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Cited by 37Dementia and Cognitive Impairment ResearchAlzheimer's disease research and treatmentsChromosomal and Genetic Variations

A retrotransposon storm marks clinical phenoconversion to late-onset Alzheimer’s disease

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Macciardi, Fabio, Giulia Bacalini, Maria, Miramontes, Ricardo, Boattini, Alessio, Taccioli, Cristian, Modenini, Giorgia, Malhas, Rond, Anderlucci, Laura +8 more·2022·GeroScience
DOI 10.1007/s11357-022-00580-wPMC PMC9213607
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Abstract

Recent reports have suggested that the reactivation of otherwise transcriptionally silent transposable elements (TEs) might induce brain degeneration, either by dysregulating the expression of genes and pathways implicated in cognitive decline and dementia or through the induction of immune-mediated neuroinflammation resulting in the elimination of neural and glial cells. In the work we present here, we test the hypothesis that differentially expressed TEs in blood could be used as biomarkers of cognitive decline and development of AD. To this aim, we used a sample of aging subjects (age > 70) that developed late-onset Alzheimer’s disease (LOAD) over a relatively short period of time (12–48 months), for which blood was available before and after their pheno conversion, and a group of cognitive stable subjects as controls. We applied our developed and validated customized pipeline that allows the identification, characterization, and quantification of the differentially expressed (DE) TEs before and after the onset of manifest LOAD, through analyses of RNA-Seq data. We compared the level of DE TEs within more than 600,000 TE-mapping RNA transcripts from 25 individuals, whose specimens we obtained before and after their phenotypic conversion (pheno conversion) to LOAD, and discovered that 1790 TE transcripts showed significant expression differences between these two timepoints (logFC ± 1.5, logCMP > 5.3, nominal p value < 0.01). These DE transcripts mapped both over- and under-expressed TE elements. Occurring before the clinical pheno conversion, this TE storm features significant increases in DE transcripts of LINEs, LTRs, and SVAs, while those for SINEs are significantly depleted. These dysregulations end with signs of manifest LOAD. This set of highly DE transcripts generates a TE transcriptional profile that accurately discriminates the before and after pheno conversion states of these subjects. Our findings suggest that a storm of DE TEs occurs before pheno conversion from normal cognition to manifest LOAD in risk individuals compared to controls, and may provide useful blood-based biomarkers for heralding such a clinical transition, also suggesting that TEs can indeed participate in the complex process of neurodegeneration.

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  • Several groups have independently detected elevated TE transcripts in human AD, adding to an intriguing phenomenon of TE dysregulation in neurodegenerative diseases.

    “Several groups have independently detected elevated TE transcripts in human AD [122–124], adding to an intriguing phenomenon of TE dysregulation in neurodegenerative diseases [125–128].”

    From What would it take to prove that a chronic infection is a causal agent in Alzheimer’s disease? (2025) · cites this paper as [123]

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Cited by

Sorted by citations

Authors
Macciardi, F., Giulia Bacalini, M., Miramontes, R., Boattini, A., Taccioli, C., Modenini, G., Malhas, R., Anderlucci, L., Gusev, Y., Gross, T. J., Padilla, R. M., Fiandaca, M. S., Head, E., Guffanti, G., Federoff, H. J., & Mapstone, M.
Affiliations
  • University of California, Irvine (US)
  • University of Bologna (IT)
  • University of Padua (IT)
  • Georgetown University Medical Center (US)
  • Harvard University (US)
Corresponding author
Macciardi, Fabio
ORCID
Venue
GeroScience
Publisher
Springer Science and Business Media LLC
Published
2022-05-19
Volume
44
Issue
3
Pages
1525-1550
ISSN
  • 2152-4041 (ISSN-L)
  • 2509-2715
  • 2509-2723
DOI
10.1007/s11357-022-00580-w
PMC
PMC9213607
OpenAlex
W4280496883
Cited by
37
References
15
Citations by year
2026: 2 · 2025: 15 · 2024: 13 · 2023: 5 · 2022: 2
FWCI
5.70
Type
journal article
Language
en
Open access
Licence
Locations
  • GeroScience (publishedVersion, cc-by)
  • PubMed Central (publishedVersion, cc-by)
  • PubMed (publishedVersion)
  • Archivio istituzionale della ricerca (Alma Mater Studiorum Università di Bologna) (submittedVersion, cc-by)
  • eScholarship (California Digital Library) (submittedVersion, cc-by)
  • Padua Research Archive (University of Padova) (submittedVersion, cc-by)
Funders
  • National Institute of Mental Health (R21-MH115327-01)
  • National Institute on Aging (U19AG068054-01)
Topics
  • Health Sciences › Medicine › Psychiatry and Mental health › Dementia and Cognitive Impairment Research
  • Health Sciences › Medicine › Physiology › Alzheimer's disease research and treatments
  • Life Sciences › Agricultural and Biological Sciences › Plant Science › Chromosomal and Genetic Variations
Keywords
transposable elements, retrotransposons, late-onset Alzheimer's disease, phenoconversion, blood-based biomarkers, cognitive decline, lines, LTR retrotransposons, SINEs, SVA, neurodegeneration, aging
MeSH terms
Alzheimer Disease, Humans, RNA, Biomarkers, Retroelements

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