Other Lipid-Related
Conditions

Research suggests that lower cholesteryl ester transfer protein (CETP) activity is
associated with a decreased risk for other cardiometabolic and neurodegenerative
diseases, including type 2 diabetes and Alzheimer’s disease.^1,2

NewAmsterdam Pharma is currently investigating CETP inhibition as a potential
treatment for these diseases.

Jump to:
Alzheimer’s Disease | Type 2 Diabetes

CETP Inhibition and Alzheimer’s Disease

Elevated cholesterol levels have been linked to an increased risk of Alzheimer’s disease later in life.³ The key link between lipid dysregulation and Alzheimer’s disease is the status of apolipoprotein E (ApoE), the key lipoprotein for cholesterol transport in the brain.⁴

The APOE4 variant is associated with less efficient cholesterol transport compared to APOE2 and APOE3 variants. APOE4 carriers have increased risk for both cardiovascular disease and Alzheimer’s disease.^3,5-6

Genetic studies suggest that CETP loss-of-function variants may be associated with reduced dementia risk, particularly in APOE4 carriers.² A Mendelian randomization analysis demonstrated that lower CETP activity is associated with higher total brain volume, decreased risk of Lewy body dementia, and reduced risk of Parkinson’s disease-associated dementia.²

We are conducting research on the potential for CETP inhibition to be a viable treatment strategy for dementia.

~25%

of people carry at least one copy of the APOE4 variant⁷

~60%

of patients with Alzheimer’s disease carry a copy of the APOE4 variant⁸

22%-45%

increased risk of cardiovascular disease in APOE4 carriers⁹

Cholesterol’s Role in Alzheimer’s Disease

Learn more about cholesterol and CETP inhibition’s role
in the brain and Alzheimer’s disease.

Definitions

Apolipoprotein E (ApoE): plays a role in how cholesterol is moved around within the body

APOE gene: provides the body instructions for how to make the protein

Amyloid plaques: a main feature of Alzheimer’s disease, amyloid plaques are clumps of amyloid-beta that accumulate in the brain, affect cell function and contribute to disease progression

Biomarker: a measurable molecule, signal or characteristic that can be used to understand how healthy or sick a person is or how they respond to a medicine

p-tau217: a specific type of p-tau and a reliable blood-based biomarker that can be used to help diagnose and monitor Alzheimer’s disease

Phosphorylated tau (p-tau): tau protein that has undergone chemical changes (addition of too many phosphate groups) that result in an increased tendency of the protein to clump together (also called pathological tau)

Tau tangles: also called neurofibrillary tangles, these clumps of pathological tau are a key marker of Alzheimer’s disease and are believed to contribute to disease progression by causing brain cells to die

Amyloid-beta: a protein found within the brain that can clump together, forming amyloid plaques. These proteins and plaques are key markers of Alzheimer’s disease and are believed to contribute to disease progression by causing brain cells to die

APOE2: A variant of the APOE gene. Individuals who carry this form of the gene have a lower risk of developing Alzheimer’s disease and are considered to have a protective genetic profile

APOE3: A variant of the APOE gene. This is the most common form and is considered the neutral reference allele, associated with average risk for developing Alzheimer’s disease

APOE4: a variant of the APOE gene. Individuals who carry this form of the gene have a higher risk of developing Alzheimer’s disease

p-tau217: a specific type of p-tau and a reliable blood-based biomarker that can be used to help diagnose and monitor Alzheimer’s disease

High-density lipoproteins (HDL): typically referred to as the ‘good’ cholesterol, HDL transports cholesterol from around the body back to the liver where it can be removed

Low-density lipoproteins (LDL): typically referred to as the ‘bad’ cholesterol, high concentrations of LDL cholesterol can cause it to build up in the arteries, raising the risk of serious medical conditions such as heart disease and stroke

Cholesteryl ester transfer protein (CETP): a protein produced by the liver and found in the blood and that plays a role in increasing levels of LDL-C

High-density lipoproteins (HDL): typically referred to as the ‘good’ cholesterol, HDL transports cholesterol from around the body back to the liver where it can be removed

Amyloid plaques: a main feature of Alzheimer’s disease, amyloid plaques are clumps of amyloid-beta that accumulate in the brain, affect cell function and contribute to disease progression

APOE4: a variant of the APOE gene. Individuals who carry this form of the gene have a higher risk of developing Alzheimer’s disease

Tau: a protein found in brain cells (neurons) that helps form their structure

Cholesterol’s Role in Alzheimer’s Disease

Learn more about cholesterol and CETP inhibition’s role
in the brain and Alzheimer’s disease.

