Educational overview

ApoB, Lifetime Exposure, and Atherosclerotic Cardiovascular Disease

Mohammad Ghalichi, M.D. on December 4, 2025

Cardiovascular disease, specifically what doctors call atherosclerotic cardiovascular disease (ASCVD), is the top cause of death worldwide. This disease is the slow formation of plaque in the blood vessels over time. People do not feel it when they make plaque, and it usually takes many years (decades) to develop. As plaques get bigger they cause blockages, which is why someone might need a heart stent or bypass surgery. As plaques grow they also become more unstable and the risk of a plaque rupturing increases. When a plaque breaks inside an artery it becomes a site of injury. When blood comes into contact with that injury it forms a clot. If this plaque rupture happens in a coronary artery that feeds the heart it causes a heart attack. If it happens in one of the carotid arteries in the neck it causes a stroke. The tragedy is that remains the top killer while it is also the most preventable of all the major causes of death.

One of the most important drivers of ASCVD is the number of ApoB containing lipoproteins in the blood over time. These particles carry cholesterol into the artery wall. The key idea is not only how high the level is, but how long the arteries are exposed to that level.

1. Mendelian randomization and lifelong low ApoB

Mendelian randomization studies use natural genetic differences as a kind of lifelong randomized trial. Some people are born with variants that keep their LDL cholesterol and ApoB a bit lower from birth.

• People with genetic variants that lower LDL-C or ApoB from early life have much larger reductions in coronary heart disease than you would expect if you only looked at their LDL level in midlife and compared it with statin trials.
• Roughly, every 1 mmol/L (about 39 mg/dL) lower LDL-C across a lifetime is linked with around 50 to 60 percent lower risk of coronary heart disease which is about three to four times the benefit of lowering LDL-C by the same amount for only five years with medication in adulthood.

These findings support the cumulative exposure model: what matters most is the total cholesterol burden the arteries see over decades. In other words, ApoB exposure is like pack years of smoking. Higher level for longer time means more plaque.

2. Randomized trials with very low LDL and ApoB in adults

Large randomized trials have tested powerful cholesterol lowering drugs on top of statins in people who already have ASCVD. These trials move LDL-C into ranges that used to be considered “too low” and allow us to see what happens when ApoB is pushed down aggressively in mid to late adulthood.

Across these trials, lowering ApoB containing particles to very low levels in adults with known ASCVD shows:

• Continued risk reduction as LDL-C falls down toward at least the 20 to 30 mg/dL range.
• No clear safety problem from very low LDL over the typical 2 to 5 year trial follow up.

These trials are not 50 year experiments starting in someone’s twenties, but they strongly support the idea that there is no harmful “too low” threshold in midlife, at least in the ranges tested so far.

3. Population, epidemiologic, and ancestral evidence

Populations with naturally low ApoB and very low ASCVD

Some traditional and rural populations offer a real world look at what happens when ApoB and other risk factors stay low over a lifetime.

• The Tsimane, an indigenous group in the Bolivian Amazon who live a subsistence lifestyle with high physical activity, low saturated fat intake, and minimal smoking, have the lowest levels of coronary atherosclerosis ever reported in a population study. In a CT study of more than 700 adults, the vast majority had zero or minimal coronary calcium far into older age.
• These populations tend to have low LDL-C (often in the 50 to 90 mg/dL range) along with low blood pressure, lean body weight, and high daily movement. Clinical heart attacks and strokes are rare compared with industrialized nations.

Autopsy studies in modern youth

In contrast, autopsy studies of teenagers and young adults in modern societies tell a different story.

• The Pathobiological Determinants of Atherosclerosis in Youth (PDAY) studies examined arteries from people aged 15 to 34 who died from accidents or other non cardiac causes. Many already had fatty streaks and early plaques in their aortas and coronary arteries.
• The burden of these early lesions tracked with conventional risk factors such as higher LDL cholesterol, lower HDL, high blood pressure, smoking, obesity, and abnormal blood sugar.

These findings show that in a typical Western environment, atherosclerosis often begins in youth while blood tests are still labeled “normal for age”.

4. Putting it together

Across genetic studies, randomized trials, population research, and autopsy data, several themes repeat:

• ApoB containing lipoproteins are causal in the development of ASCVD.
• Risk relates to how high the ApoB is and how long the arteries see that level. Think lifetime exposure, not just a single lab result.
• When ApoB is kept low for long periods and other risk factors such as blood pressure, smoking, weight, and glucose are also favorable, clinically significant ASCVD becomes uncommon.

This does not mean that lowering ApoB guarantees you will never have a heart attack or stroke. Other factors such as genetics, inflammation, blood pressure, kidney disease, and lifestyle still matter. It does mean that keeping ApoB as low as is safe and practical over the course of life is one of the most powerful levers we have to reduce the risk of the world’s leading killer.

Key references and further reading

This page is for educational purposes only and is not a substitute for personalized medical advice. Decisions about testing and treatment should be made with your own clinician.