Amyloid and Alzheimer’s
By R. Scott Turner, PhD, MD
Abeta/amyloid protein is produced by all cells and tissues in the body, throughout life, as a product of normal turnover and breakdown (specifically of the amyloid precursor protein, or APP). Production and turnover of APP occurs within in a matter of hours, but clearance from the brain slows with aging. The Abeta fragment of APP can change its shape to become less soluble (similar to egg white protein becoming less soluble with cooking) to form amyloid. As it changes shape it also aggregates – ultimately growing into the large amyloid clumps (plaques) scattered in brain tissue and visible under the microscope. The process is similar to water molecules in the air aggregating to form clouds or fog and then raindrops. Amyloid plaques in brain are a defining pathology of AD. The paper in question reports that a specific aggregate (14 Abeta/amyloid molecules, or Abeta*56) is the toxic culprit in AD. Other investigators were immediately skeptical when they failed to reproduce this finding.
The amyloid hypothesis of AD does not rest on the results of a single paper, investigator, or laboratory. The hypothesis is supported by thousands of scientific publications, with reproducible results generated by independent laboratories and researchers. In general, a new concept or hypothesis only becomes accepted by the scientific community as a consensus develops from multiple independent sources. This is the scientific process in action, which also includes occasionally uncovering fraudulent data. A hypothesis or theory is never truly proven, but only supported (or not) by new information, and can certainly be disproven in favor of an alternate competing hypothesis. The rationale for testing anti-amyloid therapies for the treatment and prevention of AD remains solid. However, we also know that amyloid is necessary but not sufficient to cause dementia and AD. For example, amyloid is recognized by the immune system as a novel “foreign” protein – thus triggering inflammatory responses. Competing hypotheses of AD must be vigorously tested in parallel, and combination treatments may be essential.
The amyloid hypothesis of AD remains just that – a hypothesis. If and when anti-amyloid therapies have proven clinical benefits in humans, the hypothesis will be supported. There is no doubt that anti-amyloid antibodies remove amyloid from the brain and this appears to have beneficial effects in downstream pathologies. We await the results of anti-amyloid and other clinical trials in progress – with readouts on clinical efficacy in the next few months and years.
Truth will out (The Merchant of Venice).