| • Cerebral aging is a complex and heterogenous process of high-degree intraindividual variability involving neuronal and synaptic functions, signal transduction, mitochondrial dysfunctions, oxidative stress, energy failure, neurotransmitter changes, and many other factors inducing functional network disruptions. |
| • Neuroimaging studies of the aging brain show hemispheral and hippocampal atrophy, white matter changes, and subcortical small-vessel disease. |
| • Cognitive decline in aged subjects is more likely associated with synapse dysfunction/loss than with neuronal loss and white matter changes. |
| • Nondemented, cognitively unimpaired elderly subjects frequently show only mild to moderate Alzheimer's disease (AD)-related lesions and frequent mixed pathologies/comorbidities. |
| • The best morphological correlates of cognitive impairment/dementia are the severity of neocortical tau pathology (neurofibrillary tangles, neuritic plaques) and loss of synapses. In the oldest-old, however, plaques and tangles are less important, dementia being only moderately related to AD pathology, while non-Alzheimer and other (cerebrovascular) pathologies are more important. Thus, the distinction between “normal” and “pathological” aging (asymptomatic AD) may be difficult. |
| • Neuroplasticity, defined as the ability of the neuronal system to respond to intrinsic and external stimuli by reorganizing is structure, connections, and functions, is of great importance for the aging brain. |
| • Cognitive reserve is a set of variables including intelligence, education, and mental stimulation to adapt the brain to underlying pathologies by maintaining cognitive functions and to minimize clinical manifestations. |
| • Recent neuroimaging data have provided changes in aging brain that reflect compensatory mechanisms or neuronal restitution. Larger brain and hippocampal volumes and neuronal hypertrophy were associated with preserved cognition despite a high burden of AD pathology. |
| • The structural basis of neuroplasticity includes synaptic and dendritic remodeling, axonal sprouting and neurogenesis induced by biochemical changes (endogenous β-amyloid, receptor protein kinases, growth factor changes, etc). |
| • Environmental modulations and both physical and mental activities can induce brain plasticity. |
| • Neurogenesis originating from pluripotent precursor cells does occur in the adult brain and is a key factor to response to environmental mental stimuli. |
| • Neurogenesis continues throughout life but declines with increasing age due to reduction of the proportion of neuronal stem cells that may become mature neurons. |
| • Dysregulated or impaired neurogenesis may compromise neuronal plasticity and functions and exacerbate neuronal vulnerability. |
| • The cholinergic system, severly involved in AD, that has a detrimental influence on neurogenesis, together with fibrillary (β-amyloid, causes a decrease of neuronal differentiation and early death of newly formed neurons. |
| • Resiliance to AD is related to genetic factors (APOE ε2), increased premorbid brain volume, hypertrophy of neurons, and compensatory metabolic changes. |
| • Understanding how brain reserve may be influenced to minimize the impact of pathologies associated with dementia has enormous public health implications, and further research is warranted to understand how lifestyle, physical, and mental activities could mitigate the negative impact of pathology on the aging brain as a basis for potential prophylactic and therapeutic options. |
