We examined presynaptic cholinergic markers and β-secretase activity during progressive central nervous system amyloidogenesis in Tg2576 Alzheimer mice (transgenic for human amyloid precursor protein Swedish mutation; hAPPswe). At 14, 18, and 23 months of age there were no significant differences between wild-type and transgenic mice in four distinct central nervous system cholinergic indices - choline acetyltransferase and acetylcholinesterase activities, and binding to vesicular acetylcholine transporter and Na+-dependent high-affinity choline uptake sites. A novel enzyme-linked immunosorbent assay measuring only the secreted human β-secretase cleavage product (APPsβswe) of APPswe also revealed no change with aging in Tg2576 mouse brain. In contrast, transgenic but not wild-type mice exhibited an age-dependent increase in soluble Aβ40 and Aβ42 levels and progressive amyloid deposition in brain. Thus, aging Tg2576 mice exhibited presynaptic cholinergic integrity despite progressively increased soluble Aβ40 and Aβ42 levels and amyloid plaque density in brain. Older Tg2576 mice may best resemble preclinical or early stages of human Alzheimer's disease with preserved presynaptic cholinergic innervation. Homeostatic APPsβswe levels with aging suggest that progressive amyloid deposition in brain results not from increased β-secretase cleavage of APP but from impaired Aβ/amyloid clearance mechanisms.