key: cord-0053395-r9jzdqmm authors: Torrandell‐Haro, Georgina; Branigan, Gregory L.; Vitali, Francesca; Geifman, Nophar; Zissimopoulos, Julie M.; Brinton, Roberta Diaz title: Statin therapy and risk of Alzheimer's and age‐related neurodegenerative diseases date: 2020-11-25 journal: Alzheimers Dement (N Y) DOI: 10.1002/trc2.12108 sha: e19467c8a1b0eb82bf1a8881969cd9574fa8bb34 doc_id: 53395 cord_uid: r9jzdqmm INTRODUCTION: Establishing efficacy of and molecular pathways for statins has the potential to impact incidence of Alzheimer's and age‐related neurodegenerative diseases (NDD). METHODS: This retrospective cohort study surveyed US‐based Humana claims, which includes prescription and patient records from private‐payer and Medicare insurance. Claims from 288,515 patients, aged 45 years and older, without prior history of NDD or neurological surgery, were surveyed for a diagnosis of NDD starting 1 year following statin exposure. Patients were required to be enrolled with claims data for at least 6 months prior to first statin prescription and at least 3 years thereafter. Computational system biology analysis was conducted to determine unique target engagement for each statin. RESULTS: Of the 288,515 participants included in the study, 144,214 patients (mean [standard deviation (SD)] age, 67.22 [3.8] years) exposed to statin therapies, and 144,301 patients (65.97 [3.2] years) were not treated with statins. The mean (SD) follow‐up time was 5.1 (2.3) years. Exposure to statins was associated with a lower incidence of Alzheimer's disease (1.10% vs 2.37%; relative risk [RR], 0.4643; 95% confidence interval [CI], 0.44–0.49; P < .001), dementia 3.03% vs 5.39%; RR, 0.56; 95% CI, 0.54–0.58; P < .001), multiple sclerosis (0.08% vs 0.15%; RR, 0.52; 95% CI, 0.41–0.66; P < .001), Parkinson's disease (0.48% vs 0.92%; RR, 0.53; 95% CI, 0.48–0.58; P < .001), and amyotrophic lateral sclerosis (0.02% vs 0.05%; RR, 0.46; 95% CI, 0.30–0.69; P < .001). All NDD incidence for all statins, except for fluvastatin (RR, 0.91; 95% CI, 0.65‐1.30; P = 0.71), was reduced with variances in individual risk profiles. Pathway analysis indicated unique and common profiles associated with risk reduction efficacy. DISCUSSION: Benefits and risks of statins relative to neurological outcomes should be considered when prescribed for at‐risk NDD populations. Common statin activated pathways indicate overarching systems required for risk reduction whereas unique targets could advance a precision medicine approach to prevent neurodegenerative diseases. Discussion: Benefits and risks of statins relative to neurological outcomes should be considered when prescribed for at-risk NDD populations. Common statin activated pathways indicate overarching systems required for risk reduction whereas unique targets could advance a precision medicine approach to prevent neurodegenerative diseases. age, Alzheimer's disease, amyotrophic lateral sclerosis, bioinformatics, biology pathway analysis, cholesterol, multiple sclerosis, neurodegenerative diseases, Parkinson's disease, statins It is estimated that nearly 100 million Americans are afflicted by at least one neurological disease, costing 800 million dollars per year in the United States. 1 As the elderly segment of the population grows, the number of patients and cost will increase. 1 The prevalence of In the face of the increasing incidence of age-related neurodegenerative diseases (NDD), 1,2,5 we conducted this study to identify currently prescribed therapeutics that may alter NDD risk and their biological pathways. Specifically, several studies have suggested an association between hypercholesterolemia and dementia [6] [7] [8] [9] and AD. 6, 7, [10] [11] [12] [13] The drug class of 3-hydroxy-3-methylglutaryl-coenzyme A reductase (HMGCR) inhibitors, commonly known as statins, are the primary pharmacological treatment for prevention and lowering cholesterol levels in blood. 6, 7, [13] [14] [15] As such, statins are the first-line treatment for hyperlipidemia and prevention of coronary heart disease. 10, [14] [15] [16] [17] [18] Statins are potent inhibitors of cholesterol biosynthesis via their primary mechanism of inhibiting HMGCR; 15 24 Multiple studies report an association between statin use and AD, 10-13,20 dementia, 7,21,25,26 MS, 27,28 PD, 29, 30 and ALS. 31, 32 Current meta-analyses for AD, 21, 33 dementia, 21 MS, 34 PD, 35 and ALS 36 suggest that statin use is associated with NDD risk decrements, except for ALS-as the evidence is insufficient to draw any conclusion-and all call for the addition of further studies to add to the existent literature. Analyses reported herein were designed to determine potential associations between statin therapies and NDD risk. Our study was conducted using a United States-based population insurance claims records data set and a large patient population to survey a variety of NDD outcomes and their association with statin exposure. Furthermore, we report the association of individual statin types with each NDD outcome and we describe common and divergent biological networks in an attempt to understand the mechanism of risk reduction. The Humana database as described in Branigan et al. 37 37 an analysis of comorbidities known to be associated with NDD outcomes was conducted (Table S3 ). Statistical analyses were conducted between February 6 and May 9, 2020. Patient demographic statistics (Table 1 ) and incidence statistics were analyzed using unpaired two-tailed t-tests or χ2 tests, as appropriate, to test the significance of the differences between continuous and categorical variables. In all analyses, a two-sided P < .05 was considered statistically significant. To estimate the association between statin and NDD, a propensity score-matched population was generated as previously described 37 to account for confounding variables between treatment/control group assignment and NDD outcomes. Logistic regression was first used to estimate the probability for each subject to receive statin therapy given their age, sex, race, region, comorbidities of interest, Biological pathway analysis was conducted using network-based approach. First, for each statin identified, the related gene targets were extracted using DrugBank database. 