Exploring How the Hallmarks of Aging Contribute To Dementia

Researchers recognize a set of “hallmarks of aging” as important molecular, cellular, and systemic contributors to aging and age-related diseases, including Alzheimer’s. Understanding the hallmarks of aging, and how they interact across the lifespan and in response to stressors and other factors, is critical to better understanding of the causes and progression of these diseases and informing further research, including identifying potential targets to inform preclinical efforts.

Understanding hallmarks in disease pathways

NIH-funded research has advanced our understanding of the roles of these hallmarks in disease pathways that play critical roles in dementia-related neurodegeneration, identifying new pathways for further exploration.

Senescence

Cellular senescence is a process in which cells lose normal function, including the ability to divide and replicate, but continue to release molecules that may damage neighboring cells. Senescence has been implicated in Alzheimer’s, with one NIH-funded study finding that more neurons have markers of senescence in brains with Alzheimer’s compared to brains without the disease.

Genomic instability

An NIH-funded study showed that the accumulation of DNA damage in neurons leads to changes in how the genome is arranged and impacts genes related to connections between neurons, which could contribute to neurodegeneration in Alzheimer’s.

Changes in gene expression

NIH-funded researchers explored the differences in gene activity between brains with and without Alzheimer’s. Using brain samples from people with Alzheimer’s, the researchers found altered activity in genes involved in various functions , including clearance of beta-amyloid, a hallmark of Alzheimer’s, and immune function, among others. They were able to link some of these changes to Alzheimer’s-associated genetic variants such as APOE4, indicating potential therapeutic targets.

Dysfunction of mitochondria

Mitochondria produce most of the energy that cells use to function. However, mitochondrial function declines with aging. NIH-funded researchers found that lower mitochondrial function in human skeletal muscle increases the risk of mild cognitive impairment and dementia and can also increase brain amyloid and blood proteins associated with brain inflammation. The findings suggest that age-related mitochondrial dysfunction may contribute to the development of Alzheimer’s and that strategies to improve mitochondrial function in muscle may be beneficial for brain health.

Microbiome changes

NIH-funded researchers found that changes in the human gut microbiome precede Alzheimer’s cognitive decline . Study participants with preclinical Alzheimer’s had markedly different communities of gut bacteria than those without preclinical Alzheimer’s. The team also found that these microbiome changes were correlated with amyloid and tau levels in the brain. Researchers are now conducting a follow-up study to better understand whether the differences observed in the gut microbiome are a cause or consequence of the brain changes seen in Alzheimer’s.

Spotlight: The role of immune dysfunction in Alzheimer’s and related dementias

Research suggests that dysfunction of the immune system plays an important role in the development of Alzheimer’s and related dementias, including the buildup of amyloid plaques and tau tangles in the brain. NIH funds research to better understand how immune system dysfunction may be involved in the disease processes and identify new disease pathways for further studies to discover potential therapeutic targets.

  • Researchers compared brain tissues from people with and without Alzheimer’s and found changes in the activity of many genes with known links to the disease in the prefrontal cortex of the brain. These changes most often occurred in microglia, immune cells that engulf and clear waste, including beta-amyloid.
  • Another study showed that more microglia enter an inflammatory state in the Alzheimer’s brain compared to a healthy human brain. The findings suggest a role for microglia and inflammation in the development of Alzheimer’s.
  • A study in a mouse model of high blood pressure suggests that immune cells around and within the brain become abnormally activated under conditions that mimic a common form of high blood pressure. This activation leads to impaired brain function. These findings underscore the importance of managing high blood pressure to reduce the risk of cognitive impairment.

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