate climates, Lim said. There’s evidence that seasonal rhythms in immune gene expression are flipped in the Southern and Northern hemispheres, he said, “so one would speculate that the same thing would apply in the brain.”

Eric Reiman, MD, executive director of the Banner Alzheimer Institute in Phoenix, who was not involved with the new study, called the findings “exploratory” but “very provocative.” More studies are needed to “pinpoint those biological and environmental factors that might drive these fluctuations and see if they can be harnessed in helping to promote resilience even in those more vulnerable winter and spring months,” he said.

Lim suspects that more daylight hours and warmer temperatures in summer affect other cognition-influencing factors that are modifiable, like physical activity, vitamin D, dietary habits, mood, sleep, and socializing. His team was able to adjust for some of these factors in the study—specifically physical activity, sleep, and depressive symptoms—but the data were self-reported and therefore may not be entirely reliable.

David A. Merrill, MD, PhD, a neurologist and adult and geriatric psychiatrist at Providence Saint John’s Health Center in Santa Monica, California, agreed that light and warmth may be proxies for being outdoors more often and being more physically active. “There’s a growing body of research [showing] that physical exercise may be the best prescription for preserving and even enhancing cognitive function across the life span,” he said. “I think it will be important to follow up this study with objective tracking of physical activity levels across the year, and seeing how those vary with cognition across the population level, but also within the individual.”

For people living with cognitive impairments, as well as their physicians and caregivers, Lim’s study raises an important question: to what extent does the time of year affect functional disability and increase the need for health care resources and support? A retrospective analysis of the ROS and MAP cohorts will examine the seasonality of functional disability, Lim said.

Genetic Hints

Finding modifiable factors for cognitive decline will only become more important as the growing US population continues to age. Regardless of what those environmental and behavioral factors are, Lim and De Jager believe they may exert their influence by modulating gene expression in the brain via epigenetic mechanisms. In their final observation in the new study, they demonstrated an association between season and frontal lobe gene expression in postmortem brain tissue samples from ROS and MAP participants.

In participants both with and without Alzheimer disease, the expression of 4 of 47 assessed clusters of genes, or “modules,” was found to be seasonally rhythmic, in phase or antiphase with cognition, and associated with cognitive performance around the time of death. Genes that were associated with better cognitive performance were expressed at higher levels in the fall, while those that were associated with poor cognitive performance were expressed at higher levels in the late winter, Lim said.

The researchers are drilling down on the data from the ROS and MAP participants to ascertain which genes in the modules are responsible for the seasonal improvements. Their long-term goal: to boost the genes’ expression or directly stimulate their targets to reproduce their cognition-enhancing effects. “If we’re able to find a small molecule or some other therapeutic that can mimic this effect, perhaps we can basically maximize the level of function to a summer-type level all year round,” De Jager said.

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