Hidden Causes of Chronic Disease: Dr. Paul Ewald on Infections, Alzheimer’s, Cancer & More

This episode of Live Longer World features Dr. Ewald, who discusses his research and the central thesis of his book, "Plague Time." The conversation delves into the often-overlooked role of infectious agents—such as viruses, bacteria, and other parasites—as significant causative factors in a wide range of chronic diseases, including Alzheimer's, various cancers, atherosclerosis, and diabetes. Dr. Ewald argues that current mainstream explanations for these diseases, which predominantly focus on genetics, lifestyle, or metabolic dysfunction, are often incomplete and fail to account for many observed phenomena. The episode emphasizes the complex interplay between infections, genetic predispositions, environmental factors, and lifestyle choices, advocating for a more integrated approach to understanding and tackling these pervasive health issues. This topic is highly relevant for individuals seeking deeper insights into the root causes of chronic illnesses, for healthcare professionals, and for anyone interested in the cutting edge of medical research that challenges conventional wisdom.

Key Insights

• Infections are a major, underestimated cause of chronic diseases: Dr. Ewald posits that infectious agents (viruses, bacteria, protozoa, etc.) play a far more significant role in the development of chronic conditions like Alzheimer's, cancer, and heart disease than is commonly acknowledged in mainstream medicine, which often overlooks this "big category of causation."
• Current disease explanations have significant "holes": Prevailing theories focusing solely on genetics, lifestyle, or metabolic factors often fail to provide complete explanations for chronic diseases. For instance, the amyloid plaque theory in Alzheimer's doesn't fully explain why plaque-targeting interventions often yield minimal benefits, and overlooks the antimicrobial properties of amyloid beta itself.
• Chronic diseases result from complex interactions: Causation is rarely singular. Infections interact intricately with genetic vulnerabilities (e.g., APOE4 allele increasing susceptibility to certain pathogens), environmental factors (including social factors like access to dental care), and lifestyle choices (e.g., oral hygiene, diet). Understanding these multifactorial interactions is key.
• Pathogen persistence is crucial in chronic illness: Unlike acute infections that are quickly resolved, many chronic diseases may involve pathogens that persist in the body for long periods, sometimes in a seemingly latent or low-activity state, continually provoking damage or altering cellular functions (e.g., EBV's role in shifting cellular reproduction, pushing cells towards cancer).
• The "arms race" between hosts and pathogens maintains disease susceptibility: Harmful genetic variants often persist in populations because they may confer vulnerability to ever-evolving pathogens. The rapid evolution of infectious agents means natural selection struggles to eliminate host vulnerabilities, leading to an ongoing dynamic conflict.
• Recognizing infectious links opens new avenues for prevention and treatment: Understanding the infectious components of chronic diseases can lead to novel preventive strategies (e.g., improved oral hygiene for Alzheimer's, vaccines for certain oncogenic viruses) and treatments (e.g., antivirals for conditions like glioblastoma or to mitigate long-term damage from persistent infections).
• Research silos and funding biases hinder progress: The traditional separation of research fields and biases in funding (e.g., prioritizing mutation-centric cancer research over viral oncology for many years) have slowed the acceptance and investigation of infectious causes of chronic diseases, despite accumulating evidence.

The Overlooked Role of Infections in Chronic Diseases

Dr. Ewald begins by explaining that his book, "Plague Time," aims to highlight a significantly neglected area in the understanding of chronic diseases: the role of infection. He argues that medical science has historically tackled easier problems first, leaving complex chronic diseases poorly understood. A major missing piece in this puzzle, according to Dr. Ewald, is the contribution of infectious agents. This isn't to say infections are the sole cause, but rather that their role can only be understood through their interaction with other factors like genetic vulnerabilities and environmental circumstances. He stresses that understanding one risk factor often reveals its connection to others, creating a complex web of causation that explains why many chronic diseases remain enigmatic despite extensive research.

The discussion points out the frustration among researchers in this field who present compelling data on infectious links, only to see it dismissed by those adhering to standard explanations. This dismissal often occurs without a critical examination of the limitations of existing theories or how incorporating infectious causation could resolve these shortcomings. Dr. Ewald clarifies that "infection" is a broad term, encompassing not just viruses but also bacteria, protozoa, and even parasitic worms.

Alzheimer's Disease: A Case Study in Complex Causation

Alzheimer's disease, particularly the common non-familial, sporadic form, serves as a prime example of Dr. Ewald's thesis. The conventional focus has been on amyloid plaques and neurofibrillary tangles in the brain as causative agents. However, Dr. Ewald points out a "circularity" in this logic, as Alzheimer's is often defined by the presence of these features. He questions why the body would produce plaques that are detrimental, suggesting they might be a consequence of an underlying process rather than the primary cause.

A critical insight is that beta-amyloid fragments, which form plaques, also possess antimicrobial properties. This suggests the brain might produce beta-amyloid in response to pathogens (bacteria or viruses). The plaques, then, could be a byproduct of an ongoing battle between these pathogens and the brain's defense mechanisms. The damage seen in Alzheimer's could stem from this battle, not just the plaques themselves. Dr. Ewald specifically mentions pathogens causing gum disease (periodontitis), such as Porphyromonas gingivalis, which are invasive, can enter the bloodstream, and have been found in the brains of Alzheimer's patients and in atherosclerotic plaques. Animal studies support the idea that these pathogens can generate brain-damaging molecules, while amyloid production helps control these harmful substances.

