Can the genetic risk for cognitive disorders be mitigated by treatable lifestyle factors?
Previous research has shown that modifying certain lifestyle factors in mid- to late life can help moderate the risk for late life dementia. Some of these beneficial factors include: treating hypertension, depression, hearing impairment, smoking, obesity, or diabetes; reducing excessive alcohol consumption; and sustaining physical activity and social contact. On the other hand, risk factors such as major depressive disorder, cardiovascular disease, and hypertension are associated with differences in brain structure and may influence the risk for dementia via this mechanism.
In this study, lead author Dr. Peter Zhukovsky along with principal investigators Dr. Aristotle Voineskos and Dr. Daniel Felsky analyzed markers of brain and cognitive health from over 50,000 individuals in an effort to better understand the relationship between brain structure and genetic risks for poor brain and cognitive outcomes. Their findings suggest that treating depression and hypertension in mid- to late life has the potential to mitigate some of the genetic risks that may lead to dementia, allowing for clinicians to better select preventative interventions for individuals who possess this genetic risk.
What is cortical thickness and how is it related to risk for developing dementia, particularly in those who have depression or cardiovascular conditions?
Cortical thickness is an important marker of brain health in older adults. In people with dementia, we see gray matter loss, often measured with MRI scans as reduced cortical thickness. We also find reduced cortical thickness in some people with depression and in many elderly people with cardiovascular and cerebrovascular conditions.
What motivated this research?
Overall, we wanted to understand factors in mid- to late life that may relate to risk for dementia, and in particular better understand mechanisms (e.g. genes, brain health) via which common conditions such as depression and cardiovascular health influence that risk. Epidemiologically, it seems all of these conditions are linked. But it’s very important to understand the mechanisms via which they are linked, so that we can develop better treatments and preventative approaches. So, we used the UK Biobank to evaluate these mechanisms, which is a great sample to understand dementia risk since it studies people in mid- life and early late life (mid-40s through mid-70s)
What was the most important finding of this study, in your opinion?
First, we were interested to see how our genes may create risk for determinants of brain health, including cortical thickness and changes to other areas of the brain, which are linked to stroke and brain injury, called white matter hyperintensities. Second, we wanted to test whether the effects of these newly identified genetic factors on cognitive health were modulated by the presence of depression or cardiovascular conditions; a nature vs. nurture approach. We found that individuals’ genetic makeup does affect brain health, with the same genetic features also affecting cognitive health in late life. Second, we found that these genetic effects were in part modulated by the presence of conditions such as depression or cardiovascular disease.
What was the most important finding of this study, in your opinion?
First, we were interested to see how our genes may create risk for determinants of brain health, including cortical thickness and changes to other areas of the brain, which are linked to stroke and brain injury, called white matter hyperintensities. Second, we wanted to test whether the effects of these newly identified genetic factors on cognitive health were modulated by the presence of depression or cardiovascular conditions; a nature vs. nurture approach. We found that individuals’ genetic makeup does affect brain health, with the same genetic features also affecting cognitive health in late life. Second, we found that these genetic effects were in part modulated by the presence of conditions such as depression or cardiovascular disease.
How does this change treatment in the future?
Our findings further emphasize the importance of treating depression and cardiovascular disease in mid-late life and provide novel avenues for the search of treatments for conditions affecting brain and cognitive health in late life. This research also underscores the importance of conceptualizing the individual as a unique combination of biological and environmental influences, which may interact to yield unique prognoses. Our research complements recent work showing that lifestyle and overall health (e.g. diet, exercise, hypertension etc.) in mid-life is essential for brain and cognitive health in late life.
Any next steps?
We would like to understand the how other environmental factors in addition to cardiovascular health and depression and lifestyle factors that are known to change risk for dementia interact with genetic risk to influence brain and cognitive health.
What is the major take home message for the public?
Treating and preventing late-life conditions such as depression and cardiovascular disease is critical to reducing one’s risk for dementia, and may even mitigate genetic risk for worse brain and cognitive health outcomes.
Dr. Zhukovsky, Dr. Felsky, and Dr. Voineskos would like to acknowledge the following organizations for making their research study possible:
Rush Alzheimer's Disease Center (RADC) (X; @rushalzheimers)
The Canadian Longitudinal Study on Aging (X; @clsa_elcv)
The UK Biobank (X; @uk_biobank)
CIHR (X; @CIHR_IRSC)
CAMH and KCNI (X; @CAMHnews, @CAMHResearch, @CAMH_KCNI)
Zhukovsky P, Tio ES, Coughlan G, Bennett DA, Wang Y, Hohman TJ, Pizzagalli DA, Mulsant BH, Voineskos AN, Felsky D. Genetic influences on brain and cognitive health and their interactions with cardiovascular conditions and depression. Nature Communications 15, 5207 (2024). https://doi.org/10.1038/s41467-024-49430-7
