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With as many as 24 million people worldwide having developed Alzheimer's disease, ongoing investigations on risk factors for and potential causes of the condition continue to capture significant attention. Some recent research has focused on the role of a specific set of cells (see Infographic).
In healthy brains, a protein called beta-amyloid is cleared away by microglia. However, it can sometimes build up owing to certain gene mutations; traumatic brain injury (TBI); and, potentially, microglial function. In individuals with Alzheimer's disease, too much amyloid accumulates between brain cells and in vessels that supply the brain with blood. Once this happens, it triggers the accumulation of another protein, called tau. This buildup of tau sends microglia and other mechanisms into overdrive, leading to the inflammatory immune response that many researchers believe harms brain vitality in Alzheimer's disease.
Investigators have determined that the genes CD33 and TREM2 are largely responsible for microglia behavior. The theory is that treatments that could decrease CD33 activity or increase TREM2 activity may help slow or stop the progression of dementia. Many failed investigational drugs have targeted the amyloid itself; however, some experts believe that medications that halt the immune response to amyloid may provide more efficacy in Alzheimer's disease.
Long-term stress may contribute to the role microglia in development of Alzheimer's disease. A review of human and animal epidemiologic studies found that chronic stress and genetic factors may act through the hypothalamic-pituitary-adrenal axis to contribute to Alzheimer's disease development. "There is an intimate interplay between exposure to chronic stress and pathways influencing the body's reaction to such stress," senior author David Groth, PhD, said in a statement. Individuals vary regarding how sensitive they are to stress and glucocorticoid responses. "Genetic variations within these pathways can influence the way the brain's immune system behaves, leading to a dysfunctional response. In the brain, this leads to a chronic disruption of normal brain processes, increasing the risk of subsequent neurodegeneration and ultimately dementia," Groth said.
Researchers suggest that these variations may prime microglia to cause inflammation in the brain. "Genome-wide association studies have found that of the genes identified as being associated with Alzheimer's disease, 60.5% are expressed in microglia," the authors noted. To connect the roles of chronic stress and brain inflammation in Alzheimer's disease, the researchers proposed a "two-hit" hypothesis: Early or mid-life exposure to stress primes the microglia to enter an inflammatory state in response to a secondary stimulus later in life.
Another recent investigation explored the role of concussion in the development of Alzheimer's disease. New research suggests that posttraumatic amnesia (PTA) and chronic vascular lesions caused by TBI are tied to an increased risk. Results from the case-controlled retrospective study showed that the presence of PTA or of vascular lesions on neuroimaging in patients with TBI was significantly associated with up to an almost fourfold increased risk for Alzheimer's disease.
Using medical records and medical insurance data, researchers identified 5642 patients with a TBI admitted to a tertiary trauma center over a 12-year period (2000-2012). The current analysis included 30 patients with TBI who developed Alzheimer's disease dementia before the end of 2018 and 80 individuals who did not have dementia to act as the control group. Among the study population, 25.5% were diagnosed with PTA, which is characterized by confusion and disorientation; 16.7% had a history of at least one TBI. Results showed a significant association between PTA and Alzheimer's disease dementia, with higher odds for those with vs without an AD diagnosis (odds ratio, 2.88; 95% CI, 1.06-7.81; P = .04).
Depression, which has long been associated with Alzheimer's disease, has also recently been found to potentially have a causative role. Investigators used data from the largest and most recent genome-wide association studies (GWAS). These included a 2019 analysis of depression among 807,553 individuals and a 2019 study of Alzheimer's disease among 455,258 individuals, all of European ancestry. The researchers also accessed postmortem brain samples, which allowed use of deep brain proteomic data to help determine molecular links between depression and Alzheimer's disease. Results showed a small but significant positive genetic correlation, suggesting that the two conditions have a shared genetic basis. After assessing the effect of 115 independent single-nucleotide polymorphisms (SNPs) from the GWAS of depression, researchers uncovered significant evidence "that the SNPs cause depression, which in turn cause Alzheimer's disease."
As rates of dementia continue to increase, the hope is that research into potential causes will lead to the development of effective prevention or therapeutic treatments. Developments are being closely watched, as is evident by the fact that the possible causative cells, microglia, became this week's top trending clinical topic.
Learn more about Alzheimer's disease.
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Cite this: Ryan Syrek. Trending Clinical Topic: Microglia - Medscape - Feb 11, 2022.