About the 100-plus study

Currently, there is no cure that prevents or slows down dementia development. Results from clinical trials with drugs designed to inhibit the key player in Alzheimer biology, the amyloid protein, have been extremely disappointing. Even to the extent that many in the research community have begun to doubt the widely accepted ‘amyloid hypothesis’. This opens the door for a radically different approach to confront the biology underlying Alzheimer development.

A successful cure should intervene in aberrant biochemical mechanisms that lead to cognitive decline. Detection of aberrant processes requires the knowledge of the biochemical mechanisms underlying long term retained cognitive health.

Why do some people develop dementia symptoms at the age of 70 and why do others become old with great mental health?
Mrs. Hendrikje van Andel-Schipper reached the age of 115 years and became the oldest woman in the world, with a sharp mind until the end of her life. Examination of her brain tissue after death revealed no signs of decline, demonstrating that it is possible to become extremely old without the devastating effects of dementia. Interestingly, Mrs. van Andel’s mother died at 100 years of age, also without any signs of dementia. Indeed, the combination of cognitive health and extreme old age often occurs within families, suggesting that heredity plays an important role in protection against dementia. Therefore, the key to detect elements that protect against AD may be found in the genome. What genetic ‘secret’ do these extraordinary people carry with them, and what can we learn from this?

Recently, one such protective genomic element was detected in the amyloid precursor protein (APP) in the Icelandic population: carriers of this rare allele have a reduced risk to develop AD. Presumably, this APP variant is not the only variant that protects against AD, as this variant has so far not been detected in other populations. We believe that the genomes of the growing group of cognitively healthy centenarians (100+) could provide key information to identify such protective factors.

Genetic profiles that can differentiate between genomes from cognitively healthy persons and AD patients may aid with the identification of persons at risk to develop AD and those genetically protected. More importantly, the identification of the molecular processes that are differently expressed in brain tissues from individuals with retained vs. declining cognitive health may yield druggable targets for the design of synthetic interventions. Together, this may allow us to synthetically improve performance of these pathways that may ultimately lead to prevention of AD onset altogether.

The 100-plus study
To identify these protective genetic factors we designed the 100-plus study in which we will (i) establish a cohort of 500 - 1000 DNA samples and matching brain tissues of cognitively healthy centenarians and their close relatives; (ii) analysis of these valuable genomes, and (iii) validate candidate protective factors in donated centenarian brain tissues. This unique cohort of DNA and brain tissues will allow us to detect genomic variants that are unique for cognitively healthy centenarians but that do not occur in genomes of patients suffering from Alzheimer Disease. To make this project succeed we have united expertise in all relevant areas by setting up collaborations with the VU University Medical Center Alzheimer Center, the Department of Clinical Genetics of the VUmc, the Delft Bioinformatics Lab of the TU Delft and the Netherlands Brain Bank.