Researchers unravel the genetic contributions to familial Alzheimer’s disease development

A group of researchers in the prof. Lucía Chávez Gutiérrez (VIB-KU Leuven) have unraveled the genetic contributions to family Alzheimer’s disease development and revealed how specific mutations work as a clock to predict the disease of the disease. These insights, published in Molecular neurodegenerationClinicians can help improve early diagnosis and adjust treatment strategies.

Alzheimer’s disease remains one of the most challenging and common neurodegenerative disorders that affects 50 million people worldwide. To date, the exact cause of the disease is still not fully understood. One of the most important visible characteristics in the brain of people with Alzheimer’s disease is the presence of amyloid plaques. These plaques are formed in the neurons and consist of lumps of incorrectly folded amyloid-β (AP, pronounced as ‘a-beta’) fragments. These fragments are produced by an advanced molecular processing system orchestrated by the γ-secretase enzyme and various important proteins.

Family Alzheimer’s disease is a rare, early type of Alzheimer’s disease caused by mutations involved in this system: amyloid precursor protein (app), Preseniline 1 (Psen1) or Preseniline 2 (Psen2). Their exact role in the disease is not well understood and has been discussed by scientists for several decades. Insight into more about the relationship between specific types of mutations and the age of the beginning for the disease of family Alzheimer’s can be useful for doctors to make more accurate clinical diagnoses.

“In family Alzheimer’s disease, patients are often seen that they have spontaneous genetic mutations, but so far doctors are unable to give patients more specific information about them,” explains Prof. Lucía Chávez Gutiérrez. “We have developed a method to experimentally test how likely a mutation is to cause the disease, and to predict the start of the disease.”

Mutations that behave like ticking clocks

The Laboratory of Prof. Lucía Chávez Gutiérrez at the VIB-KU Leuven Center for Brain & Disease Research has recently shown that mutations in PSSen1 are strongly correlation with the age of the start for Alzheimer’s disease. Now they performed the same analysis for mutations in all three causal genes: Psen1, Psen2 and App. They found very clear correlations between specific mutations and the age of the beginning for the disease of Family Alzheimer’s.

When we put together all our data, it gives us a much clearer picture of how each of the causal genes contributes to the development of the family Alzheimer’s disease – we can measure the exact contribution of each gene and even predict when the first symptoms will appear. “

Sara Gutiérrez Fernández, first author of the study

Alzheimer’s genes: a countdown to beginning

For a long time, scientists have understood that the accumulation of longer AP peptides in the brain can be involved in activating the molecular and cellular programs that lead to Alzheimer’s disease. Recent studies, including research from Prof. Lucía Chávez Gutiérrez, have demonstrated a strong link between the share of long-to-chest AP-Peptides and the pathogenesis of Alzheimer’s disease.

In this study, researchers saw direct and linear relationships between the share of long-to-korter AP fragments and the age of the start of the disease. These parallel relationships shifted over genes, which suggests the presence of a common pathogen mechanism with gene -specific start times.

“Our data predicts that a shift of 12% in the AP profile could delay the age of the start in the disease of Family Alzheimer’s with a maximum of 5 years,” says Prof. Lucía Chávez Gutiérrez. “This emphasizes the potential of therapies that focus on γ-secretasis in the brain to create shorter forms of AP and in turn postpone or prevent the start of the disease.”

From genes to personalized medicine: strategies for early diagnosis and treatment at Familiale Alzheimer

In addition to exposing important disease mechanisms, the researchers also developed a framework that serves two usable functions for genetic research. Firstly, it can be assessed how capable a genetic variant is to cause family Alzheimer’s disease. Secondly, it can help to identify people who wear genetic modificators or who are exposed to other environmental factors that influence the expected age of the beginning of dementia.

This dual-role framework improves the ability of researchers to interpret genetic data and to understand the complex interplay of factors that influence the disease progression of family Alzheimer’s. Not only that, but it also supports new roads for therapeutic interventions in family Alzheimer’s, and possibly in more common forms of the disease.

“We have developed a predictive model for the age of the beginning that the road could pave for personalized approaches for the management of Family Alzheimer’s,” the Sara Gutiérrez Fernández shares. “In the future, this can help clinics to design more effectively strategies for early diagnosis and treatment for patients with genetic forms of the disease. Our lab is now aimed at doing more research with the aim of developing therapies using this model.”