Alzheimer’s Disease Research Grant Program

Congrats to our 2024 awardees

• 

  Yuhong Fu, MD

  The University of Sydney

  Bacterial Traces in Alzheimer’s Brains: Implications for Pathogenic Routes

  While Alzheimer’s disease (AD) is a primary neurodegenerative disease, pathomicrobes may contribute to neuroinflammation, amyloid plaque and phosphorylate tau formation, and neuronal damage through multiple mechanisms. We hypothesize that individual AD patients present different pathomicrobes, depending on the host’s susceptibility to certain chronic or repetitious infections. Despite being anatomically proximal to the brain, the eye-brain pathogenic route has not yet been investigated compared to mainstream studies on gut, oral, and nasal evidence. This project aims to seek ocular bacterial traces in postmortem AD brains. We will first detect the paucimicrobial DNAs in frozen samples of the orbitofrontal cortex, the brain region earliest impacted in AD and near the ocular apparatus. Translocated bacterial RNAs will be examined using a novel subcellular spatial transcriptomics method, detecting human brain genes and genes of ocular bacteria in formalin-fixed paraffin-embedded sections of the frontal cortex and dorsal pontine. The laLer structure contains the principal sensory trigeminal nucleus (innervating ocular area), locus coeruleus (impacted early in AD), and nucleus incertus (associated with cognitive functions). This project will provide a pioneering view of contextual brain changes in 

  AD cases with and without ocular paucimicrobial traces by comparing AD and healthy controls. Further detection of translocated bacterial proteins may be applied with multiplexing imaging. Project outcomes will warrant unique insights into whether the eye-brain pathogenic route contributes to AD, hence facilitating the repurposed translation of ocular findings in developing peripheral biomarkers and preventions for AD. Besides publication, online resources may also be generated for pathogenic-Alzheimer’s disease research community. 

• 

  Roger Lippé

  Centre Hospitalier Universitaire Sainte-Justine

  Molecular links between HSV-1 and APP

  Alzheimer's disease (AD) is a devastating neurodegenerative condition that currently affects an estimated 6.5 million Americans and 55 million individuals worldwide, with projections indicating this number could soar to 139 million by 2050. AD is characterized by neuronal death, cognitive decline, neuroinflammation, hyperactive glia,synaptic disruption, neurofibrillary tangles, alternative amyloid protein precursor (APP) processing, amyloid-beta (Aβ) oligomerization, and senile plaques. Familial AD, linked to mutations in the APP, presenilin 1/2, and ApoE genes, accounts for only 1-5% of all cases (1) but the root causes of non-familial AD remain elusive. Intriguingly, some evidence suggests an infectious etiology, particularly involving herpes simplex virus type 1 (HSV-1), which is present in the brains of most AD patients. Establishing a causal link is challenging, as both healthy and AD- affected individuals harbor this latent virus. However, recent studies demonstrating that HSV-1 can recreate AD hallmarks in tissue culture and animal models strongly support this emerging concept. This proposal explores the exciting possibility that HSV-1 directly impacts AD through its glycoprotein M (gM) and its interaction with the APP processing modulator ITM2B (Bri2). We aim to characterize how HSV-1 gM alters the expression levels of Bri2 and APP, their binding, intracellular localization, processing, and Aβ oligomerization in tissue culture and mice. This work will elucidate direct molecular links between HSV-1 and AD, ultimately enabling the design of innovative therapies targeting these host-pathogen interactions . 

• 

  Kamada Lwere

  Islamic University in Uganda

  Exploring the Gut-Brain Axis in Alzheimer's: Microbiome and Neuroimaging. 

