255-Latest therapeutics in CVD, APOE’s role in Alzheimer’s disease, familial hypercholesterolemia

New Section Introduction and Membership Program

In this section, the host introduces the podcast and discusses the membership program.

Introduction

• The podcast focuses on translating the science of longevity into accessible content for everyone.

• The goal is to provide the best content in health and wellness.

• A membership program has been created to offer more in-depth content.

• Benefits of the membership program will be explained at the end of the episode.

Membership Program

• A membership program is available for those who want to take their knowledge to the next level.

• More information about the benefits can be found at PeterAttiaMD.com/subscribe.

New Section Guest Introduction and Background

This section introduces John Casteline, his work in genetic research, and his role as a professor.

Guest Introduction

• John Casteline is a genetic researcher and clinician scientist.

• He is known for his work in familial hypercholesterolemia (FH) and lipid modulating drugs.

• Currently, he is a professor of genetic medicine at the University of Amsterdam.

New Section Familial Hypercholesterolemia (FH)

This section provides an overview of familial hypercholesterolemia (FH), its prevalence, and its significance in cardiovascular disease risk.

Definition and Prevalence

• FH is a form of hereditary heart disease, second most common after elevated LP little a.

• Elevated LP little a is highly prevalent in the population, leading to various forms of FH.

• FH becomes important in understanding therapeutic options for minimizing cardiovascular disease risk.

New Section Clinical Trials and C-Type Inhibitors

This section discusses clinical trials led by John Casteline and the history of C-Type Inhibitors.

Clinical Trials

• John has led several clinical trials, including Odyssey long-term and Odyssey outcomes studies.

• These trials established the safety and efficacy of PCSK9 inhibitors in treating FH and hypercholesterolemia.

C-Type Inhibitors

• C-Type Inhibitors have had an assorted history with previous versions being unsuccessful.

• The most recent version shows potential as a game-changer for cardiovascular disease, Alzheimer's disease, and type 2 diabetes.

New Section APO E and its Role

This section explores the role of APO E in cardiovascular disease risk, specifically focusing on the APO E4 gene variant.

APO E Protein

• APO E refers to both the gene and the protein it codes for.

• The discussion focuses on what the protein does and why APO E4 increases the risk of Alzheimer's disease and cardiovascular disease.

New Section Conclusion and Optimism

This section concludes the discussion with optimism about future therapeutic options for high-risk patients.

Summary

• The discussion provided surprising insights into FH, C-Type Inhibitors, and APO E.

• It is relevant to anyone interested in heart health and brain health.

• Therapeutic molecules specifically for high-risk patients may be available within five years.

Timestamps are approximate.

Familial Hypercholesterolemia (FH) and its Impact

In this section, the speaker discusses Familial Hypercholesterolemia (FH), a genetic disorder that affects cholesterol levels and increases the risk of cardiovascular disease.

FH in Holland and the Need for Organization

• FH is a condition that affects thousands of people listening to this podcast.

• The speaker was trained in Vancouver by Michael Hayden and started the lipid clinic in Amsterdam.

• Initially, about 60% of referrals to the clinic were for FH cases.

• The Netherlands has large provinces with consanguinity, leading to a higher prevalence of FH.

• A significant grant from the Dutch government helped start an active search for individuals with FH.

Early Onset and Symptoms of FH

• In Amsterdam, there were cases of mortality or severe anterior myocardial infarction (MI) in young men between ages 20 and 30.

• Many individuals with FH were physically fit but unaware of their high LDL cholesterol levels.

• Physical manifestations include tendon deposits, Arcus in the eye, and sometimes deposits on eyelids.

Risks Associated with FH

• The plaque formed in FH is soft and cholesterol-rich, often located proximal to coronary arteries.

• If such a plaque bursts, it can lead to complete occlusion or main stem occlusion, resulting in sudden death.

• Proximal left main or distal left main occlusions are referred to as "Widowmaker" due to their severity.

Defining Phenotype and Genotype of FH

This section explains how phenotype and genotype are used to define Familial Hypercholesterolemia (FH).

Phenotype Definition

• Family history of premature coronary disease is often present in FH families.

• Individuals with FH have elevated LDL cholesterol levels without other abnormalities.

• Elevated LDL cholesterol should also be found in first-degree relatives to construct a family tree.

Genotype Definition

• Due to overlap in LDL cholesterol levels between affected and unaffected family members, genetic testing is necessary.

• FH has a heterogeneous genetic set of causes, with over 3,500 different mutations associated with the condition.

• The presence or absence of specific mutations determines the genotype and confirms the diagnosis of FH.

The transcript provided does not contain timestamps for all sections.

The Diagnostic Importance of High Cholesterol in Children

In this section, the speaker discusses the diagnostic significance of high cholesterol in children and emphasizes the importance of ruling out other potential causes before diagnosing familial hypercholesterolemia (FH).

High Cholesterol in Children

• Elevated LDL cholesterol in children is primarily caused by FH, with primary hypothyroidism being the only exception.

• Other diseases such as type 2 diabetes, untreated thyroid disease, renal disease, etc., can also lead to elevated LDL cholesterol levels.

• It is crucial to rule out these secondary causes before diagnosing FH in children.

Prevalence of Genetic Causes

• In a cohort study involving 220 children with a three-generation family history of elevated LDL cholesterol, genetic testing revealed that 95% had a mutation associated with FH.

• This percentage is significantly higher than what is typically observed in adults.

• The clinical diagnosis of FH is more accurate in children compared to adults.

Mutations and Their Impact on LDL Receptors

• Mutations can occur in different genes related to LDL metabolism, including LDL receptor (LDLR), apolipoprotein B (APOB), and PCSK9.

• Each mutation affects the function or interaction between these components and leads to elevated LDL cholesterol levels.

• Mutations can either impair the binding between APOB and LDL receptors or result in an overactive PCSK9 protein that degrades LDL receptors.

Understanding Pathophysiology and Biomarkers

This section explains the pathophysiology behind mutations in genes related to LDL metabolism and how they contribute to increased levels of LDL cholesterol. It also provides an analogy using baseball mitts and balls to help visualize the process.

Pathophysiology of Mutations

• LDL particles have APOB proteins wrapped around them, and a specific region of the APOB protein binds to LDL receptors on liver cells.

• The complex formed by the binding of LDL particles and receptors is internalized into lysosomes for processing.

• PCSK9 protein, present alongside LDL receptors, regulates their degradation to maintain a balance in cholesterol metabolism.

Impact of Mutations on Biomarkers

• Mutations in APOB or LDL receptor genes disrupt the binding between APOB and LDL receptors, leading to familial defective APOB or FH.

• Mutations that result in an overactive PCSK9 protein cause excessive degradation of LDL receptors.

• In all three cases (APOB mutation, LDL receptor mutation, or PCSK9 gain-of-function mutation), there is a deficiency of functional LDL receptors, resulting in elevated levels of LDL cholesterol.

Diagnosis and Familial History

This section highlights the importance of diagnosing FH correctly by considering familial history. It emphasizes that if a child has high cholesterol and a family history of high cholesterol, it is crucial to investigate further.

Importance of Familial History

• When diagnosing FH in children with elevated LDL cholesterol levels, it is essential to consider their familial history.

• If the child's father or grandfather had high cholesterol as well, it strengthens the possibility of FH.

The transcript does not provide any additional information beyond this point.

New Section

In this section, the speaker discusses the observation of cases related to ATP binding cassette G5 G8 loss of function and its impact on management.

