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Latest Research in Alzheimer’s Disease
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Latest Research in Alzheimer’s Disease

A Special Issue of International Journal of Molecular Sciences (ISSN 1422-0067) belonging to the section "Molecular Neurobiology".

Deadline for manuscript submissions: closed (20 May 2026) | Viewed by 4966

Editor

Dr. Prashant R Bharadwaj

E-Mail Website
Guest Editor
School of Medical and Health Sciences, Edith Cowan University, Joondalup, WA 6027, Australia
Interests: Alzheimer’s disease; beta amyloid; amyloid precursor protein
Special Issues, Collections and Topics in MDPI journals

Special Issue Information

Dear Colleagues,

Alzheimer’s disease (AD) is the most prevalent neurodegenerative disorder and a leading cause of dementia worldwide. Despite decades of research, its complex molecular underpinnings remain only partially understood, and effective disease-modifying therapies are still limited. Recent advances in molecular and cellular neuroscience, proteomics, genomics, and imaging have significantly expanded our understanding of the mechanisms driving AD pathogenesis. Key pathways, including amyloid-β aggregation, tau hyperphosphorylation, autophagy impairment, proteostasis imbalance, oxidative stress, and neuroinflammation, are being revisited through the lens of modern molecular technologies.

This Special Issue, titled “Latest Research in Alzheimer’s Disease”, will highlight cutting-edge molecular discoveries that shed light on disease initiation and progression, as well as emerging therapeutic approaches. We welcome original research articles, comprehensive reviews, and short communications focusing on molecular signaling, biomarker identification, and mechanistic studies on AD. Submissions exploring novel therapeutic compounds, gene regulation, stem cell and organoid models, and multi-omics integration for personalized medicine are particularly encouraged. By bringing together recent breakthroughs in molecular biology and translational neuroscience, this Special Issue will provide a holistic view of the evolving landscape of Alzheimer’s research and stimulate innovative strategies for prevention and treatment.

Dr. Prashant R Bharadwaj
Guest Editor

Manuscript Submission Information

Manuscripts should be submitted online at www.mdpi.com by registering and logging in to this website. Once you are registered, click here to go to the submission form. Manuscripts can be submitted until the deadline. All submissions that pass pre-check are peer-reviewed. Accepted papers will be published continuously in the journal (as soon as accepted) and will be listed together on the special issue website. Research articles, review articles as well as short communications are invited. For planned papers, a title and short abstract (about 250 words) can be sent to the Editorial Office for assessment.

Submitted manuscripts should not have been published previously, nor be under consideration for publication elsewhere (except conference proceedings papers). All manuscripts are thoroughly refereed through a single-anonymized peer-review process. A guide for authors and other relevant information for submission of manuscripts is available on the Instructions for Authors page. International Journal of Molecular Sciences is an international peer-reviewed open access semimonthly journal published by MDPI.

Please visit the Instructions for Authors page before submitting a manuscript. There is an Article Processing Charge (APC) for publication in this open access journal. For details about the APC please see here. Submitted papers should be well formatted and use good English. Authors may use MDPI's English editing service prior to publication or during author revisions.

Keywords

  • Alzheimer’s disease
  • neurodegenerative disease
  • disease diagnosis
  • biomarker development
  • drug development
  • disease models

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Published Papers (4 papers)

