Statins and cognitive decline in patients with Alzheimer’s and mixed dementia: a longitudinal registry-based cohort study

We performed a longitudinal cohort study of patients with AD or mixed dementia and indication for lipid-lowering treatment, registered in the Swedish registry for dementia (SveDem). SveDem is a nationwide quality-of-care registry, established in 2007 [42]. All memory clinics and 78 % of primary care centres in Sweden report to SveDem [43]. From this registry, we obtained demographic information (age, sex, living arrangements), date and care unit of registration, type of dementia diagnosis and cognitive status of the patients (MMSE scores) at baseline and follow-ups. The date of the dementia diagnosis in SveDem was set as the index date; 61% of patients had only one entry, 26% had two, 8% had 3 and 5% had more than 3. In total, 80,004 individual patients with dementia were registered in SveDem between 2007 and 2018. All patients were followed until death, emigration or end of follow-up (16 October 2018).

All patients with a missing MMSE score at index date were excluded from the analyses. Only patients diagnosed with hyperlipidaemia (ICD-10 codes from E78.0 to E78.6 obtained from the the Swedish National Patient Registry (NPR), see below) in the preceding 10 years before the index date or those with a prescription of statins (ICD-10 code C10 obtained from the Swedish Prescribed Drug Registry (PDR), see below) in the preceding 6 months before the index date were included in the analyses. Furthermore, the top 1% of statins users sorted by averaged defined daily doses (DDD) were excluded as well, assuming that their consumption data was falsely high and that these individuals bought medication that they did not consume. Figure 2 shows the patient selection flowchart: 15,586 individuals were included for the main analysis.

The exposure drug use was extracted for every SveDem entry. Drug use was defined from the PDR as either the average DDD during the 6-month period preceding each SveDem entry date or simply as a categorical variable (yes/no) during the same period (time-updated exposure). Time-updated exposure means that presence/absence and dose of statins was examined in each 6-month period leading up to each measurement of MMSE (baseline or follow-up). Individual patients starting their statin treatment after the index date were excluded from the analyses because cognitive decline could have affected prescription. All other patients were included in the analyses as non-users. DDD is defined by the World Health Organization as the assumed average maintenance daily dose of a medication for its primary indication in adults [44]. One DDD of simvastatin is equivalent to 30 mg of simvastatin or 20 mg of atorvastatin.

Medication use with their corresponding ATC codes were collected from the PDR that was established in 2005, which includes all prescription medication dispensed at Swedish pharmacies [45]. Lipid-lowering medications included simvastatin, pravastatin, fluvastatin, rosuvastatin, pitavastatin, fibrates, bile acid sequestrants, nicotinic acid and derivates and other non-statin lipid lowering medications. Comedications were calculated as time-updated exposures (yes/no) during the 6-month period preceding the index date. Comedications were selected based on known relevance for patients with dementia and included cardiac drugs, vasoprotectives, platelet aggregation inhibitors, anticoagulants, antipsychotics, anxiolytics, hypnotics, antidepressants, cholinesterase inhibitors, memantine and vitamin D (Appendix). Assumption on the adherence was made based on the collection of the medication at the pharmacy.

Comorbidities were obtained with their corresponding ICD-10 codes from the NPR and were coded dichotomously up to 10 years before index date. NPR covers all diagnoses from in-hospital and specialist clinics. Comorbidities were selected based on their known relevance for cognition in patients with dementia and included diabetes mellitus, arrythmia, heart failure, atrial fibrillation, alcohol-related disease, chronic kidney disease, cardiovascular disease, ischemic heart disease, respiratory disease, stroke, anaemia, liver disease, malignancy and obesity (Appendix).

Covariates that were considered included age at baseline, sex (male/female), residency (living with another adult/alone/nursing home/missing), type of dementia diagnostic unit (special memory clinic/primary care centre) and calendar year of dementia diagnosis, all at index date. We selected the covariates that are likely associated with cognitive functions or the probability of receiving statins, based on previous research and/or our clinical knowledge.

The linkage of data from the forementioned registries—SveDem, Swedish National Patient Registry, and Swedish Prescribed Drug Registry—was allowed by the personal identification number of each Swedish citizen. Patient identification was pseudonymized and blinded to the researchers.

