Alzheimer's disease accounts for the majority of dementia cases among older adults. Dementia is where - due to progressive changes in the brain - a person's capacity to think, remember, and reason gradually diminish. At first, the symptoms of dementia are mild and hardly affect daily functioning, but eventually they become so severe that the person cannot live an independent life and must rely on others for help with their most basic daily tasks. Today, there are over 46 million people living with dementia worldwide. Without successful treatment or intervention, this number is expected to rise to 131.5 million by 2050.
People who develop Alzheimer's usually first experience symptoms in their mid-60s, although there are forms of the disease where they appear earlier.
While estimates vary, experts suggest there are over 5 million people in the United States living with Alzheimer's disease.
Need for preclinical stage diagnosis
Scientists are still trying to understand the complex changes that take place in the brains of people who develop Alzheimer's disease. However, it seems likely that these start at least 10 years before memory and thinking problems begin.
During this preclinical stage - when people seem to have no symptoms - abnormal deposits of amyloid beta and tau proteins are forming plaques and tangles throughout the brain. Eventually, these clog up brain cells to the point where they stop working, lose connections with each other, and die.
In their study report, the authors explain that the failure of drug trials to reverse clinical symptoms of Alzheimer's disease suggests that for treatment to be effective, it must start during the preclinical stage.
"Therefore, there is an urgent need to identify and validate biomarkers that are present at preclinical stages," they note.
Their study concerns a new compound called Fluselenamyl, which appears to detect amyloid beta protein plaques better than currently approved compounds.
The researchers believe attaching a radioactive atom to the compound would allow its location in a living brain to be tracked in positron emission tomography (PET) scans.
Senior author Vijay Sharma, a professor of radiology, of neurology, and of biomedical engineering, says :
"Fluselenamyl is both more sensitive and likely more specific than current agents."
Detecting diffuse amyloid beta plaques
Amyloid plaques can be either diffuse or compact, say the researchers. The compact form has long been linked to Alzheimer's disease, but there is a belief that diffuse plaques are not a sign of disease because they are found in the brains of people with and without Alzheimer's disease.
However, Prof. Sharma believes that diffuse amyloid plaques may mark the earliest stage of Alzheimer's disease. He notes:
"It is a relatively underexplored area in the development of Alzheimer's pathology. Since current approved agents don't detect diffuse plaques, there is no reliable noninvasive imaging tool to investigate this aspect in animal models or in patients. Our compound could be used to study the role of diffuse plaques."
In their study, he and his colleagues found Fluselenamyl bound to human amyloid beta proteins 2-10 times more effectively than three other imaging agents approved by the Food and Drug Administration for the detection of amyloid beta protein.
This means the compound is more likely to detect the early brain changes associated with Alzheimer's disease, because it shows ability to detect smaller clumps of amyloid beta.
The researchers also carried out further tests. In one, they used the compound to stain brain slices from patients who had died of Alzheimer's disease and also of age-matched patients who had died of other causes (controls) and did not have the disease.
The team found Fluselenamyl correctly identified plaques in the brain slices of the Alzheimer's patients but not the controls.
'No indiscriminate binding' to white matter
In another test, the researchers inserted a radioactive atom into Fluselenamyl and showed there was very little interaction between the compound and healthy white matter in the human brain slices.
Prof. Sharma explains this is a big advantage, because a significant drawback of the approved compounds currently in use is that they tend to bind "indiscriminately" to white matter and generate false positives on scans.
In a further experiment, the team used the compound to compare mice engineered to develop amyloid beta plaques with normal mice. They found Fluselenamyl showed the same high sensitivity for amyloid beta plaques and low binding to healthy white brain matter.
Also, when they injected radioactively-tagged Fluselenamyl into the diseased mice, the researchers found it crossed the blood-brain barrier, bound to amyloid beta plaques, and lit up in PET scans. But in mice without the plaques, the compound was rapidly flushed from the brain and excreted.
The team is now planning to test the compound in human patients and has already submitted an application for a trial to test its safety.
In the long term, the researchers envisage Fluselenamyl being used as part of screening for people at risk for developing Alzheimer's disease.