About twenty years ago, neuropathologists studying the brains of deceased dementia patients noticed a striking trend: the majority of them suffered from more than one disease.
This isn’t just a matter of two separate diagnoses listed in a medical file. In reality, at the microscopic level, two entirely different and destructive processes develop in parallel within the patient’s brain.
In the neural tissues of nearly 50% of individuals diagnosed with Alzheimer’s, researchers also find alpha-synuclein inclusions—the specific marker characteristic of Parkinson’s disease. Similarly, half of Parkinson’s patients who develop dementia exhibit high levels of the primary Alzheimer’s biomarkers, beta-amyloid and tau protein. In the elderly population, specifically those over 85, this clinical picture is often complicated by yet another independent neurodegenerative agent: the protein TDP-43.
This phenomenon is known scientifically as co-pathology (co-existing pathology). Experts believe this overlap is clearly not a random occurrence. A deep understanding of this factor is essential to answering why the fight against dementia remains such a formidable challenge for modern medicine.
Practical Significance
Clinicians have traditionally attributed the rapid decline of a patient’s neurological status or resistance to established pharmacotherapy to the aggressive nature of Alzheimer’s disease itself. However, the concept of co-pathology offers an alternative mechanism: the destruction of neuronal structures is significantly accelerated by a second, latent pathological process occurring simultaneously in the brain.
According to Lea Grinberg, a neuropathologist at the Mayo Clinic, co-existing pathologies explain the discrepancies between clinical symptoms and biomarkers, the differing trajectories of progression, and the unpredictable outcomes of therapy.
From a practical clinical standpoint, this factor is of strategic importance. During clinical trials for Alzheimer’s drugs, the presence of hidden Parkinson’s markers in the brain can reduce the drug’s perceived efficacy and trigger adverse reactions. Consequently, the current evidence base for managing neurodegenerative diseases may be inaccurate, as researchers have historically treated patient cohorts based on the principle of a single pathology (monopathology) when they were actually suffering from multiple lesions.
A Process That Begins Early
According to the traditional model, co-pathology was considered a hallmark of extreme old age. Because the brain accumulates damage over decades, it seemed logical that an 85-year-old would have several co-existing processes. While it is true that the frequency of co-pathologies increases with age—as one neurologist noted, “at age 80, virtually no one has just one pathology in their brain”—this phenomenon is not restricted to the elderly.
Studies of individuals with genetic (familial) Alzheimer’s—which can develop as early as age 40—have shown that post-mortem, 50% of these patients exhibit Lewy bodies specific to Parkinson’s alongside their primary markers. Furthermore, scientific data from this year indicates that even relatively young patients in the early stages of Parkinson’s show high titers of Alzheimer’s biomarkers in their blood.
It appears that these diseases do not wait for old age to interact synchronously.
Why Does Co-pathology Develop?
Science does not yet have a definitive and exhaustive answer to this question. However, researchers are increasingly convinced that the process is not accidental. “It seems they stimulate each other,” Grinberg states. The presence of one specific pathological process may create a microenvironment in the neural tissue that facilitates the manifestation of a second disease or significantly accelerates existing destruction. The proteins involved—amyloid, tau, alpha-synuclein, and TDP-43—may interact in such a way that they amplify each other’s toxic effects.
Investigating these molecular and biochemical interactions is currently one of the highest priorities in dementia research.
Modern Diagnostic Capabilities
In the past, most co-existing pathologies could only be identified through post-mortem autopsy or high-tech research in specialized university centers. For the vast majority of patients, it was practically impossible to know during their lifetime whether a second disease was lurking in their system.
Today, this reality is changing rapidly. A new cerebrospinal fluid test developed by Amprion Diagnostics accurately detects Parkinson’s disease, dementia with Lewy bodies, and related conditions at an early stage. Meanwhile, innovative blood biomarkers currently in the preclinical trial stage offer doctors and patients a much more complete picture of ongoing brain processes.
One of the most promising methods relies on microscopic particles called extracellular vesicles. These are tiny “packages” secreted into the blood by nerve cells, carrying various proteins from within the cell. Researchers at Columbia University believe that by studying the contents of these particles, it is entirely feasible to find several proteins characteristic of different forms of dementia simultaneously through a simple blood test.
Last month, a team at Washington University in St. Louis developed an experimental blood test that monitors 15 protein markers. By analyzing this data collectively with the help of Artificial Intelligence, the program can easily distinguish between major types of dementia and even estimate the precise share of each in the brain. While this test is currently undergoing clinical validation and is not yet used for predicting outcomes in asymptomatic individuals, the information it provides is of extraordinary value for patients already living with dementia.
The Therapeutic Challenge
Identifying multiple co-existing diseases is one issue; selecting a treatment for them presents an entirely different level of complexity.
Currently, therapeutic options are very limited. Only one group of drugs—monoclonal antibodies for Alzheimer’s—can clear disease-causing amyloid proteins from the brain. We do not yet possess similar effective tools against alpha-synuclein, TDP-43, or other destructive proteins. Furthermore, even these anti-amyloid medications do not guarantee results in patients who have other co-existing pathologies alongside Alzheimer’s.
An innovative clinical trial is planned to begin this year, specifically designed to combat this complex combination of pathologies. The study will enroll patients in the early stages of dementia with Lewy bodies (the second most common form after Alzheimer’s) who have confirmed high levels of amyloid in their brains. The experiment will test whether the Alzheimer’s drug donanemab can slow the progression of neurological symptoms. Study coordinator Sharon Sha, a neurologist at Stanford University, believes that the interaction between beta-amyloid and alpha-synuclein sharply accelerates brain damage. Her hypothesis is that reducing the amyloid burden may hinder the overall pathological cascade, even if it does not directly affect the structure of Lewy bodies.
This is only an initial step. However, it marks the first time that a major scientific study will select patients based on two different pathologies simultaneously, rather than a single specific disease.
Some scientists are convinced that the future of dementia treatment lies not in searching for disease names, but in measuring the unique “cocktail” of proteins in each patient’s brain and providing targeted therapy. As Johannes Attems, a neuropathologist at Innsbruck University, notes: “In the future, we will no longer use the term ‘Alzheimer’s disease’.” Instead, based on molecular analysis, a clinician will determine that a patient’s brain has high amyloid levels, moderate tau, a small amount of alpha-synuclein, and traces of TDP-43, and will plan targeted treatment based on this data. “That’s it. And you will have a specific medication to give them.”
This medical model requires drugs that do not yet exist, tests that are still in the validation stage, and a fundamental shift in the structure of clinical trials. Nevertheless, the general direction of development is already quite clear.
Source: Science
