Cholesterol at the Center of Alzheimer’s Disease: A Unifying Hypothesis on the Pathogenic Mechanism

It is hypothesized that in most cases of sporadic late-onset Alzheimer’s disease (LOAD), the abnormally-elevated cholesterol level in brain neurons represents a critical caus­ative factor that drives the pathogenic processes of LOAD. Specifically, it is hypothesized that the abnormally-elevated neuronal cholesterol will disrupt mitochondrial structure and metabolic activity, resulting in ATP deficiency as well as reduced formation of neuroactive metabolic intermediates (such as mevalonate and geranylgeraniol) along the cholesterol synthesis pathway in brain neurons. In addition, the abnormally-elevated neuronal cholesterol will cause direct neuronal damage as well as other pathogenic changes in the brain, including increased formation and aggregation of amyloid (Aβ) plaques. It is speculated that Aβ accumulation and plaque formation in a majority of LOAD cases only represent a characteristic secondary pathological change, and are usually not the driving force in the pathogenesis of LOAD. As discussed in this paper, the abnormally-elevated neuronal cholesterol in conjunction with ATP deficiency and lack of neuroactive metabolic intermediates will not only cause learning and memory impairment, but will also reduce the formation of cholinergic vesicles and induce tauopathy. It is expected that these pathogenic changes are more readily seen initially in ischemia-sensitive neurons in the hippocampus and posterior parietal cortex, which is then followed by progressive neurodegenerative and atrophic changes in many other brain regions along with progressive cognitive decline. As explained in this paper, ApoE4 is a major risk factor in LOAD because ApoE4 has a drastically reduced ability than ApoE2 and ApoE3 to efflux excess cholesterol out of neurons. Overall, there is a large body of direct, indirect and circumstantial clinical and experimental evidence which jointly supports the cholesterol-centered hypothesis on the etiology and pathogenesis of LOAD.