The Unexpected Link Between LDL and Brain Health

In 2024, The Lancet – a highly-respected, peer-reviewed British medical journal – published a major update to its report on modifiable risk factors for Dementia. The report announced finding “new and compelling evidence that high LDL cholesterol and untreated vision loss are risk factors for dementia”, so the commission added these two factors to its most recent list. (Dementia Prevention, Intervention, and Care - 2024 Report of The Lancet Commission).

As people live longer, dementia continues to rise around the world, and new evidence suggests that reducing the risk of dementia not only “increases the number of healthy years of life, but also compresses the duration of poor health for people who do get dementia.”

Adding high LDL and untreated vision loss underscores an important point about the commission’s work and the work of dementia prevention: Risk factors for dementia aren’t static – they operate at different time points in a person’s lifespan. (For example, obesity and high blood pressure are considered risk factors for dementia in midlife, possibly necessitating early intervention, but those factors aren’t associated with cognitive decline and dementia if those conditions develop in later life.)

The Lancet commission understands the nuance of complex disease processes with multifactorial causes, like dementia, and it uses a “life-course approach” when trying to evaluate and educate the public and healthcare professionals about the best-studied, evidence-based methods to reduce or prevent dementia.

The 2024 report highlights another important point too: Prevention is hard and “involves both policy changes at national and international levels” (to address factors like education or air pollution) and individually-tailored interventions (to address factors like diabetes, smoking, and hypertension).

The Lancet sums it up this way: “Being ambitious about prevention means staying flexible and considering both policy changes and individual things” people can do to improve their brain health and lower their risk factors for dementia.

Low Density Lipoprotein (LDL)

The medical community has long-known that high LDL is a significant risk factor for coronary artery disease (including heart attack, stroke, and peripheral artery disease), and it has long-recognized the most effective methods (like lifestyle changes and statin drugs) for modifying that risk factor. Of all fourteen modifiable risk factors for dementia listed in the latest Lancet report, high LDL is likely one of the easiest to eliminate.

LDL cholesterol (along with total cholesterol, HDL cholesterol, and triglycerides) is also relatively cheap and simple to check and monitor; to manage and treat. This makes LDL cholesterol a particularly pertinent and practical risk factor for a younger patient population (entering or in the midst of midlife) to pay attention to.

People in midlife in the United States aren’t doing a great job of keeping their LDL levels low enough. The Center for Disease Control and Prevention reports that 86 million adults in the United States have total cholesterol levels above 200 mg/dL (the cutoff point for high cholesterol) and nearly 25 million adults in the US have total cholesterol levels above 240 mg/dL. It’s worth noting that about 7% of US children and adolescents (6-19) have high total cholesterol too. (Centers for Disease Control and Prevention)

At the time of Lancet’s 2020 report, the evidence on LDL’s role as a risk factor for dementia was inconclusive. But, just as risk factors for dementia can strengthen (or weaken) or shift categories – from later life to midlife, etc. – between commission reports, evidence can also strengthen. And, since the previous Lancet commission report, many large-scale studies have solidified the case for adding high LDL cholesterol to the list - and placing it at the top spot tied with hearing loss for one of the two most significant risk factors for dementia we know about.

The Short Story on LDL | What Are Lipoproteins and Why Do They Matter So Much?

LDL (low density lipoprotein) first entered the zeitgeist of modern medicine in the mid-1950s when John Gofman, a physician and physicist at the University of California – Berkeley, used a newly-invented centrifuge to separate lipoproteins according to their densities. The two types of lipoproteins he discovered were dubbed low-density lipoprotein (LDL) and high-density lipoprotein (HDL).

Later, when Dr. Gofman studied heart attack patients, he noticed a significant increase in LDL particles in these people. Taken together, these two happy scientific accidents – his discovery of LDL and his observation that people with cardiovascular disease tended to have high levels of it – established an undeniable association between lipoproteins and coronary artery disease.

Even if he didn’t know it at the time, Dr. Gofman put LDL on the map of the medical community as a major risk factor for heart disease, and his work charted the course of cardiovascular disease prevention, management, and treatment for decades to come.

Cholesterol (which is a type of lipid or fat) is a hydrophobic molecule (”water-hating”), which means it can’t dissolve in water and must be transported through the bloodstream attached to a hydrophilic molecule (“water-loving”). In this case that’s a protein.

