Unveiling blood biomarkers for neuronal hyperplasticity: Insights from AD molecular subtyping, a comprehensive review

Abstract

Alzheimer's disease (AD) is the most prevalent neurodegenerative disorder, predominantly affecting the aging population. Early detection through biomarkers is essential for early intervention. Recent sub-classification of AD through extensive cerebrospinal fluid (CSF) proteomic analyses revealed distinct characteristics of each subtype, necessitating tailored therapeutic strategies. While CSF proteomics has identified potential biomarkers, the need for non-invasive and cost-effective substitutions highlights the importance of blood-based biomarkers (BBMs). This review is a comprehensive review that categorizes potential BBMs based on neuronal hyperplasticity (subtype 1), underlining their role in refining subtype classification and enabling precision medicine. Early AD is often marked by cortical and hippocampal hyperactivity, followed by hypoactivity during later stages of neurodegeneration. While the exact mechanisms remain unclear, factors like Ca2+, glutamate, amyloid beta, tau, genetic factors, and impaired glial function play a role. Advancements in blood-based diagnostics would improve detection, individual treatment strategies, and evaluation of therapeutic response, eventually reducing the burden of AD on health-care systems. HIGHLIGHTS: Alzheimer's disease (AD; subtype 1) exhibits neuronal hyperplasticity, mild cortical atrophy, and moderate microglial activation. The neuronal hyperplasticity subtype of AD is characterized by an upregulation of synaptic and plasticity-related proteins, distinguishing it from other AD subtypes. Identifying biomarkers specific to neuronal hyperplasticity would enable real-time monitoring of therapeutic responses, allowing for individualized therapy as opposed to a one-size-fits-all strategy. The treatments based on neuronal hyperactivity reduction, restoration of synaptic plasticity, and anti-inflammation/metabolic dysfunction would be useful in this AD subtype. Blood-based biomarkers offer a cost-effective and accessible alternative to cerebrospinal fluid and neuroimaging methods. © 2025 The Author(s). Alzheimer's & Dementia published by Wiley Periodicals LLC on behalf of Alzheimer's Association.