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First Cases of Medically Acquired Alzheimer's Disease Reported

Five people in the United Kingdom have been diagnosed with Alzheimer's disease (AD) resulting from a medical treatment they received decades earlier, new research shows.

Kelli Whitlock Burton, Medscape, Jan 29, 2024

Five people in the United Kingdom have been diagnosed with Alzheimer's disease (AD) resulting from a medical treatment they received decades earlier, new research shows.

Investigators said that they are the first known cases of medically acquired AD in living people, but outside experts say the findings should be interpreted cautiously.

The individuals received treatment as children with human growth hormone extracted from pituitary glands of cadavers (c-hGH). Between 1958 and 1985, an estimated 30,000 people worldwide, mostly children, were treated with c-hGH for genetic disorders and growth hormone deficiencies.

The therapy was halted in 1985 after three patients in the United States who received the treatment later died of Creutzfeldt-Jakob disease (CJD) transmitted through batches of c-hGH that were contaminated with disease-causing prions.

The new study builds on the investigators' earlier work that showed the batches of c-hGH also contained amyloid-beta protein and that the protein could be transmitted decades later. These five cases were referred to or reviewed by researchers and clinicians at a prion clinic led by one of the lead researchers.

There are no reports of amyloid-beta transmission through any other medical or surgical procedures, researchers stress, and there is no evidence that amyloid-beta can be passed on during routine patient care or in daily activities.

"However, 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 future," lead author John Collinge, MD, director of the University of College London Institute of Prion Diseases, London, England, and leader of the UK's National Prion Clinic, said in a press release.

"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," Collinge noted.

The findings were published online January 29 in Nature Medicine.

Building on Earlier Work

The research builds on investigators' previous 2015 work, which found that archived samples of c-hGH were also contaminated with amyloid-beta protein. In 2018, mouse studies showed that c-hGH samples stored for decades could still transmit amyloid-beta via injection.

Researchers said that the findings suggested that individuals exposed to contaminated c-hGH who did not die from CJD might eventually develop AD.

Patients in the new study developed neurologic symptoms consistent with AD between ages 38 and 55 years. The individual cases were either referred to or reviewed by experts in the National Prion Clinic in the UK between 2017 and 2022. The clinic coordinates the National Prion Monitoring Cohort, a longitudinal study of individuals with confirmed prion diseases.

Of the eight cases, three were diagnosed with AD before referral to the clinic; two others met criteria for an AD diagnosis; and three did not meet the criteria. Three of the patients, two of whom had AD, are now deceased.

All patients in the study received c-hGH prepared using a method called Wilhelmi or Hartree-modified Wilhelmi preparation (HWP).

Biomarker analyses confirmed the AD diagnosis in two patients. Other cases showed either progressive brain volume loss on brain imaging or elevated cerebrospinal fluid total tau and phosphorylated tau, or evidence of amyloid-beta deposits on autopsy.

'Potentially Transmissible'

The cases offered diverse presentations. Some were not symptomatic and some failed to meet current diagnostic criteria for sporadic AD. Treatment duration and frequency differed among those in the study, as did their age at treatment onset and completion. That and other factors could contribute to the diverse phenotype recorded in individuals, investigators noted.

Investigators examined and ruled out other factors that might explain the individuals' cognitive symptoms, including childhood intellectual disability, which has been linked to dementia risk, the underlying condition that prompted their treatment with c-hGH, growth hormone deficiency, and cranial radiotherapy, which four of the individuals had received. They also ruled out inherited disease in all five of the cases with samples available for testing.

"Taken together, the only factor common to all of the patients whom we describe is treatment with the HWP subtype of c-hGH," the authors 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."

Investigators say the findings show that, like other prion diseases, AD has three etiologies: sporadic, inherited, and rare acquired forms, 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 authors wrote.

"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 also wrote.

'Measure of Skepticism'

In an accompanying editorial, Mathias Jucker, PhD, of the Hertie Institute for Clinical Brain Research, University of Tubingen, Tubingen, Germany, and Lary C. Walker, PhD, in the Department of Neurology at Emory University, Atlanta, wrote that the findings should be considered "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 wrote.

However, they continued, "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 wrote.

Commenting on the findings for Medscape Medical News, Christopher Weber, PhD, director of global science initiatives for the Alzheimer's Association, said that the idea that amyloid-beta is transmissible between individuals has been shown before.

"We've known for a long time that it is possible to create abnormal amyloid buildup - similar to that seen in Alzheimer's - in the brain of an animal by injecting it with amyloid-beta. We also transfer human Alzheimer's genes into animals to initiate abnormal, Alzheimer's-like processes in their brains," he said. "Thus, the idea that amyloid is transferable between individuals is not so novel as implied in the new paper."

However, the study does highlight the importance of safety measures to prevent the accidental transmission of amyloid-beta, Weber added.

"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 said. "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."

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