In this retrospective complete enumeration study of older adults residing in a Japanese city, we examined the associations between the use of prescription medications for existing chronic conditions (indicating the pharmaceutical management of dementia risk factors) and NPADM (indicating the progression to clinical dementia). The NPADM incidence was 1.9% at 12 months after study initiation, and this incidence in subjects aged 87 years or older was thrice that of younger subjects aged 77–81 years. NPADM incidence was significantly higher in women and subjects who were treated with insulin, antidepressants, antineoplastics, and post-stroke medications during the IBP. In contrast, NPADM incidence was significantly lower in subjects who were treated with statins, antihypertensives, and non-steroidal bronchodilators during the IBP. While the use of steroids,6 benzodiazepines,7 anticoagulants,8 and non-steroidal anti-inflammatory drugs9 are reportedly associated with the development of Alzheimer’s disease, our analysis did not detect any significant associations with NPADM.
The results of this study should be interpreted with the understanding that the effects of the target medications on NPADM cannot be separated from those of the underlying conditions. Previous studies have asserted that controlling cardiovascular risk factors can mitigate the onset and progression of Alzheimer’s disease.10,11 Based on those findings, we included antianginals, antiplatelets, anticoagulants, antihypertensives, and statins in our analysis. However, the multivariate analysis showed that only statins, antihypertensives and non-stroiedal bronchodilators were significantly associated with a lower incidence of NPADM (risk reductions of 18% for statins and 20% for antihypertensives). In contrast to our findings, two prospective randomised controlled trials failed to demonstrate the benefits of statins for the prevention of dementia,12,13 although beneficial effects were indicated by a cohort study.14 Our analysis differed from the two trials in that our subjects were already taking statins during the IBP, whereas statins were prescribed to the trial participants only after randomisation.12,13 Next, our analysis found that the use of non-steroidal bronchodilators was associated with a reduced incidence of NPADM. Many researchers suspect that use of medications which have anticholilnergic property is associated with the increased risk of dementia. In the study, the use of non-steroidal bronchodilators which have β-adrenergic stimulant as well as anti-cholinergic propertiy did not increase NPADM , but reduced it. Meanwile, Japanese package inserts for anti-dementia medication note that it must be cautiously prescribed to patients who are taking bronchodilators for chronic obstructive pulmonary disease or asthma.15 We posit that the reduced incidence of NPADM in subjects being treated with non-steroidal bronchodilators may also be indicative of physicians’ caution in prescribing anti-dementia medications.
Diabetes is a well-established risk factor for dementia, including Alzheimer’s disease.1,2 Insulin is generally used for patients who are unable to manage their blood glucose levels through the use of oral antidiabetics alone. In addition to its hypoglycaemic properties, oral antidiabetics (sulfonylureas and metformin) have been reported to substantially reduce the risk of dementia.16 It is therefore possible that subjects who require insulin have a higher risk of dementia than those taking oral antidiabetics as the latter could mitigate the risk of diabetes-associated dementia. History of stroke is another known risk factor for cognitive decline and its progression to dementia.17 In Japan, medications to stimulate brain metabolism or increase cerebrovascular blood flow are prescribed to patients with a history of stroke. Our study subjects who were already taking these post-stroke medications had an elevated risk of NPADM. Next, it is unclear as to whether depression is a risk factor or prodrome of dementia.2 Nevertheless, our study subjects who were taking antidepressants during the IBP were found to have a higher incidence of NPADM. Depression is a known risk factor for developing dementia subsequently, Our results, however, do not provide any evidence that antidepressants have any beneficial effects for reversing the depressive symptoms on Alzheimer’s disease or Lewy body disease. Finally, the use of antineoplastics were associated with a small, but statistically significant, increase in NPADM among our subjects. In contrast, a previous meta-analysis suggested that malignancies can reduce the risk of Alzheimer’s disease.18 Further research is required to elucidate the effects of antineoplastics on dementia, such as through the induction of injury to neuronal tissue and promotion of the neurodegenerative process. Overall, the results of our study do not contradict the recommendations of the WHO.1
Despite being widely prescribed, the currently available anti-dementia medications for Alzheimer’s disease and Lewy body disease only provide symptomatic treatment without modifying the underlying neurodegenerative process.2 Several phase III trials have failed to demonstrate the effectiveness of candidate drugs in disease modification, and many were terminated before completion.19 Trials of aducanumab, an anti-amyloid antibody, were also discontinued after a phase III futility analysis. However, additional data analyses suggest that longer exposure to higher doses may be effective. Although the manufacturer of aducanumab is seeking US Food and Drug Administration approval, it is unclear if the currently available data are sufficient to confirm its effectiveness.20 As there are no effective curative treatments at present, the WHO has recommended multidomain strategies that incorporate both lifestyle modifications and pharmaceutical management to reduce new cases of dementia and its progression.1 Several prospective randomised trials have assessed the effectiveness of such interventions to prevent cognitive decline, but have produced conflicting results: the FINGER trial reported a reduction in dementia risk,21 but two other studies found no significant effects on dementia incidence or cognitive decline.22,23
