The Lipid Invasion Model of Alzheimer's Disease

Researchers here discuss a model of Alzheimer's disease that is centered around consequences of the age-related disruption of the blood-brain barrier. This barrier of specialized cells lines blood vessels in the central nervous system, and acts to control the passage of cells and molecules to and from the brain. Unfortunately, it becomes leaky with age, failing just like every other system and structure in the body. The researchers propose an interesting hypothesis, but it stands as one of many new ways to look at Alzheimer's disease. A great deal of theorizing has been provoked by the ongoing failure to make progress in the development of therapies to meaningfully slow or reverse the progression of this form of neurodegeneration. It remains to be seen as to whether any of it will lead to better roads forward.

We propose a new hypothesis for Alzheimer's disease (AD) - the lipid invasion model. It argues that AD results from external influx of free fatty acids (FFAs) and lipid-rich lipoproteins into the brain, following disruption of the blood-brain barrier (BBB). The lipid invasion model explains how the influx of albumin-bound FFAs via a disrupted BBB induces bioenergetic changes and oxidative stress, stimulates microglia-driven neuroinflammation, and causes anterograde amnesia. It also explains how the influx of external lipoproteins, which are much larger and more lipid-rich, especially more cholesterol-rich, than those normally present in the brain, causes endosomal-lysosomal abnormalities and overproduction of the peptide amyloid-β (Aβ). This leads to the formation of amyloid plaques and neurofibrillary tangles, the most well-known hallmarks of AD.

The lipid invasion model argues that a key role of the BBB is protecting the brain from external lipid access. It shows how the BBB can be damaged by excess Aβ, as well as by most other known risk factors for AD, including aging, apolipoprotein E4 (APOE4), and lifestyle factors such as hypertension, smoking, obesity, diabetes, chronic sleep deprivation, stress, and head injury. The lipid invasion model gives a new rationale for what we already know about AD, explaining its many associated risk factors and neuropathologies, including some that are less well-accounted for in other explanations of AD. It offers new insights and suggests new ways to prevent, detect, and treat this destructive disease and potentially other neurodegenerative diseases.