NEW BIOMARKERS FOR ALZHEIMER'S DISEASE: A COHORT OF PATIENTS WITH MEMORY COMPLAINTS

• Grant number: 24/00356-4
• Support Opportunities: Research Projects - Thematic Grants
• Start date: November 01, 2025
• End date: October 31, 2030
• Field of knowledge: Health Sciences - Medicine
• Principal Investigator: Paulo Henrique Ferreira Bertolucci
• Grantee: Paulo Henrique Ferreira Bertolucci
• Host Institution: Escola Paulista de Medicina (EPM). Universidade Federal de São Paulo (UNIFESP). Campus São Paulo. São Paulo , SP, Brazil
• City of the host institution: São Paulo
• Principal investigators: Gisele Sampaio Silva ; Juliana Maria Ferraz Sallum ; Kil Sun Lee
• Associated researchers: Adriana Fernandes Nunes Vilela ; Adriana Neves de Andrade ; Alan Cronemberger Andrade ; Alline Carvalho de Souza ; Altay Alves Lino de Souza ; Ana Paula de Oliveira Ferreira ; Andreas Batista Schelp ; Caio Vinícius Barroso de Lima ; Carla dos Reis Piffer Vilela ; Carolina Arruda Nascimento ; Claiton Henrique Dotto Bau ; Cleyde Sayuri Horie Domingues ; Corina Lopes Ribeiro ; Diego Luiz Rovaris ; Elisabete Betarello ; Ellen Martins Bello Pignoli ; Eugenio Horacio Grevet ; Fernando Morgadinho Santos Coelho ; Flavio Moura Rezende Filho ; Gabriel Trigo Pereira ; Gean Antonio de Paula ; Gustavo Melo de Andrade Lima ; Igor Melo de Almeida ; Isabella Lacava Maluf ; Ivy Liger Riso ; Jessica Monteiro Volejnik Pino ; Joao Brainer Clares de Andrade ; Juliana Terzi Maricato ; Karin Zazo Ortiz ; Kil Sun Lee ; Letícia Amorim de Lucena ; Lucas Pelegrini Nogueira de Carvalho ; Luciana Cristina Esteves Garcia ; Marcella Bianca Neves ; Márcia Regina Cominetti ; Marco Antonio Lino Junior ; Maria Cristina de Almeida Gaspar ; Mariana Braga Falcão ; Marimélia Aparecida Porcionatto ; Marina Tedeschi Dauar ; Marisa Macedo Kuenzer Bond ; Marta Mika Shimabukuro ; Natalia Faiolo Rossetto Filippini ; Natália Takeda de Lira ; Patricia Cibelle Pinto de Oliveira ; Patricia Regina Manzine Moralles ; Paulo Eduardo Lahoz Fernandez ; Rairis Barbosa Nascimento ; Regina Célia Ribeiro Malta ; Renan Iegoroff ; Rhayane Vitória Lopes ; Sheilla de Medeiros Correia Marin ; Tania Regina Danieli Morello ; Thamaris Ribeiro ; Thiago Michel de Brito Farias ; Tiago Nicoliche Maria ; Valdirene Francisca Neves dos Santos ; Vera Lúcia Duarte Vieira ; Vinícius Boaventura

Abstract

Dementias are neurodegenerative conditions that lead to cognitive and functional decline, leading an individual to complete functional disability in just a few years. There is an estimated prevalence of 50 million people in the world with dementia and this number is expected to triple by 2050. Alzheimer's disease (AD) is the most common dementia found today, and it has a challenging diagnosis, yet without curative or course-modifying treatment of the disease. This project's main objective is to identify new AD biomarkers, one of which would be the thickness of the retinal layers, measured by Optical Coherence Tomography (OCT), in conjunction with intraocular vasculature study, measured by the Optical Coherence Angiotomography(OCTa). As the thickness of the retina measured by OCT is altered in the early stages of AD, it can therefore be used as a diagnostic marker that suggests the presence of the disease. A decreased macular vascular density and an increased foveal avascular zone, measured by OCTa, are present in patients with AD, and the cognitive decline correlates with these changes. ADAM10, which will also be investigated as a possible peripheral biomarker of AD, is a ± secretase that inhibits senile plaques formation and is therefore protective against the disease. This molecule is reduced in platelets of individuals with AD, and the previous research results from the group led by Dr Marcia Cominetti, a researcher associated with this project, reinforces the hypothesis of ADAM10 as a possible peripheral AD biomarker. These results suggest that the protein can be measured in patients in the prodromal disease, that is, those who have not effectively started functional decline, allowing early diagnosis and interventions that can delay or prevent the onset of the disease. Other possible biomarkers capable of improving the understanding of the disease pathology will also be evaluated, it involves the analysis of mechanisms such as neuroinflammation and oxidative stress. In addition to biomarkers, some risk factors such as consumption of ultra-processed foods, hypoacusis, comorbidities such as Depressive Disorder and Attention Deficit Hyperactivity Disorder will also be explored in this sample. For these purposes, individuals over 60 years old with memory complaints from the São Paulo region will be evaluated, although without functional impairment, but belonging to a group with a higher risk of progressing to AD. This population will be followed for 60 months, where the classic parameters of disease evolution will be evaluated and compared with new possible biomarkers such as retinal thickness, plasma levels of ADAM10 and blood metabolites, therefore the individuals in this cohort will undergo clinical evaluations, pathological and imaging techniques that will allow the accuracy in the diagnosis of AD. It is worth noting that the complementary tests used to diagnose Alzheimer's Disease have some limitations for clinical practice usage for being too invasive, or due to the high cost, as in the case of cerebrospinal fluid collection or neuroimaging capture. In this sense, OCT, ADAM10 and metabolic analysis would be less invasive tests, that are easier to reproduce and potentially accessible to the Brazilian Unified Health System, as they represent a lower cost. With that said, this study proposes longitudinal research that will evaluate the ability of OCT, through measurements of the retina, plasma ADAM10 and metabolic changes, to predict the risk that an individual with memory complaints has of progressing to dementia. The ability to prematurely identify people with the AD brings numerous benefits to the individual, family, and society, such as early intervention in disease risk factors, family planning and financial impact reduction. Furthermore, it allows public health planning for prevention and intervention in at-risk populations, socioeconomic damage reduction caused by the disease. (AU)