Cholesterol is a Critical Component of the Brain…

Cholesterol is a key component of the brain and is essential to its function.¹ The brain makes all the cholesterol it needs and has its own ways of recycling and redistributing cholesterol.¹

Apolipoprotein E (ApoE), a protein encoded by the APOE gene, is essential for cholesterol transport within the brain and body, facilitating the delivery of cholesterol to cells that need it.²

20%

cholesterol

The brain contains ~20% of the body’s cholesterol despite making up only 2% of the body’s weight.¹ Unlike other organs, the brain produces most of its own cholesterol due to the blood-brain barrier.¹

…But if Present in Excess it Can Also Contribute to Alzheimer’s Disease

Cholesterol is an important part of brain cells and can influence cell processes. Disrupted cholesterol homeostasis in brain cells has been implicated in Alzheimer’s disease pathogenesis and development.² Research suggests that cholesterol dysregulation may influence the formation and accumulation of amyloid plaques and tau tangles (comprised of phosphorylated tau, or p-tau), which are hallmark features of Alzheimer’s disease.²

Amyloid and p-tau serve as biomarkers that can be measured to both diagnose Alzheimer’s disease as well as monitor its progression³

p-tau217, a specific type of
p-tau, is a reliable blood-based
biomarker that can be used to
help diagnose and monitor
Alzheimer’s disease⁴

Individuals that are APOE4 Carriers Have Problems with Cholesterol Regulation and are at a Higher Risk of Developing Alzheimer’s Disease

APOE2, APOE3, and APOE4 are variants of the APOE allele. APOE4 carriers have a higher risk of developing both cardiovascular disease and Alzheimer’s disease.²

Levels of p-tau217 in the blood, a key biomarker of Alzheimer’s disease, have been shown to increase drastically in APOE4 carriers after age 65 years⁶

APOE4 carriers

Transport and clear cholesterol less efficiently

Experience increased build up of fat (lipids) in the brain

Experience increased buildup of amyloid beta

Approximately 25% of the population carries at least one copy of the APOE4 allele.⁵ APOE4 carriers have approximately 3-4 times higher risk of developing Alzheimer’s disease.²

Problems With Cholesterol Regulation Affect Brain Cells in
Ways That Contribute to Alzheimer’s Disease

Disruption of communication
between brain cells⁷

Changes in how brain cells process glucose⁷

Increased inflammatory
responses⁷

Impaired ability of brain
cells to repair themselves⁷

The CETP Protein Facilitates The Movement of Lipids Between Different Transporters

Cholesterol is found throughout cells in the body, but it is not easy for it to move around from place to place. It must be ‘carried’ by lipoproteins.¹

High-density lipoproteins (HDL-C) act like ‘cleanup crews,’ collecting excess cholesterol from cells and tissues throughout the body and transporting it back to the liver for recycling or removal. This is why HDL cholesterol is called ‘good’ cholesterol⁸
Low-density lipoproteins (LDL-C) deliver cholesterol from the liver to cells throughout the body that need it for normal function. However, when LDL-C levels become too high, these particles can become trapped in artery walls, where they contribute to the formation of plaques that narrow blood vessels. This is why LDL cholesterol is called ‘bad’ cholesterol⁸

HDL
‘Good cholesterol’

LDL
‘Bad cholesterol’

The CETP Protein Facilitates The Movement of Lipids Between Different Transporters

Cholesteryl ester transfer protein (CETP) mediates the transfer of cholesteryl esters from HDL to apoB-containing lipoproteins (LDL).⁹

Specifically, CETP transfers cholesterol molecules from HDL to LDL¹⁰
Increased CETP activity can result in issues with cholesterol regulation and cause subsequent health problems¹¹

Preclinical research suggests that alterations in HDL and LDL balance may influence brain lipid metabolism and potentially affect cognitive function.¹¹

CETP Inhibition: Exploring Potential Therapeutic Applications

Preclinical research shows that CETP activity increases cholesterol in the brain and may impair cholesterol clearance mechanisms.¹⁰ In clinical trials, CETP inhibition has been shown to increase HDL cholesterol (‘good’ cholesterol) and reduce LDL cholesterol (‘bad’ cholesterol).⁹

Studies suggest that modulating cholesterol metabolism in the brain could influence neurological health¹

