The Four Horsemen: Peter Attia on Chronic Disease

Peter Attia, MD, is a Canadian-born physician who trained in surgery at Johns Hopkins and in cancer research at the National Cancer Institute, and who later turned to longevity medicine; he is the author of Outlive: The Science and Art of Longevity (2023, written with Bill Gifford) and the host of the podcast The Drive.

This page sets out one of the central ideas of his work: that most deaths in later life come from four slow chronic diseases, which he calls “the four horsemen” — atherosclerotic heart and blood-vessel disease, cancer, neurodegenerative disease such as Alzheimer’s disease, and metabolic disease. It reports how he defines each one, why he places metabolic dysfunction “upstream” of the others, what his own published research on cancer and on Alzheimer’s prevention found, and what later studies on the same subjects describe. His views are reported as his, in his own words where his published text is available. Heart disease is covered only briefly here, because a separate page in this series is devoted to his view of apolipoprotein B and heart disease.

Table of Contents

  1. The Four Horsemen as Attia Defines Them
  2. From Fast Death to Slow Death
  3. Metabolic Disease: The Horseman Upstream
  4. How Common Metabolic Health Is
  5. Heart Disease: The Most Preventable Horseman
  6. Cancer: The Runaway Cell
  7. His Own Cancer Research at the National Cancer Institute
  8. Neurodegenerative Disease: Chasing Memory
  9. His Alzheimer’s Prevention Papers
  10. Later Research on Shared Threads
  11. Key Research Papers
  12. Connections

1. The Four Horsemen as Attia Defines Them

Attia uses the phrase “the four horsemen” as a way to group the diseases that end most lives in developed countries once people reach middle age. On the “Risks” section of his website he gives the definition in one sentence:

“Over 80% of deaths in people over 50 who do not smoke can be grouped into 4 main categories, what I like to call the four horsemen of chronic disease. These are: (1) atherosclerotic disease (comprised of cardiovascular disease and cerebrovascular disease), (2) cancer, (3) neurodegenerative disease (Alzheimer’s disease being the most common), and (4) metabolic disease (a spectrum of everything from hyperinsulinemia to insulin resistance to fatty liver disease to type 2 diabetes).” — Peter Attia, “Risks”

In plain terms, the four categories are:

Two features of the definition are worth noting. First, he restricts the “over 80%” figure to people over 50 who do not smoke, so it describes deaths from slow chronic disease rather than from accidents, infections or smoking-related illness. Second, his fourth horseman is not a single disease but a continuum, which is why he treats it differently from the other three, as the sections below explain.

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2. From Fast Death to Slow Death

The four horsemen sit inside Attia’s larger argument about medicine. The first chapter of Outlive is titled “The long game: from fast death to slow death”, and its second, “Medicine 3.0: rethinking medicine for the age of chronic disease”. The idea in those titles is that people once died mostly of fast causes — infections, injuries, childbirth — while today most people in wealthy countries die of the slow diseases he groups as the horsemen, which develop over decades before they cause symptoms.

On his podcast he has described the older model of care, which he calls Medicine 2.0, as strongest at acute conditions, and his proposed Medicine 3.0 as calling for “absurdly early preventative measures for chronic conditions” (The Drive, AMA #41). He frames the goal in two parts: “longevity is a balance of lifespan (living longer) and healthspan (living better).” And he connects that goal directly to the four chronic diseases: “if you want to live longer, you have to live longer without chronic disease, not live longer with chronic disease.”

The book’s chapter list follows the horsemen closely. After the opening chapters come “The crisis of abundance: can our ancient genes cope with our modern diet?”, “The ticker: confronting and preventing heart disease, the deadliest killer on the planet”, “The runaway cell: new ways to address the killer that is cancer” and “Chasing memory: understanding Alzheimer’s Disease and other neurodegenerative diseases” — one chapter for each horseman, with metabolic disease first. The framework behind this approach is covered in more depth on the Medicine 3.0 page of this series.

