Vascular Degeneration in the Brain as the Common Link Between Lifestyle and Dementia

Researchers here propose that the unifying underlying mechanism for lifestyle influences on dementia risk is chronic inflammation. That inflammation causes vascular degeneration and a consequent decline in the blood supply to the brain, which in turn contributes - to some degree - to all of the observed issues in the aging brain. When present to a large degree, these vascular issues are categorized as vascular dementia, a widely studied condition. But it is entirely plausible that subclinical vascular degeneration is an important mediating factor linking lifestyle and dementia. A competing hypothesis involves the role of persistent infection, and correlation between lifestyle factors and risk of suffering such infections. This also would be expected to proceed via raised levels of inflammation in the brain. The state of the immune system is indeed an important factor in aging.

The 2020 report of the Lancet Commission identified twelve potentially modifiable risk factors for dementia including less education, hypertension, hearing impairment, smoking, obesity, depression, physical inactivity, diabetes, and low social contact, and suggested that 40% of worldwide dementias may be due to these factors. Research has also provided two additional important observations relevant to the etiology of dementia. The first was that drugs that successfully eliminated cerebral accumulations of beta amyloid have so far shown only modest impact on cognitive deficits, although trials are still ongoing. Ever since the original description that these proteins were present in the brains of individuals dying with dementia, they were considered to be etiologically significant in inducing dementia, and the modest impact they have had to date has forced a reappraisal of our approach to dementia.

The second landmark observation was that a decline in cerebral blood flow (CBF) was an early cerebral event that heralded the decline in cognitive function and may precede the appearance of the clinical syndrome by many years. This finding confirmed that vascular insufficiency is a major etiologic factor that anticipates the onset of cognitive deficits, and that the protein deposits found in the brain of demented individuals were more likely a consequence of the disease rather than its cause. While this was a major step forward in our understanding of the etiology of dementia, it left open the question: do all harmful lifestyles lead to cerebral hypoperfusion? If so, what are the physiological mechanisms that lead to the decline in CBF when a harmful lifestyle has persisted?

Several publications have proposed that inflammation may be the link between lifestyle, genetics, and Alzheimer's disease, but the mechanisms that link inflammation to this outcome are not clear. This review will focus on three lifestyle factors that negatively impact cognition, namely obesity, sedentary behavior, and insufficient sleep. In each case, a summary of the research associating the lifestyle to subsequent cognitive decline will be presented, and the impact of the lifestyle on cerebral vascular perfusion will be explored. The potential mechanisms linking the lifestyle to its eventual impact on perfusion will then be reviewed. A unifying hypothesis will be proposed, namely, that all lifestyles that negatively impact cognition do so through the activation of inflammatory factors, which then lead to small vessel disease, resulting in a reduction in cerebral perfusion and causing atrophy of structures essential for normal cognition.


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