A New Molecular Mechanism for the Late-Onset Alzheimer's Disease Risk Gene CD2AP

Alzheimer's disease (AD) is a progressive neurodegenerative disorder that impairs memory and cognitive functions; it is the leading cause of dementia worldwide. Familial Alzheimer's disease (FAD) is rare and typically appears earlier in life (first symptoms can appear before 40 years of age and fully developed pathology before 60–65 years of age). In contrast, late-onset Alzheimer's disease (LOAD), which accounts for the majority of cases, develops at older ages (after 60–65 years of age). Unlike autosomal-dominant FAD, in which mutations in specific genes ( APP , PSEN1 , and PSEN2 ) directly cause the pathology, LOAD is driven by a combination of environmental factors and genetic factors that increase the risk of developing the disease. LOAD-linked alleles such as APOE4 increase the risk of developing LOAD, but they do not guarantee its onset. How genetic and environmental factors contribute to the development of LOAD is not fully understood and there is an urgent need to address this gap in the field. For decades, most studies on AD pathogenesis focused on the highly penetrant FAD mutations and on mechanisms leading to the deposition of amyloid-beta (Aβ) plaques and tau neurofibrillary tangles, the two main histopathological signs of AD. More recent studies have begun to investigate how the classical Aβ and tau hypotheses relate to LOAD initiation and progression, but other mechanisms have also been studied (Nasb et al., 2024). Such studies have shown that LOAD pathogenesis involves the disruption of several cellular pathways, with synaptic dysfunction and synapse loss as central pathological events (Dorostkar et al., 2015). How these processes are affected by specific gene variants in LOAD is a field of growing interest. One significant genetic risk factor for LOAD is CD2AP ( CD2 -associated protein), in particular, the K633R mutation (Vardarajan et al., 2015). CD2AP is an actin-binding protein whose complete loss … Correspondence should be addressed to Elisabetta Battocchio at elisabetta.battocchio{at}in.cnr.it.