The main outcome was cognitive decline, evaluated with MMSE points.

The data were described in terms of mean and standard deviation (SD) for continuous variables and as positive counts (percentages) for categorical variables.

Linear mixed-effects regression models with random intercept and slope were used to investigate the change in MMSE scores over time and to detect differences between statin users and non-users. The model included statin use and time from index date as continuous variables and an interaction between drug use and time. Following our previous work in SveDem [46], a linear trend over time was assumed and the model allowed for a random intercept and random slope for each patient. This model is referred to as the crude model. In an adjusted model, comedications, comorbidities and other covariates were included in the model mostly as categorical variables. Only age, MMSE scores and calendar year at index date were treated as continuous variables. Fully adjusted models included clinical and demographic characteristics (MMSE score at baseline and age at diagnosis, year of diagnosis, sex, residency, comorbidities and comedications). Inverse probability weighting was used to account for the potential effects of general attrition from those lost to follow-up due to dropout. For this purpose, a logistic regression model was fitted to the data to estimate the probability of dropping out within the subsequent year. Dropout was defined as the last observed MMSE score without death or study end occurring in the subsequent year. For more details, see Handels et al. [47].

The analyses were repeated for selected drug groups where drug use was defined as yes/no during the 6-month period before each SveDem entry date and in subgroups defined by gender and age. We split the cohort at the mean age at index date (79.5 years) to create subgroups of younger and older patients. We compared individual statin users. We considered two approaches to divide the statins regarding their functional properties: firstly, lipophilic (simvastatin, atorvastatin, fluvastatin, lovastatin and pitavastatin) or hydrophilic groups (rosuvastatin, pravastatin) [48]. Moreover, we classified them into fungus-derived (simvastatin, pravastatin, lovastatin) or synthetic statins (atorvastatin, cerivastatin, fluvastatin, rosuvastatin, pitavastatin) [15]. Finally, we compared statin users to non-statin lipid-lowering medication users. To evaluate the association between the comparison groups after 3 years, we calculated a theoretical linear extrapolation based on the mixed effect models.

Multiple imputations of MMSE scores [47] and incident users models were two additional models we performed as a sensitivity analysis to check the robustness of our results. The first model deals with bias arising from missing MMSE scores at follow-ups and the second addresses the length of treatment as confounding. Incident users were defined as drug users who did not take out any drug prescription of statins during 12 months before 6-month period preceding each SveDem entry date. Table 1 shows the design of the study.

As shown in Table 2, our cohort consisted of 15,586 AD or mixed dementia patients with a mean age of 79.5 years (SD = 6.8) at dementia diagnosis. Most patients were women (59.2%). At baseline, all patients scored on average 21 points on MMSE (SD = 5); 10,869 patients (69.7%) used statins in the observation period. The most prescribed statin in the whole cohort was simvastatin (8235, 52.8%) followed by atorvastatin (2210, 14.2%). There were 296 (1.9%) users of a non-statin lipid-lowering medication. Most of the patients resided at home (53.9% with another adult and 40.7% alone) and 5% lived nursing homes. The most common comorbidities in the cohort were hypertension (40.1%), diabetes mellitus (24.4%) and cardiovascular disease (24%).

The average time of follow-up was 0.86 (SD = 1.40) years and average number of MMSE follow-ups for a patient with measures of MMSE was 1.61 (SD = 0.97). The average decline per year of the cohort was −1.20 points MMSE (95% CI: −1.32; −1.09). The average cognitive decline observed among 6113 patients with at least two MMSE measurements was −2.61 points (SD = 4.57).

Statin users were more commonly male (44 % vs 33.5 %, p < 0.001), younger (78.7 vs 80.7 years at baseline, p < 0.001) and had a better cognitive status at baseline (21.3 vs 20.8 MMSE points, p < 0.001), compared to non-users of statins. As expected, there was a higher prevalence of comorbidities in the former compared to the latter group, such as hypertension, cardiovascular disease, liver disease and diabetes mellitus. Statin users were more likely to be prescribed co-medication, such as antithrombotics, antihypertensives, antidiabetics or psycholeptics. More detailed information is presented in Tables 2 and 3.

