Research by dr Isidora Rovčanin Dragović Rises Hope in Fighting against Alzheimer’s Bringing Global Recognition
Alzheimer’s disease (AD) begins silently, lasting for years before becoming clinically apparent, and cannot be cured at this very moment. Given the inevitability of a fatal outcome once the disease begins, the battle against it is, in fact, a battle for its early detection, making this one of the greatest challenges of modern medicine. Doctoral dissertation of Dr. Isidora Rovčanin Dragović, defended at the University of Montenegro (UMNE) in July 2024, makes an innovative contribution to global scientific efforts aimed at identifying biomarkers that could detect the disease even before symptoms appear.
As part of her multidisciplinary research, Dr. Rovčanin Dragović linked two seemingly different diseases — Alzheimer’s disease and colorectal cancer (CRC) — through a common molecular language: microRNA molecules (miRNA or miR). This innovative approach has provided new insights into the molecular mechanisms of AD, as well as the possibility of identifying individuals at risk of developing the disease through a simple blood test. Overall, the research identified three potential biomarkers for AD: miR-146a, miR-155, and miR-101.
Today, more than 50 million people worldwide are affected by this disease, which accounts for approximately 70% of all dementia cases. As life expectancy continues to increase, it is predicted that by 2050 the number of people affected will rise to as many as 139 million.
Problem is that the disease progresses silently and slowly, Dr. Isidora Rovčanin Dragović explains. By the time it becomes visible through memory loss and cognitive decline, it is often already too late. In fact, Alzheimer’s disease (AD) is a continuum that spans decades, from the asymptomatic phase to dementia. In about 30% of people, the disease is present at the neuropathological level even before any symptoms are noticed. The lack of effective and accessible methods for early detection is one of the key reasons why many cases remain undiagnosed or are misclassified. Clinical tests have their limitations, and currently available biomarkers are obtained through invasive procedures such as lumbar puncture or with the help of expensive and rarely accessible methods like PET scans.
Paradoxically, since 2021, a therapy has existed (available in Europe from November 2024) that is believed to modify the course of the disease, but its application depends on a timely and biologically well-defined diagnosis — something that is not widely available.
Therefore, due to all these factors, one of the greatest current challenges in neuroscience and neurology is the development of biomarkers that could enable the diagnosis of AD in the preclinical stage, through simple and non-invasive methods, ideally from a blood sample. This was precisely the focus of Dr. Isidora Rovčanin Dragović’s research for her doctoral dissertation.
Discovery of Potential Biomarkers Earns Recognition at a Global Neurological Conference
Among multitude of studies aiming to identify new biomarkers for early stages of Alzheimer’s disease (AD), Dr. Rovčanin Dragović approached the topic from a different perspective in her study: she utilized scientific evidence showing that individuals with AD are less likely to develop cancer, and vice versa. This inverse relationship exists, but it has yet to be explained at the pathophysiological or molecular level. In the search for answers, this multidisciplinary study focused on small non-coding genetic fragments — microRNA (miRNA) molecules — which have the power to influence the coding part of the genome. Each miRNA regulates the expression of hundreds of genes, thereby affecting numerous fundamental biological processes. It is known that these molecules are involved in the pathogenesis of both Alzheimer’s disease and cancer, but this study hypothesized that miRNAs might also constitute the biological basis for the inverse relationship between the two diseases, and that such an innovative approach could lead to the discovery of a new biomarker for AD.
Thus, the discussion in the dissertation unfolds in two directions. In the first part, the most significant result was the discovery of elevated expression levels of miR-146a and miR-155 in a subset of healthy volunteers. Objective testing revealed that, despite denying any cognitive difficulties, these individuals exhibited mild cognitive impairment without a clear medical explanation and were therefore included in the molecular-biological research. The increased expression of these molecules has been shown to be associated with early inflammation in AD, suggesting that Alzheimer’s disease could be at the root of the accidentally discovered cognitive deficits in individuals who otherwise felt physically and mentally healthy. Specific statistical analysis confirmed the significant diagnostic potential of these molecules, leading to the conclusion that miR-146a and miR-155 could serve in the early detection of the disease and the identification of individuals at risk of manifesting AD. For this work, Dr. Rovčanin Dragović and her research team received an award at the global neurological conference, CONy 2022.