This perspective integrates genetic factors like the APOE4 allele, a known risk factor for Alzheimer's. The APOE4 protein appears to interact with pathogens like *Chlamydia pneumoniae* and Herpes Simplex Virus 1 (HSV-1), potentially making individuals with this allele more vulnerable to the damage these microbes can cause. *Chlamydia pneumoniae*, for instance, uses the APOE4 protein as a "doorknob" to enter cells. Lifestyle factors also fit into this model; good oral hygiene, including flossing, can reduce periodontal disease, thereby potentially lowering the risk of Alzheimer's by limiting the invasion of these pathogens. This highlights how social factors (education, access to dental care) and diet also play interconnected roles.

The Interplay of Genetics, Infections, and Lifestyle

Dr. Ewald elaborates on a "crucial unrecognized problem with genetic causation of harmful diseases": how harmful genes maintain their presence over evolutionary time. Natural selection should effectively weed out gene variants that cause harm. However, if a genetic variant confers vulnerability to an infectious agent, the situation becomes an "arms race." Pathogens evolve rapidly, meaning host defenses (including genetic ones) are constantly being challenged and circumvented. This continuous evolution of pathogens makes it difficult for natural selection to eliminate genes that confer susceptibility, especially if those genes are involved in the immune system (like HLA alleles, which are highly variable). The APOE4 allele, for example, was the ancestral form, but its frequency has declined over the past 200,000 years, possibly due to its liability in the face of pathogens like *Chlamydia pneumoniae*. This decline is more pronounced in populations with longer histories of agriculture and denser living conditions, where pathogen transmission might be higher.

Studies have shown a strong association between *Chlamydia pneumoniae* and Alzheimer's, with individuals homozygous for APOE4 (having two copies) exhibiting the highest density of this bacterium in their brains upon autopsy. This illustrates how genetic makeup can influence the intensity of infection and subsequent disease. However, Dr. Ewald notes a common challenge: many pathogens implicated in chronic diseases are widespread (e.g., almost everyone is exposed to *Chlamydia pneumoniae* or Epstein-Barr Virus). Therefore, simply detecting the pathogen isn't enough; researchers must look at the intensity and persistence of infection, and how this interacts with individual vulnerabilities.

Vicious Cycles and Interconnected Diseases: The Role of Diabetes

The podcast highlights how different chronic diseases are often correlated. For instance, Alzheimer's is linked with cardiovascular disease and diabetes. Dr. Ewald suggests that shared underlying risk factors, including infections, might explain these connections. Periodontal pathogens like Porphyromonas gingivalis are found not only in Alzheimer's brains but also in atherosclerotic plaques and are implicated in worsening diabetes by interfering with insulin activity and glucose uptake by cells.

Diabetes itself exacerbates many chronic diseases, a phenomenon often accepted without a deep mechanistic understanding. Dr. Ewald proposes that elevated blood glucose in diabetics provides more "fuel" for infections, thereby worsening diseases that have an infectious component. Furthermore, some bacteria might manipulate insulin function to increase glucose availability for their own benefit, potentially instigating or worsening diabetic conditions. This can create a "vicious cycle": periodontal pathogens worsen glucose control, and higher glucose levels, in turn, fuel these and other infections, which then contribute to Alzheimer's, cardiovascular disease, and chronic kidney disease. Interventions like flossing could theoretically help break this cycle by controlling the initial oral pathogens.

Pathogen Persistence: From Acute Infection to Chronic Disease and Cancer

A key distinction is made between acute and chronic infectious diseases. Acute infections are typically resolved by the immune system within weeks. If a pathogen persists beyond this period (roughly one to two months), it suggests it has mechanisms to evade or withstand the immune response, leading to a chronic condition. Pathogens transmitted through intimate contact (sexual or kissing) are under particularly strong selective pressure to persist, as their transmission opportunities are less frequent than, for example, airborne pathogens.

Dr. Ewald challenges the common understanding of "latency." For example, Epstein-Barr Virus (EBV), when not producing viral particles, is often described as latent. However, he argues it's often in a different, active reproductive strategy: it causes host cells to divide and replicates along with them, hidden from the immune system. This active persistence, rather than true dormancy, is critical. By forcing cells to replicate, inhibiting cell suicide (apoptosis), and removing the cap on cell divisions (telomere shortening), these viruses push cells towards becoming immortal and potentially cancerous. This is how many oncogenic (cancer-causing) viruses work. They don't necessarily benefit from causing cancer directly, but from persisting within the host. Cancer then becomes a byproduct of this long-term manipulation of cellular machinery, often coupled with additional mutations.

This viral strategy explains why many accepted human oncogenic viruses (like HPV, EBV) share these mechanisms of altering cell cycle control, apoptosis, and replicative limits. The interaction is crucial: viruses expand the population of infected, pre-cancerous cells, dramatically increasing the chances that one of these cells will acquire the additional mutations needed to cross the threshold into full-blown cancer. This is a more powerful explanation than relying on random mutations alone.