CETP Inhibition: Exploring Potential Therapeutic Applications

Addressing the root cause of dysregulated cholesterol within the brain may prevent the formation of amyloid plaques and tau tangles that contribute to Alzheimer’s disease.^1,2

Prevention of

Amyloid plaques

Tau tangles

This could potentially lead to
Alzheimer’s disease stabilization and
improved cognitive function in individuals
that are APOE4 carriers.³

1. Mahley RW. Central Nervous System Lipoproteins: ApoE and Regulation of Cholesterol Metabolism. ArteriosclerThrombVasc Biol. 2016;36(7):1305-1315. doi:10.1161/ATVBAHA.116.307023 2. Feringa FM, van der Kant R. Cholesterol and Alzheimer’s disease; from risk genes to pathological effects. Front Aging Neurosci. 2021;13:690372. doi:10.3389/fnagi.2021.690372 3. Reiman EM, Arboleda-Velasquez JF, Quiroz YT, et al. Exceptionally low likelihood of Alzheimer’s dementia in APOE2 homozygotes from a 5,000-person neuropathological study. Nat Commun. 2020;11(1):667. Published 2020 Feb 3. doi:10.1038/s41467-019-14279-8. 4. Palmqvist S, Janelidze S, Quiroz YT, et al. Discriminative Accuracy of Plasma Phospho-tau217 for Alzheimer Disease vs Other Neurodegenerative Disorders. JAMA. 2020;324(8):772–781. doi:10.1001/jama.2020.12134 5. Gharbi-Meliani A, Dugravot A, Sabia S, et al. The association of APOE ε4 with cognitive function over the adult life course and incidence of dementia: 20 years follow-up of the Whitehall II study. Alzheimers Res Ther. 2021;13(1):5. Published 2021 Jan 4. doi:10.1186/s13195-020-00740-0. 6. Martínez-Dubarbie F, Guerra-Ruiz A, López-García S, et al. Longitudinal trajectory of plasma p-tau217 in cognitively unimpaired subjects. Alzheimers Res Ther. 2024;16(1):268. Published 2024 Dec 20. doi:10.1186/s13195-024-01642-1. 7. Jeong W, Lee H, Cho S, Seo J. ApoE4-Induced Cholesterol Dysregulation and Its Brain Cell Type-Specific Implications in the Pathogenesis of Alzheimer’s Disease. Mol Cells. 2019;42(11):739-746. doi:10.14348/molcells.2019.0200. 8. Feingold KR. Introduction to lipids and lipoproteins. In: Feingold KR, Anawalt B, Boyce A, et al, eds. Endotext [Internet]. MDText.com, Inc; 2000–. Accessed July 14, 2024. https://www.ncbi.nlm.nih.gov/books/NBK305896/ 9. Sanders AE, Wang C, Katz M, et al. Association of a Functional Polymorphism in the Cholesteryl Ester Transfer Protein (CETP) Gene With Memory Decline and Incidence of Dementia. JAMA. 2010;303(2):150–158. doi:10.1001/jama.2009.1988 10. Oestereich F, Yousefpour N, Yang E, et al. The cholesteryl ester transfer protein (CETP) raises cholesterol levels in the brain. J Lipid Res. 2022;63(9):100260. doi:10.1016/j.jlr.2022.100260 11. Phénix J, Oestereich F, Munter L. Cholesterol metabolism in Alzheimer’s disease. Alzheimer’sDement. 2021;17(suppl3):e051134.

CETP Inhibition and Type 2 Diabetes

Statin therapy, the most widely prescribed lipid-lowering treatment, has been associated with increased diabetes risk in multiple studies. In a retrospective cohort study of 83,022 matched pairs of patients with diabetes, statin use was associated with a 37% increased relative risk of diabetes progression.¹⁰

Data suggest that CETP inhibition could be a promising approach to improve beta cell function in type 2 diabetes by reducing free cholesterol accumulation in ß-cell islets, which may contribute to ß-cell dysfunction.¹¹

In meta-analysis of four large randomized controlled trials, CETP inhibitors reduced new-onset diabetes risk in patients with cardiovascular disease or at high cardiovascular risk.¹ Additionally, individual trials have also shown improvements in glycemic parameters, including reduced HbA1c levels in patients with existing diabetes.¹²

NewAmsterdam Pharma is conducting research to evaluate the effects of CETP inhibition in people with type 2 diabetes.

