New Study Links Alzheimer’s Findings to Old Medical Treatments

A new case series from the U.K. National Prion Clinic bolstered earlier findings that suggested Alzheimer’s disease could be transmitted through specific medical treatments involving contaminated biological materials.

The report focused on four male patients who developed dementia following childhood treatment with cadaveric pituitary-derived human growth hormone, reported John Collinge, MD, of University College London, and colleagues in JAMA Neurology.

One patient who died, a 57-year-old man, had autopsy findings that showed Alzheimer’s disease pathology, including extensive amyloid-beta plaques and severe hyperphosphorylated tauopathy.

All four patients developed cognitive symptoms between the ages of 47 and 60. A common clinical feature was prominent language involvement.

The study follows an earlier case series from Collinge and co-authors that suggested children treated with cadaver-derived pituitary growth hormone contaminated with amyloid-beta seeds developed iatrogenic Alzheimer’s disease.

“However, some colleagues have argued that the cases we described were not typical of Alzheimer’s pathology — in particular, that tauopathy was mild. Since this publication, we have been referred further cases, and we describe one in detail where autopsy was performed which unequivocally showed severe classical Alzheimer’s pathology,” Collinge said.

“Iatrogenic Alzheimer’s is a newly recognized condition, and its full phenotypic range is yet to be established,” he told MedPage Today. “We therefore advise clinicians to be vigilant for any cognitive changes in recipients of cadaveric human growth hormone.”

Between 1959 and 1985, cadaver-derived human growth hormone was used around the world to treat young patients for pituitary insufficiency. In the U.S., nearly 7,700 children were treated with pituitary human growth hormone under the National Hormone and Pituitary Program from 1963 to 1985. The product was withdrawn after some patients received prion-contaminated cadaveric growth hormone and subsequently died of Creutzfeldt-Jakob disease.

In 2015, Collinge and co-authors reported that some of the U.K. patients who died of iatrogenic Creutzfeldt-Jakob disease had amyloid-beta pathology at autopsy. Whether these patients also had Alzheimer’s symptoms wasn’t known because Creutzfeldt-Jakob, a universally fatal prion disease that progresses rapidly, may have masked symptoms.

Neurodegenerative diseases caused by protein misfolding — Alzheimer’s disease, frontotemporal lobar degeneration, and Parkinson’s disease — share similarities with prion diseases, noted Brian Appleby, MD, and Mark Cohen, MD, of Case Western Reserve University School of Medicine in Cleveland, in an accompanying editorial.

“However, with one exception, they have not exhibited interindividual or zoonotic transmission as observed in iatrogenic Creutzfeldt-Jakob disease and variant Creutzfeldt-Jakob disease, respectively,” they pointed out. “An important unresolved question is whether other proteinopathies are transmissible between individuals, and if so, their potential impact on public health.”

Several prion centers have re-examined cases of iatrogenic Creutzfeldt-Jakob disease caused by cadaver-derived human growth hormone and dura mater grafts, the editorialists said. “Although amyloid-beta plaques and cerebral amyloid angiopathy were commonly seen, tau pathology necessary for a diagnosis of Alzheimer’s disease was not,” they wrote.

The new cases from Collinge and colleagues are important, “given our knowledge regarding the transmissible aspects of prion disease and iatrogenic cerebral amyloid angiopathy,” Appleby and Cohen noted.

However, the evidence still supports iatrogenic transmission of amyloid-beta, not Alzheimer’s disease, they emphasized.

“Neither this report nor earlier reports provide substantial evidence of iatrogenic Alzheimer’s disease, and definitive causation may remain elusive given the heterogeneity of this population,” they wrote.

In the current case series, the autopsied patient had extensive parenchymal amyloid-beta deposition and severe cerebral amyloid angiopathy. Hyperphosphorylated tau pathology was widespread. The extent and severity of amyloid and tau pathology reached the highest diagnostic threshold for Alzheimer’s disease neuropathological change and were independent of any childhood comorbidities, Collinge and colleagues noted. The patient also had lobar intracerebral hemorrhage. Genetic testing for variants associated with adult-onset neurodegenerative disorders was negative.

This man, and the three others in the series, had a cognitive phenotype defined by early and prominent language impairment. Three of the four patients received an earlier clinical diagnosis of the semantic variant of primary progressive aphasia. Neuroimaging supported this, showing the asymmetrical temporal lobe atrophy characteristic of this variant.

The four cases highlight that iatrogenic Alzheimer’s may present as a non-amnestic, language-led syndrome, often mimicking primary progressive aphasia variants before the underlying pathology is identified, Collinge and co-authors said. However, there are inherent challenges in proving causality in iatrogenic Alzheimer’s disease, they observed.

“As stated in our earlier report, these findings do not mean that Alzheimer’s disease is contagious in a conventional sense; transmission has occurred in rare circumstances in the context of cadaveric tissues that are no longer used,” they wrote.

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