Aging inevitably increases the amount of Aβ burden in the brain, implying a strong relationship between impaired Aβ metabolism and age (Funato et al., 1998). Since heterogeneity and multimorbidity are common in the elderly (Barnett et al., 2012), dementia likely originates from a combination of different pathological substrates. As the population ages, the distribution of AD shifts to older ages in developed countries (Hebert et al., 2013), resulting in an increasing number of demented patients with numerous complicated etiologies. Given that the balance between Aβ synthesis and clearance determines brain Aβ accumulation, and that Aβ is cleared by several pathways stated above, multi-drugs combination therapy would likely be necessary for sporadic AD with complicated etiologies. Combination therapy has already been applied to various diseases, such as hypertension, diabetes mellitus, and malignant tumors. The ultimate goal will be to develop a sovereign remedy of AD, and we hope that the recent rapid advances in drug development will enable us to delay the onset or modify the progression of cognitive impairment with multi-targeting therapies. Further investigation from various viewpoints will thus be essential for the development of novel treatment for AD and CAA.