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Research

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21 pages, 3084 KB  
Article
Novel Small-Molecule Analogues of IU1 Ameliorate Amyloid-β Mediated Toxicity in Alzheimer’s Disease Cell and Worm Models
by Ajish Ariyath, Fraulein Denise Arigo, Izhar Wallach, W. M. A. D. Binosha Fernando, Ralph N. Martins and Prashant Bharadwaj
Int. J. Mol. Sci. 2026, 27(4), 1963; https://doi.org/10.3390/ijms27041963 - 18 Feb 2026
Cited by 2 | Viewed by 1256
Abstract
Dysregulation of the deubiquitinating enzyme Ubiquitin-specific peptidase 14 (USP14) is implicated in several neurodegenerative diseases, and IU1, an allosteric inhibitor, has shown neuroprotective effects by reducing protein aggregate toxicity. This study aimed to develop new IU1 analogues and evaluate their ability to mitigate [...] Read more.
Dysregulation of the deubiquitinating enzyme Ubiquitin-specific peptidase 14 (USP14) is implicated in several neurodegenerative diseases, and IU1, an allosteric inhibitor, has shown neuroprotective effects by reducing protein aggregate toxicity. This study aimed to develop new IU1 analogues and evaluate their ability to mitigate amyloid-β (Aβ) accumulation and toxicity in Alzheimer’s disease (AD) cell and Caenorhabditis elegans worm models. IU1 and 71 newly designed analogues identified using the AtomNet® virtual screening platform were assessed in an amyloid precursor protein-C terminal fragment/amyloid-β (APP-C99/Aβ)-producing AD cell model using a high-throughput toxicity assay. Lead compounds were further evaluated for their effects on neurodegeneration, behaviour, and survival. IU1 reduced Aβ-mediated toxicity and neurodegeneration in cell and worm models. Of the 71 analogues predicted to bind ubiquitin-specific peptidase 14 (USP14), two compounds, AA10 and AA51, showed >50% rescue of Aβ-induced toxicity and robust enhancement of autophagy and proteasome activity. In Caenorhabditis elegans, both compounds alleviated glutamatergic neuron loss and rescued behavioural impairments. IU1 and analogues exhibit protective effects against Aβ toxicity in AD models. Analogues AA10 and AA51 showed greater potency than IU1 and effectively enhanced proteostasis pathways. These findings support USP14 as a promising therapeutic target and provide a basis for the development of improved IU1-derived compounds for AD and related disorders. Full article
(This article belongs to the Special Issue Latest Research in Alzheimer’s Disease)
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17 pages, 980 KB  
Article
Peripheral Syndecan-3 and Neurofilament Light Chain as Complementary Blood Biomarkers for Alzheimer’s Disease
by Anett Hudák, Annamária Letoha and Tamás Letoha
Int. J. Mol. Sci. 2026, 27(3), 1600; https://doi.org/10.3390/ijms27031600 - 6 Feb 2026
Viewed by 956
Abstract
Reliable and disease-specific blood biomarkers are critically needed for Alzheimer’s disease (AD), particularly in early stages when interventions are most effective. Although phosphorylated tau and neurofilament light chain (NfL) are widely used, their diagnostic specificity has been reported to decrease in elderly populations [...] Read more.
Reliable and disease-specific blood biomarkers are critically needed for Alzheimer’s disease (AD), particularly in early stages when interventions are most effective. Although phosphorylated tau and neurofilament light chain (NfL) are widely used, their diagnostic specificity has been reported to decrease in elderly populations with multimorbidities. Syndecan-3 (SDC3), a heparan sulfate proteoglycan implicated in amyloid and tau aggregation, has recently emerged as a mechanistically relevant biomarker candidate. In this clinically realistic cohort study, we examined 46 participants, including 23 clinically diagnosed AD patients and 23 age-matched non-AD individuals with psychiatric and/or metabolic comorbidities. SDC3 expression was quantified in peripheral blood mononuclear cells (PBMCs), while soluble SDC3 and NfL were measured in plasma. Both PBMC-expressed and plasma SDC3 levels were elevated in AD compared with non-AD participants and showed a strong intercorrelation, whereas plasma NfL was likewise increased in AD. Individually, PBMC-SDC3, plasma SDC3, and NfL demonstrated moderate discriminatory performance. However, multivariable models integrating SDC3 (PBMC or plasma), NfL, and age achieved substantially improved discrimination (AUC > 0.8). SDC3 did not correlate with NfL, consistent with a biological signal distinct from neuroaxonal injury and reflective of peripheral immune–metabolic remodeling. Together, these findings identify SDC3 as a blood-based biomarker associated with systemic immune remodeling that complements established neuronal markers in a clinically realistic AD versus non-AD comparison. While exploratory, this study supports further investigation of SDC3 within integrated, multi-domain biomarker strategies in larger and independent cohorts. Full article
(This article belongs to the Special Issue Latest Research in Alzheimer’s Disease)
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21 pages, 1398 KB  
Article
Interplay Between 3D Chromatin Architecture and Gene Regulation at the APOE Locus Contributes to Alzheimer’s Disease Risk
by Eun-Gyung Lee, Lesley Leong, Sunny Chen, Jessica Tulloch and Chang-En Yu
Int. J. Mol. Sci. 2026, 27(1), 302; https://doi.org/10.3390/ijms27010302 - 27 Dec 2025
Viewed by 1366
Abstract
The ε4 allele of the apolipoprotein E (APOE) gene strongly increases Alzheimer’s disease (AD) risk, though its molecular mechanisms remain unclear. AD-associated genetic signals also extend to neighboring genes TOMM40 and APOC1, suggesting a complex cis-regulatory landscape. To investigate chromatin [...] Read more.
The ε4 allele of the apolipoprotein E (APOE) gene strongly increases Alzheimer’s disease (AD) risk, though its molecular mechanisms remain unclear. AD-associated genetic signals also extend to neighboring genes TOMM40 and APOC1, suggesting a complex cis-regulatory landscape. To investigate chromatin architecture and its impact on gene regulation across this region, we performed chromosome conformation capture in human cell lines and postmortem brain tissues, consistently identifying TOMM40–APOE and APOE–APOC1 interactions. We further developed a digital PCR assay to quantify APOE–APOC1 interaction strength and measured APOC1 mRNA via RT-qPCR. Enhanced chromatin interaction correlated with elevated APOC1 transcription in AD specimens. Genotypic analysis showed that ε3/ε4 carriers had strong chromatin interaction and transcriptional activation, whereas ε4/ε4 homozygotes exhibited minimal chromatin remodeling despite similar APOC1 expression, suggesting a decoupling of chromatin architecture and transcriptional output. These findings underscore the interplay of AD status, APOE genotype, and locus-specific chromatin dynamics in disease susceptibility. Integration of 3D genome topology with transcriptomic profiling offers a framework to study APOE-related disorders and supports broader application across neurodegenerative loci for genotype-guided therapy development. Full article
(This article belongs to the Special Issue Latest Research in Alzheimer’s Disease)
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Review

