Introduction
Alzheimer's disease (AD) is the most common form of dementia affecting millions worldwide. At present, there are 35 million cases worldwide, and this number is expected to swell to 100 million by 2050 (Hampel et al., Reference Hampel2011). AD has been heralded as a fast growing epidemic (de Vries et al., Reference de Vries, Denig, Pouwels, Postma and Hak2012). Therefore, prevention is an important therapeutic goal. The disease presents subtle memory deficits which progress to severe loss of memory and other cognitive abilities, making patients completely dependent upon caregivers. At present, AD is yet to find a cure and drugs used in treatments are mainly symptomatic. At present, there are no proven disease-modifying therapies available (Tayeb et al., Reference Tayeb, Yang, Price and Tarazi2012). Therefore, the prevention of dementia is a major therapeutic goal (Small and Dubois, Reference Small and Dubois2007).
Hypertension, diabetes, and dyslipidemia affect a large number of elderly people. Studies have shown that the greater is the number of cardiovascular risk factors, the higher is the risk of developing AD (Li et al., Reference Li2011). Apart from posing general health hazards in elderly people (e.g. acute myocardial infarction and cerebrovascular accident), vascular risk factors not only contribute to the cognitive decline but also promote conversion of mild cognitive impairment to AD (Musicco et al., Reference Musicco2009; Li et al., Reference Li2011). At present, anti-hypertensive, lipid-lowering, and anti-diabetic drugs offer some hope of primary prevention of dementia (Musicco et al., Reference Musicco2009; Dhikav and Anand, Reference Dhikav and Anand2011; Reference Dhikav and Anand2012). Although some studies have suggested that such evidence is scarce (Le Couteur et al., Reference Le Couteur2012), others have suggested that from a clinical perspective available data support the rationale for physicians to provide the effective management of cardiovascular risk factors and for patients to be compliant with such recommendations to possibly prevent cognitive decline/dementia (Le Couteur et al., Reference Le Couteur2012).
Adherence is the ability of patients to take medications as per schedule and dosages. Compliance to drugs used in the treatment of AD remains an issue (Small and Dubois, Reference Small and Dubois2007). Being male and taking multiple pills (higher pill burden) have been identified as predictors of poor medication adherence to anticholinesterases among AD patients (Borah et al., Reference Borah, Sacco and Zarotsky2010). Patients of AD are too old and forgetful and caregivers experience overwhelming amount of stress. In the absence of cure for AD, we wanted to know if patients are taking the drugs for co-morbid medical ailments that could have some role in slowing down the rate of further cognitive decline regularly or not.
Material and methods
Sixty-seven patients attending the outpatient department of a tertiary care hospital in a northern city of India were recruited in this study. Patients with subjective memory complaints were chosen randomly from the general outpatient department of neurology and were asked to attend the memory clinic for a detailed evaluation. A thorough general physical and neurological examination was performed including a complete work up for dementia.
An initial neuropsychological evaluation of all patients with memory complaints was done using the Mini-Mental State Examination (MMSE) and the Blessed Dementia Scale was used for activities of daily living (ADL) analysis. A clinical diagnosis of probable AD was made using the National Institute of Neurological and Communicative Disorders and Stroke and the Alzheimer's Disease and Related Disorders Association (NINCDS-ADRDA) criteria. This requires multiple cognitive deficits, and memory impairments, severe enough to interfere with ADL. Those with subjective memory-related complaints, not fitting into the diagnostic criteria of AD, were evaluated using the Clinical Dementia Rating Scale. A diagnosis of mild cognitive impairment or questionable dementia in patients with memory complaints was performed in those with MMSE score higher than 26 (Clinical Dementia Rating Score = 0.5). Patients who had dementias other than AD (e.g. vascular and fronto-temporal) were excluded from this study.
After diagnosing mild cognitive impairment/questionable dementia or AD, an attempt was made to identify those patients who had co-morbid hypertension, diabetes, or dyslipidemia. An analysis of the prescription pattern of these cases was done regarding the use of drugs that are used for the prevention of dementia or treating co-morbid medical ailments e.g. anti-hypertensive, anti-diabetics, and lipid-lowering drugs. A resident medical doctor, blinded to the aims and objectives of the study, was asked to note down which medications were being prescribed to the patients. Caregivers of patients who had a history of co-morbid diabetes, hypertension, or dyslipidemia were asked in detail about the use of drugs, their doses, frequency, compliance to these drugs, and reasons for non-adherence. Patients were then classified as regular on medications or irregular depending upon whether they were able to take drugs as prescribed or not. An attempt was made to list the causes of non-compliance as well.