38 Next, the gene targets were subsequently used to seed a protein-protein interaction (PPI) network, which extract protein interactors of the target gene and obtain a comprehensive overview of the statin actions. In this step, the STRING database was used to extract PPI; 39 only high-confidence PPIs were retrieved, ie, PPIs derived from only experimental and database evidence and with a STRING score cut-off of 700. 40, 41 Finally, for each drug, enrichment analysis of the related targets and their first protein interactors was performed to identify significant (P-value < .05) gene ontology biological processes (GO-BP) characteristic of each statin. GO-BP enrichment was further analyzed to exclude redundant and similar GO-BP terms. To this goal, we computed the semantic similarity between each GO-BP term resulting in the enrichment using Python package GOATOOLS 42 and filtered for redundant GO-BPs following the reported similarity threshold process. 43 Results were finally compared across the different type of statins to identify specific and common pathways and mechanisms of action. • Statins are associated with decreased incidence of Alzheimer's disease, dementia, Parkinson's disease, multiple sclerosis, and amyotrophic lateral sclerosis. • Each statin lowered the incidence of neurodegenerative diseases (NDD) with the exception of fluvastatin. • Pitavastatin and atorvastatin exerted greatest reduction of NDD diagnosis. • Unique and common pathways of statins were associated with risk reduction profile. • Unique statin targets could advance a precision medicine approach to prevent NDD. Of 1,959,483 patients in the dataset, 288,515 patients met the inclusion, exclusion, enrollment, and propensity score-matching criteria ( Figure 1 ). All analyses in the control group matched those defined in the statin exposure group (including time-based analysis) based on patient demographics and predefined NDD-relevant comorbidities. 44 Table 2 ). These data are represented in Figure 2A The incidence for all NDD for every individual statin was reduced in the statin exposed group compared to control patients ( Figure 2B ). Pitavastatin showed the strongest reduction in NDD incidence (RR, The cumulative hazard ratios with 95% CI were generated from the propensity score-matched population for development of all NDD combined, AD, dementia, and PD to evaluate the rate of disease conversion for statin versus non-statin exposed groups (Figure 3) . Differences in the rate of disease conversion in the hazard ratios corroborate the results seen in the Chi-square analysis. To better understand the differences in the risk reduction efficacy profile for each statin, we used a systems biology approach to identify protein/gene pathways associated with each statin therapy ( Figure 4 ). Figure S1 ). As this study is a retrospective analysis of a claims database, there are This study investigated the association between statin therapies and their non-canonical neurologically relevant mechanisms of action and their efficacy of risk reduction across multiple age-related NDD. Results reported herein are consistent with previously published outcomes for statin therapy and a single NDD 7, [10] [11] [12] [13] [14] 20, 21, 25, 27, 28, [31] [32] [33] [34] [35] [36] 49 thereby validating our findings. Figure S1 in supporting information. B, Unique and common gene ontology terms of interest for statin clusters. Extended version in Figure S1 into clusters was defined by shared gene ontology networks. Pathway profiles were consistent with comparable risk reduction profiles (overlapping 95% CI). For example, the cluster including lovastatin and simvastatin, which targets both ITGAL and HDAC2 genes, showed no significant differences for NDD relative risk reduction. This trend of similar cluster-based risk reduction profiles was evident across multiple NDDs. In contrast, the group containing pravastatin and fluvastatin, which act on HDAC2 and share a common pathway profile, showed statistically different relative risk ratios, where fluvastatin was the only statin to not significantly reduce the risk of NDD. Of note, fluvastatin is known to have low level of permeability at the BBB, 20 which may explain, in part, the lack of significant effect. The GO-BP analysis identified potential pathways that underlie the protective profile of statins and the differences in risk reduction efficacy between statins. We hypothesize that the non-canonical neurological targets represent pathways underlying the impact of each statin on NDD risk profile. Further, the unique pathways for each cluster may explain the differences across statins in relative risk reduction. Differences in the risk reduction profile within the same cluster may be explained, in part, through BBB permeability. Because lipid dysregulation is a common feature of NDD, the fact that all statins have a common target, HMGCR, corroborates common gene ontology pathways that may be responsible for the overall protective effect of statins on NDD. This study aimed to establish the risk profile of statin therapeutics on the incidence of NDD. In addition, a unique biology pathways analysis was conducted to elucidate potential mechanisms underlying the differences between each statin profile. Each statin varied in its efficacy to reduce NDD incidence, except for fluvastatin, and interestingly these results paralleled the neurological pathways targeted by these drugs. With this foundation, a precision medication approach will be possible in which prescription guidelines of cholesterol-lowering medication can be adapted for each population with respect to their neurological health profile. Common pathways indicate overarching systems required for risk reduction, whereas unique targets could advance a precision medicine approach to prevent and treat neurodegenerative diseases in genetic at-risk and aging populations. We would like to thank Patrick Ronaldson, Ph.D., for his insights regarding statin therapies and the blood-brain barrier. 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