Once a protein wraps itself around a lipid, the hybrid particle is called a lipoprotein. In that way, lipoprotein is just a more precise word for cholesterol. There are several types of lipoproteins, but the most important ones for our purposes are LDL and HDL.

Cholesterol gets a bad rap, but it’s actually essential for life. That sentence isn’t a typo: We can’t survive without cholesterol.

Here are a few of the critical functions cholesterol performs:

• Cholesterol is one of the main building blocks used by the body to make cell membranes (the ‘walls’ that separate the interior of cells from the external environment), and without this critical structural component, cells can’t survive or function.
• Cholesterol allows for a process called selective permeability (the movement of substances into and out of cells), which is vital for cellular signaling, transport, and survival.
• Cholesterol plays an important role in the synthesis of vitamins (like vitamin D) and steroid hormones, including sex hormones (think estrogen, progesterone, and testosterone). It has a direct impact on functions like reproduction, stress response (cortisol), electrolyte balance (aldosterone), and many of other important metabolic functions.
• Cholesterol serves as a precursor for bile acids - steroids found in bile, a fluid produced by the liver and stored in the gallbladder - that play a crucial role in the digestion and absorption of fats and fat-soluble vitamins. (Cleveland Clinic)

It’s true that cholesterol is essential for life. It’s also true that too much cholesterol can be dangerous – and even deadly, leading to cardiovascular disease, cognitive decline, dementia, and a slew of other chronic health problems.

How Cholesterol Causes Health Problems

The body is an amazing and astral thing. It’s really good at making the most important substances humans need for survival – including cholesterol. It turns out, the liver makes all the cholesterol the body needs.

This begs the questions: Where does excess cholesterol come from and how does it cause problems?

If the body doesn’t use the cholesterol made by the liver, our bodies reabsorb and transform it into harmful substances, especially plaque – a buildup of fatty deposits that accumulate on artery walls, harden over time, and restrict blood flow and oxygen to the heart, brain, and other organs.

This slow-growing process is called atherosclerosis, and it increases the risk of coronary artery disease, cardiovascular events (like heart attack, stroke, and peripheral artery disease), and other health issues.

Colloquially, LDL cholesterol is also known as “bad cholesterol, but in truth, LDL isn’t a bad substance. We need it.

Among other things, LDL plays an important role in cholesterol transport. Its primary function is to deliver newly made cholesterol from the liver to other parts of the body. Unfortunately, excess LDL stays in the bloodstream and begins layering in artery walls.

Some people don’t utilize organic LDL in optimal ways, which is where the build-up begins. This can happen for various reasons, including lifestyle habits (physical inactivity, smoking, obesity), medication, genetics, and/or health conditions, like chronic kidney disease, diabetes, autoimmune conditions, and hypothyroidism. (Mayo Clinic)

HDL is called “good cholesterol” because it removes excess cholesterol from the bloodstream and transports it back to the liver for removal. This process is called reverse cholesterol transport, and it helps prevent the buildup of cholesterol in the arteries, and in turn, reduces the risk of developing heart disease and brain pathology and its long-term sequelae.

The Pathophysiology of Dementia and Cognitive Decline

The pathophysiology of dementia and cognitive decline is complicated. Based on decades of examining patients with LDL and heart disease, however, doctors have been able to make some strong, evidence-based educated guesses about how cholesterol contributes to cognitive impairment.

Reduced Blood Flow and Oxygen Deprivation

High LDL cholesterol levels contribute to the buildup of plaque in blood vessels, which narrows arteries and restricts healthy blood flow and oxygen delivery over time. When blood flow to the brain gets diminished, brain cells don’t receive a constant supply of oxygen – and this leads to neuropathology (damage to nerves) and cognitive impairment. Based on studies, scientists already know that chronic hypoperfusion (inadequate blood flow to tissues and organs) can affect various cognitive functions, including processing speed, executive function, and memory, so it stands within reason that hypoperfusion caused by atherosclerosis of brain arteries could contribute to dementia too.

Inflammation

High LDL also causes inflammation in the brain, which can interrupt signaling or communication between neurons, damage brain tissues, and interfere with production of neurotransmitters (chemical messengers that transmit signals between nerve cells). Long-term inflammation is considered a leading risk factor for developing Alzheimer’s.

Synaptic Dysfunction

Cholesterol plays a role in the formation and function of synapses, the spaces where neurons connect and communicate with each other. Cholesterol imbalances can disrupt synaptic transmission and neuroplasticity.

