Abstract
IntroductionLower angiotensin-converting enzyme (ACE) activity could increase the risk of Alzheimer’s disease (AD) as ACE functions to degrade amyloid-β (Aβ). Therefore, we investigated whether ACE protein and activity levels in cerebrospinal fluid (CSF) and serum were associated with CSF Aβ, total tau (tau) and tau phosphorylated at threonine 181 (ptau).MethodsWe included 118 subjects from our memory clinic-based Amsterdam Dementia Cohort (mean age 66 ± 8 years) with subjective memory complaints (n = 40) or AD (n = 78), who did not use antihypertensive drugs. We measured ACE protein levels (ng/ml) and activity (RFU) in CSF and serum, and amyloid β1–42, tau and ptau (pg/ml) in CSF.ResultsCross-sectional regression analyses showed that ACE protein level and activity in CSF and serum were lower in patients with AD compared to controls. Lower CSF ACE protein level, and to a lesser extent serum ACE protein level and CSF ACE activity, were associated with lower CSF Aβ, indicating more brain Aβ pathology; adjusted regression coefficients (B) (95% CI) per SD increase were 0.09 (0.04; 0.15), 0.06 (0.00; 0.12) and 0.05 (0.00; 0.11), respectively. Further, lower CSF ACE protein level was associated with lower CSF tau and ptau levels; adjusted B’s (95% CI) per SD increase were 0.15 (0.06; 0.25) and 0.17 (0.10; 0.25), respectively.ConclusionsThese results strengthen the hypothesis that ACE degrades Aβ. This could suggest that lowering ACE levels by for example ACE-inhibitors might have adverse consequences for patients with, or at risk for AD.
Highlights
Lower angiotensin-converting enzyme (ACE) activity could increase the risk of Alzheimer’s disease (AD) as ACE functions to degrade amyloid-β (Aβ)
Alzheimer’s disease (AD) is characterized by the accumulation of extracellular amyloid-beta (Aβ) plaques and intracellular neurofibrillary tangles, which are reflected by lower Aβ, and higher total tau and tau phosphorylated at threonine 181 in cerebrospinal fluid (CSF) [1]
These data suggest that ACE is important for Aβ degradation, and low ACE activity can lead to increased Aβ-mediated neuronal damage, plaque accumulation, and risk of AD [12]
Summary
Lower angiotensin-converting enzyme (ACE) activity could increase the risk of Alzheimer’s disease (AD) as ACE functions to degrade amyloid-β (Aβ). In vitro studies showed that ACE functions to degrade Aβ, and administration of ACE inhibitors promoted the accumulation of Aβ [8,9,10], while in vivo studies on various mouse models of AD showed indirect evidence that ACE can degrade Aβ (reviewed in [11]) Together, these data suggest that ACE is important for Aβ degradation, and low ACE activity can lead to increased Aβ-mediated neuronal damage, plaque accumulation, and risk of AD [12]. One smallscale study found that administration of an ACE inhibitor did not influence AD biomarkers in CSF [15]
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