From Better Diagnostics to Earlier Treatment: The Rapidly Evolving Alzheimer's Disease Landscape

Abstract

Background and Objectives: Over the past few years, there has been a significant shift in focus from developing better diagnostic tools to detecting Alzheimer's disease (AD) earlier and initiating treatment interventions. This review will explore four main objectives: (a) the role of biomarkers in enhancing the diagnostic accuracy of AD, highlighting the major strides that have been made in recent years; (b) the role of neuropsychological testing in identifying biomarkers of AD, including the relationship between cognitive performance and neuroimaging biomarkers; (c) the amyloid hypothesis and possible molecular mechanisms of AD; and (d) the innovative AD therapeutics and the challenges and limitations of AD research. Materials and Methods: We have searched PubMed and Scopus databases for peer-reviewed research articles published in English (preclinical and clinical studies as well as relevant reviews and meta-analyses) investigating the molecular mechanisms, biomarkers, and treatments of AD. Results: Genome-wide association studies (GWASs) discovered 37 loci associated with AD risk. Core 1 biomarkers (α-amyloid Aβ42, phosphorylated tau, and amyloid PET) detect early AD phases, identifying both symptomatic and asymptomatic individuals, while core 2 biomarkers inform the short-term progression risk in individuals without symptoms. The recurrent failures of Aβ-targeted clinical studies undermine the amyloid cascade hypothesis and the objectives of AD medication development. The molecular mechanisms of AD include the accumulation of amyloid plaques and tau protein, vascular dysfunction, neuroinflammation, oxidative stress, and lipid metabolism dysregulation. Significant advancements in drug delivery technologies, such as focused Low-Ultrasound Stem, T cells, exosomes, nanoparticles, transferin, nicotinic and acetylcholine receptors, and glutathione transporters, are aimed at overcoming the BBB to enhance treatment efficacy for AD. Aducanumab and Lecanemab are IgG1 monoclonal antibodies that retard the progression of AD. BACE inhibitors have been explored as a therapeutic strategy for AD. Gene therapies targeting APOE using the CRISPR/Cas9 genome-editing system are another therapeutic avenue. Conclusions: Classic neurodegenerative biomarkers have emerged as powerful tools for enhancing the diagnostic accuracy of AD. Despite the supporting evidence, the amyloid hypothesis has several unresolved issues. Novel monoclonal antibodies may halt the AD course. Advances in delivery systems across the BBB are promising for the efficacy of AD treatments.

Keywords: APOE; Alzheimer’s disease (AD); BBB; amyloid hypothesis; biomarkers.

Figure 1

ATN profiles and corresponding biomarker categories. The biomarkers include neuroimaging and biofluids, primarily cerebrospinal fluid (CSF), and are categorized into beta-amyloid deposition (A), pathologic tau (T), and neurodegeneration (N), together referred to as the ATN criteria. The A⁺T⁺N⁺ biomarker profile supportive of AD does not exclude important comorbidities such as dementia with Lewy bodies, frontotemporal lobar degeneration, or non-AD neurodegeneration, such as limbic-predominant age-related TDP-43 encephalopathy (non-AD pathophysiology).

Figure 2

Schematic representation of molecular mechanisms involved in Alzheimer’s disease. Beta-site amyloid precursor protein cleaving enzyme (BACE); cyclin-dependent kinase 5 (Cdk5); collapsin response mediator protein-2 (CRMP2); glycogen synthase kinase 3 (GSK3); hypoxia-inducible factor 1-alpha (HIF-1α); phosphoinositide 3-kinase (PI3K); protein kinase B (Akt); reactive oxygen species (ROS); nuclear factor erythroid 2-related factor 2 (Nrf2); phosphatidylinositol 4,5-bisphosphate (PIP2); phosphatidylinositol-3,4,5-trisphosphate (PIP3); phosphatase and tensin homolog (PTEN); protein phosphatase 1 (PP1); protein phosphatase 2A (PP2A), soluble APP-beta (sAPPβ); and nuclear factor-kappa B (NF-κB).

Figure 3

A schematic representation of therapeutic strategies to cross the BBB. (A) Intranasal administration. CSF—cerebrospinal fluid; PLGA—poly(lactic-co-glycolic acid. (B) Therapeutic strategies to directly cross the BBB. FUSs—focused ultrasounds.