Although enormous efforts have been made to develop anti–amyloid therapy against mild to moderate Alzheimer's disease (AD) dementia, no single drug has succeeded in clinical trials. These failures could be attributed to 1) inaccurate clinical diagnosis, and 2) inappropriate timing for intervention. The clinical diagnosis used in previous trials are clinical criteria with low sensitivity and specificity. Thus new criteria that incorporated biomarker results has been established. In addition, various longitudinal studies revealed that Alzheimer's disease develops dementia long after it's pathological starting point where almost 15 years of asymptomatic stage precedes mild cognitive impairment (MCI) due to AD or prodromal AD. This asymptomatic stage is now called “Preclinical AD” and thought to be a promising intervention period for anti–amyloid therapy. We started an observational study in Japan which is funded by the Japan Agency for Medical Research and Development (AMED) recruiting 500 individuals in total, that follows cognition, biomarker samples, and multimodal images for 3 years. Moreover, in the US, there are multiple drug intervention studies for preclinical AD subjects. Hopefully, these efforts could help developing AD prevention.