CORRELATION OF NICOTINIC BINDING WITH NEUROCHEMICAL MARKERS IN ALZHEIMERS-DISEASE

The loss of neocortical synapses that occurs in Alzheimer's disease (A D) has been shown to correlate with cognitive decline. In addition, ma rked losses in the cholinergic system in AD, specifically choline acet yltransferase (ChAT) activity and high affinity presynaptic neuronal n icotinic cholinergic receptors (nAChRs), have also been described. We hypothesized that in AD, the loss of [H-3]-ligand binding to nAChRs, w hich are largely presynaptic, would correlate with changes in two othe r presynaptic markers: synaptophysin (Syn), a measure of synaptic dens ity, and ChAT activity. The midfrontal (MF) cortex of 36 autopsy confi rmed (NIA and CERAD criteria) AD patients (mean death age +/- SD 80.1 +/- 8.4 years) who met NINDS-ADRDA criteria for a clinical diagnosis o f probable or possible AD, and 11 nondemented controls (mean death age +/- SD 77.9 +/- 8.0) were examined. Synapse counts were quantified by a dotimmunobinding assay for Syn. ChAT activity was assessed by stand ard biochemical assays. Nicotinic cholinergic receptor binding was ass ayed using the high affinity nicotinic agonist [H-3]-(+/-)-epibatidine ([H-3]-EPI). The mean +/- SD Syn in AD (83.4 +/- 31.9 arbitrary units (AU)/mg protein) was significantly lower than controls (126.1 +/- 19. 9, p = 0.0003; t-test). The mean ChAT activity in AD (139.0 +/- 75.6 n mol A Ch/hr/ 100 mg protein) was significantly lower than controls (21 9.6 +/- 70.8, p = 0.004). The mean [H-3]-EPI total binding in AD (6.2 +/- 2.8 fmol/mg protein) was significantly lower than controls (14.8 /- 3.2; p < 0.0001). Syn correlated with [H-3]-EPI binding in AD (r = 0.48, p = 0.006; Pearson) but ChAT did not (r = -0.20, p = 0.34). We c onclude that loss of high affinity nAChR binding correlates with loss of synapses in AD. The lack of correlation between [H-3]- EPI binding and ChAT activity suggests that the targeted receptor populations may not be located exclusively on cholinergic neurons.