Further investigation assessed the significance of this finding by analysing the expression of these miRNAs in patients already diagnosed with AD. It was expected that their expression levels might correlate with the degree of cognitive impairment; however, the anticipated expression pattern was not observed. A thorough literature review, however, demonstrated that such findings represent a clinical correlate of experimental basic research on the role of miR-146a and miR-155 in the neuro-inflammatory process of AD — a pattern that had not been previously reported in the literature. Therefore, the analysis of the molecular biological status of already diagnosed patients confirmed that miR-146a and miR-155 could serve as a highly sensitive and specific test for the early detection of individuals at risk of developing Alzheimer’s disease.
MiR-101: a Molecule Connecting Alzheimer’s and Colorectal Carcinoma
In second part of the research, hypothesis concerning inverse biological connection between Alzheimer’s disease (AD) and colorectal cancer (CRC) was tested, and the expression level of microRNA-101 (miR-101) was identified in support of this assumption. It was shown that the level of miR-101 was statistically significantly higher in individuals with AD compared to those with cancer, while healthy participants exhibited values that fell between these two groups.
This finding is particularly interesting because most previous studies have reported a decreased level of miR-101 in AD, interpreted as a loss of its natural inhibitory effect on the amyloid precursor protein (APP) gene, whose extensive activity leads to accumulation of amyloid — the main hallmark of the disease. However, this study proposed a new hypothesis: that an increase in miR-101 may actually represent a defensive mechanism by which the organism attempts to limit the harmful effects triggered by the increased expression of the APP gene.
Further analysis across different stages of AD revealed that miR-101 expression actually increases only in the early stages, which are characterized by intense APP metabolism, thus supporting the author’s hypothesis. In the advanced stages of the disease, however, the expression of this molecule significantly decreases, likely as a consequence of disease progression, when compromised synaptic transmission is known to lead to a reduction in APP metabolism.
Ultimately, Dr. Rovčanin Dragović proposes a new mechanistic concept: that miR-101 functions as part of a negative feedback loop in Alzheimer’s disease, presenting a novel scientific hypothesis. This also implies the potential clinical application of miR-101 as a biomarker for AD progression and for monitoring the effects of new amyloid-reducing, disease-modifying therapies.
On the other hand, the research results are consistent with existing data showing decreased miR-101 expression in cancer, where it has a proven role in tumour suppression. Taking into account the demonstrated mechanism of miR-101 action throughout the stages of AD, a comprehensive picture emerges that supports the hypothesis of an inverse biological relationship between Alzheimer’s disease and cancer: while the organism, through increased miR-101 expression, attempts to slow down AD progression in its early stages, this microRNA simultaneously exhibits a pronounced tumour-suppressive role, potentially protecting these individuals from developing cancer.
Three Potential Biomarkers and Dual Contribution to: Science and Public Health
Doctoral dissertation titled “A New Method for Risk Stratification for the Development of Alzheimer’s Disease among Patients in Montenegro” was carried out within the framework of the national project “DEMONSTRATE”, in collaboration with researchers from the Institute for Biomembranes, Bioenergetics, and Molecular Biotechnology in Bari. The mentor and co-mentor were Nataša Popović, PhD, and Milica Martinović, PhD from the Faculty of Medicine at the University of Montenegro (UMNE), while one of key researchers on the project was Dr. Maša Ždralević, a research associate from the Institute for Advanced Studies at UMNE.
The research identified three potential biomarkers for Alzheimer’s disease — miR-146a, miR-155, and miR-101 — which holds global scientific significance. The results have been presented at international conferences and published in leading scientific journals. An additional value of the study lies in the fact that the expression of these molecules can be determined non-invasively — from blood plasma — opening the possibility for broad clinical application. Furthermore, the study offers one of the rare molecular explanations for why individuals with Alzheimer’s disease have a lower risk of developing cancer.
The research also provides multiple contributions at the national level. It revealed that a certain number of individuals with cognitive impairment in the Montenegrin population remain unrecognized. The study highlighted the need for the routine application of neuropsychological screening tests among the elderly population in Montenegro, suggesting that these tests, combined with the identified molecular markers, could become routine tools for general population screening in the context of Alzheimer’s disease.
Of particular significance is the fact that, prior to this study, there was no laboratory in Montenegro capable of determining miRNA expression from plasma samples. Moreover, this is the first doctoral dissertation at UCG written in English and the first dissertation defended at the Faculty of Medicine before an international, bilingual committee.
(The following section contains a statement by Dr. Isidora Rovčanin Dragović, delivered at the ceremony held in honour of the University of Montenegro Day, during which doctoral candidates were formally promoted.)