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3. Metabolic Disease: The Horseman Upstream

Attia gives metabolic disease a special place among the four. His website’s topic guide on metabolic health states: “Metabolic dysfunction sits upstream of nearly every major chronic disease.” In his view, problems with how the body handles fuel do not only cause type 2 diabetes; they also raise the ground on which heart disease, cancer and Alzheimer’s disease grow.

He defines the problem simply: “One way to think about metabolic disease is as a disorder in fuel processing.” And he describes it as gradual rather than all-or-nothing: “Metabolic disease exists on a continuum, from early hyperinsulinemia to insulin resistance,” continuing on, in his description, to fatty liver disease and type 2 diabetes (Peter Attia, “Metabolic health” topic guide).

The practical point he draws from the continuum is timing. Because the early stages — high insulin levels, then insulin resistance — come years before a diagnosis of type 2 diabetes, he argues that they are the stages at which change is easiest, which ties back to the “absurdly early” prevention of Medicine 3.0. The book’s chapter on the subject, “The crisis of abundance”, frames the cause as a mismatch between ancient genes and a modern food supply in which food is always available.

The site’s own pages on insulin resistance describe the condition itself in more detail. Attia’s views on diet, protein and continuous glucose monitoring are reported on the Nutrition and Sleep page of this series.

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4. How Common Metabolic Health Is

The claim that metabolic dysfunction is widespread has been measured in national survey data. Two studies of the National Health and Nutrition Examination Survey, the long-running United States government health survey that combines interviews with physical examinations and blood tests, looked at how many American adults meet every marker of good metabolic health.

These studies define “metabolic health” in their own terms, which are not identical to Attia’s continuum, but they describe the same broad picture he points to: most adults fall somewhere short of good metabolic health, including many who are not overweight. Both are observational surveys; they measure how common a state is, not what causes it.

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5. Heart Disease: The Most Preventable Horseman

Attia’s book calls heart disease “the deadliest killer on the planet” in its chapter title, and an article on his website, co-written with Birkenbach and Thomas Dayspring, calls coronary atherosclerosis “easily the most preventable of all the ‘four horsemen of chronic disease’” (“Coronary atherosclerosis is a silent killer, but we have tools to stop it”, 2024).

The reason he gives for calling it preventable is that, in his view, its cause is known. The same article states that atherosclerosis “is caused by apoB-containing lipoproteins” — the cholesterol-carrying particles that each bear one molecule of a protein called apolipoprotein B (apoB) — and that “atherogenesis depends on the number of apoB-containing lipoproteins”. In other words, he counts the particles rather than the cholesterol they carry.

On the medicines that lower these particles, the article states that cholesterol-lowering therapies — it names statins and the injectable proprotein convertase subtilisin/kexin type 9 inhibitors — “have the power to virtually stop atherosclerosis in its tracks”, and that “On a population scale, these actions have the power to put an end to mortality from coronary atherosclerosis.” These are the authors’ statements about the drugs; the article does not set out a treatment plan for readers, and this page does not either.

His full argument about apolipoprotein B, how it differs from the usual cholesterol test, lipoprotein(a), and the trials and genetic studies behind it, is on the Apolipoprotein B and Heart Disease page of this series. The site’s atherosclerosis and apolipoprotein B lab test pages describe the disease and the test themselves.

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6. Cancer: The Runaway Cell

The book’s cancer chapter is titled “The runaway cell: new ways to address the killer that is cancer”. Cancer is the horseman closest to Attia’s own research past: before he worked in longevity medicine he spent two years as a surgical oncology fellow at the National Cancer Institute, part of the United States National Institutes of Health, in the laboratory of the surgeon Steven Rosenberg, studying ways to turn the immune system against melanoma, a skin cancer that had spread through the body.

