Potential genetic test for earlier Alzheimer's diagnosis

A new study published in the journal Epigenetics in February 2020 reports that changes in the methylation status of the Presenilin 1 (PSEN1) gene could help diagnose Alzheimer's disease (AD) earlier. This study shows for the first time that methylation of this gene is a common feature in AD.

Alzheimer's disease

AD is a widespread dementia disorder, involving the loss of cognitive skills such as thinking, making decisions, remembering things in connection, and learning. It affects almost 50 million people the world over, mostly over the age of 60 years but a significant percentage at ages below 50 years. Furthermore, this is only a fourth of all cases, because most patients go undiagnosed.

The progressive and incurable nature of this disorder makes it difficult to bear for both the patient and the caregivers. The disease inevitably progresses to the point where complete care is required. Currently, available medications must be given early to have the highest odds of successfully delaying the onset of severe cognitive loss.

Image credit: Lightspring / Shutterstock
Image credit: Lightspring / Shutterstock

The PSEN1 gene

The PSEN1 gene is part of a protease complex that catalyzes a process called regulated intramembrane proteolysis. It is important in AD because it is responsible for cleaving the beta-amyloid fragment from the parent AβPP molecule. It is one of several polymorphic genes that regulate normal embryonic regulation but also promote the risk of AD.

Epigenetic modification is an important way to regulate gene activity in the body and can be triggered by environmental factors, including specific lifestyle and nutritional factors. The addition of methyl groups to the DNA (mostly to the cytosine) outside the actual genetic code, called methylation, is a well-known epigenetic modification. Methylation is typically a method to silence or downregulate the associated gene.

Earlier animal studies have shown that the PSEN1 gene can be downregulated, causing a condition very like AD.  However, little research has been done epigenetic modification of the human PSEN1 gene. It is established that people with AD already show altered PSEN1 behavior. The current study is the first to record the frequent occurrence of DNA methylation at this gene in humans with AD.

Most studies on the gene focused only on CpG-associated cytosines. The researchers used a different method that shows methylation at non-CpG sites as well, in order to understand the PSEN1 methylation patterns in a large part of the PSEN1 gene's flanking region and the resulting changes in mRNA.

In the next phase, they looked for similar PSEN1 methylation patterns in brain samples from deceased humans with AD, as well as from deceased fetuses, newborns, and adolescents. Finally, they examined blood samples from 20 patients with classical AD as well as from 20 healthy controls, to see if these changes were visible in peripheral blood.

The findings

The investigators found that in both male and female mice who were prone to AD, the PSEN1 gene was expressed at a high level. In adult female mice, overexpression of PSEN1 was linked to a lower level of DNA methylation.

In the human brain samples, the PSEN1 gene was again found to be overexpressed in patients with AD. However, this was associated with lower DNA methylation levels in both sexes, unlike in mice. This could, however, be due to the small size of the sample rather than any intrinsic differences.

The researchers are interested in finding out if there is a difference in the methylation of DNA between males and females, as it could help understand why this condition is far more prevalent in females, and to develop new treatments.

In the human blood samples, the levels of DNA methylation in PSEN1 were lower in AD patients compared to controls. The difference was observable, but its amplitude was less than that found in brain samples. This could offer a new way to diagnose AD without invasive testing compared to taking brain samples.

The researchers think that PSEN1 undergoes partial methylation but then remains stable throughout embryonic and childhood life. It usually remains downregulated throughout adult life. When it is overexpressed, hypomethylation occurs, which is linked to AD and is a disease process.


Like most methylation studies, the current research was performed using experimental mice. However, the developmental history in mice, as well as the stages of neurodegeneration in mice, are not an accurate picture of the same events in humans and reflect different types of AD. This limits the usefulness of the finding until it is validated in human trials.

Secondly, the blood samples and the brain samples were obtained from different animals, which may affect the correspondence of the findings. The researchers would like to see future studies analyzing samples of DNA taken from the same individual, but from different sites, to establish a real connection. The sample size should be more significant, too, they suggest, to validate the finding.


The scientists conclude that their research shows how epigenetic regulation at a specific gene can affect the course of the degeneration of nerve cells. The presence of non-CpG methylated DNA makes the PSEN1 promoter segment perhaps more prone to changes in response to environmental triggers compared to the stable silencing with CpG island-associated methylation. PSEN1 expression is higher in females than in males and is linked to lower levels of methylation.

Many researchers have found that non-CpG methylations occur at genes and non-gene loci, and not just in embryonic or stem cells, as was previously thought. This is not dependent on cell replication and can, therefore, occur in the brain neurons, which are not actively proliferating.

Researcher Andrea Fuso says, "We've detected an early sign of the disease in DNA modification, or epigenetic marker, that was previously overlooked, and that could even provide a starting point for developing new therapies, as well as earlier diagnosis."

Journal reference:

Monti, N., Cavallaro, R. A., Stoccoro, A., Nicolia, V., et al. CpG and non-CpG Presenilin1 methylation pattern in course of neurodevelopment and neurodegeneration is associated with gene expression in human and murine brain. Epigenetics 2020. https://doi.org/10.1080/15592294.2020.1722917.

Dr. Liji Thomas

Written by

Dr. Liji Thomas

Dr. Liji Thomas is an OB-GYN, who graduated from the Government Medical College, University of Calicut, Kerala, in 2001. Liji practiced as a full-time consultant in obstetrics/gynecology in a private hospital for a few years following her graduation. She has counseled hundreds of patients facing issues from pregnancy-related problems and infertility, and has been in charge of over 2,000 deliveries, striving always to achieve a normal delivery rather than operative.


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