Accumulation of Amyloid and Tau Proteins

Excess LDL is associated with the deposition of amyloid Beta and Tau proteins, which are strongly linked to Alzheimer’s disease. Relatedly, the gene that increases the risk of Alzheimer’s (ApoE4) is involved in the processing of cholesterol reaffirming a link between these proteins and dementia.

Why Tia is Tackling This Topic?

Tia’s mission is to ensure that women are able to live in vitality, as defined by themselves. Most chronic diseases are diseases of lifestyle, and this recent report from the Lancet indicates that Dementia follows a similar pattern: it is a multifactorial disease state that is born out a buildup of genetic luck and lifelong choices. It seems obvious that this is a disease that can negatively impact our vitality – but it is less obvious that this is a disease that can be so directly impacted by how we lead our lives on a day-to-day basis. These types of health considerations are squarely in focus for Tia – diseases and health considerations that result from a confluence on interconnected factors across several systems, and that can be directly modified by our daily habits.

Recently Tia launched a new Longevity product that seeks to build a new approach to longevity. This approach anchors on compounds we typically associate with cardio-metabolic health, like LDL. It is critical to note that actually LDL influences much more than just the heart – it also influences the brain. This is compound could have other, farther reaching impacts on health yet undiscovered.

Women Are at Greater Risk than Men for Cognitive Decline

As previously mentioned, The Lancet’s report may be especially important for women because they tend to experience more cases of dementia than men.

Recently, the editors of Women’s Health – London conducted a narrative review to examine sex and gender influences on Alzheimer’s disease, the most common type of dementia. Noting that two-thirds of people with Alzheimer’s disease are women, “The Puzzle of Sex, Gender, and Alzheimer’s Disease: Why are Women More Often Affected than Men?” attempted to better understand the “impressive differences in the incidence, prevalence, and experience of women and men with Alzheimer’s disease.

While a comprehensive review of that publication’s findings is beyond the scope of this article, it’s worth sharing the most relevant information presented in the Women’s Health review. What follows is a snapshot of some of factors that may influence the gender gap when it comes to the diagnosis of dementia:

Longevity

It’s a well-known demographic fact that women live longer than men, and since dementia incidence and prevalence increase with age, it logically follows that more women live long enough to develop dementia.

Hormones

Sex hormones, particularly estrogen, have been described as neuroprotective and important for brain health. Women experience more hormonal fluctuations throughout life – especially during perimenopause and menopause when estrogen levels dwindle. The decline in estrogen has been implicated as a probable cause of more cases of dementia in women. (Interestingly, due to the body’s ability to convert testosterone to estrogen, older men usually have higher levels of estrogen than women in menopause.)

Pregnancy

Pregnancy and its complications, such as preeclampsia, may play a part in later-life cognitive impairment in women.

Brain Structure

Men have greater brain volumes than women and, thusly, they may be naturally more resilient to neuropathological changes. This difference may impact the risk of developing cognitive decline and dementia.

Inflammation

There are many reasons why women tend to experience more systemic inflammation than men, including a higher prevalence for autoimmune conditions, which may contribute to the pathogenesis of dementia and other neurodegenerative diseases.

Social Roles

Higher education and income, occupational complexity, and physical activity are protective against dementia and, historically, women in older cohorts have had different opportunities than men in all three areas. Additionally, women are more often engaged in family and friend caregiving roles, and there is evidence that caregiving can be associated with cognitive decline and dementia.

Medication

There are known differences in the kinds of medications prescribed to women and men. For example, women are more likely to be prescribed certain classes of psychotropic medications, including sleep aids, which increases the risk of cognitive impairment. Contrarily, men are more likely than women to receive the most novel and promising treatments for dementia, like cholinesterase inhibitors, the main class of medicine used for Alzheimer’s disease. (Women's Health - London)

Diagnosing High Cholesterol and Understanding the Numbers

A basic assessment of LDL cholesterol is performed through a lipid panel, a blood test that typically measures total cholesterol, LDL cholesterol, HDL cholesterol, and triglycerides (another important blood fat that increases the risk of cardiovascular disease).

The most recent guidelines from the American Heart Association (American Heart Association) recommend a total cholesterol level of 150 mg/dL and an LDL level at or below 100 mg/dL. But keep in mind, this is for healthy adults without any obvious risk factors.

