Molecular Biomarkers in the Early Diagnosis of Alzheimer\'s Disease Beyond the Genetic Horizon

Lucas Silva^*
*Correspondence: Lucas Silva, Department of Biomedical Research, University of Rio de Janeiro, Brazil, Email:

Introduction

Alzheimer’s Disease (AD) is a progressive neurodegenerative disorder that leads to cognitive decline, memory loss, and behavioral changes, profoundly impacting the quality of life. The diagnosis of AD is often delayed until the disease has reached an advanced stage, at which point significant brain damage has already occurred. Early detection of Alzheimer's is crucial for effective intervention, especially as emerging therapies aim to slow disease progression and provide symptomatic relief. Traditionally, Alzheimer’s disease diagnosis has relied on clinical assessments, neuroimaging, and postmortem brain tissue analysis, but these methods often fail to detect the disease at its earliest, most treatable stages. Recently, the focus has shifted towards the identification of molecular biomarkers that could enable the early diagnosis of Alzheimer’s disease before significant neuronal damage occurs. While genetic biomarkers, such as the APOE ε4 allele, have been recognized for their association with AD risk, recent research is expanding the search to include non-genetic biomarkers that could provide additional diagnostic value, encompassing changes at the levels of proteins, metabolites, and other molecular signatures [1].

The growing emphasis on non-genetic biomarkers reflects the need to identify individuals at risk for Alzheimer's disease who do not carry the APOE allele, as well as to provide more personalized diagnostic tools for early intervention. Molecular biomarkers beyond genetic predisposition are revealing the complex biological processes involved in AD, including neuroinflammation, protein aggregation, and synaptic dysfunction. Advances in proteomics, metabolomics, and neuroimaging technologies have opened new avenues for identifying biomarkers that reflect these pathological processes in living individuals. For example, the detection of amyloid-beta (Aβ) plaques and tau protein tangles—hallmarks of Alzheimer’s pathology—has gained traction as biomarkers for early diagnosis. More recently, biomarkers related to neuroinflammation and synaptic dysfunction are being explored, as they might be present long before Aβ deposition. The combination of multi-omics approaches, which integrate genomics, transcriptomics, proteomics, and metabolomics, is expected to provide a more complete and precise understanding of Alzheimer's pathology, facilitating earlier diagnosis and better monitoring of disease progression [2].

Description

One of the most promising non-genetic biomarkers for Alzheimer’s disease is the Cerebrospinal Fluid (CSF) biomarkers, Particularly Amyloid-Beta (Aβ) and tau proteins. Amyloid-beta plaques, which are aggregates of the Aβ peptide, and tau tangles, which involve hyperphosphorylation of tau protein, are considered the pathological hallmarks of Alzheimer’s disease. Studies have shown that levels of Aβ42 in CSF decrease as amyloid plaques form in the brain, while tau levels rise as neurofibrillary tangles accumulate. Recent studies suggest that CSF tau and Aβ42 levels, when used together, could be indicative of early-stage Alzheimer’s disease, even before significant cognitive decline occurs. Furthermore, the ratio of Aβ42 to Aβ40, as well as the measurement of Total Tau (t-tau) and Phosphorylated Tau (p-tau), could provide valuable diagnostic insights. CSF biomarkers have shown strong predictive value in distinguishing Alzheimer’s from other types of dementia, such as Frontotemporal Dementia (FTD) and vascular dementia. However, while these biomarkers are crucial, they still have limitations, such as invasiveness in obtaining CSF samples and insufficient sensitivity and specificity when used in isolation. Therefore, combining CSF biomarkers with other diagnostic tools, such as neuroimaging or blood-based biomarkers, is becoming a critical strategy in early Alzheimer's diagnosis [3].

