Four modifiable risk factors may have the potential to cut the growing global incidence of Alzheimer's disease (AD) and Parkinson's disease (PD), a new review suggests.
Investigators at the University of British Columbia, Canada, suggest that reducing neuroinflammation by decreasing physical inactivity and taking steps to mitigate the risk factors for vascular disease–related conditions as well as obesity and type 2 diabetes mellitus (T2DM) could prevent many cases of AD and PD.
"The number of people affected by AD and PD is increasing exponentially each year, due to the aging global population. The reduction of modifiable risk factors is a practical strategy to decrease the incidence of new disease cases," the investigators write.
"Preventing and possibly treating the neuroinflammation present in AD and PD may decrease an individual's risk of developing these diseases," they add.
The study was published in Current Aging Science.
A Coherent Picture
"Much of the past research into the relationship between modifiable risk factors and neurodegenerative diseases has focused on neuronal cell loss, but the goal of this new review was to draw attention to the neuroinflammatory aspect that mainly involves the non-neuronal glial cells," study author Andis Klegeris, PhD, University of British Columbia Okanagan Campus in Kelowna, told Medscape Medical News.
"What is less studied is the possibility that these risk factors affect viability of neurons indirectly, by immune cells of the nervous system," he added.
By packaging the available information and providing "a coherent picture," Dr Klegeris said he hopes other researchers will be encouraged to further "tease out" possible neuroimmune mechanisms involved in AD and PD.
Both AD and PD are characterized by adverse activation of microglia by disease-specific pathologic stimuli. This results in reactive gliosis and eventually leads to a chronic neuroinflammatory state.
This alteration in neuroinflammatory status may result in collateral damage to surrounding brain cells, including neurons and glia. This is hypothesized to contribute to the neurodegenerative process observed in AD and PD.
The study report describes the involvement in this process for each of the four modifiable risk factors.
Physical inactivity is estimated to contribute to about 13% of all AD cases worldwide, said the authors.
"The implications of physical inactivity are tremendous, as a 25% increase in the number of people participating in physical activity could potentially prevent the development of nearly 1.5 million cases of AD across the globe," they write.
The authors cite several studies that reveal the potential efficacy of exercise as a therapeutic strategy for preventing and/or treating AD.
For example, a meta-analysis that included 29 randomized controlled trials confirmed that aerobic exercise improved attention and memory, as well as processing speed and executive functioning, especially among those affected by AD and mild cognitive impairment.
Hypertension, Diabetes, Obesity
Physical activity is also a potential nonpharmacologic strategy for the prevention and/or treatment of PD, the authors note. A sedentary lifestyle is associated with a two-fold increased PD risk. In addition, physical activity has been shown to improve PD motor symptoms, including the abnormal gait and disequilibrium common in these patients.
The authors refer to a recent study concluding that the best way to prevent PD is physical exercise, including walking, jogging, swimming, and tai-chi. However, the research is inconclusive about whether exercise can slow overall disease progression.
Hypertension and other vascular disease–related conditions are characterized,in part, by increased inflammation. The authors note that vascular disease–related risk factors are partially linked to lifestyle and so are modifiable, although they also involve a substantial nonmodifiable genetic component.
Some experts have calculated that midlife hypertension increases the relative risk for AD by 1.6-fold, and others have confirmed that hypertension increases the odds of developing AD by about 50%, the authors note.
Studies reveal that conditions closely related to hypertension, including hyperlipidemia and atherosclerosis, also elevate the likelihood of developing AD.
Evidence suggests that hypertension and hypercholesterolemia are also associated with an increased risk for PD. One study in the review that was based on national population surveys in Finland found that hypertension was associated with a greater than 60% increase in risk for PD among women.
The authors also point to clinical trials that helped uncover a possible link between hypercholesterolemia and PD. One of these showed that simvastatin, which inhibits 3-hydroxy-3-methylglutaryl-coenzyme A reductase and lowers blood cholesterol levels, significantly reduced the incidence of PD.
The investigators present evidence demonstrating how the related disorders of obesity and T2DM may induce and exacerbate AD and PD pathologies by propagating neuroinflammation. Both risk factors can be controlled through changes in diet, physical activity, and pharmacologic intervention.
The link between T2DM and AD is well established. For example, the authors pointed to a recent systematic review showing that a previous diagnosis of T2DM increased the risk for cognitive decline by 1.5-fold and increased the risk for AD up to 2.3-fold.
Advanced glycation end products (AGEs), a vast group of macromolecules bound to sugar molecules, are another feature common to both AD and T2DM. The researchers note studies that uncovered correlations between lower cognition and high levels of dietary AGEs, which are formed in foods processed at high temperatures and are absorbed from the diet into the circulation.
The Role of Diet
Dr Klegeris noted the complexity of studying diet as a risk factor for neurodegenerative diseases.
"Information about diet is very fragmented," he said. For example, he said, following the Mediterranean diet is likely a good idea, "but where do you start in terms of looking at what in that diet is helpful?"
Although dietary changes are one of the most important tools to control T2DM, some prescription medications are also helpful; if started before cognitive impairment, they may reduce the risk of developing AD later in life, said the authors.
The interaction among neurodegeneration, T2DM, and obesity extends to PD. The authors refer to some of the large body of evidence supporting diabetes and obesity as risk factors for the development and progression of PD.
Sleep, or lack of it, is receiving increased attention as being possibly linked to dementia, but it was not included in the review as a modifiable risk factor.
"Up until recently I would not have known how to approach it from a neuroinflammation standpoint," said Dr. Klegeris.
It has only come to light in the last few years that immune cells in the brain play an important role in cleaning up unnecessary synapses, he said.
Getting insufficient sleep, or disturbed sleep, doesn't clear away enough of these synapses, he added.
Epidemiologic studies have shown that long-term use of nonsteroidal anti-inflammatory drugs (NSAIDs) is associated with reduced risk for AD, presumably through inhibition of neuroinflammation. These observations have led to multiple clinical studies exploring the effectiveness of NSAIDs in AD.
Overall, these clinical trials demonstrated that NSAIDs are not effective. However, they had several limitations, including the significant participant dropout rate due to the adverse effects of the treatment.
Striking Similarities
Dr Klegeris hopes the new review will spur researchers to look for other anti-inflammatory drugs. "That NSAIDS didn't work doesn't mean that there are no other alternative classes of anti-inflammatories which could possibly work," he said.
It's unlikely that there will be a single "magic drug" to cure dementia. "Unless something really fantastic comes along, it most likely will be a cocktail," said Dr Klegeris.
A key ingredient of that "cocktail" would be an anti-inflammatory compound. But Dr Klegeris doesn't like to use the term "anti-inflammatory."
"It's too simplistic; this is probably going to involve an immune-modifying drug, so an agent that turns an adverse immune response into a good immune response, perhaps an immune activator," he said.
t may be that the immune-modifying ingredient would be the same for AD and PD. "There are striking similarities in terms of how cells respond in both cases," said Dr. Klegeris.
Dr Klegeris has disclosed no relevant financial relationships.
Curr Aging Sci. 2017;10:158-176. Abstract
http://www.medscape.com/viewarticle/885271#vp_1
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