We believe that CSF / blood-based biomarker discovery and development should be a crucial part of drug discovery and development programs throughout all stages from preclinical to clinical stages. A drug-biomarker co-development pipeline allows an objective go/no-go decision-making, reducing frictions and accelerating the process.
The APMI is currently focused on investigating the existence of a characteristic molecular “Alzheimer’s Disease profile” (or molecular “signature”), i.e., a specific set of fluid (CSF and blood) molecules that may serve at several Context(s)-of-Use.
Neurochemical fluid biomarker-based research is focused on the effort to in-vivo track multiple key pathophysiological mechanisms occurring in early stages of Alzheimer’s Disease, such as reflected by neuroinflammation (YKL-40, TNF receptor complex, the IL-6 receptor complex, ferritin), axonal damage and neurodegeneration (neurofilament light chain [NFL] and total-tau protein), synaptic dysfuntion (neurogranin, alpha-synuclein), tauopathy (phosphorylated tau protein [ser199, thr181, thr231], amyloidogenic pathway (amyloid beta species, TACE and BACE1), and microvascular and endothelial damage (under development).
Alzheimer’s Disease Liquid Biopsy
CSF and blood analysis enables the simultaneous investigation of multiple pathophysiological mechanisms (i.e. ATN+ system), for different Context(s)-of-Use, including screening, diagnosis, prognosis, disease-staging and related therapeutic decision-making.
The comprehensive biological signature provide by a fluid matrix has the potential to constituting the Liquid Biopsy for Alzheimer’s Disease.
Liquid Biopsy has already become reality in more advanced biomedical areas including Oncology, Hematology and clinical Immunology.
Structural brain changes are induced mostly by genetic factors and aging. Structural MRI biomarkers have been introduced to investigate brain volumes and gray matter changes. Several tools have also been developed to track white matter changes, cortical thickness analysis, voxel-based DTI analysis of the whole, identifying anatomical neural networks using advanced tractography. Functional MRI represent the cutting-edge neuroimaging to explore brain connectivity and large-scale networks.
Metabolic imaging, such as FDG-, Amyloid-, and Tau-PET enable to explore synaptic integrity / loss and brain proteinopathies. Novel radioligands to track inflammation and other pathophysiological mechanisms are expected. Current neuroimaging research focuses on understanding how brain structural and functional networks interact with molecular pathways during aging and in early stages of neurodegenerative diseases.
The development of high-throughput technologies such as next generation sequencing (NGS) combined with highly sophisticated bioinformatics software for data analysis/visualization allowed investigating whole genomes, transcriptomes, proteomes, and metabolomes in unprecedented detail. Genome-wide association studies (GWAS) enabled to map more than 20 common genetic variants associated with Alzheimer’s Disease. Moreover, recent NGS-based studies led to identify several rare variants exerting large effects on Alzheimer’s Disease risk, thus indicating that not only common variants with small effect sizes, but also rare or low-frequency coding variants with moderate-to-large effect sizes contribute to Alzheimer’s Disease risk. These findings certainly point to specific pathophysiological pathways, namely Aβ and tau pathology, immune response and inflammation, cell migration, microglial/myeloid cell function, hippocampal synaptic function, cytoskeletal function and axonal transport, gene expression regulation, and post-translational modifications. Exploring these definite molecular pathophysiological pathways as major mechanisms involved in Alzheimer’s Disease etiology provides substantial information for elucidating the pathophysiology of the disease and helps identifying targets for prevention and treatment.