Research over the last decade has shown that aggregated Aβ seeds can be transferred between people during rare medical procedures, sparking amyloidosis in the recipient. Could this result in full-blown Alzheimer’s disease? In the January 29 Nature Medicine online, researchers led by John Collinge at University College London offer the first evidence for this. Collinge runs the U.K.’s National Prion Clinic, which evaluates neurological disease in people who, as children, were treated with growth hormone or tissue taken from cadavers. Out of a total of eight people referred to this clinic since 2017, most of whom were diagnosed with dementia or cognitive problems in their mid-40s, four were positive for Alzheimer’s biomarkers. In one person who died with mild cognitive impairment, an autopsy found widespread amyloid plaques and neurofibrillary tangles in the cortex. All eight had received growth hormone preparations known to be contaminated with Aβ seeds.
- Several people who received Aβ-contaminated growth hormone in childhood developed dementia in midlife.
- Four of them had biomarker or pathological evidence of Alzheimer’s disease.
- This is the first evidence of iatrogenic AD transmission.
“[The authors] provide tantalizing evidence that, under extraordinary circumstances, Alzheimer’s disease is transmissible by a prion-like mechanism,” Mathias Jucker at the University of Tübingen, Germany, and Lary Walker at Emory University, Atlanta, noted in an accompanying editorial.
Experts agreed. “This is a very important and impactful study providing the first convincing evidence that AD can be transmitted in humans, and that the incubation time is around 35 years,” Jochen Herms at Ludwig-Maximilians University, Munich, wrote to Alzforum. David Knopman at the Mayo Clinic in Rochester, Minnesota, concurred, “These observations show iatrogenic transmission of Alzheimer pathology is possible.”
At the same time, some caution that the findings fall short of definitive proof of iatrogenic AD. “Pathological evidence, so far available in two of three deceased patients, suffered either from incomplete sampling or was too sparse to allow a state-of-the-art AD diagnosis,” said Herbert Budka at the Medical University in Vienna. Gaël Nicolas at Rouen University Hospital, France, noted that sporadic Alzheimer’s pathology can start in midlife. “Overall, I feel it difficult to be sure that AD-related changes were of iatrogenic origin,” he wrote (comments below).
Alzheimer’s Evidence. A middle-aged man exposed to Aβ seeds in childhood had temporal lobe (top left) and parietal lobe (bottom left) atrophy (arrows), as well as amyloid PET tracer uptake in frontal, temporal, and parietal lobes (right). [Courtesy of Banerjee et al., Nature Medicine.]
A Mixed Clinical Picture
Previously, Collinge and colleagues at the NPC had found cerebral amyloid angiopathy (CAA) and parenchymal Aβ in seven out of eight people who died in their 40s from iatrogenic Creutzfeldt-Jakob Disease transmitted by contaminated growth hormone preparations (Sep 2015 news). The authors went on to show that archived vials of the suspect growth hormone extract contained Aβ seeds that triggered amyloidosis in mice, making this the likely cause of the early onset AD pathology (Dec 2018 news). Still, none of the CJD patients had Alzheimer’s symptoms, and their pathology did not meet the criteria for AD, leaving unclear whether they would have developed the disease had they lived longer.
In the new work, first author Gargi Banerjee and colleagues reported case studies from the next eight patients referred to the NPC, all of whom had received injections of the contaminated batches of growth hormone. At the time of referral, five of them had dementia; one had mild cognitive impairment, one, subjective cognitive impairment, and one was cognitively healthy. Two of them had memory problems characteristic of Alzheimer’s, while the others had varied deficits including language difficulties, problems with executive function, and behavior changes. Their symptoms began at a mean age of 46. Four of the eight had pathological or biomarker evidence consistent with AD.
The sole pathological evidence came from the man with MCI, who died at age 47 after a childhood brain tumor had returned. In his neocortex, the investigators found a moderate density of neuritic plaques, equivalent to CERAD stage 2, along with severe CAA. He had neurofibrillary tangles in his insular cortex, but because medial temporal lobe samples were unavailable, his Braak stage could not be determined. His cognitive changes were mostly behavioral.
Another man, who is still living, developed language and memory problems at age 38 and was diagnosed with early onset AD 10 years later. At that time, amyloid PET showed widespread plaques in his frontal, parietal, and temporal lobes, and his cerebrospinal fluid measures of Aβ42 and total tau met the cutoff for Alzheimer’s. MRI showed shrinkage in his hippocampus and temporal lobe (see image above).
Likewise, a woman who began having memory and language problems at age 46 was diagnosed with EOAD. She did not have fluid biomarker testing, but MRI revealed medial temporal lobe atrophy characteristic of AD. The fourth case was a 57-year-old man without cognitive symptoms, but with CSF Ab42/40 and p-tau181 in the AD range.
The other four cases lacked evidence specific for Alzheimer’s. One woman died at age 57 with dementia, but her autopsy showed only diffuse amyloid deposits, no plaques or tangles. Another woman died at 54 with dementia that primarily manifested via language and behavior problems. An autopsy was not done, but a previous MRI indicated frontal atrophy. A 48-year-old man with amnestic dementia initially had CSF Aβ42/40 that was borderline for AD, but repeat testing generated values in the normal range for Aβ42/40, p-tau181, and total tau. Finally, a 52-year-old man with subjective cognitive impairment was negative on amyloid PET and CSF biomarkers.