Jump to: Research

24 pages, 3850 KB  
Review
Small-Molecule Targeting of the Iron-Responsive Element in the APP mRNA 5′-UTR to Control Amyloid Translation in Alzheimer’s Disease
by Mateen A. Khan and Hassan S. Shaibah
Int. J. Mol. Sci. 2026, 27(9), 3978; https://doi.org/10.3390/ijms27093978 - 29 Apr 2026
Viewed by 797
Abstract
Amyloid-β (Aβ) protein, a cleavage product of the amyloid precursor protein (APP), is the main component of neuritic plaques in Alzheimer’s disease (AD), and its accumulation has been considered as the molecular driver of Alzheimer’s pathogenesis. Aβ has been a primary target for [...] Read more.
Amyloid-β (Aβ) protein, a cleavage product of the amyloid precursor protein (APP), is the main component of neuritic plaques in Alzheimer’s disease (AD), and its accumulation has been considered as the molecular driver of Alzheimer’s pathogenesis. Aβ has been a primary target for therapy since the amyloid cascade theory was put forth, with methods designed to prevent the generation of Aβ. The APP 5′-untranslated region (UTR) mRNA encodes a functional structured iron-responsive element (IRE) that represents a potential target for small molecule inhibitors as an anti-amyloid therapy for AD. Here, we offer a comprehensive strategy that uses RNA-targeted binding to inhibit APP translation. The IRE family is among the few 3-D mRNA regulatory elements with a known 3-D structure. Accordingly, we exploit these structural and functional characteristics as our strategy to target APP IRE structured mRNA to identify anti-amyloid drugs. The mRNA encoding proteins involved in iron metabolism are regulated by this family of similar nucleotide sequences. Post-transcriptional control of cytoplasmic mRNA is a rapidly developing area of biomedicine. Across animals, evolutionarily conserved IRE mRNAs serve as a model system for 3-D mRNAs. IRE mRNAs have shown great promise for chemical manipulation of mRNA and protein expression in biological systems by yielding “proof of principle” data for small molecules targeting mRNA structures. A novel approach to identifying RNA-directed therapeutics to regulate APP expression and Aβ-peptide generation for AD treatments is exemplified by APP 5′-UTR-directed small molecule inhibitors. Full article
(This article belongs to the Special Issue Latest Research in Alzheimer’s Disease)
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