Why some neurologists are eyeing CETP inhibitors for Alzheimer’s

Conservative estimates say that around 14 million Americans will have been diagnosed with Alzheimer’s disease (AD) by 2060.^[] One area of emerging research is especially meaningful for neurologists, cardiologists, and physicians who treat dementia—that which investigates the cholesterol-dementia link.

Recent studies have indicated that cholesterol's role in neurodegenerative processes may be more substantial than previously understood. Consider the following:

• A report published in Brain highlighted disruptions in cholesterol homeostasis within the brain as a contributing factor to AD pathophysiology.^[]

• Excess neuronal cholesterol can lead to increased amyloid precursor protein (APP) processing, resulting in amyloid-beta accumulation.

• A study published in The Lancet identified high levels of low-density lipoprotein (LDL) cholesterol in midlife as a significant risk factor for dementia, attributing 7% of cases to elevated LDL levels.^[]

• Genetic studies have identified variants in the ATP-binding cassette transporter A7 (ABCA7) gene as risk factors for late-onset AD. ABCA7 is involved in lipid transport and homeostasis, and loss-of-function mutations in this gene have been associated with increased amyloid-beta production.^[]

On Instagram, neurologist Kellyann Niotis, MD, a neurodegenerative disorders specialists, said CETP inhibition is a "promising drug target for neurodegenerative disease prevention, especially in those that carry the ApoE4 gene."

Emerging evidence on next-generation drugs

According to board-certified physician Alok Mohta, MD, MBBS, emerging evidence suggests that CETP, a hydrophobic plasma glycoprotein, facilitates the transfer of cholesteryl esters from high-density lipoprotein (HDL) to other lipoproteins, influencing plasma lipid levels and potentially impacting cerebral cholesterol homeostasis.

However, as Marschall S. Runge, MD, Dean of the Medical School at University of Michigan, explains, “The relationship between LDL-C–lowering therapies and cognitive function is unclear, with mixed findings in the literature.”

In preclinical studies, CETP inhibitors have been observed to cross the blood-brain barrier and influence central nervous system cholesterol metabolism. For instance, a study involving CETP transgenic mice administered evacetrapib at a dose of 40 mg/kg intravenously revealed detectable levels of the drug in brain tissue as early as 30 minutes post-injection, with concentrations of 16.7 nmol/g observed. This finding suggests that evacetrapib may effectively inhibit cerebral CETP activity, modulating cholesterol dynamics within the brain.^[]

Clinical investigations

“The ApoE4 allele is a well-established genetic risk factor for Alzheimer's disease, influencing lipid metabolism and amyloid-beta deposition,” Dr. Mohta tells MDLinx. “CETP inhibitors could have a potentially beneficial role in such cases as well.”

A report from Alzheimer’s Research and Therapy indicates that individuals carrying the ApoE4 allele exhibit altered cholesterol transport, which may exacerbate amyloidogenic processes.^[] Inhibition of CETP has been proposed as a strategy to mitigate these effects by enhancing HDL-mediated cholesterol efflux, thereby reducing amyloid-beta accumulation and neuronal toxicity. ​

Nevertheless, the research on this class of drugs is still in its infancy, and as Dr. Runge says, “Genetic studies have linked CETP to cognitive function and certain forms of Alzheimer’s disease, but research in this area remains limited. So far, this connection has been explored mainly in animal models and in humans only through the effects of existing CETP-lowering drugs.”