The sensitivity analysis revealed that a majority of our cohort had used statins at some point in time. Overall, 844 patients were incident users of statins. Compared to incident simvastatin users (n = 557), incident atorvastatin users (n = 267) had a lower baseline MMSE (20.5 vs 21.4 points, p = 0.01) and less commonly received their dementia diagnosis at special memory clinic (60.3 % vs 78.8 %, p < 0.001). (Supplementary table 7).

Simvastatin was the most used statin in Sweden when our data was collected. Accordingly, this makes comparisons among different statins or groups difficult, often lacking enough power. A beneficial role of simvastatin in early dementia is biologically plausible, when there are high levels of neuroinflammation as this lipophilic statin readily crosses the BBB and could exert various neuroprotective properties, such as protection against tau hyperphosphorylation and mediation of brain cholesterol homeostasis [18]. Research on animal models of AD further support the beneficial effects of simvastatin on cognition through different mechanisms [49, 50]. Clinical trials in patients with mild to moderate AD reported a neutral [35] or a beneficial effect of simvastatin [51], using MMSE as a cognitive outcome. Findings were limited by relatively short trial duration and low number of participants and were therefore possibly underpowered. To our best knowledge, our study is the first observational study to compare cognitive decline between different statins in patients with established AD and mixed dementia. A careful adjustment for comedication in general and cholinesterase inhibitors in particular is important, as our group previously discovered a small long-term beneficial effect on cognition in AD and mixed dementia patients treated with cholinesterase inhibitors [46].

In our study, the analysis including only incident users showed an opposite association. A possible explanation to inconsistent results of incident user design may be related to a temporally dependent biphasic effect of statin therapy on cholesterol metabolites, as shown in a study which included asymptomatic patients at risk of AD [52]. In this study, statins initially reduced cholesterol metabolites in the cerebrospinal fluid, reaching a nadir at 6–7 months, followed by a return to baseline and an overshoot at two years. Moreover, several differences between incident users compared to all users exist which could partly contribute to the discrepancies. The individual characteristics of incident users, such as baseline MMSE differences, or a possible selection of these smaller groups of patients through individual physicians’ preferences, might have influenced their cognitive trajectories which could not be accounted for in adjusted models.

Several biochemical characteristics of statins probably influence the functional effects of statins on cholesterol metabolism and cognition. Statins with a higher lipophilicity (e.g., simvastatin, atorvastatin, fluvastatin) may cross the BBB more easily compared to more hydrophilic statins (rosuvastatin, pravastatin) [18]. Additionally, the size and orientation of a statin molecule may influence the BBB permeability of statins which explained a low ability of a lipophilic atorvastatin to cross the BBB, due to its large size [18]. In our study, we did not observe a difference in cognitive decline when comparing users of lipophilic to hydrophilic statins in most models and subgroup analyses. However, MMSE decline was faster in incident users of lipophilic statins. Due to forementioned Swedish prescription patterns, the comparisons in our study were driven by simvastatin and atorvastatin users compared to rosuvastatin users. To the best of our knowledge, we are not aware of another observational study which compared cognitive decline between lipophilic and hydrophilic statin users in AD patients.

Fungal statins (simvastatin and pravastatin) differ from the synthetic statins (atorvastatin, rosuvastatin, fluvastatin) in several functional characteristics. Synthetic statins were shown to form more interactions which leads to a stronger inhibition of HMG-CoA reductase and a higher potency [53]. Moreover, fungus-derived statins were observed to have a high permeability through the blood–brain barrier and cause a reduction of cholesterol levels as well as lower a burden of neurofibrillary tangles in animal models [54]. In our study, this comparison between fungal and synthetic statins was driven by simvastatin and atorvastatin users, so this classification did not add further information. To the best of our knowledge, no previous studies compared cognitive decline in AD or mixed dementia patients among fungal and synthetic statins. A recent cohort study comparing different incident statin users found a higher risk of AD in fungal statins compared to synthetic, as well as higher risk in lipophilic statins compared to hydrophilic statins; however, the risk was reduced in sensitivity analysis [55].

