May 29, 2026

Theragnostic potential of aptamers in neurodegenerative diseases: A protocol for a sytematic review and meta-analysis

DOI
https://dx.doi.org/10.17504/protocols.io.x54v92eo4l3e/v1
  • 1University of Aberdeen;
  • 2UK;
  • 3Italian Institute of Technology;
  • 4Italy
Jenna Gregory
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DOI: https://dx.doi.org/10.17504/protocols.io.x54v92eo4l3e/v1
Document Citation: Alexander T Jackson, Fergal M Waldron, Gian Gaetano Tartaglia, Jenna Gregory 2026. Theragnostic potential of aptamers in neurodegenerative diseases: A protocol for a sytematic review and meta-analysis. protocols.io https://dx.doi.org/10.17504/protocols.io.x54v92eo4l3e/v1
License: This is an open access  document  distributed under the terms of the  Creative Commons Attribution License,  which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited
Created: March 22, 2024
Last Modified: May 29, 2026
Document  Integer ID: 97146
Keywords: Aptamer, Neurodegeneration, Diagnostic, Therapeutic, aptamer technology, aptamer design, current use of aptamer, neurodegenerative disease, translational use of aptamer, aptamer, theragnostic potential of aptamer, specific biomarker, rna oligonucleotide, limited diagnostic biomarker, due to limited diagnostic biomarker, therapeutic target
Funders Acknowledgements:
Target ALS
Grant ID: FS-2023-ESC-S2
Target ALS
Grant ID: BB/2022/C4/L2
LifeArc
Grant ID: A20170
NHS Grampian
Grant ID: GCA25107
Motor Neurone Disease Association
Grant ID: Gregory/APR24/2374-791
European Research Council
Grant ID: ERC ASTRA_855923
European Innovation Council
Grant ID: IVBM4PAP_101098989
Italian National Recovery and Resilience Plan
Grant ID: CN00000041, EPNRRCN3
Abstract
Background: Aptamers are DNA or RNA oligonucleotides capable of binding targets with high affinity and specificity, and are exciting new tools that can be used as diagnostic and therapeutic targets. Neurodegenerative diseases are devastating and debilitating conditions which often carry poor prognoses, partly due to limited diagnostic biomarkers with interventions being implemented too late in the disease process. There is an urgent need for more sensitive and specific biomarkers that can detect the disease in the earliest phases with accuracy, prior to substantial disability, which may represent an ideal research space for the deployment of aptamer technology.

Aim: This systematic review aims to characterise the current use of aptamers in neurodegenerative diseases.
Method: Database searching was performed using Medline, PubMed, and Embase with pre-determined search terms. Papers identified by this search underwent screening, followed by data extraction, meta-analysis, and qualitative review.

Summary: Through this timely review we hope to evaluate the most common pipelines used for aptamer design and to understand structural considerations and commonly used modifications that may enable aptamers to become more successfully deployed in neurodegenerative diseases. We hope that this review will provide a platform to expedite the translational use of aptamers in neurodegenerative diseases.
Introduction:

Aptamers
Aptamers are small, single-stranded DNA or RNA oligonucleotides which are able to bind to a complimentary target molecule with high specificity and affinity1. Indeed, aptamers may be described as “chemical antibodies” 2, with a range of potentially favourable properties when compared to traditional antibodies. For example, aptamers are chemically synthesized and demonstrate very little batch-to-batch production variation compared to antibodies. Moreover, aptamers synthesised in the laboratory negate the need for animals necessary for antibody production, representing a time- and cost- effective alternative, in line with the principles of the 3Rs (Replacement, Reduction, and Refinement) framework for performing more humane research3. Aptamers, once identified, are also cheap to produce and can be easily modified without impacting binding affinity. Furthermore, aptamers can be produced for a wide range of targets, whereas antibodies require targets with high immunogenicity2, 4-5.

