75–78 Moreover, in the oldest-old, an ApoE ε2 allele—which is considered protective against AD—was associated with a somewhat reduced risk of dementia, despite its association with increased AD neuropathology.79 Some of the above-mentioned studies (e.g.4,74,75) found these weaker relationships in the oldest-old not only for AD pathology, but also for other types of neuropathologies (hippocampal sclerosis, atrophy, vascular dementia, and diffuse Lewy body disease). Consistent with that,

cerebrovascular pathologies, such as small-vessel disease and/or infarcts, were strongly Inhibitors,research,lifescience,medical associated with dementia in younger elderly but not in the oldest-old.4 Contrary to these findings, a recent study from the Baltimore Longitudinal Study of Aging found that plaques and tangles were significant predictors of dementia independent of age.80 This study also found that in participants older than 90 years Inhibitors,research,lifescience,medical of age, intracranial atherosclerosis predicted dementia in subjects with low Alzheimer’s pathology scores. A study of a relatively large number

of autopsies found that mixed AD pathology and vascular pathology accounted for most dementia cases in very old persons.81 The cumulative effects of AD-type pathologies and Inhibitors,research,lifescience,medical vascular pathologies on cognition have been demonstrated in several studies.82,83 Another feature of aging and dementia is synaptic Inhibitors,research,lifescience,medical protein loss, which may dissociate oldest-old individuals with

and without dementia. Head and colleagues studied several synaptic proteins in the frontal cortex of aged individuals (92–105 years) with a range of cognitive function. Synaptophysin protein levels were lower in individuals with dementia and correlated with cognitive function scores.84 The investigators concluded that these protein levels may protect neuronal function in oldest-old individuals and reflect compensatory responses that may be involved with maintaining cognition. Similarly to these Inhibitors,research,lifescience,medical findings, we have also found that gene and protein expression levels of synaptic markers decrease in persons with dementia, regardless of age.85 This considerable discrepancy between pathology and dementia in the oldest-old has until focused attention on the importance of neuronal loss, rather than the accumulation of abnormal protein deposits, in causing cognitive impairment. Contrary to the traditional view, it now appears that neuron loss is restricted in normal brain aging and unlikely to PF-4708671 clinical trial account for age-related impairment of neocortical and hippocampal functions.86 Consistent with this idea, Savva et al. found that neocortical cerebral atrophy maintained a relationship with dementia across all age groups.4 The value of cerebral atrophy in predicting dementia was supported by in vivo87,88 and postmortem89 magnetic resonance imaging (MRI) studies.