Loss of serotonin 5-HT2A receptors in the postmortem temporal cortex correlates with rate of cognitive decline in Alzheimer's disease

Rationale: Previous studies have demonstrated reductions of serotonin 5-HT2A receptors in the neocortex of Alzheimer's disease ( AD) patients. However, it is unclear whether such losses play a role in the cognitive decline of AD. Objectives: To correlate neocortical 5-HT2A receptor alterations with cognitive decline in AD. Methods: Postmortem frontal and temporal cortical 5-HT2A receptors were measured by [H-3] ketanserin binding in aged controls as well as in a cohort of AD patients who had been longitudinally assessed for cognitive decline and behavioral symptoms. Results: 5-HT2A receptor densities in both regions were reduced in severely demented AD patients compared to age-matched controls. In the temporal cortex, this reduction also correlated with the rate of decline of Mini-Mental State Examination (MMSE) scores. The association between 5-HT2A receptor loss and cognitive decline was independent of the effects of choline acetyltransferase ( ChAT) activity and presence of behavioral symptoms. Conclusions: Our data suggest that loss of neocortical 5-HT2A receptors may predict for faster cognitive decline in AD, and point to serotomimetics as potentially useful adjuvants to cholinergic replacement therapies.