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Risk factors and type of dementia: Vascular or Alzheimer?
Archives of Gerontology and Geriatrics 47 (2008) 25–34 www.elsevier.com/locate/archger
Risk factors and type of dementia: Vascular or Alzheimer? Mustafa Cankurtaran a,*, Burcu Balam Yavuz a, Eylem Sahin Cankurtaran b, Meltem Halil a, Zekeriya Ulger a, Servet Ariogul a a
Hacettepe University, Faculty of Medicine, Department of Internal Medicine, Division of Geriatric Medicine, 06100 Sihhiye, Ankara, Turkey b Ankara Oncology Hospital, Department of Psychiatry, Kurtulus 06100, Ankara, Turkey Received 27 March 2007; received in revised form 22 June 2007; accepted 25 June 2007 Available online 10 August 2007
Abstract The most efficient strategy for combating Alzheimer’s disease (AD) is to prevent the onset of clinically significant symptoms. Determining the clinical characteristics, risk factors, and indices of cognitive reserve would help in achieving this goal. The aim of this study was to determine the risk factors for AD and vascular dementia (VD) in the elderly and to highlight the importance of risk factor modification in the early diagnosis. Consecutive 1436 patients (mean age = 72.7 6.9 years, 34.2% male) were enrolled in the study. After a comprehensive geriatric and cognitive assessment, patients were grouped as AD group (n = 203), VD group (n = 73) and normal cognitive status (NCS) group (n = 1160). Thirty-three possibly related factors including demographic characteristics, coexisting diseases and laboratory parameters were examined. The results revealed that female sex, advanced age, depression, and intake of vitamin supplements were independent related factors for AD; whereas depression and low-density lipoprotein-cholesterol (LDL-C) were independent related factors for VD. For every geriatric patient admitted for any reason, cognitive assessment should be performed, risk factors should be determined and the patients at high risk should be followed up carefully. # 2007 Elsevier Ireland Ltd. All rights reserved. Keywords: AD; Senile dementia; Risk factors; VD; Vascular factors
* Corresponding author. Tel.: +90 312 3053 071; fax: +90 312 3051 538. E-mail address: [email protected] (M. Cankurtaran). 0167-4943/$ – see front matter # 2007 Elsevier Ireland Ltd. All rights reserved. doi:10.1016/j.archger.2007.06.005
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1. Introduction In view of the present demographic evolution, AD is becoming increasingly common in older people (Fratiglioni et al., 2000). If left untreated, patients rapidly progress to the stage with marked severity, increased costs of caring, and result in severe morbidity together with caregiver burden. Besides, it is clear that treatments for AD have substantial limitations, including the inability to delay progression of the disease. Therefore, the most efficient strategy for combating AD is to prevent, or at least delay, the onset of clinically significant symptoms (Scalco and Van Reekum, 2006). Achieving this goal is feasible by determining the risk factors for the disease. A better knowledge of the natural history of the disease, such as the risk factors is useful for planning the medical strategies for the care and the follow-up of patients (Soto et al., 2006). Risk factors for AD which were examined in previous studies include advanced age, genetics, family history of dementia, female sex, low level of education, head trauma, smoking, apolipoprotein e-4 allele (Apo-E4), alcohol intake, diet rich in fat, systolic hypertension, cerebrovascular events, depression, dyslipidemia, vascular risk factors, homocysteine, neurotoxic agents, oxidative stress, inflammation, and infections. Among these risk factors, only age, female sex, family history, and genetics are definite risk factors (Souder and Beck, 2004; Kim et al., 2005; Mielke and Zandi, 2006; Scalco and Van Reekum, 2006; Yip et al., 2006). The combination of clinical characterization, risk factor determination, and indices of cognitive reserve would provide a more complete picture of the status of a patient, and may help the early diagnosis (Stern, 2006). The aim of this study is to determine the risk factors for AD and VD. Recently, by getting evidence about the role of vascular risk factors in AD, the question ‘‘Are AD and VD different manifestations of the same disease?’’ is raised (Launer, 2002; Pansari et al., 2002). Therefore, the other aim is to point out the shared risk factors of AD and VD. Determining individual risk of developing AD enables frequent follow-ups and early diagnosis; as well as planning specific strategies to delay the onset of clinically evident cognitive dysfunction (Soto et al., 2006). We aimed at giving evidence of risk factors determined in a geriatric medicine outpatient setting, in order to highlight the role of geriatric medicine in the early diagnosis of dementia and risk factor modification.
