J Alzheimers Dis. 2015;44(1):153-62. doi: 10.3233/JAD-131496.

Angiotensin-converting enzyme in cerebrospinal fluid and risk of brain atrophy.

Jochemsen HM1, van der Flier WM2, Ashby EL3, Teunissen CE4, Jones RE3, Wattjes MP5, Scheltens P6, Geerlings MI7, Kehoe PG3, Muller M8.
  • 1Alzheimer Center & Department of Neurology, Neuroscience Campus Amsterdam, VU University Medical Center, Amsterdam, The Netherlands Julius Center for Health Sciences and Primary Care, University Medical Center Utrecht, Utrecht, The Netherlands.
  • 2Alzheimer Center & Department of Neurology, Neuroscience Campus Amsterdam, VU University Medical Center, Amsterdam, The Netherlands Department of Epidemiology and Biostatistics, VU University Medical Center, Amsterdam, The Netherlands.
  • 3Dementia Research Group, Institute of Clinical Neurosciences, School of Clinical Sciences, University of Bristol, Frenchay Hospital, Bristol, UK.
  • 4Department of Clinical Chemistry, Neurochemistry Laboratory, VU University Medical Center, Amsterdam, The Netherlands.
  • 5Department of Radiology, VU University Medical Center, Amsterdam, The Netherlands.
  • 6Alzheimer Center & Department of Neurology, Neuroscience Campus Amsterdam, VU University Medical Center, Amsterdam, The Netherlands.
  • 7Julius Center for Health Sciences and Primary Care, University Medical Center Utrecht, Utrecht, The Netherlands.
  • 8Department of Gerontology and Geriatrics, Leiden University Medical Center, Leiden, The Netherlands.

 

 

Abstract

BACKGROUND:Higher angiotensin-converting enzyme (ACE) activity might increase the risk of Alzheimer’s disease by increasing blood pressure, and subsequent development of cerebral small vessel disease (CSVD). Yet, it may also decrease this risk, as it functions to degrade amyloid-β, thereby reducing brain atrophy.

OBJECTIVE: To examine the cross-sectional associations of serum and cerebrospinal fluid (CSF) ACE protein levels and activity with brain atrophy and CSVD in a memory clinic cohort.

METHODS: In 118 subjects from the memory clinic based Amsterdam Dementia Cohort (mean age 66 ± 8 years), ACE protein levels (ng/ml) and activity in CSF and serum were investigated. Poisson regression analyses were used to associate ACE measurements with rated global cortical atrophy, medial temporal lobe atrophy, lacunar infarcts, white matter hyperintensities, and microbleeds on brain MRI.

RESULTS: Higher CSF ACE activity was associated with a reduced risk of global brain atrophy. The relative risk (95% CI) of having global cortical atrophy ≥2 per SD increase in CSF ACE activity was 0.67 (0.49; 0.93). ACE levels were not significantly related to measures of CSVD.

CONCLUSIONS: These results show that high ACE might have protective effects on the brain. This could suggest that ACE inhibitors, which may lower CSF ACE levels, are not preferred as antihypertensive treatment in patients at risk for Alzheimer’s disease.

KEYWORDS: Alzheimer’s disease; angiotensin-converting enzyme; brain atrophy; cerebral small vessel disease; hypertension

PMID: 25201786

 

Supplements:

Angiotensin Converting Enzyme and Alzheimer’s Disease

Majon Muller, MD PhD1; Hadassa Jochemsen, MD PhD2; Wiesje M van der Flier2, MD PhD; Patrick Kehoe PhD3.

1 Leiden University Medical Center, The Netherlands

2 VU University Medical Center, The Netherlands

3 Bristol University, United Kingdom

 

Alzheimer’s disease (AD) is characterized by the accumulation of extracellular amyloid-beta (Aβ) plaques and subsequently neurodegeneration and brain tissue loss. In the last decade, the role of the renin–angiotensin system in the etiology of Alzheimer’s disease (AD) has received increasing attention.

