Alzheimer’s disease (AD) is the most common form of dementia and is characterized by the accumulation in the brain of two types of abnormal proteins:
• Amyloid plaques, formed by the beta‑amyloid (Aβ) peptide.
• Neurofibrillary tangles, composed of hyperphosphorylated tau protein.
Alzheimer’s disease is the only neurodegenerative disorder that simultaneously presents both alterations, with Aβ accumulation being its most distinctive hallmark. Aβ originates from the amyloid precursor protein (APP), which can be processed by different enzymes known as secretases.:
• β‑secretase (BACE1) and γ‑secretase generate the Aβ peptide, which is responsible for plaque formation.
• α‑secretase (ADAM10) prevents Aβ formation by cleaving APP through an alternative pathway.
An imbalance among Aβ forms—particularly the increase in the Aβ42 variant, which is more prone to forming toxic fibrils—is a key factor in the development of the disease. Although Aβ42, total tau (T‑tau), and phosphorylated tau (P‑tau) proteins are analyzed in cerebrospinal fluid (CSF), the results are not entirely reliable.
• Tau and P‑tau levels are elevated, but this also occurs in other diseases.
• Aβ42 decreases in CSF because it accumulates in the brain.
For this reason, there is still no routine or fully specific diagnostic test, which makes it difficult to detect the disease in its early stages. The APOE gene has three variants (ε2, ε3, and ε4). The ε4 allele is the main genetic risk factor for sporadic Alzheimer’s disease, increasing the likelihood of developing it by between 2‑ and 10‑fold depending on the number of inherited copies. The team has conducted studies on new CSF biomarkers related
• Secretase enzymes (BACE1, ADAM10, PS1, BACE2, and meprin‑β), which show specific alterations in Alzheimer’s disease.
• Alternative APP fragments other than Aβ, which may provide more direct information about brain status
• Changes in the glycosylation (sugar‑based modification) of proteins such as APP, apoE, and their receptors, which distinguish AD patients from healthy controls.
• The relationship between APP, apoE, and their receptors (apoER2), whose alterations may serve as new indicators of the disease.
In addition to CSF, the group is exploring other, more accessible fluids such as plasma, saliva, and especially tears, given that the eye is part of the central nervous system. Preliminary findings have detected the presence of apoE in tears, opening a new diagnostic avenue.
The project is being carried out in collaboration with the prestigious group led by Henrik Zetterberg (Gothenburg, Sweden), a world leader in Alzheimer’s biomarkers. The ultimate goal is to refine the combination of biomarkers that will allow:
• Diagnose Alzheimer’s disease with greater accuracy.
• Monitor the progression of the disease.
• Evaluate the response to treatments.
