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NRTIs Do Not Protect Against Alzheimer-Type Amyloidosis
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International Workshop on HIV and Aging, October 13-14, 2022
By Mark Mascolini for NATAP and Virology Education
Autopsy analysis of 3 elderly people with HIV infection and of a larger younger HIV cohort yielded no evidence that treatment with nucleoside reverse transcriptase inhibitors (NRTIs) prevents Alzheimer-type cerebral amyloidosis [1]. Researchers from the University of California, San Diego (UCSD) concluded "it is premature to propose to treat or prevent Alzheimer's disease using NRTIs" because of their well-known toxicity and lack of evidence that they prevent amyloidosis.
A report in Nature suggested that NRTIs might protect against cerebral amyloidosis [2], a much-studied potential mechanism for Alzheimer's disease [3]. Since most people with HIV take or have taken NRTIs, they could be protected from Alzheimer's disease if this mechanism were correct, and the drugs could be offered as Alzheimer's prevention in people without HIV. The UCSD team explored these issues by studying HIV-positive people who had taken NRTIs for many years and were enrolled in a prospective 2009-2019 study of the neurologic consequences of HIV infection.
The researchers had brain autopsy specimens or cerebrospinal fluid test results from 3 men with HIV who had taken NRTIs for more than a decade. The first case, a man in his 80s, had HIV infection for an estimated 18 years and took NRTIs for 16 years. His autopsy specimens showed immunohistochemistry evidence of amyloid deposition seen mostly as diffuse plaques and occasional consolidated plaques in the frontal cortex and amygdala.
A second man in his 60s had diagnosed HIV infection for 20 years and had taken NRTIs for 17 years. Immunohistochemistry of brain autopsy samples showed abundant amyloid deposition seen as diffuse plaques in the frontal cortex and prominent neurofibrillary tangles in the hippocampus.
A third man in his 70s had HIV infection for 34 years and had taken NRTIs continuously for 12 years. Repeat neurocognitive testing indicated global moderate to severe neurocognitive impairment. Cerebrospinal fluid samples from this man had evidence of Alzheimer's disease (phosphorylated-Tau, total-Tau, and Aβ42).
The researchers also reviewed brain autopsy findings from 250 people with HIV infection who had neuropathological analysis of frontal lobe Aβ and ApoE genotyping as part of a clinical study. Cerebral amyloidosis was frequent in these people with HIV. Amyloidosis prevalence did not differ significantly between people taking NRTIs and those not taking the drugs, a finding "arguing against a protective role of RTIs in amyloid deposition."
The USCD team advised that NRTIs should not be considered to prevent or treat Alzheimer's disease because evidence of a protective effect against cerebral amyloidosis is lacking and their toxicities are "substantial."
References
1. Pal S, Ellis R, Achim C, Sundermann E, Moore D, Soontornniyamkij V, Feldman H. Alzheimer-type cerebral amyloidosis in the context of HIV infection: implications for a proposed new treatment approach. International Workshop on HIV and Aging, October 13-14, 2022. Abstract 20.
2. Lee MH, Siddoway B, Kaeser GE, et al. Somatic APP gene recombination in Alzheimer's disease and normal neurons. Nature. 2018;563:639-645. doi: 10.1038/s41586-018-0718-6.
3. Ma C, Fenfang Hong F, Shulong Yang S. Amyloidosis in Alzheimer's disease: pathogeny, etiology, and related therapeutic directions. Molecules. 2022;27(4):1210. doi: 10.3390/molecules27041210. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8876037/
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