Revolutionizing Alzheimer's Diagnosis and Management: The Dawn of Biomarker-Based Precision Medicine

Abstract

Alzheimer's disease (AD), a leading cause of dementia, presents a formidable global health challenge intensified by the aging population. This review encapsulates the evolving landscape of AD diagnosis and treatment with a special focus on the innovative role of fluid biomarkers. Pathologically, AD is marked by amyloid beta (Aβ) plaques and neurofibrillary tangles of hyperphosphorylated tau, which lead to synaptic dysfunction, neuronal loss, and cognitive decline. These pathological changes, commencing decades before symptom onset, underscore the need for early detection and intervention. Diagnosis traditionally relies on clinical assessment, neuropsychological testing, and neuroimaging techniques. However, fluid biomarkers in cerebrospinal fluid and blood, such as various forms of Aβ, total tau, phosphorylated tau, and neurofilament light chain, are emerging as less invasive, cost-effective diagnostic tools. These biomarkers are pivotal for early diagnosis, differential diagnosis, disease progression monitoring, and treatment response evaluation. The treatment landscape is shifting toward personalized medicine, highlighted by advancements in Aβ immunotherapies, such as lecanemab and donanemab. Demonstrating efficacy in phase III clinical trials, these therapies hold promise as tailored treatment strategies based on individual biomarker profiles. The integration of fluid biomarkers into clinical practice represents a significant advance in AD management, providing the potential for early and precise diagnosis, coupled with personalized therapeutic approaches. This heralds a new era in combating this debilitating disease.

Keywords: Alzheimer’s Disease; Amyloid Beta; Fluid Biomarker; Neurofilament Light Chain; Phosphorylated Tau.

Fig. 1. Neuropathological features of Alzheimer’s disease.

Fig. 2. Schematics of the AD continuum. (A) Amyloid proteinopathy is the initial neuropathological change of AD, which can be detected by amyloid PET or fluid biomarkers including Aβ42/40 and p-tau. (B) Anti-amyloid drugs, aducanumab, lecanemab, and donanemab, target amyloid. (C) The next stage is tau proteinopathy, which can be detected by tau PET or fluid biomarkers, including pT205 and MTBR-243. (D) Neurodegeneration can be monitored by anatomical brain MRI, FDG PET, or fluid biomarker NfL. (E) Finally, clinical symptoms appear. Medications including donepezil, rivastigmine, galantamine, and memantine, are targeting patients in this stage. Neuroinflammation, which can be monitored by GFAP, affects the progression of AD in diverse stages.

GFAP: glial fibrillary acidic protein, p-tau: phosphorylated-tau, PET: positron emission tomography, MTBR: microtubule-binding region, MRI: magnetic resonance imaging, CT: computed tomography, FDG: fluorodeoxyglucose, NfL: neurofilament light chain, AD: Alzheimer’s disease.