There are also, however, a number of significant limitations to the widespread deployment of aptamers. One such drawback is that, as aptamers exist as a nucleic acid sequence, they possess a limited range of functional groups through which to accomplish a high selectivity6. Additionally, aptamers demonstrate rapid clearance; although aptamers can be stored in a stable form long-term, they undergo rapid renal clearance and nuclease degradation once deployed in vivo. Indeed, the pharmacokinetic properties of aptamers can demonstrate high variability and may be difficult to predict7-9. These issues can be, at least partly, overcome through direct chemical modification of aptameric structure. For example, modification of the phosphate backbone, changes to the shape of the aptamer, and bioconjugation at the 3’ and 5’ terminals (among other such techniques) may improve stability, increase affinity, or reduce clearance of aptamers8.

Creating Aptamers
The most common method of aptamer production is through systematic evolution of ligands by exponential enrichment (SELEX)10. SELEX involves the selection of aptamers with high affinity for a target from a large library of single stranded DNA or RNA oligonucleotides. This is achieved by incubating an ssDNA or ssRNA library pool with the desired target cells. Oligonucleotides which have bound to target cells are segregated whilst non-binding sequences are discarded. Bound oligonucleotides are eluted and exposed to a control cell/molecule, thereby removing sequences which may bind to common molecules (i.e. non-specific). Binding sequences are eluted again, and undergo PCR, producing a large volume of oligonucleotides with which to repeat the process. After iterative steps, the most sensitive and specific aptamer is chosen and produced10-12. Whilst SELEX is the most popular method of producing aptamers, other approaches exist. In silico approaches such as catRAPID allow for computational generation of RNA aptamers, overcoming the need for large oligonucleotide library pools and facilitating iterative mutational improvement of candidate oligonucleotides to improve binding affinity13.

Neurodegenerative Diseases
Neurodegenerative diseases are progressive, devastating conditions of the central nervous system characterised by gradually worsening loss of function. Such diseases, although frequently unified under a single banner, represent unique and diverse pathophysiological backgrounds and challenges. These diseases are currently incurable, with extremely limited diagnostic and therapeutic options15.

Although the full pathophysiological mechanisms of many neurodegenerative diseases are yet to be elucidated, protein misfolding and aggregation appears to be implicated in many such conditions. Indeed, amyloid aggregates and tau protein tangles are key factors in the pathogenesis of Alzheimer’s disease16-18; TDP-43 aggregates are the pathological hallmark of amyotrophic lateral sclerosis (ALS)19-20, as well as in frontotemporal dementia21; and Parkinson’s disease and Lewy body dementia are characterised by misfolded α-synuclein22-23. This characteristic, disease-associated accumulation of misfolded proteins represents a context in which aptamer technology could be very well utilised, due to the fact that many of the misfolded protein species in these diseases are difficult to target using conventional antibody-based approaches24. Antibodies require the availability of a specific recognition motif known as an epitope to detect a specific protein. As proteins involved in neurodegenerative disease are classically misfolded, these specific epitopes may be buried within the core of the protein aggregate, thereby limiting detection by antibodies25. Aptamers can be designed to bind to surface structures or parts of the protein that are not involved in the aggregation process, improving detection. Due to their smaller size, aptamers can typically bind many more targets in aggregates than antibodies, with potential for greater structural resolution5, 26-27.

The Use of Aptamers in Neurodegenerative Disease
In neurodegenerative diseases, aptamers are typically either utilised in the development of therapeutics or are combined with a recognition element in use as a biosensor26. Both techniques often utilise the proteinopathic background of many neurodegenerative diseases to provide a range of potential targets for aptamer technology, where traditional antibody techniques may be less suitable. For example, Aβ oligomers demonstrate significant immunogenic heterogeneity, which has been shown to directly affect the binding capabilities of antibody staining27. This dependence on immunogenicity (among other drawbacks previously mentioned) bolsters the use of aptameric technology in neurodegenerative research.
One of the key limiting factors in the management of neurodegenerative diseases is the dearth of sensitive, specific, and appropriate biomarkers able to detect presence of disease before onset of significant disability28-29. This current obstacle could represent a key opportunity for the deployment of aptameric technology. Indeed, one in vitro study has already utilised electrochemical aptasensors to produce a point-of-care saliva test as a non-invasive method of detecting and monitoring α-synuclein in Parkinson’s patients30. This represents an important proof of concept for the use of aptasensors in the detection of neurodegenerative disease biomarkers, and, crucially, demonstrates its use in a point-of-care platform. Furthermore, a study utilising aptamers as biosensors to detect nuclear TDP-43 aggregates in post-mortem ALS patient tissue samples allowed successful detection of protein aggregates, including some that were not identified by more traditional antibody stains31. Another study directly compared aptamers to antibodies in the detection of Aβ-42 in Alzheimer’s disease and showed that aptamers demonstrate greater binding affinity than antibodies directed against the protein32. This evidence suggests that not only are aptamers suitable for the detection of neurodegenerative biomarkers, but may indeed be preferable to other techniques (e.g. antibodies).

