These lines of evidence, together with the absence of endosomes enlargement in other neurodegenerative diseases and in aging, as well as in advanced stages of familial form of AD caused by mutations in Presenilin‐1 or ‐2 (PSEN1/2) (Cataldo et al., 2000), strongly identified endolysosomal activation as a typical and early intracellular change occurring in sporadic LOAD, rather than a secondary effect of Aβ deposition. This evidence concerns the gene PSEN1 and Alzheimer disease.