Lipid lowering and Alzheimer disease risk: A mendelian randomization study

Abstract

Objective To examine whether genetic variation affecting the expression or function of lipid‐lowering drug targets is associated with Alzheimer disease (AD) risk, to evaluate the potential impact of long‐term exposure to corresponding therapeutics. Methods We conducted Mendelian randomization analyses using variants in genes that encode the protein targets of several approved lipid‐lowering drug classes: HMGCR (encoding the target for statins), PCSK9 (encoding the target for PCSK9 inhibitors, eg, evolocumab and alirocumab), NPC1L1 (encoding the target for ezetimibe), and APOB (encoding the target of mipomersen). Variants were weighted by associations with low‐density lipoprotein cholesterol (LDL‐C) using data from lipid genetics consortia (n up to 295,826). We meta‐analyzed Mendelian randomization estimates for regional variants weighted by LDL‐C on AD risk from 2 large samples (total n = 24,718 cases, 56,685 controls). Results Models for HMGCR, APOB, and NPC1L1 did not suggest that the use of related lipid‐lowering drug classes would affect AD risk. In contrast, genetically instrumented exposure to PCSK9 inhibitors was predicted to increase AD risk in both of the AD samples (combined odds ratio per standard deviation lower LDL‐C inducible by the drug target = 1.45, 95% confidence interval = 1.23–1.69). This risk increase was opposite to, although more modest than, the degree of protection from coronary artery disease predicted by these same methods for PCSK9 inhibition. Interpretation We did not identify genetic support for the repurposing of statins, ezetimibe, or mipomersen for AD prevention. Notwithstanding caveats to this genetic evidence, pharmacovigilance for AD risk among users of PCSK9 inhibitors may be warranted. ANN NEUROL 2020;87:30–39

Vascular and Alzheimer Disease in Dementia

“…In multivariate adjusted analyses, only serum cholesterol was significantly associated with dementia with vascular features, whereas none of the midlife vascular risk factors were related to pure AD-findings supporting the Swedish study. 1 The relationship of midlife cholesterol that was specific to vascular-type dementia may also shed light on the results of a further recent study 5 using Mendelian randomization (MR); in agreement with observational findings, genes encoding targets of several lipid-lowering drug classes were not related to diagnosis of AD (not separating pure and mixed types) in people aged 70 years and older. Further explanation may be selection bias associated with MR studies, especially for earlier and later developing health conditions that have shared etiology.…”

Coming Back to Physiology: Extra Hepatic Functions of Proprotein Convertase Subtilisin/Kexin Type 9

“…In such experiments, an increased expression of two acetyltransferases protects BACE-1 from PCSK9-dependent downregulation (Ko and Puglielli, 2009). In line with these studies, the use of PCSK9 inhibitors was associated with a moderately increased risk of AD in an AD risk patient collective but not associated with the general development of cognitive dysfunction (Giugliano et al, 2017;Williams et al, 2020). To what extent PCSK9 regulates neuronal apoptosis under physiological or pathophysiological conditions is still a matter of debate.…”

Cholesteryl Ester Transfer Protein as a Drug Target for Cardiovascular Disease

“…The drug target MR analyses showed that lower CETP concentration was additionally associated with not only with CHD (OR 0.95 per µg/ml CETP concentration; 95%CI 0.91; 0.99), but also HF (OR 0.95; 95%CI 0.92; 0.99) and CKD (OR 0.94; 95%CI 0.91; 0.98), but with a higher risk of AMD (OR 1.31; 95%CI 1.22; 1.40). Similar to the ontarget effects of CETP, genetically-instrumented PCSK9 concentration was associated with a lower risk of CHD, HF and CKD, and additionally with any stroke, ischemic stroke, AF, MS, as well as an increased risk of asthma and AD 38 . We showed that CETP and PCSK9 had distinct effect patterns on different lipoprotein sub-fractions, with lower CETP being associated with higher HDL-C and lower VLDL-C subfractions, and PCSK9 with lower LDL-C sub-fractions alone.…”