Two threads link cancer to the rest of his framework. The first is the immune system, which was the subject of his own papers (see the next section). The second is metabolism, his “upstream” horseman. Both threads appear in a widely cited review of how cancers develop. In 2011 the cancer biologists Douglas Hanahan and Robert Weinberg updated their list of the “hallmarks of cancer” — the abilities a tumour acquires as it develops, such as sustaining its own growth signals and resisting cell death. Their update added two “emerging hallmarks”: the reprogramming of energy metabolism, and the evasion of destruction by the immune system.

The link between excess body weight and cancer had been measured earlier in a very large American study. Calle and colleagues followed more than 900,000 adults who were free of cancer in 1982 for 16 years, during which 57,145 died of cancer. Among the heaviest participants (a body-mass index of at least 40), death rates from all cancers combined were 52 percent higher in men and 62 percent higher in women than in people of normal weight. Higher body weight was also linked with deaths from cancers of the esophagus, colon and rectum, liver, gallbladder, pancreas and kidney, among others. The authors estimated that overweight and obesity could account for 14 percent of cancer deaths in men and 20 percent in women in the United States. This was an observational study: it shows an association, not proof that the weight itself caused the cancers.

The book’s chapter title also names early detection as part of “new ways to address” cancer. His own fetched writings on specific screening tests are not covered here.

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7. His Own Cancer Research at the National Cancer Institute

Attia’s best-known paper from his National Cancer Institute years, published in 2005 with him as first author, studied a then-experimental approach that later became a mainstream cancer treatment: releasing a brake on the immune system. The brake is a protein on immune cells called cytotoxic T-lymphocyte antigen-4; an antibody that blocks it lets immune cells attack more freely — including, sometimes, the body’s own healthy tissues.

The study treated 56 patients with advanced (stage IV) melanoma with this antibody together with a peptide vaccine, testing two dose schedules. Its findings, as the abstract reports them:

The authors concluded that the treatment could cause durable responses and that those responses went together with the development of autoimmunity — in other words, the same immune release that attacked the tumours also caused the side effects. This was a non-randomised study of a small group of patients, so it describes a correlation within that group rather than a comparison against untreated patients.

His other work at the institute, also with Rosenberg’s group, studied regulatory T cells — immune cells that hold other immune cells back — and tried to remove them so that the immune system could attack tumours more strongly; that work and his wider career are described on the Life and Career page. Antibodies of this immune-checkpoint kind were later tested in large trials, and immune-checkpoint therapy went on to become an established treatment for advanced melanoma and several other cancers.

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8. Neurodegenerative Disease: Chasing Memory

The book’s chapter on the third horseman is titled “Chasing memory: understanding Alzheimer’s Disease and other neurodegenerative diseases”. In his website definition, Attia names Alzheimer’s disease as the most common of the neurodegenerative diseases, and it is the one his own co-authored papers address.

A central fact in any discussion of Alzheimer’s risk is genetic. In 1993 Corder and colleagues reported that the type 4 form of the apolipoprotein E gene (APOE4) is strongly tied to late-onset Alzheimer’s disease. In 42 families with late-onset disease, the risk of Alzheimer’s disease rose from 20% to 90%, and the average age at onset fell from 84 to 68 years, as the number of copies of the apolipoprotein E type 4 gene rose from none to two. In those families, carrying two copies was, in the authors’ words, “virtually sufficient” to cause the disease by age 80.

The metabolic thread of his framework also reaches into this horseman. In a 2008 review titled “Alzheimer’s disease is type 3 diabetes”, de la Monte and Wands argued that disturbed insulin signalling inside the brain may account for many of the changes seen in Alzheimer’s disease. Their review also noted that type 2 diabetes causes brain insulin resistance and cognitive impairment but that its effects “fall far short of mimicking” Alzheimer’s disease; part of the evidence they reviewed came from experiments in animals. The term “type 3 diabetes” is their proposal, not an accepted diagnosis.

Attia’s view of sleep as one of the most important factors for the brain, including his discussion of sleep and Alzheimer’s risk, is reported on the Nutrition and Sleep page.