None of the eight patients had known AD genes, and their medical histories suggested no risk for dementia. Banerjee and colleagues believe the overall data imply that at least some of these patients acquired iatrogenic AD from growth hormone injections, despite atypical clinical symptoms. Since acquired prion diseases often present differently than sporadic forms, it would make sense that the same thing could happen in Alzheimer’s, they argued.
Many commenters found the data persuasive. “The authors … provide convincing arguments why the iatrogenic exposure to Aβ seeds seems to be the most likely underlying cause,” Barbara Stopschinski at the University of Texas Southwestern Medical Center in Dallas wrote to Alzforum (comment below).
Others wanted a more complete demonstration. “Definitive proof … must await neuropathological demonstration of the disease. None of the brains that underwent postmortem examination fulfilled currently accepted criteria for diagnosis of AD,” Seth Love at the University of Bristol, U.K., wrote to Alzforum (comment below).
What Does It Mean for Public Health?
Despite these differences of opinion, researchers agreed that the findings are not cause for alarm. Use of cadaveric brain tissue was once common in Europe and the U.S., but was discontinued in 1985. Around 1,800 people in the U.K. were treated with cadaver-derived growth hormone injections; of those, two-thirds are estimated to have received the contaminated preparation, Banerjee said in a press conference. Researchers have identified 80 cases of iatrogenic CJD in this group, but no AD until now. There may be fewer recognized AD cases because amyloidosis progresses more slowly than prion disease, the authors speculated.
In people exposed to Aβ seeds, vascular amyloidosis seems to be more common than AD. Researchers have now identified more than 100 cases of CAA in people who received dura mater grafts or had neurosurgery as children (Jan 2016 news; Feb 2018 news; Jan 2019 news). Steven Greenberg at Massachusetts General Hospital, Boston, noted that in all iatrogenic CAA cases that have come to autopsy, some sparse parenchymal deposits were present as well. “Identifying the factors that favor AD progression versus CAA progression remains an important area of study,” he wrote to Alzforum.
Although high-risk practices have been stopped, researchers are still grappling with the risk of potentially transmitting Aβ seeds during more common procedures such as neurosurgery or blood transfusions (Sep 2023). A white paper on this topic called for common-sense measures such as enzymatic cleaning of surgical instruments and using separate tools for children and adults (Sep 2020 news), while an NIH panel recommended more research into how aggregated proteins spread (Oct 2020 news).
Giovanna Lalli at the U.K. Dementia Research Institute in London, a co-first author on the white paper, said that these recommendations led the U.K. to tighten laboratory safety standards (Mead and Evans, 2021). Budka said the new findings should not change these practices. “Conclusions and recommendations in recent documents by international consortia still make sense,” he wrote (comments below).
Neurosurgeon Ville Leinonen at Kuopio University Hospital, Finland, believes the risk of accidental Aβ transmission during neurosurgery is quite low using current sterilization protocols, though he also recommends more study of the issue. Resources such as FinRegistry, which tracks lifetime surgical procedures for each patient, could help, he suggested (Viippola et al., 2023). Meanwhile, Colin Masters and Steven Collins at the University of Melbourne, Australia, suggested using low-cost fluid biomarkers to screen for signs of preclinical AD in people who had childhood procedures that may have put them at risk (comments below).
Could Aβ Treatments Foster Resistance?
With regard to understanding mechanisms of pathogenesis, researchers said the new findings strengthen the evidence for prion-like transmission of AD.
The authors suggest one potential consequence for therapies: If aggregated Aβ exists as a soup of different conformations in the brain, as do prion strains, then treatments that clear a specific form could allow minor species to take over, thus creating resistance to the medication. This has been described in cell culture with prion treatment (Oelschlegel and Weissmann, 2013; Bartz et al., 2021).
How likely is this? Some studies have found evidence of distinct Aβ strains in different subtypes of AD, but it is unclear if multiple conformations are present in a single brain (Jan 2017 news; Jan 2022 news).
Dieter Willbold of Heinrich-Heine University in Düsseldorf, Germany, thinks it is possible in principle for Aβ aggregates to develop resistance to therapeutic agents that have a strain-specific effect (comment below). Willbold has a small molecule in Phase 2 that binds Aβ monomers, preventing oligomer formation and stopping strains from forming (Nov 2023 news).
It is unknown if current immunotherapies are specific to a particular conformation. Most appear to bind Aβ across a range of sizes and forms, from oligomers to fibrils and mature plaques (e.g., Nov 2021 conference news).
Beyond AD, Banerjee et al.’s findings hint that other proteopathic diseases could have rare, acquired forms as well. “This work adds important data to support the idea that prion biology is not limited to prion protein, and probably extends to other proteins such as Aβ, tau, and α-synuclein,” Marc Diamond at UT Southwestern wrote to Alzforum (comment below). Jucker and Walker agree. “Given the growing list of disorders in which misfolded proteins are a defining feature, the expanded prion paradigm may well become one of the most important disease principles to have emerged in the past 50 years,” they wrote in their editorial.—Madolyn Bowman Rogers
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