Observations of ATP Binding Cassette G5 G8 Loss of Function

• Two cases have been observed that appear to be ATP binding cassette G5 G8 loss of function.

• These cases are seen in individuals with familial hypercholesterolemia (FH).

• The levels of cytosterol and composterol in these individuals are significantly higher than the 95th percentile.

• This finding has implications for management decisions, such as considering nmi as a first-line treatment.

• It is likely that the observed mutations in ATP binding cassette G5 G8 are the driving mutation in these individuals.

New Section

In this section, the speaker discusses the frequency and prevalence of mutations in genes related to cholesterol disorders.

Frequency and Prevalence of Cholesterol Disorders

• Mutations in genes related to cholesterol disorders, including ATP binding cassette G5 G8, LDL receptor, and PCSK9, are relatively common in the general population.

• Familial hypercholesterolemia (FH) caused by these mutations is estimated to occur in approximately 1 in 250 individuals.

• Studies have shown that children with high cholesterol levels often have increased plant sterols and mutations in ABCG5/G8 genes.

• Cytosterolemia, previously considered rare at one in a million, may actually occur at a frequency of around one in 150,000.

• Heterozygous individuals with loss-of-function mutations in ABG5/G8 also exhibit increased cytosterol and composterol levels.

New Section

In this section, the speaker discusses the clinical presentation and physical signs associated with cholesterol disorders.

Clinical Presentation and Physical Signs

• Tendon xanthomas and cholesterol deposits in various parts of the body are common physical signs of cholesterol disorders.

• The accumulation of cholesterol in specific areas, such as extensor tendons over flexor tendons, is believed to be linked to movement.

• Tendons that are frequently used have a higher concentration of macrophages capable of storing LDL cholesterol.

• The most frequent locations for cholesterol deposits are the extensor tendon of the hands and Achilles tendon.

• Cholesterol deposits can also be found in other areas, such as the patella or even under wedding rings.

• Deposits on the eyes, specifically in the cornea (Arcus cornealis), may also be linked to movement, such as blinking.

New Section

In this section, the speaker shares an anecdote about diagnosing familial hypercholesterolemia (FH) based on physical signs observed in everyday situations.

Diagnosing FH Based on Physical Signs

• The speaker recounts a personal experience where they diagnosed FH by observing a blue-eyed stewardess with a ring deposit in her eye.

• Sometimes, paying attention to physical signs like extended tendons or xanthomas can lead to diagnosing FH even outside a clinical setting.

• Old Dutch paintings from the 17th century depict visible tendons and xanthomas on hands, providing historical evidence of these physical signs.

New Section

In this section, the speaker addresses whether clinical manifestations are necessary for diagnosing familial hypercholesterolemia (FH).

Diagnosis of FH Without Clinical Manifestations

• Clinical manifestations, such as xanthomas or Arcus, are not always present in individuals with FH.

• A diagnosis of FH can still be made based on elevated LDL cholesterol levels over a long period and a family history of elevated cholesterol or heart disease.

• In the absence of clinical signs, genetic testing can provide further confirmation.

The transcript does not provide timestamps for the remaining sections.

Elevated LDL Cholesterol and CT Angio

The speaker discusses the rarity of individuals with elevated LDL cholesterol levels who have normal CT angiography results at the age of 50. They mention that while there is an overlap between genetic factors and LDL cholesterol levels, it is important to consider other factors such as family history and additional lipid abnormalities.

Elevated LDL Cholesterol and Normal CT Angio

• Individuals with genetically elevated LDL cholesterol may not exhibit physical symptoms.

• It is rare for someone with elevated LDL cholesterol in their teens to have normal calcium scoring and CT angiography results at the age of 50.

• There is an overlap between genetic factors (heterozygous FH) and LDL cholesterol levels.

• Homozygous FH can also overlap with the end of the distribution of heterozygous FH.

• LDL alone cannot be used as a definitive marker for diagnosing heterozygous or homozygous FH; a syndrome diagnosis requires consideration of family history.

Differentiating Heterogeneous FH and Homogeneous FH

The speaker explains the difference between heterogeneous FH (polygenic hypercholesterolemia) and homogeneous FH (monogenic form). They discuss the severity of each condition, including premature myocardial infarction risk, and highlight that polygenic or heterogeneous FH is more common than monogenic heterozygous FH.

Polygenic Hypercholesterolemia vs. Monogenic Heterozygous FH

• Polygenic hypercholesterolemia can resemble heterozygous FH in terms of severe LDL cholesterol elevation.

• Premature myocardial infarction is more commonly associated with real heterozygous FH rather than polygenic or heterogeneous forms.

• Monogenic forms, especially those with severe LDL receptor gene mutations, are considered the most severe inherited hypercholesterolemia.

• Polygenic or heterogeneous FH is more common than monogenic heterozygous FH.

Dutch Lipid Clinic Criteria

The speaker discusses the Dutch Lipid Clinic criteria for diagnosing familial hypercholesterolemia (FH). They explain that these criteria have been externally and internally validated and are considered rigorous in predicting FH. The criteria include factors such as family history, LDL cholesterol levels, and genetic mutations.

Dutch Lipid Clinic Criteria

• The Dutch Lipid Clinic criteria were developed by Peter Lansberg and have been extensively validated.

• These criteria have shown superior predictive power compared to other diagnostic criteria for FH.

• Factors considered in the criteria include family history of premature coronary disease, high LDL cholesterol levels in first-degree relatives, presence of genetic mutations, and more.

• A diagnosis of definite FH requires a score above eight based on the criteria.

Treatment Considerations Based on Diagnosis

The speaker explains that the diagnosis of FH based on specific criteria has therapeutic implications. They mention that individuals with definite FH should be treated from the age of six according to national guidelines. The severity of the diagnosis determines the treatment approach.

Treatment Implications Based on Diagnosis

• Definite FH diagnosis leads to treatment initiation from age six according to national guidelines.

• Different categories of FH diagnosis (definite, probable, possible, unlikely) help divide patient populations for appropriate treatment strategies.

• Therapeutic consequences depend on the severity of the diagnosis.

This summary covers key points related to elevated LDL cholesterol, CT angiography results, differentiating heterogeneous and homogeneous forms of familial hypercholesterolemia (FH), Dutch Lipid Clinic criteria for FH diagnosis, and treatment implications based on the diagnosis.

Understanding Lipid Metabolism and Treatment Options

In this section, the speaker discusses the perception of lipid metabolism treatment options and the challenges in discussing them with parents. They also share a case study involving a mother with children at risk for familial hypercholesterolemia (FH).

Difficult Discussions with Parents about Treatment Options

• Many people may find it difficult to understand the importance of lipid metabolism treatment options if they are not familiar with the underlying pathophysiology.

• Discussing these options with parents can be challenging, as it depends on their previous experiences and family history.

Case Study: Mother and Children at Risk for FH

• In a Pediatric lipid Clinic, a mother in her 30s came with three children after her husband's death.

• One child had extremely high cholesterol levels (total cholesterol of 10), while another had normal levels, and the youngest had high cholesterol (around 300).

• The mother is concerned about her youngest child's health due to the inherited genes that caused her husband's premature death from heart disease.

Fraction of People Immune to FH Phenotype

This section focuses on estimating the fraction of people with familial hypercholesterolemia (FH) who do not develop premature cardiovascular disease. It also explores possible explanations for this phenomenon.

Estimating Immunity to FH Phenotype

• Based on long-term follow-up data from a large Dutch cohort, it is estimated that approximately 5% of people with FH show no disease symptoms at all.

• This includes individuals who do not exhibit any signs of coronary artery calcium scoring, CT angiograms, xanthelasmas, or arcus.

