ALZHEIMER DISEASE: WHAT’S NEW, WHAT’S TRUE?
Authors: Franczak Malgorzata 
Published: September 2024

Alzheimer’s Disease (AD) is a devastating disorder estimated to affect 55 million individuals worldwide with 6.2 million cases in the US. AD is a significant clinical problem and numbers are only expected to increase. Alzheimer’s disease is characterized by structural changes in the brain including abnormal amyloid beta (Aβ) and neurofibrillary tau aggregation, neuroinflammation, and neuronal death. There is no effective treatment for AD and AD-related dementia (ADRD). For decades, the hypothesis that brain deposition of the amyloid-beta (Aβ) peptide initiates AD has dominated research and clinical trials. However, the FDA- approved antibody treatments targeting Aβ have yet to show convincing evidence for slowing the progression of disease symptomatology3, including no benefit to women and ApoE4 carriers over a period of 1.5 years4. Treatment failures can be attributed, at least in part, to an incomplete understanding of the pathogenic mechanisms of AD, which underscores the urgent need to examine alternative pathogenic mechanisms and therapeutic targets for AD. AD has been increasingly recognized as a multifactorial and heterogeneous disease with multiple contributors to its pathophysiology, where neuroinflammation is considered one of the cardinal features of AD. Traditionally, the pathways of Aβ production and neuroinflammation have been considered independently; however, recent studies suggest that these processes may converge to promote the pathology associated with AD. Surmounting evidence supports chronic dysregulation in inflammatory and immune pathways as drivers of AD neurodegeneration and provides insights into possible microbial mechanisms involved in the onset and progression of AD. Mounting evidence implicates gut microbiome dysbiosis in AD, even at the preclinical/asymptomatic and prodromal stages of the disease. Links have been made between the gut microbiome and established biomarkers of AD, including Aß, ApoE status, and tau. Further, links between the gut microbiota and brain connectivity, as measured by functional magnetic resonance imaging (fMRI), have recently emerged but are poorly understood in AD. Our research group previously demonstrated cerebrovascular dysfunction in prodromal AD, correlated with cognitive dysfunction. Specifically, reduced cerebral blood flow (CBF) and cerebrovascular reactivity (CVR) are associated with lower cognitive functioning in prodromal AD. Findings from our recent cross-sectional study indicate that pro-inflammatory gut bacteria more abundant in prodromal AD are associated with reduced CBF and CVR and elevated arterial transit time (ATT). Conversely, beneficial gut bacteria, more abundant in normal controls, are associated with better CBF and CVR and shorter ATT. Further, we identified the bile acid and lipid metabolism modifying organism and the oral pathogen (causes gingivitis and periodontal disease), to be differentially abundant in prodromal AD and CU cohorts, respectively. These results are undeniably promising for the future of AD in many ways including novel mechanistic discovery, non-invasive diagnostic testing, and novel treatment targets.