Iatrogenic Alzheimer's disease in recipients of cadaveric pituitary-derived growth hormone

Alzheimer's disease (AD) is a neurodegenerative disorder characterized by amyloid-beta (Aβ) plaques and tau tangles in the brain. Compelling evidence points to Aβ as a primary driver of AD pathogenesis. Previous studies demonstrated the transmission of Aβ pathology and cerebral amyloid angiopathy (CAA) in young adults who died from iCJD after receiving contaminated c-hGH. This raised the possibility that c-hGH recipients who did not develop iCJD might still develop AD. Prion diseases, caused by misfolded proteins, are known to have sporadic, inherited, and acquired forms. This study investigates whether AD also displays this tripartite etiology, focusing on the possibility of iatrogenic AD resulting from contaminated c-hGH.

The authors review prior research on prion diseases, including their transmission mechanisms and strain diversity. They discuss the established link between Aβ and AD, noting the presence of Aβ in neuritic plaques and CAA. The review also highlights previous reports of iatrogenic CAA transmission via cadaveric dura mater or neurosurgical procedures. However, before this study, there was no clinical evidence of iatrogenic AD caused by c-hGH, despite experimental evidence supporting this possibility.

This retrospective cohort study examined eight individuals who received c-hGH prepared using the Hartree-modified Wilhelmi preparation (HWP) method between 1959 and 1985. The researchers excluded iCJD based on clinical presentation, neuroimaging, and biomarkers. Five of the eight individuals presented with symptoms consistent with early-onset dementia. The study reviewed clinical investigations, including biomarker changes compatible with AD (amyloid/tau/neurodegeneration or AT(N) criteria). Genetic testing for adult-onset neurodegenerative disorders was performed, and the study considered alternative explanations for the observed cognitive decline, including childhood intellectual disability, underlying diagnoses, growth hormone deficiency, and cranial radiotherapy. Post-mortem examinations were conducted in some cases to assess Aβ and tau pathology. The authors analyze the findings considering the possibility of Aβ strains and other contributing factors to phenotypic diversity.

Five of the eight c-hGH recipients developed dementia with symptoms consistent with early-onset AD, showing biomarker changes compatible with the disease. Three individuals met diagnostic criteria for probable AD before referral. One patient exhibited mild cognitive impairment, another had subjective cognitive symptoms, and one remained asymptomatic. Post-mortem examinations revealed widespread Aβ deposition and CAA in some cases. Genetic testing largely ruled out inherited forms of AD. The study found a strong association between the observed symptoms and the HWP method of c-hGH preparation, with HWP batches previously shown to contain Aβ and transmit Aβ pathology to mice. The latency period between c-hGH exposure and symptom onset was three to four decades. The authors discuss potential Aβ strains as a factor contributing to phenotypic differences between iatrogenic and other types of AD. Alternative explanations for the findings were considered and largely ruled out.

The findings strongly suggest that contaminated c-hGH can cause iatrogenic AD. The relatively young age of onset in these individuals and the exclusion of inherited causes make iatrogenic transmission the most plausible explanation. The clinical presentation of iatrogenic AD differs from sporadic and familial forms, possibly due to Aβ strains. The study highlights the importance of recognizing the potentially transmissible nature of AD and underscores the need for preventative measures, particularly in medical procedures that involve potential exposure to contaminated tissue. The authors discuss implications for therapeutic strategies targeting Aβ assemblies, considering the possibility of strain diversity and the potential for resistance.

This study provides compelling evidence for iatrogenic AD, expanding the known etiologies of AD to include a rare acquired form. The findings highlight the need for continued vigilance in preventing accidental transmission of Aβ through medical procedures and emphasize the potential implications for therapeutic strategies. Further research is needed to fully elucidate the clinical and pathological spectrum of iatrogenic AD and to understand the role of Aβ strains in shaping disease phenotype.

The retrospective nature of the study, the limited sample size, and variations in patient investigations are limitations. Genetic data were unavailable for some patients, and the study primarily focuses on a specific c-hGH preparation method, limiting the generalizability of findings to other contexts. The study also acknowledges variations in the duration and amount of c-hGH exposure and the potential influence of unidentified host factors.