Fight Aging!

The dominant view of Alzheimer's disease remains the amyloid cascade hypothesis: amyloid-β accumulates over time in the brain, which generates immune dysfunction, inflammation, and finally tau aggregation that kills large numbers of brain cells. After a great deal of work and expense, the research and development community has produced a number of immunotherapies capable of reducing levels of amyloid-β in the brain. Unfortunately, these treatments don't appear to do all that much to improve the symptoms of Alzheimer's disease in patients. There is certainly no clear and evident gain in function across the board, and even where clinical trial data is sliced finely to try to uncover a subpopulation in which benefits do occur, these benefits are not large.

One hypothesis on this lack of efficacy is that only early intervention will work, given that Alzheimer's develops over years of growing levels of amyloid-β, while in the later stages it is the case that chronic inflammation and tau aggregation become the driving mechanisms causing neurological dysfunction and cell death. An alternative hypothesis is that amyloid-β aggregation is a side-effect, of little importance to outcomes, while some combination of persistent infection, cellular senescence, and chronic inflammation are the primary mechanisms of Alzheimer's disease.

Given therapies that can reduce amyloid-β levels in the brain, and given a huge sunk cost to date in targeting amyloid-β, it is certainly the case that the early intervention hypothesis is going to be tested aggressively. Big Pharma entities are in search of some way to recoup the costs incurred to date, by demonstrating a beneficial use for these treatments. Today's research materials are one illustrative example selected from a broad range of efforts to find viable points of intervention in the very early development of Alzheimer's disease, with an eye to preventing the condition from progressing.

The Long Road to Dementia

Alzheimer's disease develops over decades. It begins with a fatal chain reaction in which masses of misfolded beta-amyloid proteins are produced that in the end literally flood the brain. Researchers have found that this chain reaction starts much earlier in mice than commonly assumed. This means that in addition to the well-known early phase of the disease with protein deposits but without symptoms of dementia, there is an even earlier phase in which the chain reaction is triggered by invisible tiny seeds of aggregation.

searched among the already known antibodies directed against misfolded beta-amyloid proteins for antibodies that can recognize and possibly also eliminate these early seeds of aggregation that currently escape biochemical detection. Of the six antibodies investigated, only aducanumab had an effect: Transgenic mice that were treated for only 5 days before the first protein deposits manifested, later on in life showed only half of the usual amount of deposits in their brains. "This acute antibody treatment obviously removes seeds of aggregation, and the generation of new seeds takes quite some time, so that much less deposits are formed in the weeks and months after the treatment. Indeed, the mice had only half the brain damage six months after this acute treatment."

Acute targeting of pre-amyloid seeds in transgenic mice reduces Alzheimer-like pathology later in life

Amyloid-β (Aβ) deposits are a relatively late consequence of Aβ aggregation in Alzheimer's disease. When pathogenic Aβ seeds begin to form, propagate and spread is not known, nor are they biochemically defined. We tested various antibodies for their ability to neutralize Aβ seeds before Aβ deposition becomes detectable in Aβ precursor protein-transgenic mice. We also characterized the different antibody recognition profiles using immunoprecipitation of size-fractionated, native, mouse and human brain-derived Aβ assemblies. At least one antibody, aducanumab, after acute administration at the pre-amyloid stage, led to a significant reduction of Aβ deposition and downstream pathologies 6 months later. This demonstrates that therapeutically targetable pathogenic Aβ seeds already exist during the lag phase of protein aggregation in the brain. Thus, the preclinical phase of Alzheimer's disease - currently defined as Aβ deposition without clinical symptoms - may be a relatively late manifestation of a much earlier pathogenic seed formation and propagation that currently escapes detection in vivo.