First cell-level gene maps created for Alzheimer's disease

The first cell-type-specific maps of the brain during Alzheimer's disease have been created, revealing which genes may actively drive the disease rather than simply change in response to damage.

Alzheimer's disease is a neurodegenerative disease that affects millions of people worldwide, yet it is still unclear how genetic risk factors disrupt the inner workings of brain cells. Most cases are not caused by a single gene but by complex changes in how many genes interact across different types of brain cells. Researchers have now produced the most comprehensive maps yet of how genes directly influence one another in different types of brain cells impacted by Alzheimer's disease, shedding light on the genetic mechanisms at work in patients' brains.

'Different types of brain cells play distinct roles in Alzheimer's disease, but how they interact at the molecular level has remained unclear,' said Professor Min Zhang at the University of California, Irvine, co-corresponding author of the paper published in Alzheimer's & Dementia. 'Our work provides cell type-specific maps of gene regulation in the Alzheimer's brain, shifting the field from observing correlations to uncovering the causal mechanisms that actively drive disease progression.'

The study combined large-scale genetic data with single-cell technologies to trace how differences in DNA alter gene activity inside individual brain cells of different types. The researchers analysed brain tissue from 272 people with Alzheimer's disease who participated in the Religious Orders Study and Rush Memory and Ageing Project. They used a method known as single-nucleus transcriptomics, which measures which genes are switched on or off in individual cells, to examine thousands of cells across six different brain cell types.

The researchers then combined this information with each person's genetic data and used a novel machine learning framework they call SIGNET to build detailed gene regulatory networks. The networks are like maps which reveal how certain genes control the activity of many other genes within each cell type, distinguishing genes that are likely driving the disease from those that are merely responding to the damage caused by the disease.

Within their maps they identified the most influential genes within specific cell types, called hub genes, which could represent new targets for therapeutics. Some of the study's findings revealed entirely new pathways and cell-type-specific mechanisms that had not been previously linked to Alzheimer's disease.

Future research will need to test these newly identified hub genes to confirm their roles in disease progression and explore whether they can be safely targeted for therapeutics. The authors also suggest that their analysis approach could be applied to other complex disorders, such as cancer, helping untangle the biology of a wide range of diseases.