The insertion allele in the gene encoding angiotensin-converting enzyme (ACE) is a risk factor for Alzheimer's disease (AD) and ACE is one of several peptidases that have the ability to degrade the neurotoxic amyloid-beta peptide. ACE is a membrane-bound peptidase that is also present in a soluble form in plasma as a result of a zinc metalloprotease-mediated shedding event. Here we aimed to determine whether there is a difference in ACE in the plasma of late-onset clinically diagnosed AD patients (n = 94) as compared to age-matched non-demented control subjects (n = 188). Plasma ACE was lower in the AD subjects as compared to the controls both at baseline (p = 0.072) and after two years (p = 0.05). There was a greater reduction in plasma ACE in the AD subjects as compared to the control subjects over the two years. Plasma ACE did not correlate with cognitive function. The observed reduction in plasma ACE in AD may reflect a general decrease in the zinc metalloprotease-mediated shedding of a subset of membrane-bound proteins.