genomic alzheimer's unique signatures on our cells

Genomic Forensics: Looking for Alzheimer’s “Signatures” on Cells

By Simon Spichak, MSc | May 4th, 2022

Brain cells from people with Alzheimer’s have a unique pattern of mutations, which may help explain why the cells begin to die. 

The genetic code is a list of instructions which is stored within each of our cells. Some of these genes may cause early-onset Alzheimer’s, while others, like ApoE4, are associated with increased risk. Even if you’re born with genes that aren’t associated with a risk of developing the disease, could they change over time?

Like a well-used reference book, the genetic code accumulates damage and mutations over time. This is fine with many of the cells in the body, since a new one can be produced to replace it if it becomes too damaged to function. However, the neuronal cells in the brain cannot be replaced, even when they accumulate genetic damage and errors.

If these errors continue piling up, neuronal cells will not be able to follow instructions properly and this may lead to diseases. Some scientists speculate that the accumulated damage may lead to Alzheimer’s, dementia and other age-related diseases. 

Alzheimer’s Brain Cells Keep Making the Same Mistakes

A recent study published in Nature compared 29 post-mortem brains which belonged to healthy young people, healthy older adults, and adults with Alzheimer’s. Researchers in the study led by Michael Miller, a neuropathologist and lecturer at Brigham and Women’s Hospital, isolated genetic material from individual cells, allowing them to look in depth at 319 neurons.

“There are more mutations in Alzheimer’s disease neurons than there are in normal neurons and neurons from people that don’t have Alzheimer’s disease,” Miller told Being Patient. 

The study also found that mutations accumulate within cells as a person ages. In the healthy post-mortem neurons, the genes that were used most often were most likely to get these mutations. 

But with Alzheimer’s, there’s an extra twist: The neurons had a unique mutational signature. 

A helpful way to think about this is to imagine the different DNA bases as individual letters. In Alzheimer’s, a certain substitution where a C tends to become an A is much more common. 

“You can start to have so-called knockout cells where a cell either has a gene where you need both copies and one of the copies has a damaging mutation,” Miller said. “We can model and see that there’s going to be more of that in Alzheimer’s disease and will start to reach a threshold where you’re going to see problems with the function of that cell.”

Miller is especially excited about the promise of the signature analysis technique, which he likens to a fossil record. “It lets you take a cell or a sample from someone that has already passed away and it lets you work backwards,” he said, adding that it allows a researcher to “figure out what actually happened in that sample in a way that you wouldn’t otherwise be able to.”

What Else Can Mutations Tell Us About Aging?

This study adds to a growing body of evidence that mutations contribute and may cause aging and age-related disorders. 

Another study published in Nature in April 2022, studied the mutation rates across 16 different mammals including ferrets, giraffes, rats, and humans. It found that higher mutation rates were associated with a shorter lifespan. 

Looking specifically at the brain, a 2019 study in Nature Communications found potentially pathogenic mutations in approximately a quarter of post-mortem brain samples from people who died of Alzheimer’s. The researchers weren’t checking for mutations passed along from parents, but rather mutations that have occurred at some point during the lifespan. 

The rate of genetic mutations that cells acquire over the lifetime are associated with longevity. Specific types of changes within individual cells may be characteristic of Alzheimer’s. Future research will look to see why this pattern of mutations is tied to Alzheimer’s, bringing us closer to understanding its underlying cause.

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