Horrifying: 91% of Known Biological Pathways Linked to Alzheimer’s

A comprehensive review of the scientific literature reveals that immunological, metabolic, and depression-related pathways are the most often reported disease mechanisms.

Alzheimer’s disease affects almost six million adults in the US, and by 2050, that figure is anticipated to double. Alzheimer’s disease, a complicated neurological condition that is already the sixth biggest cause of mortality, impairs people’s capacity to live independently by causing memory loss, confusion, poor judgment, depression, delusions, and agitation. There are currently few effective treatments and no known cure for Alzheimer’s disease since the biological mechanisms behind the condition are not well understood.

Researchers from Beth Israel Deaconess Medical Center (BIDMC) recently conducted a study to understand the breadth and diversity of biological pathways — important molecular chain reactions that trigger cell changes — that contribute to Alzheimer’s disease by research over the last 30 years. They did this by conducting a systematic assessment of more than 200,000 scientific publications.

The team discovered that despite significant technological advancements, the most frequently associated biological mechanisms, such as those related to the immune system, metabolism, and long-term depression, have not changed significantly in the past 30 years, despite nearly all known pathways having been linked to the disease. The researchers’ work, which was published in Frontiers in Aging Neuroscience, will further study the causes of neurodegeneration.

Complexity of Alzheimer’s Pathology

“The burden of Alzheimer’s disease is steadily increasing, driving us towards a neurological epidemic,” said Winston A. Hide, PhD, director of the Precision RNA medicine Core Facility at BIDMC and an associate professor of medicine at Harvard Medical School. “Our findings suggest that not only is this disorder incredibly complex, but that its pathology includes most known biological pathways. This means that the disease’s effects are far broader in the body than we realized.”

The group conducted a thorough text search of 206,324 abstracts of publications on dementia-related pathways that have been released since 1990. After that, they examined 341 biological pathways that are known to exist and counted the publications that connected each pathway to the disease.  All but seven of the pathways, according to the study’s findings, were connected to Alzheimer’s disease, or 91% of them. In more than 100 academic studies, over half of the pathways were associated with Alzheimer’s disease.

They also found that the top-ranked 30 pathways most frequently referred to in literature remained relatively consistent over the last 30 years suggesting that most studies of the disease have focused on a small subset of all the known disease-associated pathways.

Expanding the Approach to Alzheimer’s Treatment

“Clinical trials aiming to either delay the onset or slow the progression of Alzheimer’s disease have largely failed,” said study first author Sarah Morgan, a postdoctoral researcher at BIDMC during the extent of this research and now a lecturer at the Queen Mary University of London. “Given that an unexpected diversity of pathways is associated with Alzheimer’s disease, a wide range of disease processes are not being successfully targeted in clinical trials. We hypothesize that comprehensively targeting more of the associated underlying mechanisms in Alzheimer’s disease will increase the chances of success in future drug trials.”

Reference: “Most Pathways Can Be Related to the Pathogenesis of Alzheimer’s Disease” by Sarah L. Morgan, Pourya Naderi, Katjuša Koler, Yered Pita-Juarez, Dmitry Prokopenko, Ioannis S. Vlachos, Rudolph E. Tanzi, Lars Bertram and Winston A. Hide, 24 June 2022, Frontiers in Aging Neuroscience.
DOI: 10.3389/fnagi.2022.846902

The study was funded in part by the Cure Alzheimer’s Fund. The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.

The findings can be further explored at www.adpathways.org.

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