Shared cellular mechanisms found across three major dementias

A research team led by the University of California, Los Angeles (UCLA) has identified degeneration-associated ‘molecular markers’ — observable changes in cells and their gene-regulating networks — that are shared by several forms of dementia that affect different regions of the brain.

The researchers have also identified markers specific to different forms of dementia, with their combined findings, published in the journal Cell, representing a potential paradigm shift in the search for causes, treatments and cures.

Previous studies have focused on a single disorder at a time. Called case-control studies, they compared ‘diseased’ cells with normal ones and often just focused on one brain region. But in this research, the scientists also looked at molecular changes across three different forms of dementia that can involve ‘tau pathology’, the accumulation of abnormal tau protein in vulnerable regions that differ across disorders.

The team performed single-cell genomic analysis on more than 1 million cells to identify distinct and shared molecular markers in three related conditions: Alzheimer’s disease (AD), frontotemporal dementia (FTD) and progressive supranuclear palsy (PSP). In addition to validating changes previously observed in AD, they identified dozens of cell types whose changes are shared across multiple dementias and several cell types whose changes in disease were specific to a single disorder, many of which had not been previously identified.

“Different conditions have different patterns of degeneration,” said senior author Professor Daniel Geschwind. “We reasoned that comparison across cases from different disorders, in addition to the typical case-control comparison, would be useful to identify shared components of neurodegeneration and to understand cell type-specific changes that underlie all these conditions.” Most studies profile only one brain region — typically the frontal lobe.

“In dementia and neurodegenerative disease more generally, specific brain regions and cells are most vulnerable in each disease; this is what leads to the different symptoms and signs across disorders,” Geschwind said. “Since regional vulnerability is a core feature of the disorders, we reasoned that studying more than one region would give new insights, and that was the case. In addition to identifying shared and distinct molecular markers, we showed how genetic risk relates to these disease-specific pathways that are altered in the brain.”

Using this study design, the investigators found four genes that marked vulnerable neurons across all three disorders, highlighting pathways that could be used to develop new therapeutic approaches. Assistant Professor Jessica Rexach, who was first author on the study, said the work “profoundly shifted” her perspective on the mechanisms underlying disease susceptibility.

“It is remarkable and humbling to have identified several distinct molecular differences that set apart cells from individuals with one form of dementia from those with closely related diseases,” Rexach said. “Although these disease-specific differences were among the minority of the changes observed in diseased brains, they were strongly linked to heritability. This surprising finding opens new avenues for understanding why and how certain genes influence the risk of developing one brain disease over another closely related condition.”

Combined, Alzheimer’s, FTD and PSP affect more than 28 million people worldwide. Although Alzheimer’s has been studied extensively, there is no cure, and existing, approved medications only slow disease progression. There are few clinical trials available for FTD and PSP.

“We have created an extensive data resource that paves the way for identifying and exploring new therapeutic candidates for neurodegenerative dementias,” Rexach said. “We have pinpointed specific molecules that can now be advanced as potential novel regulators of disease in experimental systems — importantly, grounded in primary human disease data. Additionally, we’ve uncovered unexpected conceptual phenomena that may explain why certain cells exhibit more resilience or vulnerability to disease, and we’re eager to investigate these findings further.”

The researchers identified unique changes specific to Alzheimer’s disease and demonstrated that several findings in Alzheimer’s were also observed across the other disorders, identifying targets for therapeutic development. They also found that ‘cellular resilience programs’ — molecular mechanisms that support cells in response to injury — activated or failed differently, when comparing the same cell types across disorders.

The team were surprised to discover that each of the three disorders had changes in cells of the primary visual cortex — the area of the brain that processes visual information and which was thought to be unaffected by dementia. They also identified specific changes in the expression of certain tau-related genes and others in PSP. These appear to correlate with the unique pattern of brain cell degeneration that is observed in PSP.

The researchers concluded that their work “underscores the importance of examining multiple brain regions to understand causal disease pathways at the cellular level”. With the team soon to begin experiments to validate the causal nature of their findings, they believe their study will inspire similar cross-disorder research.

Image credit: iStock.com/Alexander Sikov