Statin therapy and risk of Alzheimer's and age‐related neurodegenerative diseases

Abstract

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.

Preventing Alzheimer's disease within reach by 2025: Targeted‐risk‐AD‐prevention (TRAP) strategy

“…Similarly each statin shares a common target, HMGCR, whereas specific statins target pathways unrelated to cholesterol such as HDAC2 and ITGAL. 33 Further, the estrogen receptor ESR1 is targeted by both the estradiol and testosterone hormone therapies. Of note, lisinopril, metformin, and vitamin A are multi‐target drugs that do not overlap with other nodes in the network.…”

“…From this analysis, the most impactful risk factors that target biological mechanisms and pathways underlying AD risk include the metabolic, immune, cardiovascular, and endocrine systems. 9 , 33 , 47 , 48 , 49 , 50 …”

“…Drug‐target interactions (DTIs) were extracted from DrugBank 21 to construct DTI networks as previously described in Torrandell‐Harlow et al. 27 Networks were visualized by using Cytoscape software 3.8.2. 28 …”

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“…Interestingly, there is evidence for a potential therapeutic role of statins in targeting Aβ-mediated neurotoxicity [ 15 ]. Moreover, statin therapy has been associated with a lower incidence of neurodegenerative diseases, including Alzheimer’s disease [ 76 ]. Finally, the use of statins was related to a decreased prevalence of vision-threatening diabetic retinopathy [ 77 ], where a role of soluble AK1 in maintaining high pro-inflammatory ATP levels in diabetic retinopathy eyes has been recently recognized [ 52 , 53 ].…”

Cross–trait analysis of Alzheimer’s disease and gastrointestinal tract disorders identifies shared loci highlighting immune-related and statin pathways

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