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Underlying all our research on Alzheimer’s disease and related dementias is the understanding of how processes in our cells lead to these diseases. NIH conducts and funds basic research to understand the genes, biological pathways, and cells involved. Equipped with this kind of information, scientists can pursue new avenues of research into diagnostic methods and interventions to prevent, delay, or treat dementia.
Abnormal, misfolded forms of TDP-43 protein affect the development of some brain diseases
NIA and the National Institute of Neurological Diseases and Stroke (NINDS) fund basic research into the many types of dementia, including under-recognized forms involving a protein called TDP-43. TDP-43 is usually found in the nucleus, where genes are activated. However, misfolded forms of this protein cannot enter the nucleus. Two independent research teams discovered how having TDP-43 in the wrong place alters the genetic instructions for a gene called UNC13A . UNC13A is important for maintaining connections between neurons, and changes to this gene can raise the risk of both amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD).
Limbic-predominant age-related TDP-43 encephalopathy (LATE) is a recently recognized brain disorder that mimics the clinical features of Alzheimer’s. A recent study found that people in the advanced stages of LATE are more likely to have certain types of small blood vessel disease in the brain . The study analyzed data from the NIA- funded Religious Orders Study and Memory and Aging Project (ROSMAP) and Minority Aging Research Study (MARS).
Researchers have also discovered that TREM2, a protein found on certain immune cells, helps protect the brain from TDP-43-related harm . The results suggest that treatments that enhance the activity of TREM2 might be helpful for people with ALS and FTD.
Specific forms of the tau protein are linked to different brain diseases
Abnormal tangles of the tau protein form harmful structures in Alzheimer’s, FTD, and a number of other diseases, known collectively as tauopathies. Researchers have recently been able to describe the 3D structures of these tau forms , identifying distinct structures in different tauopathies. The findings could help scientists develop biomarkers that differentiate between diseases.
Immune system contributes to brain aging
Inflammation is part of the immune system’s natural response to infection or injury, but it can also cause problems if it is not responding properly in specific circumstances. Recent research findings have linked inflammation and issues with the immune system to the development of Alzheimer’s and related dementias.
- Scientists discovered a process that switches immune cells from protecting the brain to driving inflammation . They also found a way to block this process, improving cognition in older mice and suggesting a potential treatment for Alzheimer’s and other cognitive diseases.
- Another team of researchers identified “immune hubs” around the brain where the peripheral immune system monitors the brain . In those hubs, cellular waste leaving the brain interacts with immune cells; this may initiate the inflammatory responses seen in Alzheimer’s and other neurodegenerative diseases. The finding points to new ways to target brain inflammation.
- The lymphatic system is a series of vessels running alongside blood vessels to carry immune cells and waste to lymph nodes. A recent study points to the importance of this drainage system in removing amyloid buildup in Alzheimer’s. The findings suggest that anti-amyloid immunotherapies may be more effective if the drainage function of the lymphatic system is improved with certain therapies .
- B cells are immune cells that make immunoglobulin, which could in theory target beta-amyloid plaques to slow the progression of Alzheimer’s. However, researchers found that B cells actually contributed to Alzheimer’s progression in mice because the cells penetrate the brain and deposit immunoglobulin around beta-amyloid plaques. Depleting B cells with a therapeutic antibody improved many aspects of the disease, suggesting a therapeutic strategy for humans.
- In Lewy body dementia, abnormal deposits of alpha-synuclein protein form in the brain. Recently, researchers identified how a specific type of T cell involved in autoimmune diseases may travel to the brain to destroy neurons . Their findings indicate that drugs already used to treat certain autoimmune diseases may block this undesirable T cell activity.
- The gene apolipoprotein E ε4 (APOE4) is one of the most significant genetic risk factors for Alzheimer’s and has been linked to several related dementias, but how it promotes neuron death is unclear. Using data from the NIA-funded Alzheimer’s Disease Knowledge Portal and ROSMAP , as well as mouse studies, researchers have found that high levels of APOE4 in neurons trigger an immune pathway that leads to tau tangles and cell death .
Normally, APOE4 is made mainly by a type of brain cell called an astrocyte. In a study, selectively deleting APOE4 in astrocytes lowered inflammation and neuron damage in mice, even after tau tangles had started to form. The results suggest that targeting APOE4 or its downstream effects could be a treatment strategy for Alzheimer’s .
Specific hormone may be key to sex differences in Alzheimer’s
Women are at greater risk than men of developing Alzheimer’s over their lifetimes. The disease also tends to get worse faster in women, who experience a broader range of cognitive symptoms.
One possible explanation for this difference in risk is follicle-stimulating hormone (FSH), which rises sharply in women around the time of menopause. In 2022, researchers found that giving FSH to both female and male mouse models of Alzheimer’s sped up the disease’s progression . In contrast, blocking the hormone improved Alzheimer’s symptoms in mice. NIA-funded research will expand on these initial results by conducting preclinical research to test the safety and efficacy of humanized FSH-blocking antibodies .
Problems with DNA repair in neurons may contribute to the onset of Alzheimer’s disease and related dementias
Unlike other cells, neurons generally cannot be regenerated, making it especially important for our bodies to be able to repair damage to DNA in neurons. But the ability to repair DNA tends to decline with age. To learn more about how neurons maintain their DNA, NIA-funded scientists developed a technique called Repair-seq. Using Repair-seq, they found that when repairing DNA, neurons prioritize certain “hot spots” in the genome that contain essential genes .
When they examined the proteins made from the genes associated with hot spots, the researchers discovered that some of these proteins showed changes similar to those seen in Alzheimer’s. This finding suggests that problems with DNA repair may contribute to the onset or progression of the disease. Repair-seq offers a powerful new tool for exploring the role of DNA repair during the aging process.
Exercise may help protect against brain inflammation
Evidence suggests exercise may help slow cognitive decline in older adults and may be associated with a lower risk of Alzheimer’s. Findings from two new studies have helped clarify how inflammatory pathways may link exercise and brain health:
- An anti-inflammatory protein called clusterin rises in the blood of people who have exercised regularly . Clusterin binds to the blood vessels in the brain and reduces the expression of genes associated with inflammation.
- In a mouse model of Alzheimer’s, mice engineered to make a hormone called irisin, which is induced by exercise, performed better on cognitive tests and had less brain inflammation than mice without the hormone . These results suggest that irisin could have a therapeutic benefit in Alzheimer’s and other cognitive disorders.
Brain’s “cleaning system” declines during Alzheimer’s disease
The body has a system for clearing out damaged proteins from cells. But scientists found that this process declines in a mouse model of Alzheimer’s, growing worse as the disease advances. Encouragingly, an experimental drug developed by the team to boost this process reduced Alzheimer’s symptoms in these mice .
NINDS initiative harnesses the power of single-cell technologies
In 2021, NINDS launched a new basic research initiative for identifying cellular signatures of Alzheimer’s and related dementias , such as FTD and Lewy body dementia. The aim is to encourage researchers to use cutting-edge technologies to examine disease-associated changes at the level of a single cell. This could help them identify how the most vulnerable brain cells change in the earliest stages of these dementias, which could ultimately better guide the development of biomarkers and therapies for these conditions.