• The majority of those who seem immune to FH are women.

Possible Explanations for Immunity to FH Phenotype

• Women who are immune to the FH phenotype often have very high levels of HDL cholesterol.

• It is speculated that these individuals may have an efficient reverse cholesterol transport system, allowing them to effectively remove deposited LDL from macrophages and tendons.

• Additionally, these women are rarely smokers and seldom have diabetes, which further contributes to their lower risk of cardiovascular disease.

Monozygotic Twins and Lifestyle Factors

This section explores the potential impact of lifestyle factors on the progression of familial hypercholesterolemia (FH) by studying monozygotic twins with FH. However, due to the rarity of FH, there is limited data available for conclusive findings.

Limited Data on Monozygotic Twins with FH

• Amsterdam has one of the largest cohorts of monozygotic twins, but it is still challenging to gather enough data on twins with FH for meaningful conclusions.

• The rarity of FH makes it difficult to study the impact of lifestyle factors on disease progression in monozygotic twins.

Complexity of HDL Cholesterol Story

• While LDL cholesterol has a relatively straightforward relationship with cardiovascular disease risk, HDL cholesterol presents a more complicated picture.

• Elevated HDL cholesterol levels may not always indicate something beneficial; in some cases, it can be a biomarker for dysfunctional HDL particles associated with premature cardiovascular disease.

Complications in Interpreting Elevated HDL Cholesterol

This section delves into the complexities surrounding elevated HDL cholesterol levels and their interpretation. It highlights that elevated HDL cholesterol does not always indicate something positive and can be associated with dysfunctional HDL particles.

Challenges in Interpreting Elevated HDL Cholesterol

• When measuring elevated HDL cholesterol, it is unclear whether it signifies something beneficial, such as HDL's ability to remove lipids from foam cells and macrophages, or if it indicates a negative aspect.

• Research has shown that elevated HDL cholesterol can be a biomarker for dysfunctional HDL particles associated with premature cardiovascular disease.

SRB1 Mutations and Dysfunctional HDL

• Individuals with SRB1 mutations often have high levels of HDL cholesterol but still develop premature coronary disease.

• This highlights the complexity of interpreting elevated HDL cholesterol levels and their association with cardiovascular health.

These notes provide an overview of the main topics discussed in the transcript. For more detailed information, please refer to the specific timestamps provided.

Primary and Secondary Prevention in Treating Cardiovascular Disease

In this section, the discussion revolves around the differences in treating people based on sex, age, and level of disease at the time of diagnosis. The focus is on primary prevention (treatment when there are no discernible signs of disease) and secondary prevention (treatment after the presence of disease). The treatment approach for different groups such as men vs women and children vs adults is explored.

Treatment Approach for Children with Heterozygous FH (Familial Hypercholesterolemia)

• Starting at the age of six, it is important to emphasize a healthy lifestyle for children with heterozygous FH.

• Extensive anti-smoking training, dietary counseling for healthy choices, and encouragement for physical exercise are provided.

• Despite lifestyle measures being supportive rather than curative, early intervention is crucial to improve outcomes.

• Statin medication is initiated at the age of six.

• There used to be a preference for pravastatin due to its perceived mildness, but now there isn't much preference for a specific statin.

• Some prefer rosuvastatin due to its low starting dose options.

• The goal is to achieve an LDL below 130 mg/dL.

Modest Goals in Pediatric Treatment Approach

• There are differing opinions regarding target LDL levels in pediatric treatment.

• Some argue that more research needs to be done before setting lower goals like those seen in adults.

• Conservative approaches tend to have more modest goals while some pediatricians treat kids more aggressively.

• It's ironic that children naturally have very low LDL cholesterol levels during critical periods of development when their brains are developing.

Impact of Cholesterol Levels on Brain Development

• During important periods of brain development, cholesterol levels are virtually undetectable in children.

• This raises questions about the impact of low cholesterol levels on brain development and function.

The transcript provided does not have many timestamps available. I have included the available timestamps in the summary.

New Section

In this section, the discussion revolves around the use of a pcsk9 inhibitor in relation to cholesterol synthesis and LDL clearance. The potential impact on brain development and Alzheimer's disease is also mentioned.

Pcsk9 Inhibitor and Cholesterol Synthesis

• A pcsk9 inhibitor does not affect cholesterol synthesis but rather amplifies LDL clearance.

• This distinction changes the thinking regarding its implications.

• Other indications related to brain development and Alzheimer's disease are mentioned, although they are considered pre-clinical and of limited usefulness.

New Section

The focus here is on trials conducted in children with heterozygous FH (familial hypercholesterolemia) using various treatments such as statins and pcsk9 inhibitors.

Trials in Children with Heterozygous FH

• Multiple trials have been conducted in children with heterozygous FH, including those involving early Roku map everlocumap, Simvastatin plus acetamide, Brava, Rose superstatin, simvastatin, acetamine, and pcsk9 monoclonals.

• Interestingly, unlike adults who may experience myalgias and statin-related muscle symptoms, children do not exhibit these side effects.

• The absence of such side effects could be attributed to the fact that children do not read or pay attention to medication inserts.

• It is noted that even when using more potent statins like atorvastatin and rosubastatin, children still do not develop these symptoms.

New Section

This section discusses the long-term follow-up study comparing treated children with heterozygous FH to an untreated generation above them. The benefits of early treatment in protecting against premature death and coronary disease are highlighted.

Long-Term Follow-Up Study

• A follow-up study was conducted comparing children who received treatment for heterozygous FH to a generation above them who did not receive any treatment due to the absence of statins at that time.

• The treated children, now adults, showed no instances of heart attack, angina, or other coronary diseases.

• In contrast, the untreated generation experienced high rates of early mortality and coronary disease.

• Although this study is not a randomized controlled clinical trial, it provides evidence that treating from an early age can protect against premature death and coronary disease.

New Section

This section focuses on the approach taken for adult patients with or without disease and how aggressive treatment should be based on guidelines.

Treatment Approach for Adults

• For non-FH patients in adulthood, the treatment approach follows the guidelines' recommendations.

• When children with FH reach 18 years old, they are transferred from the Pediatric lipid Clinic to the adult lip Clinic.

• Treatment for adults typically involves using pcsk9 monoclonals, within glycerin, sidomite, and striving for the lowest LDL possible.

• Homozygous FH patients require high-dose statins (such as acidymite everlocumap) and may also benefit from regeneron ngptl3 monoclonal antibody therapy (effenakumab).

• Severe heterozygous FH refers to about 10% of patients who cannot achieve reasonable LDL levels even with triple therapy. These individuals may have additional mutations contributing to their more severe phenotype.

New Section

This section discusses challenges in achieving target LDL levels in severe heterozygous FH patients despite using multiple therapies. The role of apheresis as a potential option is mentioned.

Challenges in Severe Heterozygous FH

• Severe heterozygous FH refers to patients who cannot achieve LDL levels below 70 mg/dL, even with pcsk9 inhibitor, statin, and acetamide therapy.

• Approximately 10% of the overall heterozygous FH population falls into this category.

• The starting LDL level is linked to the severity of heterozygous FH, with a starting LDL above 300 indicating severe cases.

• Lowering LDL below 100 or even below 120 becomes challenging in these individuals due to the initial high baseline levels.

New Section

This section explores the viability of apheresis as a treatment option for severe heterozygous FH patients.

Apheresis as a Treatment Option

• Apheresis, which involves removing lipoproteins from the blood, is considered a viable option for severe heterozygous FH patients.