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9. His Alzheimer’s Prevention Papers

During his years in private practice, Attia co-authored two papers with the Alzheimer’s prevention clinic of the neurologist Richard Isaacson, then at Weill Cornell Medicine in New York. Both papers list Attia’s practice as his affiliation.

2018: Mechanisms of risk reduction

The first, led by Schelke with Attia as second author, is a review published in Frontiers in Aging Neuroscience. It starts from the observation that attempts to develop drugs that change the course of late-onset Alzheimer’s disease had “so far” not shown efficacy in humans, and argues that the long gap between the first changes in the brain and the first symptoms offers a window in which reducing risk early might lower the number of cases, delay them or prevent them. The review discusses six mechanisms involved in the disease that it considers targets for risk reduction:

It also offers what it calls a blueprint for a clinical programme of risk reduction using several approaches at once, and concludes that focused risk reduction “may transform” Alzheimer’s disease into a preventable disorder “in select cases”. The first item on its list — glucose metabolism — is the same metabolic thread that runs through Attia’s whole framework.

2019: Individualized clinical management

The second paper, led by Isaacson and published in Alzheimer’s & Dementia, reports the clinic’s results. Attia is one of 28 authors. In it, 174 patients aged 25 to 86 were given individually tailored plans that combined education, medication and non-drug measures, and were rated on how closely they followed them. Patients were sorted into a prevention group (normal thinking, subjective decline or early changes without symptoms) and an early-treatment group (mild cognitive impairment or mild Alzheimer’s disease).

After 18 months, the paper reports that the prevention group improved on its main thinking-test score more than matched historical comparison groups did, both among patients who followed the plans closely and among those who followed them less closely. In the early-treatment group, patients who followed the plans closely improved more than those who did not, and more than the historical comparison groups; those who followed them less closely did not differ from the comparison groups. Risk scores and blood markers also improved. The authors concluded that individualised plans of this kind “may improve cognition” in people at risk of Alzheimer’s dementia. The design matters for reading the result: patients were compared with earlier, separate groups rather than randomly assigned, so the study shows what happened in this clinic’s patients rather than proving the plans caused the change.

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10. Later Research on Shared Threads

Several larger studies have looked at the ideas behind the four-horsemen framework — that the same lifestyle and metabolic factors run through several diseases at once, and that acting early on several of them together may matter. They are described here as research, not as part of Attia’s own statements.

Several measures at once against cognitive decline

The Finnish FINGER trial randomly assigned 1,260 people aged 60 to 77, all at raised risk of dementia, to either a two-year programme of diet, exercise, brain training and monitoring of blood-vessel risk factors, or to general health advice. On a combined score of thinking tests, the intervention group’s score rose by 0.20 over two years against 0.16 in the control group, a small but statistically significant difference. Adverse events were reported in 7% of the intervention group and 1% of the control group, most often muscle and joint pain. The authors concluded that a multidomain programme “could improve or maintain” thinking in at-risk older people. Unlike the clinic paper above, this was a randomised controlled trial.

Dementia risk factors across life

In 2020 the Lancet Commission on dementia prevention, intervention and care published a report reviewing the risk factors for dementia that can be changed across a person’s life. Several of the factors it reviews are conditions that also belong to the other horsemen, which is the kind of overlap Attia’s framework emphasises.

Inflammation in heart disease

Attia’s website has also published an article on anti-inflammatory medication for atherosclerotic cardiovascular disease. One trial in that area, LoDoCo2 (2020), randomly assigned 5,522 people with long-standing coronary artery disease to a low daily dose of the anti-inflammatory drug colchicine or to placebo, for a median of 28.6 months. Heart-related death, heart attack, ischaemic stroke or urgent procedures to reopen a coronary artery occurred in 6.8% of the colchicine group and 9.6% of the placebo group (hazard ratio 0.69). The trial was in people who already had heart disease, so it does not describe effects in people without it.

