With one of the largest segments of the U.S. population rapidly advancing into their golden years, the continued study of age-related neuropathies, such as Alzheimer’s diseases (AD) has become paramount. Importantly, the greatest risk factor for AD is advancing age, as the incidence rate doubles every 5 years after age 65. Moreover, 40% of people 85 and older are estimated to be living with AD.
Now, researchers from the Washington University School of Medicine in St. Louis have been able to identify some important changes within aging brains that they believe contributes significantly to the increased risk of developing AD. The changes are focused around a peptide named amyloid beta 42 (Aβ42), the main constituent of AD brain plaques.
“We found that people in their 30s typically take about four hours to clear half the Aβ42 from the brain,” explained senior author Randall Bateman, M.D., professor of neurology at Washington University. “In this new study, we show that at over 80 years old, it takes more than 10 hours.”
The findings from this study were published recently in the Annals of Neurology through an article entitled “Age and amyloid effects on human central nervous system amyloid-beta kinetics.”
Typically, Aβ42 is a natural byproduct of brain activity and is normally cleared from the brain before it can clump together into plaques. However, scientists have long suspected it is a primary driver of the disease. The slowdown in clearance results in escalating levels of Aβ42 within the brain. Higher levels of the protein increase the chances that it will clump together to form Alzheimer's plaques.
For the current study, investigators tested 112 volunteers ages 60 to 87. Half of whom had clinical signs of Alzheimer's disease, such as memory problems. Plaques had begun to form in the brains of 62 participants. The volunteers were given detailed mental and physical evaluations, including brain scans to check for the presence of plaques. The researchers also studied participants' cerebrospinal fluids using a technology known as stable isotope-linked kinetics (SILK)—allowing researchers to monitor the production and clearance of Aβ42.
“The findings reveal a mechanistic link between human aging and the risk of amyloidosis, which may be owing to a dramatic slowing of Aβ turnover, increasing the likelihood of protein misfolding that leads to deposition,” stated the scientists. “More generally, this study provides an example of how changes in protein turnover kinetics can be used to detect physiological and pathophysiological changes and may be applicable to other proteinopathies.”
Reduced rates of clearance for Aβ42, as seen in older participants, were associated with more clinical symptoms of AD, such as memory loss, dementia, and personality changes. The researchers believe that the brain disposes of amyloid beta through one of four routes: moving into the cerebrospinal fluid, shuttling it across the blood-brain barrier, degrading or absorbing the protein, or most notably for AD, depositing it into plaques.
“Through additional studies like this, we're hoping to identify which of the first three channels for amyloid beta disposal are slowing down as the brain ages,” Dr. Bateman noted. “That may help us in our efforts to develop new treatments.”