As such, aptamers have shown significant promise in the research of neurodegenerative diseases, within both therapeutics and diagnostics. This systematic review will examine and characterise the current state of aptamer use in the research of neurodegenerative disease and will explore future uses of the technology within the field.

Approach:
A systematic review will be performed to assess and characterise studies utilising aptamer technology to investigate neurodegenerative disease.

Identified studies will undergo qualitative analysis to characterise the current use of aptamers in the research of neurodegenerative diseases (Alzheimer’s, MND, Parkinson’s, Huntington’s etc). These studies will be divided into (1) diagnostic and (2) therapeutic subtypes. All studies will be analysed with an aim to specifically characterise the aptamers in use, including data on structure and modifications. (1) Diagnostic papers will be further assessed to determine the nature of new diagnostic technologies utilising aptamers.

Objectives
This systematic review was structured around the PICOS framework:
Population: All studies including preclinical and clinical studies
Intervention: All interventional and non-interventional studies utilising aptamers in the research of neurodegenerative disease.
Comparison: Control or vehicle groups where appropriate
Outcome Measures:
• Type of aptamer (DNA vs RNA)
• Type of neurodegenerative disease
• Aptamer target
• Technique of aptamer generation
• Aptamer use (therapeutic vs diagnostic)
o If diagnostic, characterisation of diagnostic methodology (e.g. imaging, tissue biopsy, biofluid etc)
o If therapeutic, characterisation of in vitro stability
• Modifications of aptamers
o Phosphate backbone modification
o 3’ and 5’ terminal modification
• Aptamer structure
o Nucleotide length
o Secondary structures
• Blood brain barrier penetrance – in vivo studies
Study Design: All study types (preclinical and clinical) that utilise aptamer technology in the research of therapeutic and diagnostic modalities targeting neurodegenerative disease.


Methods

Search Terms
Source databases were selected as: (1) PubMed (2) Embase (3) Medline. No restrictions were chosen for date or language. The search was performed on 19/03/2024.

PubMed
((aptamer) AND (brain OR CNS OR neuro*)) NOT (review[Publication Type])
• Limit English
N= 1036

Ovid ((Medline 1946-03/2024) AND (Embase 1974-03/2024))
((aptamer) AND (brain OR CNS or neuro*)).mp. not Review.pt
• Limit English
N= 1316

Other Sources
Relevant studies referenced within papers identified by the search that were not included by the original search terms and/or screening process.

Screening
All papers identified by the stated search criteria will be screened using the systematic review facility (SyRF) online tool (https://syrf.org.uk). Each title and abstract will be screened by two reviewers, and, using the pre-determined inclusion and exclusion criteria, processed appropriately. For texts in which reviewer concordance was <0.66, the paper will be screened by a third reviewer. Papers included after screening will be exported to Endnote, with duplicate texts discarded in the process.

Inclusion/Exclusion Criteria

Inclusion Criteria:
• All studies mentioning aptamers and neurodegenerative diseases

Exclusion Criteria:
• Narrative review
• Systematic review
• Conference abstract
• Letters
• Commentary

Study Characteristics for Data Extraction
• Study ID: (1) Authors (2) Year
• Type of neurodegenerative disease being studied
• Aptamer target
• Technique of aptamer generation
• Aptamer use (therapeutic/diagnostic)
o If diagnostic, method of diagnostic technique (i.e. molecule only/biofluid/tissue sample/imaging)
o If in vivo, metadata r.e. stability
• Aptamer structure
o Nucleotide number
o Secondary structures
• Modifications of aptamers
o Phosphate backbone modification
o 3’ and 5’ terminal modification
o Other modifications
• Blood brain barrier penetrance (in vivo studies only)

Protocol references
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