PSEN1 Gene Alteration May Be Early Biomarker for Alzheimer’s, Study Suggests

A specific chemical alteration present in the presenilin1 (PSEN1) gene may be a biomarker for earlier Alzheimer’s disease (AD) diagnosis and treatment response monitoring, a study suggests.

The modification, called DNA methylation, was observed both in brain samples of Alzheimer’s mouse models and post-mortem brain tissue of Alzheimer’s patients. It was also measurable in blood samples from patients with late-onset AD, suggesting its detection is a new, non-invasive way to diagnose the illness.

The study, “CpG and non-CpG Presenilin1 methylation pattern in course of neurodevelopment and neurodegeneration is associated with gene expression in human and murine brain,” was published in Epigenetics.

Genetics are thought to play a central role in the development of Alzheimer’s, with the PSEN1 gene being identified as one of the genes that may be linked to the development of the disease.

In addition to mutations in certain genes, epigenetic changes may also play a role in Alzheimer’s. These are changes in gene activity that do not involve the alteration of the DNA sequence itself and are often induced by environmental factors, such as diet and lifestyle. For example, a person may be born with a capacity to be tall, but if undernourished as a child, will likely not grow as much as his or her genes would allow.

One such example is DNA methylation, a chemical modification whereby addition of small chemical groups (methyl) are able to turn off a gene, or prevent it from being expressed. Gene expression is the process by which information in a gene is synthesized to create a working product, like a protein.

The researchers had previously shown, in cell and animal models, that DNA methylation could regulate PSEN1 activity. One study showed that environmental factors, such as B vitamin dietary deficiency, lowered methylation of the gene, which led to worsening of Alzheimer’s features in a mouse model of the disease.

In another study, prevention of low methylation of the gene, by supplementation with a chemical compound, limited the accumulation of amyloid deposits in the brains of mice, improving the animals’ cognition.

“In contrast to the animal studies, the few human studies of PSEN1 methylation in AD patients have been inconsistent,” the researchers wrote.

The researchers characterized PSEN1 DNA methylation at different stages of neurodevelopment and neurodegeneration in the brains of humans and mice. To do so, they analyzed brain tissue samples of Alzheimer’s and healthy control mice at different stages of development, as well as post-mortem prenatal and postnatal human brain samples, and those from adolescents and older adult Alzheimer’s patients and controls.

To see whether changes to PSEN1 DNA methylation could be detected in human blood, they analyzed blood samples from 20 Alzheimer’s patients (mean age 75.5) and 20 healthy-matched controls (mean age 75.6).

In Alzheimer’s mice, the PSEN1 gene was over-expressed, or expressed at higher levels. This was associated with a lower methylation pattern, but only in female mice. Age did not influence any pattern in mice. “Such sex-specific epigenetic regulation would be extremely interesting, and could help [account] for the higher prevalence of AD among women than among men,” the researchers wrote.

The researchers found that the the PSEN1 gene was over-expressed in the post-mortem brain human samples of Alzheimer’s patients. In both sexes, there was a significant inverse relationship between the levels of gene expression and DNA methylation. The fact that sex-specific differences were not found in human tissue could be due to the small sample size, they said.

They saw that PSEN1 gene activity changed with age. It appeared to be stable during embryonic development, downregulated (expressed at lower levels) at 17 years of age and then upregulated, or over-expressed, in older adults and Alzheimer’s patients.

The levels of PSEN1 methylation in the blood were significantly lower in Alzheimer’s patients than in controls. This “opens the door to developing this assay as a potential biomarker for the disease,” the researchers wrote.

Furthermore, lower PSEN1-related methylation levels corresponded to increased PSEN1 activity.

Because the blood and brain samples came from different subjects, the researchers said, further studies “in a larger cohort using DNA from blood and post-mortem brain tissue obtained from the same individuals [are necessary] to validate this potential biomarker.”

“Our results offer an exciting new area of investigation, deploying the methods we used to study DNA methylation so that modifications won’t be missed. If found to be causal, our findings would provide a starting point for developing epigenetic therapies,” Andrea Fuso, professor at the Sapienza University of Rome and the study’s lead author, said in a press release.