Results
Out of a sample of 75 cases, 67 met the inclusion criteria of which 53 were males (79%) and 14 were females (21%). Excluded patients had vascular dementia (5), fronto-temporal dementia (2), and thyroid dementia (1). The mean age of patients was 72.2 ± 8.8 years. The mean MMSE of all patients was 18.9 ± 7.9. The mean score of the Blessed Dementia Scale (ADL) was 5 ± 4.5. The mean duration of illness was 3.1 ± 2.5 years. Fifty-two patients had a diagnosis of probable AD (77.6%), while the rest (15) had mild cognitive impairment/questionable dementia. The mean MMSE with mild cognitive impairment/questionable dementia was 28.3 ± 1.1.
We found that out of 67 patients, 41 had hypertension (61%). The mean duration of hypertension was 8.76 ± 4.35 years. Twenty out of 41 patients were not taking regular treatment for hypertension (48.7%). The remaining patients (21) were taking regular treatment (Table 1).
Medication compliance in this study
Out of 67, 20 patients (30%) were diabetic and the mean duration of diabetes was 9.79 ± 6.78 years. A total of 13 patients (19.4%) had both diabetes and hypertension. Out of them, only five were receiving regular treatment and the rest were irregular. Twenty-three out of 67 patients (34.3%) had a deranged lipid profile. Lipid profiles were not known in 14 patients (21%). That means, almost half of the study population either did not have a known lipid profile or it was deranged (Table 2). Only 15 of 23 patients (65.2%) with a deranged lipid profile were receiving lipid-lowering therapy in terms of either statins or fenofibrate in combination. Of a sample of 67, irregular patients on the treatment of both diabetes and hypertension were 25 (41%). Fifteen patients had AD, while the rest had mild cognitive impairment/questionable dementia.
Reasons for non-compliance in this study
In this study, the reasons for poor compliance with drugs were the lack of awareness, ignorance, medicines being “too expensive,” and pressure of taking medicines regularly. In none of the patients, side effects were responsible for non-adherence to medications (Table 2).
Fifteen out 25 non-compliant patients (60%) were either illiterate or not educated until high school. The remaining were graduates (7), postgraduate (1), and doctorates (2).
Discussion
Dementia of Alzheimer's type (DAT) is a slow and relentless neurodegenerative disorder of uncertain etiology (Fillit et al., Reference Fillit, Nash, Rundek and Zuckerman2008; Borah et al., Reference Borah, Sacco and Zarotsky2010). β-amyloid deposition and glucocorticoids are among the predominant theories explaining its occurrence. Age is the most common risk factor, but the contribution of vascular factors is significant in many studies, while inconsistent or inconclusive/negative in some. However, controlling blood pressure, lipid levels, and diabetes can potentially reduce the rate of further cognitive decline in a case with mild cognitive impairment/AD. The possibility of improving general health by controlling these factors among the aged is indisputable. Therefore, we wanted to know as to what extent were patients with either subjective memory complaints or those with a diagnosis of AD taking drugs that have utility in the prevention of cognitive decline in AD. People are living longer than ever and the need to prevent DAT is ever increasing (Ligthart et al., Reference Ligthart, Moll van Charante, Van Gool and Richard2010; Merrill and Small, Reference Merrill and Small2011). There is a definite need for keeping hypertension, diabetic, and blood lipids in control for maintaining a healthy lifestyle and preventing vascular complications among the aged. In addition, these have a potential or real favorable effect in slowing down cognitive decline. Hypertension affects over two-thirds of individuals after the age of 65. In this study, 61% had hypertension (41 out of 67).
