by: Sarah Sharman, PhD, Science writer

Alzheimer’s disease and other dementias are progressive neurodegenerative diseases that slowly rob affected individuals of their memory, personality, and, eventually, their life. As devastating as these diseases are anywhere, members of a family in Antioquia, Colombia, suffer from a particularly cruel version that strikes them in their mid-40s and results in death within 10 to 12 years. Several decades ago, a neurologist named Francisco Lopera began studying the family because of their high incidence of very early-onset Alzheimer’s disease. Lopera and colleagues discovered that the large Colombian family carries a specific mutation in a gene called presenilin 1 (PSEN1). Having the PSEN1 E280A mutation, as it is called, ensures with certainty that an individual will eventually develop a type of Alzheimer’s disease called autosomal dominant Alzheimer’s disease.

Lopera and other colleagues have enrolled more than 6,000 individuals from 26 extended families in the study. The dementia field is learning a lot about the cause and progression of Alzheimer’s disease from this family. In return, they received an answer to their decades-long question about why so many family members were suffering from, and ultimately dying from, the devastating disease. HudsonAlpha Institute for Biotechnology Faculty Investigators Nick Cochran, PhD, and his lab were part of a recent study that dove deeper into the individuals’ genomes and identified new potential gene variants linked to Alzheimer’s disease.

Globally, Alzheimer’s disease and other dementias affect about 55 million people. That number is expected to reach 139 million by 2050, making the need for better targets for diagnostics and treatments critical.

Most members of the Colombian family with PSEN1 E280A mutations predictably develop autosomal dominant Alzheimer’s disease in their 40s; however, some individuals do not report symptoms until nearly three decades later. The predictable age of onset and existence of rare outliers provides researchers a valuable opportunity to study genetic variation linked to the age of Alzheimer’s onset. This information could help scientists create better diagnostic tools to identify individuals with Alzheimer’s disease before symptoms are present, affording them the chance to try early interventions.

“Understanding the genetic contributors to Alzheimer’s disease is imperative for developing new approaches to diagnose and treat the disease. In this study, we contribute to understanding how underlying genetics associate with age of onset in individuals with dominant Alzheimer’s. We believe this is an important advance, but also that we should do everything that we can to help shine a light on every possible contributor to disease for these individuals that have taught the Alzheimer’s research community so much through their generous involvement in research over many years,” says Cochran.

The results of the largest study to date looking at genetic modifiers of the age of onset of dementia were recently published in Alzheimer’s & Dementia: The Journal of the Alzheimer’s Association. Cochran, along with collaborators from HudsonAlpha, the University of California, Santa Barbara, University of Miami, Columbia University, Universidad de Antioquia, Icahn School of Medicine at Mt. Sinai, and Washington University in St. Louis, analyzed the genomes of 340 individuals from the Antioquia family as well as similar families from other studies to gain insight into the genetic landscape of age of disease onset.

The team identified several gene candidates likely involved in Alzheimer’s disease’s age of onset. The gene candidates were part of biological processes and pathways that could be responsible for Alzheimer’s disease pathology. One promising hit was a new variant near the gene CLU, previously implicated as a genetic risk factor for late-onset Alzheimer’s disease, and two other top candidate variants also might affect CLU-related biology. Two variants the group identified were related to heparin sulfate, which has been implicated in the cell-to-cell spread of tau protein. In Alzheimer’s patients, tau protein builds up in brain cells, leading to cell damage and death. Amyloid-beta is another protein that wreaks havoc in Alzheimer’s disease brain, and the research team identified variants in genes associated with amyloid processing.

“While this is the largest study of genetic contributors to dominant Alzheimer’s ever conducted, the study is still small in the world of genetics. For that reason, we are hopeful that the scientific community will follow up on these findings with additional functional studies so that we can better understand the biological consequences of our findings,” says Cochran.

Cochran also indicated that recruiting more patients with early-onset dementias from South American countries, an active ongoing effort, will help overcome this limitation in future studies.