 

Recent advancements in blood-based biomarkers have significantly improved the potential for non-invasive early diagnosis of Alzheimer’s disease. Blood biomarkers offer advantages such as ease of collection, cost-effectiveness, and the ability to be repeatedly assessed over time. One of the most promising blood biomarkers is plasma amyloid-beta levels, which, although less sensitive than CSF markers, have shown potential in distinguishing individuals with Alzheimer’s disease from healthy controls. Another emerging biomarker is Neurofilament Light Chain (NfL), a protein released into the bloodstream following axonal damage. Elevated levels of NfL have been associated with neurodegenerative diseases, including Alzheimer's, and recent studies have shown that plasma NfL levels correlate with disease progression and may serve as an early indicator of Alzheimer's pathology. Furthermore, tau proteins in blood, specifically phosphorylated tau (p-tau181), have gained attention for their potential to reflect Alzheimer’s pathology. The development of blood-based assays for tau and amyloid biomarkers could transform Alzheimer’s diagnostics, enabling early identification and ongoing monitoring of patients without the need for invasive procedures like lumbar punctures or expensive neuroimaging [4].

In addition to proteins and genetic markers, the study of metabolomics and microRNA profiles is gaining traction as a promising avenue for Alzheimer's disease biomarker discovery. Metabolomics involves the comprehensive analysis of metabolites in biofluids such as blood, urine, and CSF, offering a snapshot of the biochemical processes occurring in the body. In Alzheimer's, changes in metabolic pathways related to energy production, oxidative stress, and neurotransmitter synthesis have been observed. For example, altered glucose metabolism, which can be measured by levels of lactate or pyruvate, is a well-known hallmark of Alzheimer's, as the brain’s ability to utilize glucose diminishes as the disease progresses. Lipids are another class of metabolites that are affected in Alzheimer’s disease, particularly phospholipids that are involved in the structural integrity of cell membranes. Early changes in these metabolic markers may be detectable long before clinical symptoms manifest, providing a window for intervention. Similarly, microRNAs, small non-coding RNA molecules involved in gene regulation, are being explored as potential biomarkers for Alzheimer's. Studies have shown that specific microRNA profiles are altered in Alzheimer’s patients and may play a role in regulating amyloid-beta production and tau phosphorylation. By analyzing these molecular signatures, researchers hope to identify a panel of biomarkers that can be used in combination with existing diagnostic tools for earlier and more accurate detection of Alzheimer’s disease [5].

Conclusion

In conclusion, the integration of molecular biomarkers beyond genetic factors is transforming the early diagnosis of Alzheimer's disease. Proteomic, metabolomic, and neuroimaging approaches are providing valuable insights into the pathophysiology of Alzheimer’s, particularly with respect to neuroinflammation, protein aggregation, and synaptic dysfunction. CSF biomarkers such as amyloid-beta and tau proteins, along with blood-based markers Like Neurofilament Light Chain (NfL) and Phosphorylated tau (p-tau181), offer promising non-invasive diagnostic tools. In addition, the growing field of metabolomics and the study of microRNAs are uncovering additional biomarkers that reflect disease processes at a biochemical level. Combining these diverse biomarkers into a unified diagnostic platform could enable earlier and more accurate detection of Alzheimer's, allowing for the implementation of disease-modifying therapies before irreversible brain damage occurs. As research continues to advance, the application of multi-omics approaches in the early diagnosis and monitoring of Alzheimer's disease will be critical in achieving personalized treatments tailored to the individual’s molecular profile. Early diagnosis, coupled with personalized treatment strategies, could significantly improve patient outcomes, delaying the onset of severe cognitive decline and enhancing the quality of life for individuals living with Alzheimer’s disease.

References

1. Kaur, J., R. Jacobs, Y. Huang, N. Salvo and C. Politis. "Salivary biomarkers for oral cancer and pre-cancer screening: A review." Clin Oral Investig 22 (2018): 633-640.

Google Scholar  Cross Ref Indexed at  

2. Adeoye, John and Yuâ?Xiong Su. "Artificial intelligence in salivary biomarker discovery and validation for oral diseases." Oral Dis 30 (2024): 23-37.

Google Scholar  Cross Ref Indexed at