A complex interaction between hypertension, cardiovascular diseases, and AD is well known. Hypoxia, neuronal injury, free radical generation, aberrant β-amyloid deposition, and abnormal neuronal functions are consequences of hypertension among the aged. Overall, there appears to be a close link between hypertension and microvascular disease in the brain, the latter particularly relevant to cognitive dysfunction in later life. One possible mechanism by which anti-hypertensive treatment may help to minimize the occurrence of cognitive dysfunction is to reduce the incidence of microvascular disease (Ligthart et al., Reference Ligthart, Moll van Charante, Van Gool and Richard2010). Compared with people with no cardiovascular risk factors, any single cardiovascular factor significantly increased risk for AD dementia by 70%, two risk factors by 150%, and three or four risk factors by an alarming 240% (Fillit et al., Reference Fillit, Nash, Rundek and Zuckerman2008). Therefore, addressing the vascular risk factors could be worthwhile. Diabetic patients are at increased risk of developing the DAT. It has been seen that some anti-diabetic agents have a protective effect on hippocampal formation or structure which is vitally important to learning and memory. Lipid-lowering agents have a major clinical benefit in the primary prevention of cardiovascular and cerebrovascular diseases (Merrill and Small, Reference Merrill and Small2011). Likewise, a large amount of evidence suggests that cholesterol dysregulation plays an important role in the pathogenesis of AD (Merrill and Small, Reference Merrill and Small2011; de Vries et al., Reference de Vries, Denig, Pouwels, Postma and Hak2012; Valenzuela et al., Reference Valenzuela, Esler, Ritchie and Brodaty2012). Microvascular damage, impaired glucose metabolism, reduced neuroprotection by insulin due to resistance and increased lipid levels are some of the many mechanisms by which diabetes increases the risk of dementia and faster progression of cognitive decline. It has been suggested that diabetes per se may not contribute to neurodegeneration but vascular complications of diabetes may do so (Sparks et al., Reference Sparks2003; Ricciarelli et al., Reference Ricciarelli2012). There is evidence that the pathophysiology of AD begins years before the clinical manifestations start. Therefore, there is a window of opportunity in preventing the disease using the pharmacological approach. This may include the optimal use of anti-hypertensives, anti-diabetics, and lipid-lowering therapies. This may not only contribute to reduction in cognitive decline but also have a chance of providing general health benefit (e.g. preventing vascular complications).
Adherence to medications is a significant issue in patients with AD (Small and Dubois, Reference Small and Dubois2007). Being on multiple drugs, aged, and on complicated medicine regimes requiring titration have been identified as factors contributing to poor adherence (Borah et al., Reference Borah, Sacco and Zarotsky2010). It has been suggested that a better understanding of the causes of non-adherence is necessary, and methods to improve adherence, such as transdermal medications and educational programs, should be considered. This study shows almost the same rate of medication non-adherence (41%) as has been reported previously (42%; Borah et al., Reference Borah, Sacco and Zarotsky2010). Being male was found to be a predictor of poor compliance in a previous study (Borah et al., Reference Borah, Sacco and Zarotsky2010); our patients too were predominately males. However, the previous study investigated the compliance of only the drugs that are specific to AD (e.g. anticholinesterases). We have studied the drugs that have proven general health benefits among elderly people and also have the potential or real utility in slowing down the rate of further cognitive decline in those with hypertension, diabetes, and dyslipidemia. Low education (60%) in this study has come out to be a predictor of poor medication adherence. Medication adherence is predictably fruitful. One study investigated the relationship between anti-hypertensive medication adherence and the rate of cognitive decline in elderly people. The study concluded that good medication adherence to anti-hypertensive drugs could reduce the risk and severity of cognitive decline in AD (Gard, Reference Gard2010).
So what could be done to improve patient compliance? Improving medication adherence could be challenging as there are many determinants of better patient compliance. Caregiver education, periodic mentoring, reducing pill burden, and using simple drug regimens could potentially contribute to better adherence to treatment. For example, a reduction of pill burden could result in better compliance in the treatment of AD (Emre et al., Reference Emre2010). To our mind, this is the first study that reports medication adherence to drugs that have potential or real utility in preventing further cognitive decline in AD/mild cognitive impairment. However, there are few limitations of this study apart from relatively small sample size. These include the lack of compliance comparison between both sexes as the sample size of females was small. More so, the study did not investigate the effect of patients’ forgetfulness in assessing compliance. This is because our patients live in joint families and caregivers mostly provide them medications. This is in contrast to developed countries where patients mostly administer medications themselves.
Conclusions
AD is the most common form of dementia treated mostly symptomatically. Unfortunately, present treatment has little or no disease-modifying activity. In the absence of drugs that can alter the natural history of a disease, prevention remains an important therapeutic aim especially for those who have mild cognitive impairment/questionable or mild-to-moderate DAT. Anti-hypertensive, lipid-lowering, and anti-diabetic drugs have been shown to slow down the rate of cognitive decline in many studies. Their non-cognitive health benefits are indisputable. This study shows a poor compliance to these three drugs. An attempt should be made to increase patient compliance in patients with AD so that the rate of cognitive decline and other emergencies that could develop as a result of the poor management of vascular risk factors in elderly people could be tackled.
Conflict of interest
None.
Description of authors’ roles
Vikas Dhikav conceptualized, formatted, conducted the study and wrote the paper. Pritika Singh edited the paper, noted compliance details, put references according to the journal style, and finalized the paper. Kuljeet Singh Anand supervised the study and helped in the diagnostic work up of patients and finalizing the draft for communication to IPG.
