Abstract: Advances in Alzheimer’s disease (AD) research have deepened our understanding, yet the mechanisms driving its progression remain unclear. Although a range of in vivo biomarkers is now available (e.g., measurements of amyloidbeta (Aβ) and tau accumulation – the molecular hallmarks of AD – structural magnetic resonance imaging (MRI), assessments of brain metabolism, and, more recently, blood-based markers), a definitive diagnosis of AD continues to be challenging. For example, Frisoni et al. (2022) proposed a shift from a deterministic, amyloidcentered approach to a probabilistic framework that integrates genetic and environmental factors. Similarly, Dubois et al. (2024) cautioned against diagnosing AD based solely on molecular markers in cognitively normal individuals, advocating instead for the designation of “at risk” individuals. These perspectives reflect an evolving understanding of AD that is continuously reshaping both clinical and pharmacological approaches. Moreover, the recent approval of two diseasemodifying agents (Lecanemab and Donanemab) that target misfolded Aβ proteins has underscored significant limitations, particularly their moderate impact on clinical and cognitive outcomes. The discrepancy between the improvements in AD biomarkers with anti-Aβ drugs and their limited clinical benefits underscores the need for a new paradigm. In this context, assessing Aβ levels can be compared to measuring blood pressure: just as high blood pressure does not inevitably lead to cardiovascular disease, and some individuals with the disease may not have elevated blood pressure, the multifactorial nature of AD suggests that Aβ accumulation alone does not define the disease.