In summary, this review highlights that 1) lysosomal dysfunction caused by genetic causes (PSEN1/2 mutations, APOE4 and variants of BIN1, PICALM or SOLR1), aging, or other factors such as accumulated Aβ or Tau fibril plays a critical role in initiating or amplifying the AD disease process. The gene discussed is PICALM; the disease is Alzheimer disease.