Our Clinical Programs

Learn more about obicetrapib, our investigational novel CETP inhibitor

LEARN MORE

1. Dangas K, Navar AM, Kastelein JJP. The effect of CETP inhibitors on new-onset diabetes: a systematic review and meta-analysis. Eur Heart J Cardiovasc Pharmacother. 2022;8(6):622-632. doi:10.1093/ehjcvp/pvac025 2. Schmidt AF, Davidson MH, Ditmarsch M, Kastelein JJ, Finan C. Lower activity of cholesteryl ester transfer protein (CETP) and the risk of dementia: a Mendelian randomization analysis. Alzheimers Res Ther. 2024;16(1):228. Published 2024 Oct 16. doi:10.1186/s13195-024-01594-6 3. Feringa FM, van der Kant R. Cholesterol and Alzheimer’s Disease; From Risk Genes to Pathological Effects. Front Aging Neurosci. 2021;13:690372. Published 2021 Jun 24. doi:10.3389/fnagi.2021.690372 4. Mahley RW. Central Nervous System Lipoproteins: ApoE and Regulation of Cholesterol Metabolism. Arterioscler Thromb Vasc Biol. 2016;36(7):1305-1315. doi:10.1161/ATVBAHA.116.307023 5. Abondio P, Sazzini M, Garagnani P, et al. The genetic variability of APOE in different human populations and its implications for longevity. Genes (Basel). 2019;10(3):222. doi:10.3390/genes10030222 6. Jeong W, Lee H, Cho S, Seo J. ApoE4-induced cholesterol dysregulation and its brain cell type-specific implications in the pathogenesis of Alzheimer’s disease. Mol Cells. 2019;42(11):739-746. doi:10.14348/molcells.2019.0200 7. Gharbi-Meliani A, Dugravot A, Sabia S, et al. The association of APOE ε4 with cognitive function over the adult life course and incidence of dementia: 20 years follow-up of the Whitehall II study. Alzheimers Res Ther. 2021;13(1):5. Published 2021 Jan 4. doi:10.1186/s13195-020-00740-0. 8. Ward A, Crean S, Mercaldi CJ, et al. Prevalence of apolipoprotein E4 genotype and homozygotes (APOE e4/4) among patients diagnosed with Alzheimer’s disease: a systematic review and meta-analysis. Neuroepidemiology. 2012;38(1):1-17. doi:10.1159/000334607 9. Xu M, Zhao J, Zhang Y, Ma X, Dai Q, Zhi H, Wang B, Wang L. Apolipoprotein E gene variants and risk of coronary heart disease: a meta-analysis. Biomed Res Int. 2016;2016:3912175. doi:10.1155/2016/3912175. 10. Mansi IA, Chansard M, Lingvay I, Zhang S, Halm EA, Alvarez CA. Association of statin therapy initiation with diabetes progression: a retrospective matched-cohort study. JAMA Intern Med. 2021;181(12):1562–1574. doi:10.1001/jamainternmed.2021.5714. 11. Guo W, Gong Y, Fu Z, et al. The effect of cholesteryl ester transfer protein on pancreatic beta cell dysfunction in mice. Nutr Metab (Lond). 2016;13:21. doi:10.1186/s12986-016-0082-1. 12. Barter PJ, Rye KA, Tardif JC, et al. Effect of torcetrapib on glucose, insulin, and hemoglobin A1c in subjects in the Investigation of Lipid Level Management to Understand its Impact in Atherosclerotic Events (ILLUMINATE) trial. Circulation. 2011;124(5):555-562. doi:10.1161/CIRCULATIONAHA.111.018259.

Other Lipid-Related Conditions

CETP Inhibition and Alzheimer’s Disease

~25%

~60%

22%-45%

Cholesterol’s Role in Alzheimer’s Disease

Definitions

Cholesterol’s Role in Alzheimer’s Disease

Cholesterol is a Critical Component of the Brain…

…But if Present in Excess it Can Also Contribute to Alzheimer’s Disease

Individuals that are APOE4 Carriers Have Problems with Cholesterol Regulation and are at a Higher Risk of Developing Alzheimer’s Disease

APOE4 carriers

The CETP Protein Facilitates The Movement of Lipids Between Different Transporters

The CETP Protein Facilitates The Movement of Lipids Between Different Transporters

CETP Inhibition: Exploring Potential Therapeutic Applications

CETP Inhibition: Exploring Potential Therapeutic Applications

Prevention of

CETP Inhibition and Type 2 Diabetes

Our Clinical Programs

Other Lipid-Related
Conditions