ADVANCES AND CHALLENGES IN THE EARLY DIAGNOSIS OF ALZHEIMER'S DISEASE: THE INTEGRATED ROLE OF BIOMARKERS AND NEUROIMAGING

Abstract

Alzheimer's disease (AD) is the most common form of dementia, characterized primarily by the cerebral deposition of beta-amyloid peptides and the hyperphosphorylation of tau protein (p-tau)—processes that begin decades before the onset of clinical symptoms such as memory loss. Early diagnosis is essential for timely therapeutic intervention but is complex due to symptom overlap with normal aging and other neurodegenerative conditions. Biomarker research has revolutionized the field, enabling a biological definition of the disease. Cerebrospinal fluid (CSF) analysis has established itself as the gold standard, with reduced Aβ42 and increased p-tau levels constituting the "signature" of AD. However, lumbar puncture is invasive and has limited accessibility. In response to this limitation, plasma biomarkers have emerged as a promising, minimally invasive alternative; notably, p-tau217 has demonstrated superior diagnostic accuracy (AUC of 0.94–0.96) and a strong correlation with amyloid-PET positivity. Neuroimaging complements this assessment through Positron Emission Tomography (PET)—which detects Aβ and tau deposits as well as hypometabolism (FDG-PET)—and Magnetic Resonance Imaging (MRI), which monitors cerebral atrophy. Integrating these approaches, particularly via the A+T+N (Amyloid/Tau/Neurodegeneration) framework, is crucial for accurate classification and guiding clinical trials, thereby overcoming diagnostic challenges and fostering more effective AD management. The future of diagnosis lies in the validation of plasma assays and the widespread implementation of these methods.