For individuals with a history of heart attack or stroke, with known risk factors (like diabetes, high blood pressure, and smoking), or with elevated Lp(a) levels, your doctor will likely suggest getting LDL to 70 mg/dL or lower.

For people with very high risks for cardiovascular disease, LDL should be 55 mg/dL or lower according to experts. This category includes people with existing cardiovascular disease, with multiple known risk factors, with familial hypercholesterolemia (an inherited disorder), or with very high Lp(a) levels.

Remember, these are just guidelines, and specific targets can vary based on an individual’s overall risk profile. Together, you and your healthcare professional should discuss individual goals and gameplans for getting LDL as low as practically possible.

A Powerful Longevity Tool for Women -- A Personalized Approach to Brain Health and the Long Game of Longevity

At the end of the day, The Lancet commission’s 2024 report on dementia prevention, intervention, and care is about recognizing cognitive vulnerability and taking steps – at the government level and on a personal level – to reduce its impact on the health and wellness of people and populations.

Early in the report, the commission introduces us to the concept of cognitive reserve – the ability to withstand neuropathology before showing symptoms of dementia. Brain resilience is another term used to describe a person’s capacity to cope with pathology and resistance to neuropathology.

People with more cognitive reserve are more likely to maintain brain health throughout their lives; to refute neuropathological disease; to recover from the ill effects of lifestyle choices that are less than laudable.

The Lancet report began with positive messaging, and it ends with it too: Even if reducing the risk of neuropathological changes is the overarching goal, neuropathological changes don’t inevitably lead to dementia. In fact, the majority of people with noticeable brain changes on imaging studies or cognitive function tests won’t develop dementia.

Still, since it’s impossible to ascertain a person’s inherent risk profile for brain pathology, the best course of action; the most protective factor in preventing dementia is to get healthier and to stay as healthy as possible as long as possible. The Lancet puts it this way: “People who are physically healthier are better able to withstand the effects of neuropathology than people who are physically unhealthy.”

The commission goes on: “People with healthy lifestyles, involving regular exercise, not smoking, avoiding excess alcohol, and including cognitive activity in late life, were shown not only to have a lower risk of dementia than those with less healthy lifestyles but also to have dementia onset delayed, resulting in more healthy years and fewer years of illness.”

The fourteen modifiable risk factors for dementia highlighted by The Lancet’s updated provides a roadmap. By making healthy lifestyle choices and changes as early as possible; by implementing individual interventions that include: treating hearing loss, vision loss, and depression; increasing cognitive stimulation throughout life; quitting smoking; limiting alcohol use; reducing and treating vascular risk factors (high LDL cholesterol, diabetes, hypertension, and obesity); reducing head injuries; and encouraging more regular physical activity.

The evolving understanding of LDL and its role in dementia development emphasizes the importance of regular metabolic assessments for everyone, especially women entering their middle years of life. Women often deprioritize preventive care screenings in their thirties and forties amidst the demands of daily life and the numerous barriers to care that deter too many women from seeing their doctors on a regular basis.

Longevity protocols need to prioritize LDL testing at every turn. Consistent monitoring of LDL (and other metabolic health indicators) is crucial for identifying, managing, and treating elevated levels that accumulate over time.

Routine screenings are the backbone of preventive medicine – and these simple, safe, affordable, and effective evaluations are the best way to catch potential health problems before they become more problematic.

High LDL cholesterol is a sinister health condition. Like hypertension, elevated LDL is also a ‘silent killer’ that causes quiet damage and doesn’t present with any outward signs or symptoms – until it does. Until it’s often too late.

While the clinical community has long recognized the risk posed by high cholesterol, the renewed focus on LDL cholesterol may represent a notable shift. Despite the historical understanding of the roles LDL and HDL play in atherosclerosis, research on their direct impact on cognitive health has been comparatively less prominent.

This resurgence of interest, reflected in The Lancet’s decision to include LDL on its newest list of modifiable risk factors for dementia, underscores the absolute necessity of always incorporating this key biomarker into all comprehensive heart and brain preventive health programs.

References

The concepts and information presented are based on established knowledge within the fields of cardiology, endocrinology, neurology, and dementia research, drawing from reputable sources like The Lancet, Journal of the American Medical Association (JAMA), Circulation, Atherosclerosis, and Alzheimer's & Dementia.

The Framingham Heart Study, a long-term prospective study, has provided extensive data on the age-related changes in lipid profiles, including LDL cholesterol

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