Alzheimer’s Disease (AD) is the most prevalent dementia in the adults. It affects 35 million worldwide. Late onset AD (LOAD) involves multiple genetic and environmental factors. AD pathology includes accumulation of tangles, plaques, and lipid granules in the brain. To cite three key evidences that link lipid dys-homeostasis, endosomal abnormality with LOAD: (1). Two lipid species were elevated in vulnerable brain region of LOAD: cholesteryl esters, and the glycosphingolipid GM3. Cholesteryl esters are produced by the cholesterol storage enzyme acyl-CoA:cholesterol acyltransferase 1 (ACAT1). GM3 is enriched at the plasma membranes (PM) of neurons and other cells. Degradation of GM3 occurs by the lysosomal enzyme neuraminidase 1 (NEU 1). In the lysosomal storage disease sialidosis, neuraminidase is defective causing GM3 to accumulate. (2). The soluble, oligomeric form of amyloid beta causes synapse loss and interferes with the trafficking and transport of subcellular organelles, including endosomes and mitochondria, presumably by interacting with the cholesterol rich, sphingolipid rich membrane microdomains present in these organelles. (3). The protein ATP binding cassette protein A1 (ABCA1) plays a key role in removing excess cholesterol and other lipids from brain cells, and controls the lipidation of ApoE, the major lipid transport protein in the CNS. The ApoE4 allele is the major risk factor for LOAD besides aging. In mouse models, lacking ABCA1 worsens amyloidopathy while overexpressing ABCA1 reduces amyloidopathy. In humans, a loss-of-function mutation in ABCA1 is associated with high risk of AD. Unexpectedly, expression of ABCA1 depends on the lysosomal protease cathepsin D. Thus, LOAD may be considered as a special lipid disease that involves abnormal endosomal lipid trafficking. Niemann-Pick Type C Disease (NPCD) is a rare, pediatric, genetically recessive neurological disease. This disease causes progressive neurodegeneration, hepatomegaly, splenomegaly, and ultimately early death. Currently, this disease has no cure. The disease is caused by mutations in either Npc1 or Npc2. NPC1 and NPC2 work in concert to transport cholesterol out of the late endosomes/lysosomes to various cellular compartments, including PM, endosomes, and endoplasmic reticulum (ER). Loss of function in NPC1 or NPC2 results in lysosomal accumulation of cholesterol, sphingomyelin, GM3 and GM2, sluggish endosomal motility, lower lysosomal enzymes, and lower expression of ABCA1. In these aspects, NPCD bear striking resemblances with AD, and many experts consider NPC disease as “childhood Alzheimer’s disease”. ACAT1 is a resident enzyme located at the ER. It utilizes cholesterol arriving at the ER as substrate to produce cholesteryl esters. Lacking functional NPC1 or NPC2 considerably slows the transport rate of cholesterol from the late endosomes/lysosomes to the ER. However, significant amount of cholesterol can translocate from the PM to the ER as the substrate for AC...