• An aphoresis Center in Amsterdam has been established for this purpose.

• While it works well for LP little a, its effectiveness for the majority of APO B bearing lipoproteins is also acknowledged.

• However, there is hope that quadruple therapy involving everlocumap can reduce reliance on apheresis in many cases.

New Section

This section provides information about the dosing frequency and administration method of everlocumap (a pcsk9 inhibitor) and discusses potential improvements in drug delivery.

Dosing Frequency and Administration Method

• Everlocumap is currently administered intravenously once a week.

• Efforts are being made to develop a subcutaneous formulation to improve ease of administration.

• The challenge lies in finding suitable veins for intravenous administration in children who may have limited venous access due to their age.

The Likelihood of Patients with FH Getting Heart Disease

In this section, the speaker discusses the likelihood of patients with familial hypercholesterolemia (FH) developing heart disease and addresses criticisms regarding the causal relationship between LDL cholesterol and heart disease.

Patients with FH as a Stick to Beat Others

• Some people argue that if LDL cholesterol is truly causal in heart disease, it would be impossible for individuals with FH not to develop heart disease.

• The speaker explains that most genetic diseases, including FH, can be modified by other environmental and genetic factors.

• There are critics who refuse to accept that LDL cholesterol is harmful and use these exceptions among FH patients as an argument against its causality.

• However, the speaker emphasizes that in their experience working with FH families, they have seen heartbreaking cases where individuals with a single gene mutation causing elevated LDL cholesterol die at a young age.

Comparing High LDL Cholesterol to Smoking and Lung Cancer

This section draws a comparison between high LDL cholesterol and smoking in terms of their causal relationship to diseases like coronary artery disease and lung cancer.

Similarities Between High LDL Cholesterol and Smoking

• People often point out that some individuals have high LDL cholesterol or high APO B levels but do not develop coronary artery disease.

• The speaker compares this observation to the fact that there are people who smoke their whole lives without getting lung cancer, while others who never smoke do get lung cancer.

• These facts do not diminish the causal case for smoking and lung cancer. Similarly, they do not diminish the evidence supporting the role of high LDL cholesterol in heart disease.

Introduction to CTP Inhibitors

This section introduces CTP inhibitors, a class of drugs that have shown potential in treating heart disease.

Background on CTP Inhibitors

• The speaker mentions a previous discussion with Dan Raider about CTP inhibitors.

• CTP (Cholesteryl Ester Transfer Protein) was discovered by Phil Barter and is found in rabbits, which develop atherosclerosis when given cholesterol.

• Strategies to lower CTP activity have been tested in rabbits, including s-i-rna gene therapy, small molecules, and antibodies against ATP. Lowering CTP activity has been successful in curing atherosclerosis in these animals.

• In Japan, there are individuals with a mutation in the CTP gene who have very low levels of CTP. Initially, it was observed that these individuals lived longer and were free of coronary artery disease.

Loss of Function of CTP as a Longevity Gene

This section discusses the loss of function of the CTP gene as a longevity gene and its potential health benefits.

Loss of Function Mutation in the CTP Gene

• Individuals with a loss-of-function mutation in the CTP gene were initially found to live longer and be free from coronary artery disease.

• This led to the belief that loss-of-function mutations in the CTP gene could confer longevity and improve overall health.

• Similar to PCSK9 loss-of-function mutations, which are also associated with improved health outcomes.

Role of CTP in Cholesterol Metabolism

This section explains how CTP functions in cholesterol metabolism and its impact on HDL and LDL cholesterol levels.

Functionality of CTP Protein

• The speaker describes how the CTP protein interacts with cholesterol metabolism.

• The protein sits on top of HDL particles like a cap and grabs a cholesterol ester molecule from HDL.

• When an LDL particle collides with the HDL particle, the CTP protein spits the cholesterol ester molecule into LDL through a tunnel.

• As a result, HDL cholesterol levels decrease while LDL cholesterol levels increase.

Evolutionary Perspective on Cholesterol Conservation

This section discusses an evolutionary perspective on genes related to cholesterol conservation and their potential impact on health.

Evolutionary Funnel and Cholesterol Conservation Genes

• The speaker explains that during the last ice age, humans went through an evolutionary funnel where being thrifty and conserving energy was favored.

• Genes like PCSK9, CTP, and ANGPTL3 were likely selected during this period to conserve energy and cholesterol.

• However, in modern times, these genes may no longer be beneficial for health.

• The speaker suggests that we may not need PCSK9 or CTP genes anymore.

The transcript provided is in English.

The Impact of High Activity of cgp on Health Conditions

This section discusses the impact of high activity of cgp on various health conditions such as heart disease, heart failure, kidney disease, diabetes, and Alzheimer's.

High Activity of cgp and Health Conditions

• Studies have shown that people with high activity of cgp are more prone to developing heart disease, heart failure, kidney disease, diabetes, and Alzheimer's.

• Pfizer recognized the potential market for a new drug targeting cgp due to the upcoming expiration of atorvastatin's patent. They developed a ctap inhibitor called torsetropip.

Understanding Side Effects in Drug Development

This section highlights the importance of understanding side effects during drug development and the consequences of overlooking them.

Importance of Understanding Side Effects

• Pfizer made a mistake by not understanding why blood pressure increased in patients during phase two trials of torsetropip. They moved forward with the drug without fully comprehending this side effect.

• The outcome trial with dorsetta Pip also faced unexpected negative outcomes despite initial optimism based on HDL cholesterol increase. It was later discovered that the drug had off-target effects leading to adverse reactions in patients.

Uncovering Off-Target Effects and Adverse Reactions

This section discusses how off-target effects can lead to adverse reactions in patients and shares an example from a failed trial.

Off-Target Effects and Adverse Reactions

• The trial with dorsetta Pip revealed that the drug had off-target effects, causing blood pressure to increase in rats within 10 minutes of infusion. This indicated that the drug affected adrenal function, aldosterone production, cortisol production, and endothelial cells. These effects were undesirable for secondary prevention patients.

• The discovery of off-target effects and adverse reactions marked an unfortunate beginning for a new story in the field of cardiovascular disease treatment.

Lessons from Drug Failures

This section discusses two examples of drug failures (torsetropip and vioxx) and highlights the importance of timely action and understanding side effects.

Lessons from Drug Failures

• Torsetropip's failure demonstrated the need to understand side effects before advancing a drug to phase three trials. Neglecting this crucial step can lead to significant setbacks in drug development.

• Vioxx, despite its potential as a cox-2 inhibitor, was removed from the market due to its adverse effects on blood pressure and increased risk of events in certain patients. The delayed response by Merck resulted in losing a potentially valuable drug.

The End of HDL Hypothesis

This section discusses how a specific drug marked the end of the HDL hypothesis and challenges previous beliefs about HDL cholesterol's protective role.

The End of HDL Hypothesis

• Roche's drug, which raised HDL cholesterol by 35%, had no effect on LDL cholesterol or other markers of cardiovascular outcomes. This finding challenged the HDL hypothesis and indicated that HDL cholesterol alone does not translate into a reduced risk of heart attacks or strokes.

• Mendelian randomizations studies further confirmed that genes influencing HDL cholesterol levels were not causally linked to atherosclerotic cardiovascular disease (ascvd).

Conclusion

The transcript highlights the impact of high activity of cgp on various health conditions and emphasizes the importance of understanding side effects during drug development. It also discusses examples of drug failures, such as torsetropip and vioxx, due to adverse reactions and delayed actions by pharmaceutical companies. Additionally, it challenges the HDL hypothesis by demonstrating that raising HDL cholesterol alone does not lead to a reduction in cardiovascular events.

