Four Immunotherapies Now Proven to Reduce Amyloid-β in the Aging Brain

Immunotherapies that target aggregation of amyloid-β in order to treat Alzheimer's disease have a long and expensive history of failure. The tide finally seems to be turning, however, with the advent of several treatments that can reduce amyloid-β levels without resulting in an unacceptable level of risk for the patients. This newfound incremental success is taking place at the same time as the years of frustration with the lack of progress have finally blossomed into a variety of alternative theories on the causes of Alzheimer's disease, such as blocked drainage of cerebrospinal fluid or persistent microbial infection, some of which have advanced to the point of development of therapies.

The challenge for amyloid-β clearance therapies is now to show benefits in patients, and there are good reasons to believe that this will be challenging in the late disease state. The present consensus on Alzheimer's disease is that amyloid-β accumulation is an early phase, damaging yes, but nowhere near as damaging as the tau aggregation that occurs later on. Further, Alzheimer's patients also tend to have other forms of neurodegeneration, such as vascular dementia, that are unlikely to be greatly affected by amyloid-β clearance. It is a challenging business: therapies for neurodegeneration will most likely have to tackle most or all of the important mechanisms in the aging brain in order to be reliably beneficial.

After years of fits and starts, anti-amyloid immunotherapies are finally hitting their target effectively. At least four drugs have now demonstrated the ability to clear plaques from the brain: aducanumab, gantenerumab, Lilly's LY3002813, and BAN2401. At the Alzheimer's Association International Conference, held in July, researchers presented new data from gantenerumab and LY3002813, aka N3pG. It clinched the case that these antibodies can mop up brain amyloid, bringing many people with early symptomatic Alzheimer's disease (AD) below the threshold for amyloid positivity. At one to two years, this clearance took a long time. But still: researchers claimed that two years of treatment with high-dose gantenerumab essentially resets a person's trajectory of amyloid accumulation. "We are setting back the clock by 15 years."

To achieve these rates of clearance, researchers have had to greatly boost antibody dose, in many cases quadrupling the amounts used in earlier, unsuccessful trials. These high doses bring a greater risk of infusion site reactions and ARIA-E, the occurrence of leaky blood vessels causing edema in the brain. Scientists argued that these side effects are manageable with careful monitoring of patients. Moreover, ARIA-E can be lessened by gradually titrating up the antibody dose. However, clinicians noted that the jury is still out on how much this will help AD patients. "Several of the antibodies are looking good at removing amyloid, but the clinical efficacy still needs to be demonstrated."



Is there any good candidates for tau clearance?

Posted by: Antonio at August 23rd, 2018 9:24 AM

Would tau clearance reverse damage, or just stop the progression of AD? In other words, once you have tau causing tangles, would clearing tau restore anything?

Posted by: Matthew at August 23rd, 2018 9:45 AM

If the further damage is truly stopped then the brain might recover or readjust, so it would still show some , albeit slow, improvement even

Posted by: Cuberat at August 23rd, 2018 12:03 PM

In Aubrey de Grey's August bi monthly review of Theses relevant to combating aging he highlighted a paper suggesting that perhaps amyloid beta plaques don't actually cause damage in Alzheimers, it is the fact that they rupture cellular endosomes that results in cell death. Getting an antiamyloid protease to the lysosomes via gene therapy may therefore deal with Alzheimers.

Posted by: Jim at August 24th, 2018 2:35 AM
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