A new discovery, announced in a Nature Medicine paper published on November 4, 2019, offers insight into the mystery of Alzheimer’s Disease (AD). The specter of AD is one of the most frightening aspects of growing older. The gradual erosion and final disappearance of the mental activity that defines personhood is much worse than a sudden, violent death.

A tremendous amount of time, effort, and money have gone into researching possible treatments of this dread disease, with limited success. A new finding appears to illuminate a possible path forward. It is important to understand that there are two distinct types of AD, heredity and sporadic. The heredity version is relatively rare and typically manifests itself in men and women in their forties. It occurs in people who have a mutation in a gene called presenilin 1. The sporadic type, meaning that it could crop up unexpectedly in anyone, is much more common and generally arises decades later. There is a common genetic link between the two types, the APOE gene on chromosome 19. APOE is the principal cholesterol carrier in the brain.

APOE comes in three different forms, or alleles, APOE-ε2, APOE-ε3, and APOE-ε4. The differences between these three alleles are slight in terms of structure, but significant in terms of their effect on a person’s susceptibility to AD. It has been known for a long time that people with two copies of the APOE-ε4 allele are more likely to contract AD than are people with only one copy of the APOE-ε4 allele, who in turn are more likely to contract AD than are people with no copies of the APOE-ε4 allele, but instead some combination of the APOE-ε2 and the APOE-ε3 alleles.

The discovery described in the Nature Medicine paper comes from a decades long study of a family living in the vicinity of Medellin, Colombia. The family tree of this family contains over 6,000 members, many of whom suffer or have died from early-onset AD. It was thought that everyone who has the E280A mutation in the presenilin 1 gene was guaranteed to contract early-onset AD. This proved true in case after case, until a woman was discovered who had the mutation, but nevertheless remained cognitively normal into her seventies. After an exhaustive genetic study, it was found that the woman had two APOE-ε3 alleles that both had a very rare mutation called the Christchurch mutation. It was first discovered in a subject living in Christchurch, New Zealand. This Christchurch mutation, designated APOE-ε3ch, apparently protected the woman from early onset AD.

When post-mortem examinations are done on the brains of people who have died of AD, two characteristic pathologies are observed, beta amyloid plaques and tau tangles. Many treatments that eliminate beta amyloid plaques have been tried, but in over 200 clinical trials, none have slowed the progression of the disease. One astonishing finding from an MRI of the Medellin case is that she had far more plaques on her brain than did much younger people with severe cognitive impairment. This is the first indication that the plaques are not a cause of the disease, and that trying to eliminate them is probably a wasted effort.

The importance of this study is that now researchers can turn away from the fruitless pursuit of a treatment based on eliminating beta amyloid plaques and instead direct their efforts toward the study of the APOE gene and specifically what the Christchurch mutation does that seemingly negates the damage done by the E280A mutation of the presenilin 1 gene. There is good reason to hope that pursuing this line of investigation will help produce effective treatments not only for sufferers of the hereditary form of the disease, such as the Medellin family, but also the many more people who suffer from the sporadic form of the disease

Bio:

Allen G. Taylor is a 30-year veteran of the computer industry and the author of over 30 books, including Develop Microsoft HoloLens Apps Now, Get Fit with Apple Watch, Cruise for Free, SQL For Dummies, 8th Edition, Crystal Reports 2008 For Dummies, Database Development For Dummies, Access Power Programming with VBA, and SQL All-In-One For Dummies, Second Edition. He lectures internationally on astronomy, databases, innovation, and entrepreneurship. He also teaches database development and Crystal Reports through a leading online education provider. For the latest news on Allen’s activities, check out his blog at www.allengtaylor.com or contact him at allen.taylor@ieee.org.