Disease Mechanisms

Discovering genetic risk factors for Parkinson’s disease and Lewy body dementia

Multiple gene mutations are implicated in the development of Parkinson’s disease, which is associated with the Alzheimer’s disease-related Lewy body dementia. By growing the knowledge of how Parkinson’s, Alzheimer’s, and related dementias develop, scientists gain insights into the complexity of brain diseases.

Over the past year, several NIH-funded projects led to significant progress in understanding more about the genetic causes of Parkinson’s disease:

• LRRK2 gene: Two teams led by NIH researchers reported discovering mechanisms that suggest the biological role of leucine-rich repeat kinase-2 (LRRK2) gene in the development of Parkinson’s disease. This means that a drug that inhibits LRRK2 might help those living with this disease. By better understanding how Parkinson’s develops, researchers may be able to find new, more effective treatments for this disease.
  A separate project funded in part by NIH solved the 3D structure of the LRRK2 protein . Understanding how a protein bends or twists can aid researchers in exploring the role that a specific structure plays in disease development.
• APOE ε4 gene: Previous research has shown that the APOE ε4 gene plays a role in the cascade from amyloid plaques to tau tangles in Alzheimer’s. Now two independent studies found that APOE ε4 also directly influences the development of alpha-synuclein protein , the hallmark protein in Parkinson’s disease and Lewy body dementia. In people with Parkinson’s, those with APOE ε4 had faster rates of cognitive decline . The findings suggest that APOE has direct effects on alpha-synuclein. These results reinforce the importance of APOE as a potential therapeutic target in several forms of dementia.

Connecting the microbiome with brain health

Scientists have been exploring how the community of microbes in our digestive tract — known as the gut microbiome — affects our health. Some of the substances released by the gut microbiome are beneficial to our body whereas others are harmful. Early research suggests that these substances can impact brain health. The Alzheimer’s Gut Microbiome Project is an NIA-funded program exploring the role of the gut microbiome and metabolism in Alzheimer’s.

Products of metabolism, such as fatty acids and bile acids, can travel through the bloodstream and enter the brain. Previous studies have linked cognitive decline and Alzheimer’s to an increase in the level of certain bile acids from microbes. A recent analysis of publicly available data from the NIA-funded Alzheimer’s AD Knowledge Portal of more than 2,000 brain samples provided more evidence that microbial bile acids may play a role in Alzheimer’s .

The Alzheimer’s Gut Microbiome Project and other NIH-supported projects have only just begun to investigate the gut-brain connection and how it may play a role in cognitive impairment and dementia.

Advancing knowledge about multiple biological pathways

Following are examples of the wide array of recent findings from NIH-supported studies of multiple pathways potentially leading to dementia:

• IFITM3’s role in amyloid plaques: Researchers are seeking drug candidates that can turn off the formation of the hallmark sign of Alzheimer’s, which is amyloid plaques in the brain . A recent report describes how interferon-induced transmembrane protein 3 (IFITM3) turns on gamma-secretase, an enzyme that boosts the formation of amyloid . As people age, IFITM3 levels increase.
• Clearing the brain of amyloid: Scientists have not yet determined what drives the regular clearance of wastes from the brain . Findings from a recent study in mice showed that proteins may flow through spaces that are very close to blood vessels and that this flow is caused by the natural expansion and constriction of blood vessels. The research suggests that enhancing this motion may help flush from the brain the misfolded proteins thought to contribute to dementia.
• Why certain neurons are vulnerable to changes linked to dementia: Previous studies have noted that tau tangles develop in certain neurons in people with Alzheimer’s but not in other neurons.
• Explaining the vulnerability of certain neurons: A recent paper detailed specific genes and molecular pathways that may explain the vulnerability of certain neurons and that provide insight about what may drive the development of tau tangles and Alzheimer’s disease.
• How tau tangles spread: Two research teams recently investigated this process. The first team reported that the spread of tangles in the mouse brain depended on the shape of the long tau fibrils. The second team discovered a mechanism for tau protein moving from cell to cell in the brain. The findings from these two studies could lead to the design of treatments to prevent the spread of tau protein.
• Linking forms of tau protein with how fast dementia worsens: A new study found that people with Alzheimer’s may worsen at different rates because of the different physical and biochemical properties of the many forms of tau protein . These findings may aid the development of personalized treatments for the disease.