Imagine a wild dance party where cholesterol, myelin, and toxic proteins called Abeta are the star performers. In this chaotic event, myelin injury releases cholesterol, setting off a wild chain reaction that leads to Abeta dysmetabolism and the formation of amyloid plaques. This intricate interplay between white matter injury, cholesterol dysmetabolism, and Abeta dysmetabolism is thought to contribute to the development and progression of Alzheimer’s disease (AD). While the amyloid cascade theory has long been the leading hypothesis for AD, recent discoveries have shed light on the role of cholesterol in the disease. It turns out that an important genetic factor in AD, the apolipoprotein E type 4 allele (APOE4), is closely linked to cholesterol metabolism. Manipulating cholesterol levels in animal models has shown promising results in altering disease pathology and cognitive deficits. Moreover, studies have revealed that white matter injury is a hallmark of AD brains and can precede the formation of plaques and tangles. Restoring white matter integrity has even been shown to improve cognitive function in these models. So, whether it’s cholesterol playing a symphony with myelin or white matter injury taking the stage before plaques appear, there’s still much to uncover about the complex mechanisms behind AD. If you’re ready to dive into the fascinating world of Alzheimer’s research, check out the full article for all the juicy details!

We postulate that myelin injury contributes to cholesterol release from myelin and cholesterol dysmetabolism which contributes to Abeta dysmetabolism, and combined with genetic and AD risk factors, leads to increased Abeta and amyloid plaques. Increased Abeta damages myelin to form a vicious injury cycle. Thus, white matter injury, cholesterol dysmetabolism and Abeta dysmetabolism interact to produce or worsen AD neuropathology. The amyloid cascade is the leading hypothesis for the cause of Alzheimer’s disease (AD). The failure of clinical trials based on this hypothesis has raised other possibilities. Even with a possible new success (Lecanemab), it is not clear whether this is a cause or a result of the disease. With the discovery in 1993 that the apolipoprotein E type 4 allele (APOE4) was the major risk factor for sporadic, late-onset AD (LOAD), there has been increasing interest in cholesterol in AD since APOE is a major cholesterol transporter. Recent studies show that cholesterol metabolism is intricately involved with Abeta (Aβ)/amyloid transport and metabolism, with cholesterol down-regulating the Aβ LRP1 transporter and upregulating the Aβ RAGE receptor, both of which would increase brain Aβ. Moreover, manipulating cholesterol transport and metabolism in rodent AD models can ameliorate pathology and cognitive deficits, or worsen them depending upon the manipulation. Though white matter (WM) injury has been noted in AD brain since Alzheimer’s initial observations, recent studies have shown abnormal white matter in every AD brain. Moreover, there is age-related WM injury in normal individuals that occurs earlier and is worse with the APOE4 genotype. Moreover, WM injury precedes formation of plaques and tangles in human Familial Alzheimer’s disease (FAD) and precedes plaque formation in rodent AD models. Restoring WM in rodent AD models improves cognition without affecting AD pathology. Thus, we postulate that the amyloid cascade, cholesterol dysmetabolism and white matter injury interact to produce and/or worsen AD pathology. We further postulate that the primary initiating event could be related to any of the three, with age a major factor for WM injury, diet and APOE4 and other genes a factor for cholesterol dysmetabolism, and FAD and other genes for Abeta dysmetabolism.

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