The Challenges of Linking Infections to Cancer and Other Chronic Conditions

The episode details the slow and often contentious process of establishing infectious causes for chronic diseases, using multiple sclerosis (MS) and various cancers as examples. For MS, the link to Epstein-Barr Virus (EBV) has been debated for decades, but a consensus is now emerging, supported by genetic data (an HLA gene variant used by EBV as a receptor) and the near-universal presence of significant EBV infection in MS patients. Initially, EBV was considered a "trigger," but evidence suggests it's more likely a persistent provoker.

Similarly, for Type 1 Diabetes, certain enteroviruses are increasingly recognized not just as triggers for an autoimmune response, but as persistent causal agents found in the pancreas of deceased patients. The distinction between a "hit-and-run" trigger and a "persistent provocation" is vital: if the pathogen remains, targeting it could offer a cure, not just symptomatic relief.

In cancer research, the path to accepting viral causation has been arduous. For Hodgkin's lymphoma, EBV is now largely accepted as a cause, even though only about 1 in 100 cells in the tumor may be infected. Crucially, these few EBV-infected cells are the cancerous ones. This finding challenges the dogma that all cells in a tumor must be cancerous or infected for a virus to be causal. The tumor mass can be composed of non-cancerous cells stimulated to proliferate or immune cells infiltrating the area. This "cryptic" nature of infectious causation means that low viral loads in tumors, as sometimes seen in studies of EBV and breast cancer, should not be grounds for dismissal. Meta-analyses of numerous global studies do show strong associations between EBV (and other viruses like HPV and mouse mammary tumor virus) and breast cancer, despite variable findings in individual studies and historical underfunding of such research in some countries like the US.

The example of glioblastoma and Cytomegalovirus (CMV) further illustrates these challenges. Early studies around 2000 suggested a link. Despite initial skepticism and conflicting results often due to insensitive assays, a consensus began to form that CMV plays a role. Antiviral treatments in some studies (e.g., at the Karolinska Institute) have shown promise in prolonging life for glioblastoma patients, though the mechanism (direct antiviral effect vs. general anti-replicative effect) needs further clarification. However, this progress has faced setbacks and continued debate.

Dr. Ewald recounts the historical "war on cancer" where research split into "virus" and "mutation" camps, hindering an integrated approach. While oncogenes are undeniably important, focusing solely on them ignores how viruses can drive the processes leading to the accumulation of oncogenic mutations. Despite the initial dominance of the mutation theory, evidence for viral causes of cancers like cervical cancer (HPV), Burkitt's lymphoma (EBV), liver cancer (Hepatitis B & C), and stomach cancer (H. pylori, though a bacterium) gradually forced a partial shift. Still, Dr. Ewald estimates that while 20-30% of cancers are accepted as infection-caused, the true figure could be much higher, with many remaining cancers having more cryptically-caused infectious components.

Implications for Prevention, Treatment, and Future Research

Recognizing the infectious roots of chronic diseases opens pathways for prevention and treatment. For example, the HPV vaccine prevents cervical cancer, and Hepatitis B vaccines prevent liver cancer. While developing vaccines for persistent viruses like EBV is challenging because these viruses have evolved to evade the immune system (which vaccines stimulate), it's not impossible, as shown by the shingles vaccine (for Varicella-Zoster Virus). In the absence of vaccines, behavioral changes like improved oral hygiene (for periodontal pathogens), safer sex practices, and general measures to support immune function (good diet, sleep, exercise, stress reduction) can be beneficial. If infections are identified, antiviral or antibiotic treatments might be considered, even for conditions not traditionally thought of as infectious, or to prevent long-term sequelae.

Dr. Ewald expresses cautious optimism about a growing openness to more integrated, broader perspectives in research, driven partly by frustration with the slow progress against many chronic diseases. He emphasizes the need to move beyond research silos and for funding structures that support long-term investigation into complex, multifactorial causes. The ultimate goal is to assemble the complete "jigsaw puzzle" of disease causation by fitting together insights from genetics, immunology, virology, lifestyle research, and environmental health.

Conclusion

The core message of this Live Longer World episode with Dr. Ewald is a compelling call to re-evaluate our understanding of chronic diseases by giving due consideration to the profound and often underestimated role of infectious agents. Dr. Ewald argues that many conditions, from Alzheimer's to cancer and heart disease, are not simply the result of faulty genes or lifestyle choices alone, but arise from a complex interplay where pathogens act as persistent provocateurs, interacting with our genetic predispositions and environmental exposures. By acknowledging these infectious components, medicine can unlock new, more effective strategies for prevention—such as targeted vaccinations or public health measures like promoting oral hygiene—and for treatment, potentially through antimicrobials or therapies that bolster the immune system's ability to control persistent infections. The discussion underscores the necessity of breaking down research silos and fostering a more holistic, integrated approach to unravel the intricate causal webs of chronic illness, ultimately aiming for a healthier future by addressing these deeply embedded microbial adversaries.