More than 2 million years ago, a segment of DNA flipped its orientation in the genome of some of our ancestors. Scientists are now investigating whether that ancient genetic change could help explain why people have different risks of developing Alzheimer's disease and other neurodegenerative disorders.
The DNA change occurred in the MAPT locus, which contains the gene that encodes tau. Tau is a protein strongly associated with Alzheimer's disease and related conditions known as tauopathies.
The region has since evolved into two major forms, or haplotypes, that differ by thousands of genetic variants. These versions are associated with substantially different risks for several neurodegenerative diseases.
But knowing that the genetic versions are linked to disease risk is only the beginning. Researchers still want to understand what the differences actually do inside the brain.
Why Scientists Are Interested in the MAPT Gene
The MAPT gene provides instructions for making tau, a protein that helps maintain the structure of nerve cells.
Tau becomes abnormal in several neurodegenerative diseases. In Alzheimer's disease, for example, abnormal tau accumulates inside neurons and is one of the defining features of the disease.
That makes the genetic region surrounding MAPT an important area for researchers studying how inherited differences may influence brain health.
The challenge is that the region is unusually complicated. The ancient inversion is accompanied by thousands of other genetic variants, making it difficult to identify which differences have the greatest biological effects.
Rather than looking at a single genetic change in isolation, researchers are examining how the region behaves as a whole.
One Ancient Change Created Two Distinct Genetic Versions
The original DNA inversion happened approximately 2.3 million years ago, according to the Gladstone Institutes.
Over evolutionary time, the inverted and non-inverted versions developed into distinct haplotypes. Each contains a large collection of genetic variants that tend to be inherited together.
Those haplotypes are now associated with different risks for several neurodegenerative conditions. Researchers, however, have not established that the ancient inversion itself directly causes Alzheimer's disease or another neurological disorder.
Instead, the association gives scientists a starting point for a more specific question: What biological differences between these two versions might influence disease susceptibility?
The Answer May Depend on Which Brain Cell Is Being Studied
The brain contains many different types of cells, and they do not all use genes in exactly the same way.
A genetic difference that affects a neuron could have a different effect in a microglial cell or another type of brain cell. That means studying the brain as one large mass of tissue can potentially hide important details.
Cathrine Sant, PhD, a NOMIS–Gladstone Fellow, is examining this question using single-cell sequencing data from human brains.
This approach allows researchers to examine gene activity in individual cells rather than averaging signals across an entire tissue sample. Sant is investigating whether the different MAPT haplotypes influence gene regulation and RNA splicing in particular brain cell types.
If certain genetic differences affect how MAPT is regulated in specific cell types, that could help explain why the same genomic region is associated with several neurological diseases.
A Computational Approach Is Helping Sort Through the Genetics
The amount of information contained in modern genomic datasets can make these questions difficult to answer manually.
During her doctoral training in neuroscience at the University of California, San Francisco, Sant developed CHOIR, a computational method designed to identify biologically distinct cell types within complex datasets.
The tool has also been used to investigate the potential effects of lowering tau levels in specific brain cell populations.
That experience is particularly relevant to the MAPT research. Instead of simply identifying a genetic variant associated with disease, computational analysis can help researchers examine patterns of gene activity and regulation across thousands of individual cells.
The aim is to connect genetic differences with measurable biological changes.
What Researchers Still Do Not Know
The biggest unanswered question is how the MAPT region influences disease risk.
Scientists know that its two major haplotypes are associated with different risks for several neurodegenerative diseases. What remains unclear is which molecular mechanisms create those differences.
Sant is investigating whether changes in gene regulation and RNA splicing across specific brain cell types could help explain this.
This distinction is important. A genetic association does not mean that someone carrying one version of the MAPT region will inevitably develop Alzheimer's disease.
Neurodegenerative disorders are complex and can involve many genetic and biological factors. The current research aims to understand one potentially important piece of that puzzle, not to predict an individual's future.
Why an Ancient Genetic Change Matters Today
The MAPT region offers researchers an unusual opportunity to examine how ancient genetic variation can remain relevant to human health millions of years later.
The DNA inversion itself is not a newly discovered mutation occurring in today's population. Instead, scientists are studying how the two forms of this ancient region evolved and how their differences may affect the modern brain.
Understanding that relationship could eventually shed light on the biology of tauopathies, including why some people are more susceptible to particular neurodegenerative conditions than others.
It could also point researchers toward biological pathways that might be worth exploring for future treatments. But that possibility remains speculative until the underlying mechanisms are established.
For now, the research is focused on a more fundamental question: what is this ancient stretch of DNA actually doing inside the human brain?
By examining the MAPT region at the level of individual cells, researchers hope to move closer to an answer. And if they can determine how these ancient genetic differences alter brain biology, they may gain another piece of the puzzle behind diseases that remain difficult to predict, prevent, and treat.
