The genetic association between ACE1 and Alzheimer's disease: Genetics/genetic factors of Alzheimer's disease. (7th December 2020)

• Record Type: Journal Article
• Authors: Guzel, Ozge; Tayler, Hannah Mary; Skrobot, Olivia Anna; Miners, Scott; Kehoe, Patrick Gavin
• Is Part Of: Alzheimer's & dementia. Volume 16(2020)Supplement 2
• Page Start: n/a
• Page End: n/a
• Publication Date: 2020-12-07
• Subjects: Alzheimer's disease -- Periodicals; Alzheimer Disease -- Periodicals; Dementia -- Periodicals; Démence; Maladie d'Alzheimer; Périodique électronique (Descripteur de forme); Ressource Internet (Descripteur de forme); 616.83
• DOI: 10.1002/alz.042822
• Languages: English
• ISSNs: 1552-5260

Abstract

Abstract: Background: ACE1 is a reported risk gene for Alzheimer's disease (AD), highlighted by several meta‐analysis and recent GWAS studies (Marioni et al ., 2018; Kunkle et al ., 2019) . ACE1 encodes angiotensin II converting enzyme‐1 (ACE‐1), a rate‐limiting enzyme in the classical renin‐angiotensin system (cRAS) and is overactivated in AD (Miners et al., 2008, Miners et al., 2009). ACE‐1 generates Ang‐II, itself elevated in AD, and is increased in relation to parenchymal Aβ load. We investigated the relationship between the ACE1 variant (rs4343) (Abdollahi et al., 2008) (a proxy marker for the more commonly studied indel polymorphism) and Aβ plaque and tau tangle load (assessed by IHC) and levels of Aβ40 and Aβ42 (soluble and insoluble) and Ang‐II level, measured by ELISA. Method: We studied a total cohort of 318 dementia cases (AD, Mixed AD and vascular dementia) and 116 controls from the South West Dementia Brain Bank, University of Bristol, UK. The ACE1 indel proxy polymorphism, rs4343, was genotyped using PCR based method. The A and G alleles for rs4343 are equivalent to the insertion and deletion variation in ACE1, respectively. Parenchymal Aβ plaque and tau tangle load was quantified by computer‐assisted field fraction analysis in the frontal and parietal cortex for 134 AD and Mixed dementia cases. Aβ40 and Aβ42, and Ang‐II level, was also measured by ELISA in 254 dementia cases and controls. We performed logistic regression to determine the association between ACE1 genotype and AD and non‐parametric Mann‐Whitney U test to determine the association between ACE1 genotype and Aβ and tau pathology. Result: G/G homozygotes were associated with reduced risk of AD and Mixed dementia (p = 0.037). AD and Mixed dementia cases with the G/G genotype also had significantly lower (p = 0.0109) parenchymal Aβ load in the frontal cortex compared with A/A and A/G genotypes, but this was not evident in the parietal cortex. We will further explore the relationship between rs4343 variants and levels of Aβ (soluble and insoluble) and Ang‐II and examine the potential interaction with tau pathology. Conclusion: Our initial findings indicate that the ACE1 rs4343 polymorphism may associate with both AD risk and AD‐related Aβ pathology.