Angiotensin-converting enzyme (ACE) is a key enzyme in the renin–angiotensin system, which is one of the mechanisms that regulates blood pressure. Renin converts angiotensinogen in angiotensin I, and ACE in turn converts angiotensin I in angiotensin II, which is a potent vasoconstrictor (Figure 1A). Higher ACE levels could therefore lead to higher blood pressure levels that can cause cerebral (small) vessel disease and subsequently cognitive decline. However, higher ACE levels could also have favorable effects on the brain by reducing accumulation of amyloid-β (Aβ) (Figure 1A). This is supported by numerous laboratory-based findings (in vitro and in animal models). In addition, some studies have shown that patients with genotypes or haplotypes containing the so-called I-allele of the ACE gene, associated with lower serum ACE levels, have an increased risk of the development of AD and brain atrophy [4-7].

 

MM FIG1Figure 1. The effects of high ACE levels on the vasculature and the brain (A) and the hypothesized effect of reducing ACE levels through ACE inhibition on the brain (B).

 

Together these data suggest that higher ACE levels could contribute to reduced Aβ-mediated neuronal damage and plaque accumulation, less brain tissue loss, and reduced risk of AD. However, studies in humans relating ACE activity to markers of AD are scarce. We hypothesize that higher ACE activity and ACE protein levels in cerebrospinal fluid (CSF) are related to a reduced risk of having amyloid plaques (lower CSF Aβ42 levels) and brain atrophy.

To investigate this hypothesis we compared ACE activity and ACE protein levels with CSF Aβ42 levels and with global cortical atrophy on MRI in 118 memory clinic patients of the Alzheimer center of the VU Medical Center Amsterdam (1, 2). Of these patients 78 were diagnosed with AD and 40 had subjective memory complaints. None of these patients used antihypertensive drugs. All patients underwent a standard dementia screening including physical and neurological examination, as well as laboratory tests, a lumbar puncture to obtain CSF, a brain MRI and comprehensive neuropsychological testing. Low CSF Aβ42 was defined as having levels below 550 ng/L and severe brain atrophy was defined as a visual rated global cortical atrophy (GCA) scale of 2 or more. ACE protein levels and ACE activity in CSF were measured as described before (1, 2).

 

MM FIG2

Figure 2. Risk (RR, 95%CI) of having severe cortical atrophy per SD increase in CSF ACE activity (A) or CSF ACE protein level (B). RR’s were adjusted for age, sex, and diagnosis.

 

 

 

 

 

 

 

 

Figure 3. Risk (RR, 95%CI) of having significant low CSF Aβ42 levels per SD increase in CSF ACE activity (A) or CSF ACE protein level (B). RR’s were adjusted for age, sex, and diagnosis.

The importance of this study is two-fold. First, our results show that individuals with higher ACE levels and higher ACE activity in CSF have a decreased risk of having brain atrophy (Figure 2). In addition, higher ACE levels and activity was associated with a reduced risk of having low CSF Aβ42 levels meaning less amyloid accumulation in the brain (Figure 3). Second, these results might indicate that lowering ACE levels through for example ACE-inhibitors might increase the risk of Alzheimer pathology and related brain tissue loss and subsequent cognitive decline (Figure 1B).

 

References

  1. Jochemsen HM, Van der Flier WM, Ashby EL, Teunissen CE, Jones RE, Geerlings MI, Scheltens P, Kehoe PG, Muller M. Angiotensin-converting enzyme in cerebrospinal fluid and risk of brain atrophy. J Alz Dis 2015; 44:153-62.
  2. Jochemsen HM, Teunissen CE, Ashby EL, Van der Flier WM, Jones RE, Geerlings MI, Scheltens P, Kehoe PG, Muller M. The association of angiotensin-converting enzyme with biomarkers for Alzheimer’s disease. Alzheimer’s Research and Therapy 2014; 6:27. Doi: 10.1186/alrt257.

 

Contact:

Majon Muller, MD PhD

Associate Professor of Internal and Geriatric Medicine

Dept of Internal Medicine

Leiden University Medical Center, The Netherlands

m.muller@lumc.nl

 

 

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