Cholesterol and the brain — can lowering it harm memory?

Aim of the study: Studies on the influence of lipid-lowering therapies have produced widely conflicting results about the role of cholesterol in memory function. However, recent studies have shown that cholesterol-lowering treatment substantially reduces the risk of dementia.

Results: Moreover, a high-cholesterol diet significantly impaired memory function while increasing serum cholesterol and brain AChE levels. There is no direct correlation between brain cholesterol levels or HMG-CoA activity and the regulation of memory function. However, there is a definite link between plasma cholesterol levels and AChE levels. Long-term changes in plasma cholesterol may be important for regulating memory function, which may in turn be mediated through a pathway regulated by AChE.

Aim of the study: Cholesterol is vital to normal brain function, including learning and memory, but its role is as complex as cholesterol synthesis, metabolism, and excretion. Dietary cholesterol influences learning tasks ranging from the water maze to fear conditioning, even though cholesterol does not cross the blood-brain barrier.

Results: There is also controversy over the use of statins to alleviate memory problems in Alzheimer's disease. Findings on the relationship between cholesterol and cognitive function are mixed, and association studies show that some genetic polymorphisms are related to cognitive function while others are not. In short, the field is in flux, with a number of seemingly contradictory results and many complexities. Nevertheless, the effects of cholesterol on learning and memory are too important to ignore.

Aim of the study: Proprotein convertase subtilisin/kexin type 9 (PCSK9) plays a role in hepatic cholesterol metabolism by promoting the degradation of low-density lipoprotein receptors. PCSK9 inhibitors have revolutionized lipid-lowering therapy by substantially reducing cardiovascular risk.

Results: Preclinical studies also suggest that PCSK9 is a key regulator of neurobiological processes, including synaptic plasticity, amyloid-beta clearance, neuroinflammation, and blood-brain barrier integrity. Human genetic studies have revealed complex, sometimes conflicting associations between PCSK9 variants and the risk of Alzheimer's disease, Parkinson's disease, vascular dementia, and amyotrophic lateral sclerosis. In this review, we highlight the pathophysiological mechanisms, emerging experimental therapies, and clinical implications of PCSK9 inhibition in neurodegenerative disorders. Long-term, adequately powered trials with robust neuropsychological, biomarker, and imaging endpoints, as well as mechanistic studies using human-derived models, are needed to establish the cardiovascular and neurocognitive implications of PCSK9 inhibition and guide precision medicine strategies for people at elevated risk of neurodegeneration.