Alzheimer's disease is the most common type of senile dementia, a condition caused by a gradual loss of neuronal cells in specific areas of the brain and by an alteration of the cerebral functions, affecting, in Italy, 5% of individuals over 60 years old.

Several studies have demonstrated that epigenetic modifications caused by environmental triggers, such as lifestyle and nutrition, may affect cerebral functions and neurodegeneration. Such mechanisms can modify gene expression and compromise cell function in the body, but they cannot alter the DNA sequence, hence their action is, in fact, reversible.

This is why an early diagnosis of the disease would be of great importance to identify and prescribe a therapy able to halt the neurodegeneration or to delay a gradual progression towards the most serious phases of the disease.

A new international study, coordinated by the researches of the Department of Experimental Medicine of Sapienza University in collaboration with the Universities of Pisa, Barcelona, Amsterdam, Vienna and Jerusalem, has discovered a link between the changes in the Presenilin1 (PSEN1) gene and Alzheimer’s disease. In particular, it has been observed for the first time in human samples how such changes depend on non-CpG methylation, an epigenetic modification able to leave a specific “track” on PSEN1 and activate a series of molecular mechanisms inducing a gene overexpression.

The results, published on Epigenetics journal, indicate non-CpG methylation as a possible biomarker, which, if closely monitored, can allow both to identify the environmental triggers for neurodegeneration and to evaluate the reaction to a therapy for the disease. 

“Cytosine methylation, one of four chemical bases of DNA – says Andrea Fuso, team coordinator – is one of the epigenetic modifications able to modulate gene expression: the more methylated (a gene is) the more silenced and vice-versa. To date – continues Fuso – earlier human studies have only assessed CpG methylation, methylation of cytosine  followed by a guanosine; this study considered the methylation of all the other cytosine (non CpG) and, therefore, PSEN1 hypomethylation and overexpression in patients with Alzheimer's disease."

At first, the experimental studies were carried out on a murine model of Alzheimer's disease and then verified on human brain samples, confirming a significant inverse association between gene expression and DNA methylation in the patients. Later, blood samples of 20 patients with late-onset Alzheimer's disease were analysed and the outcomes were compared with a control group of 20 healthy individuals to verify whether the changes in PSEN1 methylation could be detected in human blood.

“Analysis of the blood samples – explains Fuso – showed that PSEN1 methylation in blood DNA was significantly lower in Alzheimer's disease patients than in the controls. This type of analysis may offer new possibilities for early and less invasive diagnoses.”

Further studies and a larger cohort of individuals are necessary to confirm this potential biomarker, but the current results already offer a new promising area of investigation. "We detected an early sign of the disease in a DNA modification, or epigenetic marker, that had been previously overlooked but – Fuso concludes – could provide a starting point for new therapies as well as an early diagnosis.”

References: 

CpG and non-CpG Presenilin1 methylation pattern in course of neurodevelopment and neurodegeneration is associated with gene expression in human and murine brain- Monti N, Cavallaro RA, Stoccoro A, Nicolia V, Scarpa S, Kovacs GG, Fiorenza MT, Lucarelli M, Aronica E, Ferrer I, Coppedè F, Troen AM, Fuso A- Epigenetics2020 Feb 5:1-19 doi: 10.1080/15592294.2020.1722917

Further Information

Andrea Fuso
Department of Experimental Medicine
andrea.fuso@uniroma1.it