Gain in Brain Immunity in the Oldest-Old Differentiates Cognitively Normal from Demented Individuals

Background: Recent findings suggest that Alzheimer's disease (AD) neuropathological features (neuritic plaques and NFTs) are not strongly associated with dementia in extreme old (over 90 years of age) and compel a search for neurobiological indices of dementia in this rapidly growing segment of the elderly population. We sought to characterize transcriptional and protein profiles of dementia in the oldest-old. Methods and Findings: Gene and protein expression changes relative to non-demented age-matched controls were assessed by two microarray platforms, qPCR and Western blot in different regions of the brains of oldest-old and younger old persons who died at mild or severe stages of dementia. Our results indicate that: i) consistent with recent neuropathological findings, gene expression changes associated with cognitive impairment in oldest-old persons are distinct from those in cognitively impaired youngest-old persons; ii) transcripts affected in young-old subjects with dementia participate in biological pathways related to synaptic function and neurotransmission while transcripts affected in oldest-old subjects with dementia are associated with immune/inflammatory function; iii) upregulation of immune response genes in cognitively intact oldest-old subjects and their subsequent downregulation in dementia suggests a potential protective role of the brain immune-associated system against dementia in the oldest-old; iv) consistent with gene expression profiles, protein expression of several selected genes associated with the inflammatory/immune system in inferior temporal cortex is significantly increased in cognitively intact oldest-old persons relative to cognitively intact young-old persons, but impaired in cognitively compromised oldest-old persons relative to cognitively intact oldest-old controls. Conclusions: These results suggest that disruption of the robust immune homeostasis that is characteristic of oldest-old individuals who avoided dementia may be directly associated with dementia in the oldest-old and contrast with the synaptic and neurotransmitter system failures that typify dementia in younger old persons.