A gigantic molecular map paves the way for curing Alzheimer's and Parkinson's.

Neurodegenerative diseases, such as Alzheimer's and Parkinson's, with 57 million people affected worldwide, are one of the greatest threats to public health in advanced countries, but early diagnosis is difficult and treatments are limited . After decades of research, their biology holds many mysteries. To accelerate understanding, the Global Neurodegeneration Proteomics Consortium ( GNPC ) was formed, an organization funded by public-private partnerships, government institutions, foundations, and pharmaceutical companies. Today, the consortium publishes the first results of a massive effort, presented in several studies appearing in the journals Nature Medicine and Nature Aging .

The consortium, to which 23 research groups from around the world have contributed data, is attempting to make sense of a vast amount of information obtained from more than 40,000 samples of fluids such as blood plasma and cerebrospinal fluid, with which they have been able to perform 250 million protein measurements. With all this data, they have created maps to compare protein abundance in various neurodegenerative diseases on a large scale in order to better define and combat them.

“The initial analyses conducted with the first version of this dataset have already yielded fundamental findings. They have shown that Alzheimer's, Parkinson's , and frontotemporal dementia share a number of common pathways related to immune response and inflammation. However, each disease also presents unique biological pathways that allow them to be distinguished from one another,” explained Carlos Cruchaga, a researcher at Washington University in St. Louis (USA) and one of the consortium leaders.

In Alzheimer's, for example, the prominent role of the ARPC2 protein, responsible for maintaining the shape and structure of neurons, has been observed, and in Parkinson's, distinct alterations in the immune response have been found. In this first phase of the work, proteins have also been found that change up to 20 years before the first symptoms appear, and proteomic profiles associated with healthy aging have been found that may help us understand what protects against neurodegeneration.

Analyses have also found links between the aging of various organs and neurodegenerative diseases. In the case of Alzheimer's and frontotemporal dementia, it was found that some people have brains that appear older than they should be and are at greater risk of developing the disease. In Parkinson's, a connection with muscle aging was also found, indicating that neurodegeneration is not only a brain phenomenon but is linked to general aging.

Blood protein analyses can also help understand the heterogeneity of these diseases. “There are people in whom, despite having amyloid protein in the brain, their disease does not progress, and others who do, and we don't know what accounts for this difference,” explains Marc Suárez-Calvet, a researcher at the Barcelona βeta Brain Research Center (BBRC) and co-author of one of the studies published today. “What we have seen with the preliminary data is that there are clear differences in the composition of blood proteins between people who progress and those who do not,” he says.

One of the studies also investigated the role of the APOE ε4 gene, traditionally associated with the risk of Alzheimer's, and found that it also plays an important role in other neurodegenerative diseases such as Parkinson's and Amyotrophic Lateral Sclerosis (ALS). Researchers identified a protein signature in the blood and cerebrospinal fluid of people with these conditions that is characterized by chronic activation of the immune system and elevated inflammation. This suggests that this gene not only increases the risk of Alzheimer's, but also presents a general biological vulnerability that, when combined with lifestyle factors, can trigger different types of neurodegenerative diseases.

In an effort to improve the diagnosis of these diseases, a signature of 256 proteins in blood plasma has been developed to assess the severity of dementia. The signature, which includes biomarkers related to neuroplasticity and immune system activation, suggests that, beyond clinical diagnoses, there are biological processes of cognitive decline in all of these diseases that can be measured objectively and noninvasively.

Among the results, there are some intriguing conclusions. One study showed that the blood-brain barrier, which protects the brain from harmful substances, becomes more permeable with age, allowing more proteins from the blood to pass into the brain. Interestingly, this permeability was greater in men, yet it is known that the risk of developing dementia is higher in women.

The work of the GNPC and the presentation of the initial data is just the beginning of a new era for research into these types of diseases. Although participants have had exclusive access to the data for a year, they will then be available to the entire scientific community for analysis. This large number of samples, obtained from large cohorts from different parts of the world, will make it easier to compare the results to ensure they are replicable and useful for patients. "This is a first description of what we have, but the most interesting part is yet to come," summarizes Suárez-Calvet. Early biomarkers for diagnosis, new targets for more effective drugs, and a precision medicine model tailored to the personal characteristics of each patient are some of the promises for a group of diseases with an increasingly significant burden.

Bill Gates, the driving force behind the consortium through his foundation, has written an opinion piece that accompanies the scientific articles published today in Nature journals, summarizing the spirit of the project: “We are closer than ever to the day when an Alzheimer's diagnosis will no longer be a death sentence, but only if we continue to support researchers and facilitate their collaboration.”