In 2012, Genentech, the Banner Alzheimer's Institute and the National Institutes of Health partnered on and initiated the first-ever study of cognitively healthy individuals who are likely to develop Alzheimer's disease due to their genetic history.
The landmark trial is the first to assess the potential of an investigational medicine to stop Alzheimer's before it starts and is the cornerstone of an international collaborative, the Alzheimer's Prevention Initiative (API), formed to accelerate the evaluation of promising, but unproven prevention therapies. The study involves a humanized monoclonal antibody, which is designed to bind to amyloid beta (Aβ), the main constituent of amyloid plaques in the brains of patients with Alzheimer's disease. Aβ is proposed to be causative in the development of the disease.
The amyloid hypothesis proposes that the accumulation of toxic Aβ in plaques are one of the key factors leading to Alzheimer's disease. By the time significant cognitive impairment starts to occur, patients already have a lot of amyloid plaque and their neurological function has begun to deteriorate.
This trial represents a significant shift in Alzheimer's disease research. Rather than trying to reverse existing damage, this trial is testing an early prevention approach — attempting to control the accumulation of Aβ in plaques decades or more before symptoms surface. If successful, this approach may allow earlier evaluation of promising medicines.
A Unique Patient Population
The prevention trial may provide the most effective test to date of the amyloid hypothesis. Two groups of patients, totaling as many as 324 people, will be involved in the study. About 300 live in the Antioquia region of Colombia, which includes the city of Medellín and is home to nearly 5,000 people who share the risk for a rare genetic mutation. This mutation, presenilin 1 (PSEN1), causes early-onset Alzheimer's in any individual who is a carrier. It was first identified in 1995.
The patient population in Colombia offers a truly unique opportunity because of its size, its shared genetic background and its long legacy with Alzheimer's. Indeed, no other location in the world offers a sufficiently large number of mutation carriers close to their age of potential disease onset for a study to determine whether a prevention treatment may work. This large, extended family has as many as 5,000 living members, many of whose own families have been devastated by the disease. The New York Times has covered the story of this family extensively (see here and here).
Just over 100 participants are mutation carriers who will receive the investigational treatment, while a proportional number of mutation carriers will receive a placebo. Because most of those involved do not want to know their genetic status, just over 100 participants are non-carriers who, since they have no risk for developing the disease at an early age, will only receive the placebo. Participants in the trial are 30 or older and within 15 years of the age when their parent's symptoms began (the age of clinical onset). Typically, mild cognitive impairment due to Alzheimer's begins in these Colombian families around 45.
A small portion of the participants in the trial are also located in the United States. Nearly two-dozen individuals in the US are also at high risk for the disease because their family history suggests other, similar genetic mutations are implicated in early-onset Alzheimer's.
Because of the potential impact, Genentech has agreed to share data and findings with the entire research community after the trial is completed in 2022. This transparency could help further advance Alzheimer's research and encourage investigation of additional disease biomarkers. Furthermore, the findings may lead to similar studies in people at risk for the disease later in life.