Report of the First Medically Acquired Cases of Alzheimer's Disease

According to recent research, five individuals in the UK have been identified with Alzheimer's disease (AD) as a result of medical therapy they got decades earlier. 

Although independent specialists advise that the results should be viewed cautiously, investigators claimed that these were the first documented cases of medically acquired AD in living individuals.

When the patients were still youngsters, human growth hormone (c-hGH) that was derived from cadaver pituitary glands was used to treat them. An estimated 30,000 individuals, primarily children, received c-hGH treatment for growth hormone shortages and genetic abnormalities between 1958 and 1985. 

In 1985, the therapy was discontinued because three American patients who had received it subsequently passed away from Creutzfeldt-Jakob disease (CJD), which was spread by c-hGH batches tainted with prions that cause the disease. 

The researchers' previous work, which shown that the batches of c-hGH also contained amyloid-beta protein and that the protein could be transmitted decades later, is expanded upon in the current study. One of the principal researchers ran a prion clinic where doctors and researchers assessed or referred these five cases.

Researchers emphasize that there is no proof that amyloid-beta can spread during standard patient care or daily activities, and there are no reports of amyloid-beta transmission through any other medical or surgical procedures.

Lead author John Collinge, MD, director of the University of College London Institute of Prion Diseases, London, England, and head of the UK's National Prion Clinic, stated in a press release that "the recognition of transmission of amyloid-beta pathology in these rare situations should lead us to review measures to prevent accidental transmission via other medical or surgical procedures, in order to prevent such cases occurring in the future."

"Importantly, our findings also suggest that Alzheimer's and some other neurological conditions share similar disease processes to CJD, and this may have important implications for understanding and treating Alzheimer's disease in the future," said Collinge.

The findings were published online January 29 in Nature Medicine. 

Expanding upon Previous Work

The work expands upon earlier research conducted in 2015 by the same researchers who discovered that stored c-hGH samples were similarly tainted with amyloid-beta protein. 2018 research on mice revealed that amyloid-beta could still be injected into c-hGH samples that had been kept for decades. 

The results, according to researchers, revealed that those who were exposed to tainted c-hGH but did not pass away from CJD would later develop AD.

Between the ages of 38 and 55, study participants experienced neurologic symptoms that were compatible with AD. Between 2017 and 2022, the individual cases were either referred to or examined by specialists at the National Prion Clinic in the United Kingdom. The National Prion Monitoring Cohort, a long-term study of people with proven prion illnesses, is coordinated by the clinic. 

Out of the eight cases, three had an AD diagnosis prior to being sent to the clinic, two more had matched the criteria, and three had not. Currently, three of the patients—two of whom had AD—have passed away. 

Wilhelmi or Hartree-modified Wilhelmi preparation (HWP) is the procedure used to prepare c-hGH, which was administered to all study participants.

In two patients, biomarker tests supported the AD diagnosis. In other cases, there was either increasing loss of brain capacity on brain imaging, increased levels of total and phosphorylated tau in the CSF fluid, or postmortem evidence of amyloid-beta deposits.

Possibly Transferable

There were a variety of presentations in the cases. Certain individuals lacked symptoms, while others did not satisfy the existing standards for diagnosing sporadic AD. Individuals in the study had different treatment lengths and frequencies, as well as different ages at the beginning and end of their treatments. The researchers observed that a variety of factors could be responsible for the varied phenotypic observed in individuals.

Growth hormone deficiency, childhood intellectual disability, which has been linked to dementia risk, the underlying condition that prompted the individuals' treatment with c-hGH, and cranial radiation therapy, which four of the individuals had received, were among the other factors that the investigators looked at and ruled out as potential explanations for the individuals' cognitive symptoms. Additionally, in each of the five cases where testing samples were available, they ruled out genetic disease. 

"Taken together, the only factor common to all of the patients whom we describe is treatment with the HWP subtype of c-hGH," the researchers write. "Given the strong experimental evidence for [amyloid-beta] transmission from relevant archived HWP c-hGH batches, we conclude that this is the most plausible explanation for the findings observed."

The results, according to the researchers, demonstrate that AD has three etiologies, similar to other prion diseases: inherited, sporadic, and uncommon acquired variants, or iatrogenic AD. 

"The clinical syndrome developed by these individuals can, therefore, be termed iatrogenic Alzheimer's disease, and Alzheimer's disease should now be recognized as a potentially transmissible disorder," the researchers concluded. 

"Our cases suggest that, similarly to what is observed in human prion diseases, iatrogenic forms of Alzheimer's disease differ phenotypically from sporadic and inherited forms, with some individuals remaining asymptomatic despite exposure to [amyloid-beta] seeds due to protective factors that, at present, are unknown," they added.

The "Metric of Skepticism"

Lary C. Walker, PhD, of the Department of Neurology at Emory University, Atlanta, and Mathias Jucker, PhD, of the Hertie Institute for Clinical Brain Research, University of Tübingen, Tübingen, Germany, wrote an accompanying editorial suggesting that the results should be viewed "with a measure of skepticism."

"The cases presented are diverse and complicated; the individuals had undergone a variety of medical interventions for various disorders earlier in life, and it is difficult to exclude a contribution of these circumstances to the complex disease phenotypes that appeared many years later," they stated.

They did add, though, that "there is good reason to take the findings seriously."

"From a practical standpoint, this report reinforces the potential of amyloid-[beta] seeds as targets for early prevention, and it underscores the importance of informed caution in the preparation of surgical instruments, handling of tissues, and implementation of therapeutic biologics, particularly those derived from human sources," Jucker and Walker stated. 

The notion that amyloid-beta is transmissible between individuals has been demonstrated previously, according to Christopher Weber, PhD, head of global research initiatives for the Alzheimer's Association, who commented on the findings for Medscape Medical News.

Animal brains can be injected with amyloid-beta to induce aberrant amyloid accumulation, akin to that observed in Alzheimer's disease, as we have long known. Additionally, we insert human Alzheimer's genes into animals to cause aberrant, Alzheimer's-like brain activities," the speaker stated. "Thus, the idea that amyloid is transferable between individuals is not so novel as implied in the new paper."

But Weber noted that the study did emphasize how crucial safety precautions are to preventing the unintentional spread of amyloid-beta.

"It is a reasonable and actionable caution that the scientific and clinical communities must understand the possible risks and ensure that all methods of transmission are eliminated — for example, with complete and conscientious sterilization of surgical instruments," he stated. "Bottom line: We shouldn't put amyloid-beta into people's brains, either accidentally or on purpose, and appropriate measures should be in place to ensure that doesn't happen."

The National Institute for Health and Care Research (NIHR), the Medical Research Council, Alzheimer's Research UK, the Stroke Association, and the NIHR University College of London Hospital Biomedical Research Centre all provided funding for the study. Collinge is a director and stakeholder of D-Gen, Ltd., a spin-out business from an academic institution that specializes in the diagnosis, treatment, and decontamination of prion diseases.  

References : https://www.medscape.com/viewarticle/first-cases-medically-acquired-alzheimers-disease-reported-2024a10001ys

Also Read: Ataxic Disorders: Understanding Causes, Symptoms, and Genetic Factors

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