Knowing the substrate of the

resilience to cognitive decline in the presence of abundant AD and/or mixed pathology might be crucial not only for the GDC-0199 purchase understanding of the pathophysiology of nondemented aged people, but also to discover new prophylactic and/or therapeutic targets for aging processes. As expected from the significant clinicopathologic Inhibitors,research,lifescience,medical correlations of synaptic and neuronal loss in AD, “high-pathology nondemented” controls have preserved densities of synaptophysinlabeled presynaptic terminals and dendritic spines as compared with AD dementia patients with a similar burden of plaques and tangles.99,168 Greater amounts of specific presynaptic proteins and distinct protein-protein intreactions may

be components of cognitive reserve that reduce the risk of dementia with aging.168 They may have no significant neuronal loss, not even in vulnerable regions, such as the entorhinal cortex and hippocampus,54,169 and have lower levels of neuroinflammatory markers than pathology-matched AD patients.170 This Inhibitors,research,lifescience,medical resistance to AD pathology has also been related to a nucleolar, nuclear, and cell body hypertrophy of the hippocampal and cortical neurons, suggestive of a compensatory metabolic activation to face the neurotoxic effects of AD lesions.108,171 Resilience to AD is also attributed to genetic factors, particularly apolipoprotein Inhibitors,research,lifescience,medical E2 and combinations of other genetic polymorphisms.172 Premorbid brain volume has been found to provide protection against clinical manifestation of dementia despite evidence of AD pathology, supporting the brain reserve hypothesis Inhibitors,research,lifescience,medical of resilience to AD.173 Although multiple factors and possible interventions may influence cognitive reserve and susceptibility to dementia, much work is required on the mechanisms of action in order to determine which, if any, may

improve the clinical Inhibitors,research,lifescience,medical and epidemiological picture.174 On the other hand, the unique observation of a cognitively intact woman aged 115 years with only slight tau pathology corresponding to Braak stage II, almost no plaques or vascular changes, and normal neuron count in the locus ceruleus indicates that the limits of human cognitive function extend far beyond the range that is currently enjoyed by most individuals and that brain disease, even in supercentenarians, is not inevitable.175 The association between Linifanib (ABT-869) “vulnerability” and “protective” factors varies with age, since the effects of these factors on the risk for AD may differ in younger (age <80) versus older (age >80) individuals. The understanding of the dynamic of these factors at different age periods will be essential for the implementation of primary prevention treatments for AD.176 TABLE I. Summary of key points on cerebral aging. The importance of understanding ageing and the complex interplay of multiple influences on successful cognitive ageing is clear.