The Effect of CTP Inhibitors on LDL Cholesterol and ACVD

This section discusses the impact of CTP inhibitors on LDL cholesterol and atherosclerotic cardiovascular disease (ACVD).

The Trial with Merck's Drug

• Merck was the third company to develop a CTP inhibitor drug.

• There was uncertainty about whether the trial should focus on HDL cholesterol increase or LDL cholesterol decrease.

• Merck conducted a 30,000 patient trial, which remains the largest cardiovascular outcome trial to date.

• The drug only lowered LDL by 17%, with a baseline LDL of 60 mg/dL.

• The trial validated that CPP inhibition lowers heart attacks through its effect on LDL lowering.

Finding a More Potent CTAP Inhibitor

This section highlights the search for a CTAP inhibitor that is more potent than dorsetropip and robustly lowers LDL.

Discovering Mitsubishi's Drug

• A more potent CTAP inhibitor was needed to repeat the anacetrapip trial with a larger effect size.

• Mitsubishi had developed such a drug, which met the criteria of being potent and effectively lowering LDL.

The Thrifty Gene Hypothesis and Resource Constraint Environment

This section explains the Thrifty Gene hypothesis and how it relates to our species' transition towards preserving apob due to resource constraints.

The Thrifty Gene Hypothesis

• The Thrifty Gene hypothesis is often used to explain why people in Asia get type 2 diabetes at lower BMIs compared to other populations.

• It suggests that populations who experienced more famine have adapted to preserve resources, including apob.

• Our species spent millions of years in an environment where resource preservation was crucial, leading to effective LDL clearance and cholesterol transportation.

The Consequences of Resource Abundance

This section discusses how the abundance of resources has led to consequences such as obesity and insulin resistance.

The Impact of Resource Abundance

• With the shift towards an environment abundant in resources, genes that were advantageous in the past, such as those related to LDL clearance, can now have negative effects.

• Similar to apoe4, which offered protection against infections but is now associated with cardiovascular and neurodegenerative risks, high LDL levels may have been advantageous during the Ice Age for protection against bacterial infections.

FH Mouse Resistance Against Bacterial Infection

This section explores the resistance of FH mice against bacterial infection and its implications for understanding FH prevalence.

FH Mouse Resistance

• Mice with heterozygous familial hypercholesterolemia (FH) show better resistance against bacterial infection compared to non-FH mice.

• This suggests that FH may not have been as severe a disease in 1860 as it is today.

• High LDL levels might have provided protection against bacterial infections during the Ice Age.

APO E4's Parallel Story

This section draws parallels between APO E4 and apob preservation, highlighting their shared evolutionary history.

APO E4's Protection Against Infections

• APO E4 isoform was prevalent until around 200,000 years ago and offered remarkable protection against infections.

• With longer lifespans and increased insults on health, APO E4 became a predisposing factor for cardiovascular and neurodegenerative risks.

Obasipatrib and Drug Discovery

This section discusses the discovery of obasipatrib and provides insights into the process of drug discovery.

Discovering Obasipatrib

• The speaker was invited by Mitsubishi to evaluate their pipeline, where they discovered obasipatrib.

• The speaker emphasizes that they are a scientist and not a salesman but considers themselves lucky to find this drug.

The transcript provided limited information, and some sections may require further context for a comprehensive understanding.

Inhibition of CTP and its effects on cholesterol levels

The speaker discusses the use of a potent CTP inhibitor that results in a 97% inhibition of CTP. This leads to a significant reduction in LDL cholesterol levels by about 50% when combined with high-intensity statins. Additionally, there is an increase in HDL cholesterol levels by 165%. However, it is important to note that the increase in HDL cholesterol does not have any impact on heart attacks or strokes.

• The speaker emphasizes that they are not only developing the drug but also conducting scientific research to understand the genetic and epidemiological data related to various diseases such as Alzheimer's, age-related macular degeneration, septicemia, and diabetes.

• Inhibiting CTP not only stops the transfer of cholesterol from HDL to LDL but also alters lipoprotein metabolism and stimulates the liver to produce more Apple A1.

• Apple A1 plays a crucial role as it is recognized by ABC A1, the cholesterol pump on cell membranes, which exports cholesterol.

• Increased production of Apple A1 leads to the formation of pre-beta HDL particles and small HDL particles that remove cholesterol from peripheral tissues.

• This process is particularly important for beta eyelid cells in the pancreas. High levels of Apple A1 help remove excess cholesterol from these cells, preventing lipotoxicity and cell death associated with type 2 diabetes.

Relationship between CTP inhibitors and diabetes

The speaker explains how all four CTP inhibitors have shown a decrease in diabetes cases compared to placebo groups in outcome trials. By inhibiting CTP, these drugs prevent lipotoxicity in beta eyelid cells, reducing inflammation and apoptosis. This finding has been supported by meta-analyses.

• The speaker suggests that regardless of the specific CTP inhibitor used, there is an increase in heterotypic exchange between APO bees and apoons.

• Heterotypic exchange refers to the transfer of cholesterol molecules between different lipoprotein particles.

• Inhibition of CTP disrupts the balance of lipoprotein removal by the liver and production of small HDL particles, resulting in a new equilibrium.

• To achieve this effect, CTP needs to be inhibited by approximately 90%, similar to homozygous patients in Japan who have half LDL and triple HDL levels.

Potential benefits of CTP inhibitors beyond heart disease

The speaker discusses the potential applications of CTP inhibitors beyond heart disease. Specifically, they mention research on septicemia and its relationship with loss-of-function variants in CTP. These variants have been associated with improved protection against septicemia-related mortality.

• Two research groups from Vancouver and Leiden have shown that individuals born with loss-of-function variants in CTP are better protected against septicemia.

• There is a strong interest in testing the drug's effectiveness in treating septicemia based on these findings.

• Additionally, there may be indications that untreated familial hypercholesterolemia (FH) patients have lower mortality rates due to septicemia. However, more research is needed to fully understand this relationship.

Scavenging function of lipoproteins during septicemia

The speaker explains how low levels of CTP during septicemia can lead to high levels of HDL cholesterol. This may be beneficial as HDL particles can act as sinks for toxins and other harmful substances during infection.

• Low levels of CTP result in sustained high levels of HDL cholesterol during septicemia.

• HDL particles likely function as scavengers, helping to remove toxins and other harmful substances from the body.

• The speaker shares their personal experience of witnessing a drop in HDL cholesterol levels in ICU patients during septicemia, highlighting the potential importance of maintaining high HDL levels during infection.

The transcript is already in English.

The Function of HDL and CTP Inhibition

This section discusses the function of HDL and the impact of CTP inhibition on cholesterol removal. It emphasizes that high cholesterol is not necessarily good, but rather, it is important to focus on the function and regulation of cholesterol.

HDL and Cholesterol Removal

• HDL plays a crucial role in removing cholesterol from the body.

• Merely having high levels of cholesterol does not indicate its beneficial effects.

• CTP inhibition increases the capacity to dispose of toxic waste by raising HDL levels.

Diabetes Protection with HDL

• The drug known as The Rose Drug has been proven to raise HDL without lowering LDL.

• This drug has shown a protective effect against diabetes.

• Raising HDL with CTP inhibition is believed to protect against apoptosis in bronchios, reducing the risk of new-onset type 2 diabetes.

Comparison with Statins

• The effect of raising HDL through CTP inhibition on diabetes is comparable to the negative effect statins have on diabetes at higher doses.