The confidence intervals for this comparison were broad and did not reach statistical significance. However, MMSE decline was slower in some subgroups of non-statin lipid-lowering medications (men and younger users). Statins and other hypolipemics, such as gemfibrozil, represent another interesting comparison group since they are both prescribed for hyperlipidaemia, therefore diminishing indication bias, and could exhibit cognitive effects through different metabolic pathways. Gemfibrozil attenuated amyloid burden as well as neuroinflammation and improved the memory in AD mouse models through activation of PPAR-alpha in a recent study [56], but our study was probably underpowered for this comparison.

The dose, potency or duration of treatment have been recognized as important factors when evaluating the effects of statins on cognition. Most work has been done on evaluating these factors in the prevention of dementia or AD [32, 33, 57]. A dose-response was observed in a large cohort study which included only AD patients [58]. In our study, a dose-effect was observed when comparing statin users and non-users. The prediction model showed a benefit after 3 years, which is an estimated brain cholesterol turnover rate in adults, but most of the data in our cohort aggregates towards earlier follow-ups. A time window of intervention with statins regarding the neuropathogenesis of dementia, or life course of a patient, might exist as the neurodegenerative pathological changes of AD begin decades prior to clinical symptoms [59]. The protective effect of statins could be achieved in a long-term amelioration of brain vascular burden, restoration of disturbed central cholesterol homeostasis and neuroprotective effects, possibly in preclinical [60] or early stages of AD [61, 62].

An extensive evaluation of the possible role of statins in preventing dementia has been performed in the last two decades [25, 26, 32, 33, 41, 63‐65] but comparably less studies included patients with already established AD [25, 31, 38‐41, 64]. Clinical trials of statin use in AD patients did not report a clear benefit to ameliorate cognitive decline [38, 40, 64]. Observational cohort studies of patients with AD and a various follow-up ranging from 10 months to over 10 years, reported a slower [61, 66‐68] or similar [69] cognitive decline in statins users compared to non-users. Findings from our analysis comparing statin use to no use which imply a possible dose-dependent beneficial role of statins in patients with AD is in accord with many of these previous studies. However, comparing statin users and no-users introduces several important biases.

Importantly, hyperlipidaemia is an indication for statin use in midlife and represents a risk factor for dementia and AD. On the other hand, low cholesterol level in late life has been recognized as a measure of frailty or prodromal stage of dementia, particularly AD [70]. These facts can lead an indication bias when comparing users to non-users. Secondly, clinicians might be less likely to prescribe statins to older patients, especially those with pre-existing cognitive decline, frailty, or comorbidities since the risk of possible side effects and diminished life expectancy outweighs the benefit of medication. Furthermore, cognitive impairment could lead to a discontinuation of statins or drop-out from study, which would lead to a false beneficial association [41, 71]. Older patients who receive statins for their hypercholesterolemia could naturally possess a lower risk of dementia or reflect a better cognitive trajectory [72], leading to reverse causation.

Our study has several strengths and limitations. We can report associations but are not able to draw the conclusions on causality. This study was meant as an exploratory analysis which requires confirmation. We considered a variety of comorbidities and comedications in our models; however, a few important covariates were not available for our analysis, such as cholesterol levels, ApoE status and possible genetic polymorphisms specific for different populations [73]. However, we addressed this issue with a selection of a population with indication for treatment and used multivariate adjusting to balance the differences between the groups as well as performed several sensitivity analyses. Patient adherence to medication was indirectly assumed based on the dispensation of medication at pharmacies. There was a considerable number of drop-out participants and missing values on MMSE. MMSE was the only measure of cognitive decline in our study and is less robust to detect cognitive changes in different cognitive domains. We chose to only include observed MMSE scores in the analyses to limit the risk of creating false data with imputation but there is, of course, a risk of selection bias. We restricted the study population to those individuals with drug use at index date to ensure that we can follow a statin user’s cognitive decline from the beginning. The results from the sensitivity analyses considering multiple imputations of MMSE are in line with our main findings and confirmed our choices. However, the results of analysis on incident users were not consistent. Another important strength of our study lies in carefully selected statistical methods. Use of linear mixed modelling with multiple imputation is currently regarded as a superior method to account for the attrition bias [72]. We considered a reasonably long follow-up and performed a large, population-based study. We examined the use of statins before dementia to explore the reverse causality of cognition influencing the adherence or use of statin but cannot completely exclude this problem with our current methods.