Higher in vivo muscarinic-2 receptor distribution volumes in aging subjects with an apolipoprotein E-epsilon4 allele.

The apolipoprotein E-epsilon4 allele confers an increased susceptibility to age-related memory problems and Alzheimer's disease. Abnormalities in the cholinergic system are also likely contributors to memory deficits associated with aging and AD. To determine the effect of the APOE-epsilon4 allele on the muscarinic component of the cholinergic system of aging subjects, 10 healthy subjects with APOE-epsilon4 alleles (APOE-epsilon4+) and 10 without (APOE-epsilon4-), ranging in age from 52 to 75 years, were tomographically scanned with the F-18-labeled muscarinic-2 (M2) selective agonist, 3-(3-(3-[(18)F]Flouropropyl)thio)-1,2,5-thiadiazol-4-yl)-1,2,5,6-tetrahydro-1-methylpyridine ([(18)F]FP-TZTP). The distribution volumes (V(T)) of [(18)F]FP-TZTP were determined by compartmental modeling of partial volume and free fraction corrected PET scans. Regional cerebral blood flow (rCBF) measurements with H(2) (15)O were also performed. Global Gray V(T) (840 +/- 155 ml plasma/ml tissue) was greater in APOE-epsilon4+ subjects than APOE-epsilon4- subjects (660 +/- 113 ml plasma/ml tissue, P = 0.01), and previously studied younger subjects. There were no significant differences between the groups with respect to rCBF, but within the APOE-epsilon4+ group there was a trend for subjects with the higher Global Gray V(T)s to have lower Global Gray CBFs (r = -0.65, P < 0.06). A lower concentration of acetylcholine in the synapse of APOE-epsilon4+ older individuals is a likely explanation for the greater [(18)F]FP-TZTP distribution volumes.