Alzheimer’s Disease Update
Scientific evidence increasingly points to brain inflammation as a major driver of Alzheimer’s disease (AD). Researchers have discovered that amyloid, one of the hallmarks of the disease, is antimicrobial and may help the immune system fight invaders to the brain. They theorize that accumulating amyloid plaques and tau tangles in response to infection set the stage and spur persistent neuroinflammation, which eventually kills enough neurons to cause dementia. This understanding of AD has recently been reinforced by discoveries from the International Genomic Alzheimer’s Disease Project. Results published in Nature Genetics validate the role of amyloid and certain immune system genes in the development of AD and identify additional gene variants associated with innate immunity and susceptibility to neuroinflammation as potentially linked to AD. The researchers also found several groups of genes that appeared to increase the risk of developing AD by working together through different disease pathways.
Further adding to the hypothesis of a connection between infection and AD risk has been the discovery of a possible link between gum disease and AD. Porphygromonas gingivalis bacteria, a cause of gingivitis, were found in the brains of people who died with AD, along with toxic proteins produced by the bacteria that are believed to disrupt tau proteins. Studies in mice have shown that the bacteria were able to trigger an AD-like condition, and drugs that blocked the bacteria’s effects protected the mouse neurons.
Another area of intense research is around AD diagnostics. The development of an easy-to-use test that can identify people at high risk of AD before symptoms appear has also been a long-sought goal. Such a test is urgently needed by drug developers who are seeking to conduct clinical studies at earlier stages of the disease. However, until now, all attempts to develop such test have failed. Now, several research groups have identified blood-based tests that might be used to identify presymptomatic individuals for clinical trials.
A team from Europe and Australia recently reported in Science Advances a potential panel of 10 blood markers that might be used as a means of identifying such early stage AD patients. They took blood from 144 cognitively healthy people in an Australian study of aging, all of whom had undergone PET imaging for brain amyloid (100 negative, 44 positive). They then used mass spectrometry to identify 560 proteins whose levels differed between the amyloid negative and amyloid positive groups, and whittled that number down to the most significant 10 proteins. The researchers then added the patients’ age and ApoE4 gene status to their analysis and validated the 12-item assessment in 94 participants in a U.K. study of aging. They found the blood panel was able to identify cognitively healthy patients with sufficient amyloid deposition to be classified as preclinical AD with an overall accuracy of 89%. The positive predictive value for the test was 85% and negative predictive value was 68%.
A second team from IBM Australia used machine learning to pinpoint four proteins found in the blood of pre-symptomatic people with the ApoEξ4 gene, which confers a high risk of AD. They discovered that these proteins can predict the build-up of amyloid-β in spinal fluid, somethings that occurs up to 10 years before PET imaging can show it’s build up in the brain, with 77% accuracy.
While neither blood test has predictive values sufficiently high for use in clinical diagnosis, either blood panel could have significant utility as a way to stratify patients for clinical trials of new drugs,