The relationship between cholesterol and Alzheimer’s disease has been predicted over the years. Such a hypothesis is the low metabolism for amyloid precursor protein and the general conclusion drawn that increased levels of cholesterol are directly proportional to the risk chances of developing and progressing Alzheimer’s disease AD.
AD is a product of a formulation of plaques- (β-amyloid (Aβ)) and the aggregation of tau proteins. There is no clinical trial that has shown successful therapies for clearing or preventing Aβ plaques, suggesting that to treat AD doctors may have to actively target tau aggregations and Aβ as well.
The science behind the study
According to Dr. Van der Kant et al, inhibitors of isoprenoid biosynthesis and cholesterol (statins) significantly reduce tau accumulation in iPSCs- induced pluripotent stem cells derived from FAD-familial AD patients with APP- amyloid precursor protein duplication and are meant to generate Aβ.
It was observed that attempting to reduce inhibiting biosynthesis was unable to reduce the accumulated tau. However, several mechanisms used to reduce cholesterol accumulation or biosynthesis effectively reduced tau accumulation. Reducing cholesterols stored in cells in form of esters was more effective in reducing tau accumulation rather than trying to reduce free cholesterols.
Aβ accumulation in the APP-null iPSC-derived neurons, as well as in the culture medium of APP-duplicated was effectively reduced by statins. By mutating the cholesterol-binding aspects in APP-null iPSC derived neurons and APP-duplicate triggered the statins to inhibit Aβ secretion and luckily did not interfere with tau reduction. This was a demonstration that statins’ ability to reduce tau accumulation is not dependent on APP or on Aβ.
Cytochrome P450 enzyme has a CYP46A1 component and facilitates the conversion of cholesterol to hydroxycholesterol that may be produced at the brain and blood barrier and disintegrated in the liver. An FDA-approved inhibitor of CYP6A1 Efavirenz reduced tau accumulation in both APP-null and APP-duplicated neurons and was found to be not as toxic to iPSC-derived astrocytes compared to statins.
According to a commentary by Tsai and Blanchard, the findings may offer an explanation of the conflicting reports surrounding the implications of statins on the progression and development of AD. They suggest that the medical approach of targeting CYP46A1 should be explored further as a potential AD intervention.
Alzheimer’s is an addition to the already long list of high cholesterol-related diseases that call for a lifestyle change and adherence to diets and exercise. The science behind the relationship between the two conclusively shows us how statins have played a valuable role in combating AD. CYP46A1 presents an interesting opportunity in dealing with the protection and management of AD and if explored further may as well be the next big medical break.
In the meanwhile stay healthy and try to reduce the cholesterol level and stay away from Alzheimer’s harm’s way.
van Dijk, G., van Heijningen, S., Reijne, A. C., Nyakas, C., van der Zee, E. A., & Eisel, U. L. (2015). Integrative Neurobiology of metabolic diseases, neuroinflammation, and neurodegeneration. Frontiers in neuroscience, 9, 173.
Crisby, M., Carlson, L. A., & Winblad, B. (2002). Statins in the prevention and treatment of Alzheimer’s disease. Alzheimer Disease & Associated Disorders, 16(3), 131-136.