Studies of rapamycin, a drug Attia has discussed in connection with the biology of ageing, are covered on the site’s Rapamycin pages; most of the lifespan findings for that drug come from studies in mice and other animals, not from trials in people.

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Key Research Papers

  1. Attia P, Phan GQ, Maker AV, Robinson MR, Quezado MM, Yang JC et al. Autoimmunity correlates with tumor regression in patients with metastatic melanoma treated with anti-cytotoxic T-lymphocyte antigen-4. J Clin Oncol. 2005;23(25):6043-53. — PubMed PMID: 16087944
  2. Schelke MW, Attia P, Palenchar DJ, Kaplan B, Mureb M, Ganzer CA et al. Mechanisms of Risk Reduction in the Clinical Practice of Alzheimer’s Disease Prevention. Front Aging Neurosci. 2018;10:96. — PubMed PMID: 29706884
  3. Isaacson RS, Hristov H, Saif N, Hackett K, Hendrix S, Melendez J et al. Individualized clinical management of patients at risk for Alzheimer’s dementia. Alzheimers Dement. 2019;15(12):1588-1602. — PubMed PMID: 31677936
  4. Araújo J, Cai J, Stevens J. Prevalence of Optimal Metabolic Health in American Adults: National Health and Nutrition Examination Survey 2009-2016. Metab Syndr Relat Disord. 2019;17(1):46-52. — PubMed PMID: 30484738
  5. O’Hearn M, Lauren BN, Wong JB, Kim DD, Mozaffarian D. Trends and Disparities in Cardiometabolic Health Among U.S. Adults, 1999-2018. J Am Coll Cardiol. 2022;80(2):138-151. — PubMed PMID: 35798448
  6. Calle EE, Rodriguez C, Walker-Thurmond K, Thun MJ. Overweight, obesity, and mortality from cancer in a prospectively studied cohort of U.S. adults. N Engl J Med. 2003;348(17):1625-38. — PubMed PMID: 12711737
  7. Hanahan D, Weinberg RA. Hallmarks of cancer: the next generation. Cell. 2011;144(5):646-74. — PubMed PMID: 21376230
  8. Corder EH, Saunders AM, Strittmatter WJ, Schmechel DE, Gaskell PC, Small GW et al. Gene dose of apolipoprotein E type 4 allele and the risk of Alzheimer’s disease in late onset families. Science. 1993;261(5123):921-3. — PubMed PMID: 8346443
  9. de la Monte SM, Wands JR. Alzheimer’s disease is type 3 diabetes-evidence reviewed. J Diabetes Sci Technol. 2008;2(6):1101-13. — PubMed PMID: 19885299
  10. Ngandu T, Lehtisalo J, Solomon A, Levälahti E, Ahtiluoto S, Antikainen R et al. A 2 year multidomain intervention of diet, exercise, cognitive training, and vascular risk monitoring versus control to prevent cognitive decline in at-risk elderly people (FINGER): a randomised controlled trial. Lancet. 2015;385(9984):2255-63. — PubMed PMID: 25771249
  11. Livingston G, Huntley J, Sommerlad A, Ames D, Ballard C, Banerjee S et al. Dementia prevention, intervention, and care: 2020 report of the Lancet Commission. Lancet. 2020;396(10248):413-446. — PubMed PMID: 32738937
  12. Nidorf SM, Fiolet ATL, Mosterd A, Eikelboom JW, Schut A, Opstal TSJ et al. Colchicine in Patients with Chronic Coronary Disease. N Engl J Med. 2020;383(19):1838-1847. — PubMed PMID: 32865380

PubMed Topic Searches

  1. Attia P and Rosenberg SA — National Cancer Institute papers
  2. Prevalence of metabolic health in national survey data
  3. Multidomain risk reduction for Alzheimer’s disease
  4. Insulin resistance and cancer mortality

Further Reading

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Connections

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