Our study design is characterized by several features. First, under Japan’s universal healthcare system, all Kashiwa city residents aged 75 years or older are, without exception, covered by the LLMCS until death, moving out of the city, or admitted to a nursing facility. The LLMCS is managed by a single payer (i.e., the Kashiwa city government). Therefore, a strength of this study is the use of an exhaustive survey of insurance claims data. Second, we used NPADM as the outcome measure because the claims records did not contain any clinical information for other outcomes. A previous study that analysed a different claims dataset from Kashiwa city reported that approximately 19% of residents aged 75 years or older had a probable diagnosis of dementia, but only 5.8% were prescribed anti-dementia medications.24 It is extremely difficult to obtain accurate diagnoses of Alzheimer’s disease or Lewy body disease without access to the complete set of clinical evaluations by physicians, laboratory test results, cognitive test results, and neurological images. It is also essentially impossible to identify the point at which mild cognitive impairment progresses to clinical dementia. For this study, we employed NPADM as a proxy to identify this progression. Third, we focused on older adults (aged ≥77 years) who often have multiple existing conditions that are treated with various medications. We examined 14 categories of medications for commonly observed conditions in the target population. In order to ensure the accuracy of identifying patients with specific conditions in the target population, we only used prescription data that are directly linked with reimbursements. Diagnostic codes were not used to identify patients with specific conditions due to the possibility that providers may assign these codes for the sole purpose of reimbursement. We believe this approach effectively utilizes the accurate and reliable information available in Japanese claims records. Efforts to integrate claims records and clinical information from electronic health records are needed to support more accurate population studies that would shed light on the effectiveness and safety profile of various therapies. The Pharmaceuticals and Medical Devices Agency of Japan established the Medical Information Database Network (MID-NET) Project to integrate these datasets in selected medical institutions, and is being used for post-marketing surveillance of marketing authorization holder products.25
An important consideration of our findings is their generalizability to the overall Japanese population or other countries. Environmental factors (such as social network size) in urban areas may be different from those in more rural regions. For example, the Hisayama Study is a population-based cohort study of a rural Japanese town (mean age: 76 years ) that examines the risk factors for various diseases, including dementia.26 The reported prevalence of Alzheimer’s disease in the Hisayama Study (12.3%) is higher than that of our study, which may be explained by the differences in primary endpoint. Alzheimer’s disease was diagnosed in the Hisayama Study through a combination of clinical assessments, imaging tests, and cognitive tests such as the Mini-Mental State Examination in accordance with the Diagnostic and Statistical Manual of Mental Disorders, Third Edition. In contrast, our study relied on the initiation of anti-dementia medications to identify disease onset. With respect to the generalizability of our findings to other countries, considerations must be made toward the differences in healthcare delivery systems, social systems, education systems, and ethnic factors.27 Several higher-income countries (including the US, the UK, Sweden, the Netherlands, and Canada) have reported recent reductions in dementia incidence,2 but the prevalence of dementia is increasing in Japan.28 Although our findings are consistent with WHO recommendations, their extrapolation to other countries should be carefully considered due to these inherent differences.
The study has several limitations. First, administrative claims collected in real world clinical practice are not designed for research purpose. Therefore, medical information including accurate diagnostic criteria for dementia was not included. Although the information on the use of prescription medications during the IBP was accurate, the exposure durations before the IBP were unknown. As we could not ascertain the delivered dose of each drug, our analysis did not take the dose-response effect into account. Second, the effects of each medication could not be distinguished from the underlying pathophysiological condition for which it was prescribed. For example, NPADM in patients taking antidiabetics may be affected by the medication, diabetes, or a combination thereof. In addition, the control of blood glucose levels is likely to be an important aspect of reducing dementia risk, but this information was not available in our dataset. Third, although we assume that NPADM captured the progression from asymptomatic into symptomatic dementia, it is entirely dependent upon the decisions of individual physicians, such as neurologists, psychiatrists, and primary care physicians. Various guidelines include recommendations on the prescription and discontinuation of cholinesterase inhibitors and N-methyl-d-aspartate receptor antagonists.29,30 However, there may be variations in the decision-making process among subspecialties and physicians. Fourth,there is a discussion that anticholinergic medications are associated with risk of dementia31. It is not yet well undrstood that what level of anticholinergic property and what class of medication have increased risk of dementia. We included antidepressant and bronchodilator which have anticholinergic properties, while other class of drugs such as for parkinson disease, and for peptic ulcer were not included in the study. To estimate the level of anticholinergic in each drug and to evaluated the effect on NPADM are out of scope in the present study. . Fifth, although anti-dementia medications are only approved for Alzheimer’s disease and Lewy body disease in Japanese regulatory approval, we cannot exclude the possibility that physicians may prescribe these medications to treat vascular dementia. As the study population is very old adults (>76 year old), it is supposed that substantial proportion of study subjects have combined pathology of vascular dementia as well as Alzheimer disease and Lewy body disease. Although, post-stroke medication prescribed for history of stroke reflected the vascular component of dementia, no obvious history of stroke such as multiple lacunar infarcts may be overlooked in the study. Finally, 2.1% of study subjects (n=879) were censored because they were admitted into nursing facility during study period because they were covered by the long-term care insurance system for disabled subjects after admission. Most of them were admitted into nursing home due to the impairment of physical function. Some of them might have concomitant cognitive decline. As incidence of NPADM in older adults who reside in nursing facility is assumed to be higher in comparison with community-dwelling subjects, the effect of medications assessed in the study might have been underestimated.