Alzheimer's disease is associated with the growing presence of solid deposits of misfolded amyloid-β and altered tau protein in the brain. A halo of complex and much debated biochemistry connects these forms of metabolic waste with the dysfunction and death of neurons; it isn't the amyloid or the tau itself, but related molecules and their interactions that cause pathology, arising as a result of the existence of the amyloid and tau. Clearing these unwanted proteins should help to turn back the progression of Alzheimer's, a goal complicated by the fact that many Alzheimer's patients also suffer from other forms of neurodegeneration, such as the vascular dementia that results from hypertension, blood vessel stiffness and structural failure, and many tiny zones of cell death caused by blood vessel failures over the years. Unfortunately in addition to these complications, safely clearing amyloid in the human brain has proven to be very challenging. Most efforts to date have used forms of immunotherapy, and only recently have good results emerged in human trials. The field of the past decade is littered with the remains of failed efforts. Clearance of tau has much further to go in order to arrive at the point of human trials, not having received the same level of attention and funding over the past decade. It is becoming apparent that it will also have to be removed from the brain, however.
Why do amyloid and tau aggregate in the aging brain? There are many competing theories. The brain, its immune system, and its surrounding support structures are enormously complex and only partially understood. In many ways the quest to understand Alzheimer's disease is one and the same with the quest to understand the brain as a whole. A cure for Alzheimer's is the goal that brings in funding for fundamental research into the mechanisms of thought, memory, and aging, as well as details of cellular behavior, inflammation and immunology in the brain, distinctly different and more complicated than elsewhere in the body. One interesting point regarding amyloid-β is that its levels in brain tissue and cerebrospinal fluid are very dynamic. It is constantly created and destroyed, and so the accumulation with age is not a matter of slow and steady creation, but rather results from the interaction and changing nature of numerous processes.
One class of theories seeking to explain increased amounts of amyloid-β with aging postulate a gradual failure in mechanisms of clearance, such as immune activity, since the immune system is responsible for removing many forms of unwanted metabolic waste, or filtration of cerebrospinal fluid by the choroid plexus. Alzheimer's becomes a tertiary consequence at the end of a chain of failures that starts with some form of age-related decline in the effectiveness of clearance of metabolic waste in the brain. Cerebrospinal fluid isn't just filtered, however. Small amounts continually drain away from the brain via a variety of small channels in the head, to be replaced by new fluid generated by the choroid plexus. In recent years some researchers have suggested that this drainage is an important mode of clearance for amyloid and tau, and that the necessary channels becomes impaired due to other forms of age-related damage and change. You might look at the efforts of Leucadia Therapeutics, for example, a startup company funded by the Methuselah Foundation, as they work to prove or disprove this mechanism as a cause of Alzheimer's disease. With that in mind, I noticed the following research today, in which the authors offer further evidence in support of the class of hypotheses that involve impaired cerebrospinal fluid drainage.
The new study examined aquaporin-4, a type of membrane protein in the brain. Using brains donated for scientific research, researchers discovered a correlation between the prevalence of aquaporin-4 among older people who did not suffer from Alzheimer's as compared to those who had the disease. Aquaporin-4 is a key part of a brain-wide network of channels, collectively known as the glymphatic system, that permits cerebral-spinal fluid from outside the brain to wash away proteins such as amyloid and tau that build up within the brain. These proteins tend to accumulate in the brains of some people suffering from Alzheimer's, which may play a role in destroying nerve cells in the brain over time.
The study closely examined 79 brains donated through the Oregon Brain Bank. They were separated into three groups: People younger than 60 without a history of neurological disease; people older than 60 with a history of Alzheimer's; and people older than 60 without Alzheimer's. Researchers found that in the brains of younger people and older people without Alzheimer's, the aquaporin-4 protein was well organized, lining the blood vessels of the brain. However within the brains of people with Alzheimer's, the aquaporin-4 protein appeared disorganized, which may reflect an inability of these brains to efficiently clear away wastes like amyloid beta. The study concluded that future research focusing on aquaporin-4 - either through its form or function - may ultimately lead to medication to treat or prevent Alzheimer's disease.
Since 2013, we have defined a brain wide perivascular pathway, termed the glymphatic system, that facilitates the recirculation of cerebrospinal fluid (CSF) through the brain parenchyma and supports the clearance of interstitial solutes including amyloid-β (Aβ) and tau. Perivascular exchange of CSF and interstitial fluid is dependent on the astroglial water channel aquaporin-4 (AQP4), which is localized to perivascular astrocytic endfeet that ensheathe the cerebral vasculature. We demonstrated that perivascular CSF recirculation and Aβ clearance are impaired in the aging mouse brain, impairment that was associated with the loss of perivascular AQP4 localization. Prior studies in postmortem human tissue show that AQP4 is up regulated and that localization of AQP4 to the cerebral vasculature is disrupted in the AD cortex. This suggests that age-related mislocalization of AQP4 may slow glymphatic function and promote protein aggregation and neurodegeneration.
In this study, we assessed AQP4 expression and perivascular localization in human brain samples including individuals of different ages and with different cognitive and neuropathological AD profiles. Expression of AQP4 was associated with advancing age among all individuals. Perivascular AQP4 localization was significantly associated with AD status independent of age and was preserved among eldest individuals older than 85 years of age who remained cognitively intact. When controlling for age, loss of perivascular AQP4 localization was associated with increased amyloid-β burden.