Fight Aging!

It took many years of development and trials for immunotherapies targeting amyloid-β aggregation to successfully clear large amounts of these misfolded protein deposits from the brain. Unfortunately, it appears that this has very little effect on patient outcomes in Alzheimer's disease. It is possible that amyloid-β, while damaging, is only relevant in the early stages of the condition, and becomes unimportant once a feedback loop of inflammation and tau aggregation is underway. Equally, amyloid-β aggregation may turn out to be largely a side-effect of persistent infection or metabolic disruption, while the core disease processes are inflammation and vascular dysfunction. Removal of amyloid-β seems like something that should be accomplished in older people, as there is little debate over its ability to cause mild cognitive impairment, but that is a different topic from its relevance to Alzheimer's disease.

The DIAN-TU study evaluated the effects of two investigational drugs - gantenerumab and solanezumab - in people with a rare, inherited, early-onset form of Alzheimer's known as dominantly inherited Alzheimer's disease or autosomal dominant Alzheimer's disease. Such people are born with a mutation that causes Alzheimer's, and experience declines in memory and thinking skills starting as early as their 30s or 40s.

Over the past few decades, scientists have pieced together the changes that occur as Alzheimer's develops, a process that takes 20 years or more. First, the protein amyloid beta starts forming plaques in the brain. Later, levels of tau and neurofilament light chain rise in the cerebrospinal fluid that surrounds the brain and spinal cord, and the brain begins to shrink. Then, tangles of tau protein form in the brain. Only then do people with the disease start exhibiting signs of memory loss and confusion.

In this study, 52 patients were randomized to gantenerumab, which led to a reduction in the amount of amyloid plaques in the brain, and lowered soluble tau and phospho-tau, and slowed the rise of neurofilament light chain levels in the cerebrospinal fluid. Neurofilament light chain is a marker that reflects neurodegeneration. Overall, gantenerumab's safety profile in this trial was consistent with that from other clinical trials of the investigational medicine, and no new safety issues were identified.

The primary endpoint of the DIAN-TU study was the prevention or slowing of cognitive decline in people who are nearly certain to develop Alzheimer's due to genetic mutations. Neither drug met the primary endpoint, although the study wasn't able to determine effects on thinking and memory in participants who entered the study without symptoms, because they exhibited little to no decline in cognitive function. However, as a secondary endpoint, the study also evaluated the effect of the drugs on molecular and cellular signs of Alzheimer's disease. On these measures, gantenerumab showed potential benefit.

Link: https://medicine.wustl.edu/news/investigational-alzheimers-drug-improves-biomarkers-of-the-disease/