  Alzheimer’s disease (AD) is a significant public health concern in sub-Saharan Africa, with a high prevalence and substantial societal burden. Recent evidence suggests that the gut microbiome may play a role in AD pathogenesis, with specific bacterial signatures associated with cognitive impairment. This study aims to investigate the gut microbiome profiles of AD patients compared to cognitively healthy controls in a diverse Ugandan population, integrating neuroimaging and cognitive assessments to elucidate the microbiome's role in 

  AD risk and progression. The study will recruit 55 AD patients, 55 individuals with mild cognitive impairment (MCI), and 55 matched controls. Participants will undergo rectal swab collection for gut microbiome profiling using metagenomic sequencing. A subset of AD participants will undergo MRI scans to assess neuroimaging biomarkers of neurodegeneration. Cognitive and psychological assessments will be conducted using validated tools. Integrative analyses will explore associations between microbial metrics, neuroimaging markers, and cognitive performance, with a focus on identifying microbial pathways linked to neuroinflammation and oxidative stress. The findings promise to provide mechanistic insights into the gut-brain axis in AD, contributing to the 

  development of microbiota-based interventions tailored to the unique environmental and genetic contexts of sub- Saharan Africa. The study's comprehensive dataset will serve as a foundation for future investigations into preventive and therapeutic strategies, informing global efforts to mitigate the burden of dementia. 

• 

  Panos Zanos, Ph.D.

  University of Cyprus 

  Sex-Specific Mechanisms of HSV-1 and EBV in Alzheimer’s Disease Risk 

  Viral infections, particularly members of the Herpesviridae family, have been associated with an increased risk of Alzheimer’s disease (AD). While research into the microbial pathogenesis of AD has identified mechanisms through which various viruses can modulate AD processes, critical questions remain unanswered: Can all these viruses contribute to AD development, and under what specific conditions each virus can contribute to AD development? Given that these viruses are widespread in the general population, why do some individuals develop AD while others remain resilient? Importantly, women face double the risk of developing AD compared to men, raising a crucial question: how do viral infections differentially affect women compared to men? This project employs an integrative approach combining in vivo experimental methods and systems bioinformatics to address these questions. We aim to investigate how Herpes Simplex Virus Type 1 (HSV-1) and Epstein-Barr virus (EBV), in combination with genetic predispositions (APOE variants), influence sex-specific AD susceptibility using transgenic mouse models. Our study will incorporate brain region-specific transcriptomic analyses, neuropathological assessments, and cognitive tests to determine how these factors interact to alter sex-specific AD risk. Additionally, using gonadectomized male and female APOE4 transgenic mice infected with EBV, we will examine how the absence of sex hormones (estrogen and testosterone) affects viral-mediated neuropathology and cognitive outcomes. For the first time, our studies will provide critical insights into how HSV-1 and EBV drive AD under specific genetic and hormonal conditions, laying the foundation for personalized, sex-specific therapeutic strategies for AD and enabling targeted prevention and treatment approaches. 

• 

  Kevin Zwezdaryk, MD

  Tulane University

  Intermittent infection and gut microbiota in Alzheimer’s Disease 

  The interplay between gut microbiome dysbiosis and Alzheimer’s Disease (AD) continues to be defined. Individuals with pre-clinical AD have different gut bacteria assemblages. Bacteria species level differences are associated with increased amyloid beta and tau levels. Less understood, is if changes in the gut microbiome are a consequence or cause of changes observed in the brain. This proposal posits that viral infections can be drivers of gut dysbiosis that may contribute to AD. Many common viral infections are known to alter the gut microbiome. It is unknown if diverse viruses impact gut dysbiosis in shared or unique mechanisms. We hypothesize that despite unique anatomical sites of infection, diverse viruses alter the gut microbiota in similar manners. 3xTg-AD mice will be used to determine if intermittent viral infection can drive the gut microbiome towards an “unhealthy” population. Corresponding alterations in blood metabolites will be monitored, focusing on the levels of branched chain and aromatic amino acids. These are neurotransmitters precursors. The changes will be correlated to amyloid beta and tau levels in the brain to determine if gut dysbiosis accelerates accumulation of classical AD hallmarks. A neurotropic virus, respiratory virus and peripheral organ virus will be used in these studies. The goal is to generate rigorous preliminary data for future NIH submissions. This project could potentially revealing novel therapeutic or preventative targets to prevent AD progression or interventions for those suffering from AD.