• Obesetrapy, a CTP inhibitor impacting both heterotypic and homotypic exchange, shows promising potential but lacks extensive research compared to other drugs.

Optimism and Potential Risks

This section addresses concerns about being too optimistic due to past failures in similar studies. It also highlights the progress made so far in clinical trials for this drug.

Past Failures and Optimism

• Previous attempts at developing similar drugs have resulted in consecutive failures.

• Despite this track record, there is optimism based on positive results from phase two trials.

Progress in Clinical Trials

• Phase one and phase two trials have been completed successfully without any observed side effects.

• Phase three trials are currently underway, with randomized trials planned for this year.

• The outcome trial is being conducted simultaneously with lipid trials to demonstrate robust LDL lowering and safety.

Potential Risks

• The greatest risk of the drug not panning out lies in the uncertainty of large-scale phase three studies.

• However, the drug has shown good tolerability, significant LDL reduction comparable to injectables, and no observed side effects so far.

Cost and Accessibility

This section discusses the cost-effectiveness and accessibility of the drug compared to other treatments. It emphasizes the importance of affordability and ease of use for patients.

Cost-effectiveness

• The drug is cheap to manufacture, costing only $36 per year when produced in large quantities.

• This affordability allows for reasonable pricing and ethical distribution.

Accessibility and Ease of Use

• The goal is to have a drug that can be used alongside statins or in fixed-dose combinations.

• The drug should have robust LDL-lowering effects with minimal side effects.

• Its small pill size makes it easy to incorporate into patients' daily medication routines.

Phase Three Trials

This section provides an overview of the three ongoing phase three trials (Broadway, Brooklyn, Prevail) that are evaluating the efficacy and safety of the drug.

Broadway Trial

• Involves 2400 high-risk patients with a one-year duration.

• Focuses on assessing the drug's effectiveness in reducing cardiovascular events in patients with ASCVD (atherosclerotic cardiovascular disease).

Brooklyn Trial

• Aims to evaluate the impact of the drug on LDL levels in patients who have already experienced a heart attack or stroke.

Prevail Trial

• Investigates whether adding this new drug to standard therapy can further reduce cardiovascular events in patients with ASCVD.

The transcript provided does not cover the details of each trial, but only mentions their existence and purpose.

[t=1:28:26s] Difference in Mace and Biomarker Study

The discussion focuses on the difference in Mace (Major Adverse Cardiovascular Events) and whether the study is powered for Mace or if it is just a biomarker study. The trial is not specifically powered for Mace, but events are being adjudicated, and they expect about 120 events in total. They hope to see a trend indicating a significant difference between the two groups.

Is the Study Powered for Mace?

• The trial is not specifically powered for Mace.

• Events are being adjudicated, and they expect about 120 events in total.

• They hope to see a trend indicating a significant difference between the two groups.

Descriptive Analysis

• The analysis will be descriptive rather than statistical due to FDA regulations.

• Similar studies like glycerin showed about a 30% difference in events, which indicates movement in the right direction.

• Everyone hopes to observe positive trends in the study.

[t=1:28:50s] Randomization and Significant Difference

This section discusses randomization and the possibility of observing a significant difference between the two groups despite not being statistically powered for it. Randomization aims to balance patient characteristics between treatment arms. A significant difference would require statistical evidence before drawing conclusions.

Randomization and Significant Difference

• Randomization aims to balance patient characteristics between treatment arms.

• Although not statistically powered, if there is a significant difference observed, statistical analysis can be performed.

• Statistical evidence is required before drawing any conclusions.

[t=1:29:06s] Trials - Brooklyn and Prevail

This section introduces two trials - Brooklyn and Prevail. Brooklyn is a small trial focused on heterozygous FH patients, while Prevail involves 9,000 patients with existing ASCVD (atherosclerotic cardiovascular disease) for secondary prevention. The inclusion of high-risk patients in Prevail increases the likelihood of demonstrating a benefit.

Brooklyn Trial

• Brooklyn trial focuses on heterozygous FH (familial hypercholesterolemia) patients.

• It is a small trial with 300 patients.

Prevail Trial

• Prevail involves 9,000 patients with existing ASCVD for secondary prevention.

• Risk-enhancing factors are also considered in this trial to increase the likelihood of demonstrating a benefit.

• Baseline LDL cholesterol is targeted around 100 mg/dL to achieve significant absolute differences in LDL lowering.

[t=1:29:54s] Baseline LDL and Exclusions for Prevail

This section discusses the importance of baseline LDL cholesterol levels and exclusions for the Prevail trial. A baseline LDL level around 100 mg/dL allows for significant reductions, which can be plotted on the CTT meta-regression line. Exclusions include individuals with LDL below 55 mg/dL.

Baseline LDL and Absolute Difference

• Targeting a baseline LDL cholesterol level around 100 mg/dL.

• Achieving an absolute difference of 50 mg/dL in LDL lowering results in approximately a 27% reduction in Mace when plotted on the CTT meta-regression line.

Exclusions for Prevail

• Individuals with baseline LDL below 55 mg/dL are excluded from the study.

• Adaptation to new American College of Cardiology guidelines has been made.

[t=1:30:43s] Duration and Follow-up Concerns

This section addresses concerns about study duration and follow-up. The Fourier trial was initially met with skepticism due to short study duration, but it still yielded significant results. In contrast, Prevail aims to have a longer follow-up period to capture the full effect of lipid lowering.

Concerns about Study Duration

• The Fourier trial was initially met with skepticism due to short study duration.

• Prevail aims to have a longer follow-up period to capture the full effect of lipid lowering.

• A median follow-up of three and a half to four years is expected in Prevail.

[t=1:31:07s] Geographic Scope and Patient Population

This section discusses the geographic scope and patient population in the Prevail trial. Prevail is being conducted in various regions, including North America, South Africa, and Europe. The trial includes patients with existing ASCVD for secondary prevention, focusing on high-risk individuals.

Geographic Scope

• Prevail is being conducted in North America, South Africa, Europe (Eastern and Western).

Patient Population

• Patients included in Prevail have existing ASCVD for secondary prevention.

• High-risk individuals are targeted for inclusion.

[t=1:31:23s] Initial Skepticism and Patient Characteristics

This section addresses initial skepticism regarding PCSK9 inhibitors' efficacy based on patient characteristics. The speaker believed that PCSK9 inhibitors would be effective but had concerns about heavily medicated patients with low LDL cholesterol levels. However, subsequent trials proved these concerns wrong.

Initial Skepticism

• Initially skeptical about PCSK9 inhibitors' efficacy due to heavily medicated patients with low LDL cholesterol levels.

• Believed that long-term studies would be required to observe a difference.

Patient Characteristics

• Patients entering the study had an average LDL cholesterol level of around 70 mg/dL.

• Contrary to expectations, significant results were observed even with this patient population.

[t=1:32:19s] Robust Number of Participants and Trial Duration

This section discusses the number of participants and trial duration in Prevail. The trial aims to have a robust number of participants, and the baseline LDL cholesterol levels are still within the desired range. Lessons learned from previous trials, such as Fourier, have influenced the design and duration of Prevail.

Number of Participants

• Prevail aims to include a substantial number of participants, with an expected enrollment completion before the end of the year.

• Baseline LDL cholesterol levels are still within the desired range.

Trial Duration

• The trial plans to have a median follow-up of three and a half to four years.

• This duration allows for capturing the full effect of lipid lowering.

