Translational Advances in Alzheimer’s and other Neurodegenerative Dementias (NDDs): (Bio-)Molecular Mechanisms, Biomarkers and Therapies

Alzheimer’s disease (AD) is the most common type of neurodegenerative dementia (NDD) afflicting the elderly, accounting for roughly 60% to 80% of cases irrespective of the collective prevalence of the other three NDD types: vascular dementia (VaD), Lewy body dementia (LBD) and frontotemporal lobar dementia (FTLD). NDD types are stratified according to their characteristic (bio-)molecular mechanisms of action, their direct or indirect dysregulation of basal cellular bioactivities and the biological pathways these subsume, their irreversible manifested symptoms, and the brain regions exhibiting unrelenting intracellular and extracellular dysfunction or disruptive breakdown of intercellular cross-talk, both of which ultimately yield, induce or arise from progressive neuronal cell death.

To date, only a handful of (bio-)molecular drug or therapeutic candidates, around eleven, are accessible for treating clinical patients. Because NDDs are lifelong and life-threatening, there remains a pressing need to rapidly make available safe, effective remedies. To shorten the translational turnaround time to patient access, the FDA offers eligible candidates one of four specialized expedited review sub-pathways, each with its own depth of inquiry, forms of required experimental evidence and primary outcomes. Crucially, a candidate reaching the clinic through such a pathway is not equivalent to one that has completed the long-term comprehensive review process behind full “FDA-Approved” status, a status achieved only upon approved New Drug Applications (NDAs) that entail increasing patient cohorts throughout long-term, multi-institution Phase I-III clinical trials. This distinction is easily misunderstood [KSH-v21.1]by the public: availability does not equal a demonstrated cure.

Indeed, all clinically available candidates are vetted for their potential to afford beneficial disease modification or ameliorative symptom management, neither of which is curative. At most, they function to limited extents, at varying time points and for varying durations.A critical gap in the standard of care therefore emerges. Patient availability and a candidate’s intended or reported effects neither equate to equivalent future outcomes nor provide curative treatment. This is borne out by the fact that most FDA-approved therapeutics have yet to demonstrate curative efficacy, and that no clinical device, method, modality or readily available physical therapeutic (for example image-guided surgery or ablation) can permanently prevent, blunt, halt, reverse or restore neuronal function.
A further gap is diagnostic. Current criteria rely on objective measures and manifested symptoms, so they capture disease only after it develops, making early, scientifically measurable detection an urgent priority. The molecular and cellular drivers, including amyloid-beta and tau pathology, neuroinflammation, metabolic and mitochondrial dysfunction and vascular injury, shape onset and progression, while distinct proteinopathies such as alpha-synuclein in LBD help separate AD from related dementias. Conditions such as traumatic brain injury, brain tumors and hydrocephalus can present with dementia-like syndromes that must be distinguished, yet precise detection in the earliest phase remains challenging.

This Research Topic brings a multidisciplinary, updated perspective on connecting the underlying molecular mechanisms of AD and related dementias to their hallmark and newly discovered biomarkers, diagnosis and therapies. We particularly welcome work on fluid biomarkers, including blood-based assays for p-tau217, p-tau181, GFAP and neurofilament light, that enable early, minimally invasive detection and staging and support a biological definition of AD, used where appropriate alongside established imaging. We also seek contributions on disease-modifying and emerging therapies, including anti-amyloid immunotherapies, and the questions they raise around patient selection, target combination and safety monitoring. By gathering mechanistic, biomarker and therapeutic studies across AD and related dementias, the topic seeks to clarify which pathways are shared and which are disease specific, and to accelerate translation from discovery to clinical practice.

We welcome submissions addressing, but not limited to:
• (Bio-)molecular and cellular mechanisms governing AD and other NDDs, including proteinopathy, neuroinflammation, remodeling, and metabolic and vascular contributions
• Blood-based and CSF biomarkers, including p-tau217, GFAP, neurofilament light and ApoE, for early detection, staging and differentiation of dementia subtypes
• Disease-modifying and emerging therapies, including anti-amyloid immunotherapies, target combinations, patient selection and safety monitoring
• Experimental studies using cellular, molecular and animal models, including the discovery and validation of novel biomarkers
• Integration of biomarker, clinical and multi-omic data, including AI-supported and non-invasive imaging approaches, with attention to interpretability and validation

We encourage a wide range of submissions, including original research, methods papers, brief research reports, data reports, systematic reviews, mini-reviews and perspectives.

Article types and fees

This Research Topic accepts the following article types, unless otherwise specified in the Research Topic description:

• Brief Research Report
• Data Report
• Editorial
• FAIR² Data
• General Commentary
• Hypothesis and Theory
• Methods
• Mini Review
• Opinion
• ... View all formats

Articles that are accepted for publication by our external editors following rigorous peer review incur a publishing fee charged to Authors, institutions, or funders.

Article types

This Research Topic accepts the following article types, unless otherwise specified in the Research Topic description:

• Brief Research Report
• Data Report
• Editorial
• FAIR² Data
• General Commentary
• Hypothesis and Theory
• Methods
• Mini Review
• Opinion
• Original Research
• Perspective
• Review
• Study Protocol
• Systematic Review
• Technology and Code

Keywords: Alzheimer’s disease (AD), neurodegenerative dementia, fluid- & blood-based biomarkers, molecular mechanisms, disease-modifying therapy

Important note: All contributions to this Research Topic must be within the scope of the section and journal to which they are submitted, as defined in their mission statements. Frontiers reserves the right to guide an out-of-scope manuscript to a more suitable section or journal at any stage of peer review.