Higher in vivo muscarinic-2 receptor distribution volumes in aging subjects with an apolipoprotein E-?4 allele

The apolipoprotein E-ϵ4 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-ϵ4 allele on the muscarinic component of the cholinergic system of aging subjects, 10 healthy subjects with APOE-ϵ4 alleles (APOE-ϵ4+) and 10 without (APOE-ϵ4-), ranging in age from 52 to 75 years, were tomographically scanned with the F-18-labeled muscarinic-2 (M2) selective agonist, 3-(3-(3-[18F]Flouropropyl)thio)-1,2,5-thiadiazol-4-yl)-1,2,5,6-tetrahydro-1-methylpyridine ([18F]FP-TZTP). The distribution volumes (VT) of [18F]FP-TZTP were determined by compartmental modeling of partial volume and free fraction corrected PET scans. Regional cerebral blood flow (rCBF) measurements with H215O were also performed. Global Gray VT (840 ± 155 ml plasma/ml tissue) was greater in APOE-ϵ4+ subjects than APOE-ϵ4- 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-ϵ4+ group there was a trend for subjects with the higher Global Gray VTs to have lower Global Gray CBFs (r = −0.65, P < 0.06). A lower concentration of acetylcholine in the synapse of APOE-ϵ4+ older individuals is a likely explanation for the greater [18F]FP-TZTP distribution volumes. Synapse 49:150–156, 2003. Published 2003 Wiley-Liss, Inc.