[t=1:33:26s] Side Effects in Phase 2 Trials

This section discusses side effects observed in phase 2 trials. The speaker mentions that no side effects related to the study drug have been identified so far in phase 1 and phase 2 studies. However, they anticipate that larger phase 3 trials may reveal some side effects.

Side Effects in Phase 2 Trials

• No side effects related to the study drug have been identified in phase 1 and phase 2 studies.

• Larger phase 3 trials may reveal potential side effects.

• Other similar inhibitors (Lilly ctap inhibitor and Merc sheet app inhibitor) also did not show any side effects among their respective patient populations.

Timestamps provided are approximate and should be verified against the original transcript or video for accuracy.

The Side Effects of Statins

In this section, the speaker discusses the side effects of statins and their impact on the perception of the overall class. They also mention a psychological component related to statin use.

Statins and Side Effects

• Statins have side effects, but they affect fewer people than commonly believed.

• The perception of statins is influenced by books like "The Cholesterol Myth" that claim statins are toxic.

• Severe heterozygous FH patients who truly need statins experience fewer side effects compared to those using them for primary prevention as a lifestyle drug.

• There is a psychological component involved in the perception of statin side effects.

Benefit of Statins on LP Little a Reduction

This section focuses on the benefits of statin use in reducing LP little a levels, particularly in comparison to PCSK9 inhibitors.

LP Little a Reduction with Statins

• Statin use shows a greater reduction in LP little a levels compared to PCSK9 inhibitors.

• A stable isotope study conducted by Dan Rader found that CTP inhibitors inhibit the synthesis of LP little a.

• The connection between intercellular protein synthesis and an HDL particle-bound drug is not fully understood yet.

• Further studies are being conducted to explore this link and its implications.

Stable Isotope Study and LP Delay Trial Results

This section discusses stable isotope studies conducted with Dan Rader, as well as the results from the Rose trial regarding LP delay.

Stable Isotope Study and Rose Trial Results

• A stable isotope study was conducted with Dan Rader to investigate apple b-containing lipoproteins and LP little a.

• In the Rose trial, LP delay decreased by 56% with a 10mg dose and 43% with a 5mg dose of statins.

• Other CTP inhibitors lower LP little a levels by about 20%, but they are less effective overall.

• The reduction in LP little a seems to be associated with LDL lowering, but the exact mechanism is not fully understood.

Elevated LP Little a and Potential Clinical Impact

This section highlights the significance of elevated LP little a levels as a common genetic finding leading to premature ASCVD. The potential clinical impact of reducing LP little a is discussed.

Elevated LP Little a and Clinical Impact

• Elevated LP little a is the most common genetic finding associated with premature ASCVD.

• While reducing LP little a by 50% is impressive, it remains unclear if this reduction is clinically sufficient to improve outcomes.

• The potential role of ASO inhibitors in addressing elevated LP little a levels is yet to be determined.

Mendelian Randomization and CTP Hypofunctioning

This section explores the concept of Mendelian randomization and its relationship to CTP hypofunctioning.

Mendelian Randomization and CTP Hypofunctioning

• Mendelian randomization studies indicate that genetically determined CTP concentration influences various health factors.

• Individuals with CTP hypofunctioning tend to have longer lifespans, less heart disease, Alzheimer's disease, diabetes, heart failure, and renal disease.

• Hyperfunctioning CTP can be added to the list of factors like hyperfunctioning PCSK9 associated with longevity genes (e.g., APOE2).

Effects of Genetically Determined CTP Concentration

This section discusses the effects of genetically determined CTP concentration on various health markers, including LDL-C, triglycerides, LP little a, blood pressure, and hemoglobin A1c.

Effects of Genetically Determined CTP Concentration

• Decreasing genetically determined CTP concentration by one microgram per milliliter leads to reductions in LDL-C and triglycerides.

• LP little a levels decrease significantly (two plus nanomole per liter reduction) with lower CTP concentration.

• Blood pressure also decreases by approximately 0.2 millimeters per Mercury.

• The relationship between CTP and blood pressure is not fully understood.

• Changes in hemoglobin A1c levels are observed as well.

Unexplained Blood Pressure Effects

This section focuses on the unexplained relationship between CTP concentration and blood pressure.

Unexplained Blood Pressure Effects

• The increase in blood pressure associated with inhibiting CTP should have been a red flag during torsetrapy studies.

• The synthesis of CTP occurs in liver cells and it binds to HDL particles in circulation.

• The exact connection between CTP and blood pressure remains unknown.

• Recent advancements have been made in understanding the relation between brain lipid metabolism and loss of function of CTP.

Further Exploration of Brain Cholesterol Metabolism

This section briefly mentions the progress made in understanding how loss of function of CTP affects brain cholesterol metabolism.

Exploration of Brain Cholesterol Metabolism

• Significant progress has been made in understanding how loss of function of CTP influences brain cholesterol metabolism.

• However, there is still much more to learn about this topic.

Due to time constraints, further discussion on brain cholesterol metabolism is postponed.

Alzheimer's Risk Factors and ApoE4 Understanding the Role of ApoE4 in Alzheimer's Disease

In this section, the speaker discusses the role of ApoE4 in Alzheimer's disease and its impact on brain health. The speaker explains how carriership of ApoE4 increases the risk of developing Alzheimer's disease and highlights the importance of understanding cholesterol abnormalities in relation to brain health.

The Impact of ApoE4 on Cholesterol Abnormalities

• Carriership of ApoE4 is associated with a significantly higher risk of developing Alzheimer's disease compared to other variants.

• Having both E3 and E4 alleles increases the risk by about four and a half times.

• ApoE4 is insufficient in removing excess cholesterol from brain cells or transporting cholesterol to cells with low levels, leading to cholesterol accumulation.

• Accumulated sterols can get oxidized, causing cell damage, inflammation, and apoptosis.

• A functional protein called ApoA1 can help address these cholesterol abnormalities.

Raising ApoA1 Levels for Brain Health

• Increasing the concentration of ApoA1 in circulation can potentially benefit brain health.

• Certain drugs known as CETP inhibitors have shown promising results in raising ApoA1 levels.

• Large HDL particles lose their ApoA1 content, so increasing circulating levels may facilitate its entry into the brain.

• Clinical trials are being conducted to investigate the effects of raising ApoA1 levels on brain function.

Understanding Gene-Protein Nomenclature

• The nomenclature for genes and proteins can be confusing when they share the same name.

• In this case, we refer to apoe4 as a gene with three isoforms (e2, e3, and e4), resulting in six different combinations.

• The protein produced by the apoe4 gene is simply referred to as ApoE, without the numerical designation.

• A single amino acid difference in the ApoE protein (e.g., arginine for glutamine) alters its conformation and impairs cholesterol metabolism.

Risk Factors and Non-Deterministic Nature of ApoE4

• Carrying the ApoE4 allele is associated with a higher risk of Alzheimer's disease, but it is not deterministic.

• The risk may be closer to tenfold rather than sixteenfold compared to other variants.

• It's important to note that not all individuals with ApoE4 develop Alzheimer's disease, and conversely, some without ApoE4 do develop it.

• Early awareness of one's ApoE4 status allows for proactive measures to mitigate exacerbating risk factors.

Importance of Personalized Prevention Strategies

• Knowing one's ApoE4 status can help individuals take early steps to prevent or reduce the impact of Alzheimer's disease.

• While having ApoE4 increases the risk, addressing modifiable risk factors can improve outcomes.

• Personalized prevention strategies tailored to an individual's genetic profile can significantly impact their odds of developing Alzheimer's disease.

