Alzheimer's disease: the role of amyloid-beta and tau, sex differences and recent therapeutic possibilities

Alzheimer’s disease (AD) is a neurodegenerative disease occurring mainly in the elder population and affecting especially women. AD causes a wide range of symptoms, from cognitive impairments and memory loss to physical disability, due to the formation of amyloid plaques and neurofibrillary tangles in the brain that compromise the physiological functions of neurons. In this elaborate are reported three studies to deepen the characteristics of AD, with a particular focus on the biological processes and gender-related differences associated with the development of the pathology, and about the most recent monoclonal antibody-based therapy developed to cure AD. Taking advantage of mice models (5xFAD and TauP301S) that were divided in different groups according to the age, genotype and sex, the role of blood-based (BB) biomarkers of both Aβ and tau have been explored in the first work, demonstrating to be valid indicators of the progression of the pathology. Interestingly, it is described a biphasic pattern of the Aβ42 concentrations in the serum, reflecting the earliest phase of AD onset in both animal models and human subjects, opening to new possibilities for both therapy and prevention. In the second work, behavioral tests and molecular analysis were conducted on 5xFAD mice, divided in groups according to sex and genotype. Thanks to the new OF-NO-SI paradigm, a significant impairment in behavioral tasks was observed mainly in 5xFAD female mice, displaying a higher level of activity and less within- and between-trial habituation compared with the other groups, highlighting an effect of both sex and genotype. These data were complemented by molecular analysis performed on ex vivo tissue, analyzing how the physiology of the organism is affected by AD pathology. In particular, increased inflammation is observed in transgenic females, correlating also to a robust presence of amyloidosis and a lower expression of neurotrophic factors and ER stress markers, thus confirming the higher vulnerability of female gender into developing AD. Concerning future perspectives about therapy, also due to the lack of an effective treatment for AD still nowadays, in the third and last work it is reported the phase 3 trial of Lecanemab, the humanized IgG1 monoclonal antibody able to specifically bind and clear Aβ aggregates. Participants involved displayed mild to moderate cognitive impairment and were ranged between 50 and 90 years old and were randomly divided in two different groups: one received the Lecanemab, the other the placebo. The results showed a moderate slowdown in cognitive decline in the group that received Lecanemab; however, due to the presence of severe adverse events further studies are needed to validate its effect and safety.