Human brain with DNA
Source: Victor De Schwanberg/Science Photo Library / Getty Images

The results of research by an international team of scientists suggest that PSEN1 gene methylation detected in peripheral blood may represent a biomarker for early detection of Alzheimer’s disease (AD). They claim their study—carried out in mice and in post-mortem human brain tissue—is the first to demonstrate a temporal correlation between PSEN1 gene CpG and non-CpG methylation patterns and mRNA expression during neurodevelopment, and AD neurodegeneration.

PSEN1 is critical for neural development, and has previously been reported as a risk factor for AD. The new study, led by Andrea Fuso, PhD, assistant professor at the Sapienza University of Rome, now suggests that patterns of methylation PSEN1 gene methylation are a common feature of the disease. The authors also suggest that the PSEN1 gene should be monitored as a biomarker to help assess which environmental triggers, such as lifestyle and nutrition, can influence brain function and neurodegeneration and/or help assess response to therapy.

The findings offer up “an exciting new area of investigation,” Fuso said. The study results indicate that the link between PSEN1 methylation and AD may have previously been missed because prior research only assessed CpG methylation, not methylation at non-CpG sites. “We’ve detected an early sign of the disease in a 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,” Fuso added. The researchers reported their findings in Epigenetics, in a paper titled, “CpG and non-CpG Presenilin1 methylation pattern in course of neurodevelopment and neurodegeneration is associated with gene expression in human and murine brain.”

Alzheimer’s disease and related dementia affect nearly 50 million people worldwide, but only 1 in 4 people with Alzheimer’s disease has been diagnosed. More than 90% of cases of AD manifest as sporadic, multifactorial, late-onset disease (late onset AD, or LOAD), and its causes are unknown, the authors wrote. However, they noted, “it is increasingly accepted that epigenetic changes may promote LOAD, perhaps in response to environmental triggers.”

The earlier Alzheimer’s can be detected, the better the chances that treatments can be developed to delay the onset of severe dementia. Epigenetic alternations to genes, induced by environmental triggers such as lifestyle and nutrition, can influence brain function and neurodegeneration. Evidence from animal models has found that changes to regulation of the PSEN1 gene is associated with Alzheimer’s-like pathology. “The most commonly studied epigenetic modification in AD is DNA methylation,” the team noted, but only a handful of studies have investigated DNA modification of the gene in humans. “Despite evidence from animal models and cell studies that epigenetic regulation of this gene is associated with AD-like pathology, only a handful of studies have investigated human PSEN1 methylation in AD,” they wrote. “ … the present study was motivated by the need to characterize the patterns of PSEN1 DNA methylation and mRNA expression in murine and human brain at different stages of neurodevelopment and neurodegeneration.”

For the current study, the authors analyzed patterns of both CpG and non-CpG methylation affecting PSEN1 gene expression during brain development and during the progression of AD in mice. They compared the mouse results with those from the analysis of post-mortem human brain tissue from Alzheimer’s disease patients and from prenatal and postnatal babies, and adolescents. “An important limitation of earlier human studies is that they only assessed CpG methylation; however, methylation also occurs at cytosine moieties that are not followed by a guanosine (non-CpG methylation),” they pointed out. “ … we analyzed and compared CpG and non-CpG DNA methylation patterns in frontal brain cortex from transgenic TgCRND8 AD model and control mice at different ages and stages of development, and post-mortem frontal cortex from fetal, adolescent, and middle-aged humans and from old AD patients and cognitively normal controls.”

To see whether changes to DNA methylation could be detected in human blood, the investigators then analyzed blood samples from 20 patients with late-onset AD, and compared the results with those from 20 healthy controls. The results showed that in both sexes of the Alzheimer’s disease mouse models, the PSEN1 gene was overexpressed, but in adult female mice only this overexpression was associated with lower DNA methylation. Findings from post-mortem human brain tissue detected upregulation of the PSEN1 gene in Alzheimer’s disease patients. In both sexes, there was a significant inverse relationship between the extent of gene expression and DNA methylation. The researchers suggested that the observation that sex-specific differences were not identified in human tissue could be due to the relatively small sample size.

“Mapping CpG and non-CpG methylation revealed different methylation profiles in mice and humans. PSEN1 expression only correlated with DNA methylation in adult female mice. However, in post-mortem human brain, lower methylation, both at CpG and non-CpG sites, correlated closely with higher PSEN1 expression during brain development and in disease progression,” they stated.

The results of blood sample tests also showed lower PSEN1 DNA methylation in Alzheimer’s disease patients, compared with controls. “PSEN1 methylation in blood DNA was significantly lower in AD patients than in controls,” the team wrote. While the difference was significant, it was not as large as in the brain samples. Nevertheless, the investigators suggested, lower PSEN1 methylation in the blood samples was associated with higher expression of PSEN1, so it could offer a new way to diagnose Alzheimer’s early, and less invasively, than sampling brain tissue. “… the finding of differential PSEN1 methylation in peripheral blood opens the door to developing this assay as a potential biomarker for the disease.”

They acknowledged additional limitations of their study, including those linked with comparing results from mouse models and humans. Murine stages of development and neurodegeneration do not correspond precisely with those of human aging, for example. And in their reported study the team noted that the blood and brain samples were obtained from different subjects. They suggested that future studies should analyze DNA from the same individuals, and in a larger cohort, to validate the biomarker. Even so, the team reported, the results “support the hypothesis that epigenetic changes can promote the pathophysiology of AD.” Added Fuso, “Differences between the sexes in DNA modifications would be extremely interesting to researchers working to better understand Alzheimer’s disease and to develop new therapies … 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.”

Moreover, the researchers suggested while PSEN1 DNA methylation in peripheral blood may provide a biomarker for AD, their results could also help researchers identify new therapeutic strategies. “… if causal, our findings would provide a starting point for developing epigenetic therapies for AD … We hope that these results will foster further analysis in larger cohorts, including a comparison of parallel brain and blood samples and correlating the methylation data with environmental determinants of biological methylation as folates, B vitamins, homocysteine, and S-adenosylhomocysteine.”

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