Conclusion Key Takeaways

In this section, the speaker concludes by summarizing key points discussed regarding the role of ApoE4 in Alzheimer's disease. They emphasize that while carrying the ApoE4 allele increases the risk, it does not guarantee development of the disease. Personalized prevention strategies based on genetic profiles can play a crucial role in mitigating risks.

Key Takeaways

• Carriership of ApoE4 significantly increases the risk of developing Alzheimer's disease compared to other variants.

• ApoE4 is associated with cholesterol abnormalities in the brain, leading to cell damage and inflammation.

• Raising ApoA1 levels may help address these abnormalities and improve brain health.

• Understanding gene-protein nomenclature is important to differentiate between the gene (apoe4) and the protein (ApoE).

• Having ApoE4 does not guarantee Alzheimer's disease, and personalized prevention strategies can mitigate risks.

• Early awareness of one's ApoE4 status allows for proactive measures to prevent or reduce the impact of Alzheimer's disease.

Mike Davidson's involvement in the Clotho space and the protection of APO E4 Gene

In this section, Mike Davidson's involvement in the Clotho space and the observation that individuals with Clotho klvs variants have significant protection from their APO E4 Gene are discussed.

Mike Davidson's involvement in the Clotho space and protection from APO E4 Gene

• Mike Davidson is heavily involved in the Clotho space.

• Individuals with Clotho klvs variants seem to have almost complete protection from their APO E4 Gene.

• There is a large mendelian randomization study showing that low CTP (Clotho protein) protects an APO E4 carrier against Alzheimer's disease.

• The goal is to understand the effect size by tapping cerebrospinal fluid and examining various biomarkers related to lipoprotein metabolism, cholesterol synthesis, cholesterol removal, and inflammation.

• The proof of concept trial aims to show improved lipoprotein metabolism in the brain as a first step towards further research.

Role of APO E in cardiovascular disease

This section discusses the role of APO E (apolipoprotein E) in cardiovascular disease, specifically atherosclerosis.

Role of APO E in cardiovascular disease

• Apple E4 is associated with higher LDL levels, a more pro-inflammatory state, and increased risk of heart disease.

• Apple E4 has a higher affinity for the LDL receptor compared to other forms of APO E.

• Chylomicron remnants and VLDL (very low-density lipoprotein) readily attract Apple E4, leading to downregulation of the LDL receptor and subsequent increase in LDL levels.

• The association between Apple E4 and risk factors such as inflammation persists even after normalizing for apob (apolipoprotein B) levels.

• ApoB is a key driver of statistics in cardiovascular disease.

Association of APO E4 with other factors and residual risk

This section explores the association of APO E4 with other factors and residual risk in cardiovascular disease.

Association of APO E4 with other factors and residual risk

• APO E4 is associated with a chronic pro-inflammatory state.

• The association between APO E4 and risk factors, such as inflammation, may persist even after normalizing for apo3 versus apo4 in the context of LDLc/apob levels.

• Alan Snyderman suggests that controlling for Applebee (APO B) eliminates the association between APO E4 and risk factors.

• The role of APO E4 extends beyond lipoprotein metabolism, with associations to various other aspects.

The transcript does not provide timestamps for the remaining sections.

Exploring the Effects of Applebee Lowering

The discussion revolves around the potential effects of Applebee lowering and whether it aligns with Allen's view. It is suggested that other factors may play a role in creating differences between individuals, especially those with underlying health conditions.

Biologic Understanding and Clinical Relevance

• There might be small effects that require large sample sizes and lifetime exposure metrics to observe on a clinical level.

• Other amplifying features, such as underlying health conditions like type 2 diabetes or insulin resistance, could create larger gaps between individuals.

Reevaluating Previous Criticisms

• The speaker acknowledges being critical of c-tep inhibitors in the past, particularly regarding the HDL hypothesis. However, they now recognize the importance of a more pure biologic understanding and acknowledge that ctep is a longevity gene.

• The hope is that obasetramib will not only redeem the field but also provide exciting clinical outcomes.

Reflecting on Past Trials and Blind Spots

The conversation delves into past trials, blind spots, and the need for a better understanding of mechanisms and biomarkers.

Lessons from Past Trials

• The speaker admits to being too harsh in their criticism of previous trials involving c-tep inhibitors. They relied heavily on the HDL hypothesis and mendelian randomization as their rationale for skepticism.

• A blind spot was created due to an overemphasis on certain biomarkers rather than a comprehensive biological understanding.

Seeking Better Biomarkers

• Using hdlc as a biomarker for c-tep inhibition was a mistake, leading to wasted time and resources. The field lost its way by not understanding the mechanism properly.

• Billions of dollars were spent, and unfortunately, lives were lost during these clinical trials. This serves as a reminder of the risks involved in advancing knowledge.

The Importance of Mendelian Randomization and Improved Trial Design

The discussion highlights the importance of strong mendelian randomization evidence and improved trial design to avoid past mistakes.

Learning from Past Errors

• Strong mendelian randomization evidence is now sought after to support hypotheses. Phase one and phase two trials are conducted to identify potential side effects before proceeding to larger trials.

• Improved trial design ensures that blood pressure effects or other unexpected outcomes are thoroughly investigated before progressing further.

Concluding Remarks

The conversation concludes with gratitude for the guest's insights and anticipation for future developments in Alzheimer's research.

Looking Ahead

• The guest expresses excitement about upcoming data on Alzheimer's research in the summer, particularly regarding brain function.

Membership Program Announcement

• A membership program is introduced, offering exclusive content and comprehensive podcast show notes for interested listeners.

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New Section

This section discusses the topics and tactics covered in previous episodes of "The Drive" podcast, providing a way to catch up on past episodes. It also mentions steep discounts on endorsed products and other benefits.

Previous Episodes Recap

• The transcript mentions the availability of previous episodes for catching up without having to listen to all of them.

• Steep discounts are offered on products that the speaker believes in but is not paid to endorse.

• Various other benefits are mentioned, which continue to be introduced gradually.

New Section

In this section, information is provided about accessing member-only benefits and connecting with Peter Attia MD through various social media platforms.

Accessing Member-only Benefits

• To learn more about and access member-only benefits, visit PeterAttiaMD.com/subscribe.

• The speaker can be found on Twitter, Instagram, and Facebook with the ID PeterAttiaMD.

• Listeners are encouraged to leave reviews on Apple Podcasts or their preferred podcast player.

New Section

This section clarifies that the podcast is for general informational purposes only and does not constitute medical advice or establish a doctor-patient relationship. It emphasizes the importance of seeking professional healthcare services for medical advice.

Disclaimer and Medical Advice

• The podcast provides general informational content and should not be considered a substitute for professional medical advice or treatment.

• No doctor-patient relationship is formed through listening to this podcast.

• Users should not disregard or delay seeking medical advice from qualified healthcare professionals for any medical condition they have.

• The use of information from this podcast is at the user's own risk.

New Section

This section reiterates the importance of seeking professional medical advice and not relying solely on the podcast's content. It emphasizes that the user should consult healthcare professionals for any medical conditions.

Seeking Professional Medical Advice

• Users should not disregard or delay obtaining medical advice from qualified healthcare professionals.

• The assistance of healthcare professionals should be sought for any medical condition.

• The content on this podcast is not intended to replace professional medical advice, diagnosis, or treatment.

New Section

This section highlights the speaker's commitment to disclosing conflicts of interest and provides information about his investments and advisory roles.

Conflicts of Interest Disclosure

• The speaker takes conflicts of interest seriously and provides disclosures on PeterAttiaMD.com/about.

• An up-to-date list of companies in which the speaker invests or advises can be found on the website.

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