Welcome to the Taglialatela lab where we focus on studying the mechanisms underscoring brain resistance and resilience to Alzheimer’s Disease (AD) neuropathology. Certain individuals remain cognitively intact despite the presence of neuropathology (Aβ plaques and tau neurofibrillary tangles) consistent with clinically symptomatic, late-stage AD. The existence of these individuals (which we termed Non-Demented with AD Neuropathology, or NDAN for short) suggests that there is a natural way for the human brain to withstand the functional havoc normally brought about by AD neuropathology. It follows that understanding the molecular and cellular mechanisms involved in such extraordinary resilience would reveal targets for the development of a new therapeutic concept centered on stimulating cognitive resilience in anyone affected by AD. This novel treatment strategy is expected to be effective in humans, as demonstrated by the existence of NDAN individuals. Laying the foundation for the future development of such an innovative therapeutic concept is the main goal of our work.

Past and ongoing research in our lab has begun to unveil multiple mechanisms associated with resistance in NDAN. These include synapses that possess a unique proteomic profile (Zolochevska et al., 2018; Zolochevska and Taglialatela, 2020) and appear to be resistant to the dysfunctional attack by both Aβ and tau oligomers (Bjorklund et al., 2012; Singh et al., 2020), the most neurotoxic species in the AD brain; resistance to synaptic calcium dyshomeostasis (Reese et al., 2008, 2011) and unaltered Calcineurin in the CNS (Reese & Taglialatela, 2011); increased numbers of neural stem cells (NSC) in the hippocampus (Briley et al., 2016), where NSC-derived exosomes may confer synaptic resilience through specific miRNA cargoes (Micci et al., 2019); modulation of antioxidant defenses (Fracassi et al., 2020); prompt removal of damaged synapses by hyper-effective microglia (Fracassi et al., 2023); and preserved autophagy (Tumurbaatar et al., 2023). Whether these are all aspects of a unifying driving event and developing methods to emulate such protective mechanisms are current focuses of our research. In addition, we are evaluating pharmacological strategies to induce resilience to AD neuropathology involving FDA-approved Calcineurin inhibitors (Taglialatela et al., 2015; Silva et al., 2023).