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Disease Mechanism Studies

NIH investments in research to identify underlying biological mechanisms that cause Alzheimer’s and other dementias are fundamental for the discovery of potential drugs targeting those processes. After a molecule, such as a protein, is identified in a disease-promoting biological pathway, researchers then study the molecule’s structure and function. The next scientific challenge is to identify a compound that will bind to that molecule and change its activity. Because Alzheimer’s is a complex pathology that is believed to involve regulation of the immune system, brain inflammation, lipid metabolism, and pathways for beta-amyloid and tau proteins, among others, there are many biological pathways that scientists can target with investigational drugs.

Here is a sample of the wide array of recent findings from NIH-supported studies of biological mechanisms:

  • Several studies have further illuminated how components of the immune system, brain inflammation, and possibly viruses and bacteria contribute to the development of Alzheimer’s and related dementias:
    • Scientists continued to gather evidence that certain cells of the immune system can play a role in the brain deterioration that causes disorders like Alzheimer’s.
    • A recent mouse study demonstrated that circumventing the activation of an immune system complex that drives inflammation could prevent the collection of abnormal tau tangles in the brain. The researchers showed that this immune system complex is a key step in the pathway between abnormal beta- amyloid plaques and tau tangles, two of the hallmarks of Alzheimer’s disease.
    • One factor that may influence the immune response in the brain is viruses, bacteria, or other microbes — or the inflammatory molecules they produce, which can travel from infections in the body through the bloodstream to the brain. Studies have suggested that this is one mechanism of influencing the cascade of events leading to beta-amyloid deposits and tau tangles. To test whether viruses may play a role in Alzheimer’s, NIH is supporting a Phase 2 clinical trial of an FDA-approved antiviral drug to determine whether it may slow or prevent Alzheimer’s in people with mild Alzheimer’s who also test positive for the herpes simplex virus.
    • Using data made available by the NIH- funded Alzheimer’s Disease Neuroimaging Initiative (ADNI), researchers analyzed levels of a protein that helps immune cells clear harmful beta-amyloid plaques from the brain. Their results suggest that a treatment that could boost that protein might slow the progression of Alzheimer’s.
  • A mouse study showed that an extremely high-salt diet leads to cognitive problems through the abnormal tangling of tau protein in the brain.
  • An analysis of more than 3,000 proteins in brain and spinal fluid samples revealed that certain sets of proteins that control sugar metabolism were strongly associated with the brain changes in Alzheimer’s.
  • Drugs that selectively removed certain cells slowed down the progression of brain changes related to dementia and enabled mice to complete maze tests in half the time.
  • In mice, researchers reversed faulty protein networks that caused abnormal brain function with a drug called PU-AD. Biotech company Samus Therapeutics is now sponsoring a Phase 2A clinical trial (NCT04311515) of people with mild Alzheimer’s dementia with PU-AD, which was developed with support through NIA’s Alzheimer’s Translational Research Program.
  • Recent NIH-funded research has identified a gene mutation associated with frontotemporal dementia and another neurodegenerative condition that seems to hinder the normal way that RNA hitchhikes through nerve cells in the brain to help with protein synthesis.

Brain Studies of Toxic Proteins

Three recent NIH-supported studies explored how the unique ways that abnormal proteins fold may account for their toxicity and accumulation in brain diseases that cause dementia. A comparison of brain tissue from people with Lewy body dementia (LBD) and Alzheimer’s suggests that, for people with LBD, the amygdala region of the brain is key to the accumulation of toxic proteins known as alpha-synuclein. The study also suggests that the alpha-synuclein form in LBD is distinct from the form in Alzheimer’s.

Two cryoelectron microscopy studies explored the intricate folding of the tau filament structure and how structures differed across several diseases that cause dementia. The research team demonstrated differences in the structure of the abnormal tau protein filaments that collect in the brains of people with Alzheimer’s versus two neurodegenerative conditions, chronic traumatic encephalopathy that boxers and football players experience from repeated head trauma and a rare brain disease called corticobasal degeneration. Understanding the specific differences between brain diseases for the folding of the tau filament structure can aid researchers in exploring the role of structural differences in disease development. The discoveries may also lead to diagnostic tests for these diseases to help differentiate between types of dementia.

Genetic Advances

Brain cells send signals and receive them through biological pathways. This is how genes are turned on and off, for example. When something goes wrong in a biological pathway, disease can result. Researchers can study all the genes, proteins, cells, and other elements in a biological pathway to better understand the processes leading to health and disease.

Scientists search for mutations or variations in genes because they might play a role in the development of disease. Twenty years ago, scientists found variants of four genes that were linked to Alzheimer’s. Because of advances in genetic sequencing technology and the ability to analyze the genes of thousands of people, many more discoveries have been made in the past decade. Today, thanks in part to the increased investment in Alzheimer’s research, scientists have identified variants in more than 50 regions of the genome that may increase risk for the disease. Of these, variants in more than 23 individual genes have been linked to increased risk of late-onset Alzheimer’s. These genetic regions appear in clusters that point toward what may be highly relevant molecular pathways. By understanding key pathways, researchers may be able to develop prevention strategies and treatments for Alzheimer’s.

In 2019, NIH-supported researchers who are part of a large data-sharing collaboration reported findings from the largest-ever genomic study of Alzheimer’s. Their analysis of the genomes of more than 35,000 people with late-onset Alzheimer’s revealed previously unknown variants in five genomic regions of interest that convey greater risk of the disease. The study also confirmed other regions that had been implicated previously in Alzheimer’s. A single genetic variant may convey only a small amount of increased risk for an individual, but groups of genes may work in combination to increase risk.

These new genetic discoveries enable scientists to explore the many biological pathways that provide a richer set of treatment targets. Having a clear understanding of groups of genes with common function may guide researchers to discover drugs that either block cellular events that are part of Alzheimer’s or enhance the events that convey resilience against it. The report also suggested certain genetic similarities between early-onset and late-onset Alzheimer’s, which raises the possibility that treatments now being developed for people with early-onset disease may also help people with late- onset disease, which is far more common.

The achievement of this largest-ever genomic study of Alzheimer’s can be attributed to the collaborative resources made possible by NIH investments. This advance in our understanding of genetics illustrates how scientific advances are multiplying the effect of infrastructure investments. The study would not have been possible without data sharing and coordination among the following consortia, research centers, and studies:

Recently, researchers provided a map for further research into the multiple gene-related molecular processes that are altered in Alzheimer’s. After analyzing protein-coding genes from more than 80,000 brain cells, the researchers identified unique clusters of genes that are turned on during Alzheimer’s in certain types of brain cells, including specific types of neurons and supporting cells in the brain region involved in high-level thinking, decision- making, and attention. Molecular processes in these brain cell types were consistently disturbed in people with Alzheimer’s. This kind of cell-specific molecular analysis is a new approach for examining the molecular and cellular basis of Alzheimer’s.

Lewy body dementia

Until recently, LBD was not thought to have a strong genetic component but results from large-scale genetic studies now suggest otherwise. In 2019, a study showed that, in addition to environmental risk factors, genetic risk factors contribute to many cases of LBD. Some of the LBD-related genes also appear to play a role in Alzheimer’s and Parkinson’s, which suggests that LBD shares biological pathways in common with these diseases. In addition, the researchers found genetic changes that appear to be unique to LBD. A better understanding of how these genetic changes impair biological function will yield a deeper understanding of what happens in the brains of people with LBD and offer researchers potential targets for therapies that could treat the disease.

For a more in-depth look at the research implementation milestones in this area, including progress and accomplishments, visit

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