2. Subjects and methods 2.1. Subjects and cognitive status assessment This study was conducted over 2 years by evaluating 1436 patients admitted to our geriatric medicine outpatient clinic. Patients underwent comprehensive geriatric assessments including the Geriatric Depression Scale (GDS1) (Yesavage et al., 1982–1983), the MiniNutritional Assessment (MNA) scale (Cohendy et al., 2001), the Activities of Daily Living (ADL) scale (Mahoney and Barthel, 1965), and the Instrumental ADL scale (Lawton and Broody, 1969). Depression diagnosis was made after performing the GDS1 and clinical evaluation. For cognitive assessment, the Mini Mental State Examination (MMSE) (Folstein et al., 1975), and the clock drawing test (CDT) were performed (Stahelin et al., 1997).
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Patients had to meet the DSM-IV criteria and the NINCDS-ADRDA criteria (McKhann et al., 1984) for the diagnosis of AD. The patients had to get the score of 7 and over from Hachinski Ischemic Score (HIS) (Hachinski et al., 1975) and had to meet the DSM-IV (APA, 1994) VD criteria, as well as the NINCDS-ADRDA criteria for VD diagnosis. The patients with dementia underwent cranial magnetic resonance (MR) neuroimaging and/or computerized tomography (CT). No infarct was detected in the AD patients. The Global Detoriation Scale (GDS2) was used to determine the stage of dementia (Reisberg et al., 1982). After this assessment, the subjects were grouped as AD group (n = 203), VD group (n = 73) and NCS group (n = 1160). Patients with mild cognitive impairment, other types of dementia, and mixed dementia were not included in the study. 2.2. Laboratory examinations A blood sample of 30 ml was obtained from each patient after a 12 h fasting. Total blood count, fasting plasma glucose, hepatic and renal function tests, albumin, serum electrolytes, vitamin B12 and folic acid levels, homocysteine, free T3, free T4, thyroid stimulating hormone (TSH), total cholesterol (TC), triglycerides (TG), LDL-C, highdensity lipoprotein cholesterol (HDL-C), lipoprotein-a (Lp-a), apolipoprotein-A (APO-A), apolipoprotein-B (APO-B), C-reactive protein (CRP), serum iron, serum iron binding capacity, ferritin levels, erythrocyte sedimentation rate (ESR) were determined. The normal ranges for various tests were considered as follows: 15 mmol/l and lower for homocysteine, 160 pg/ml and over for vitamin B12, 3 ng/ml and over for folic acid, 15 ng/ ml and over for ferritin, 0.0–0.8 mg/dl for CRP, 0.35–4.94 mIU/ml for TSH, 2.62– 5.69 pmol/l for free T3, 9–19.04 pg/ml for free T4, 12 g/dl hemoglobin for female and 13 g/dl in male, 200 mg/dl and lower for TC, 200 mg/dl and lower for TG, 130 mg/dl and lower for LDL-C, 40 mg/dl and over for HDL-C, 20 mm/h and lower for ESR, 30 mg/dl and lower for Lp-a, 115–210 mg/dl for APO-A and 55–135 mg/dl for APO-B. 2.3. Statistical analysis The statistical package for social sciences (SPSS) for Windows Version 10.0 was used for the statistical analysis. Data are presented as mean S.D. for normally distributed variables and as median (minimum–maximum) for skew distributed continuous variables. Categorical variables are shown as frequencies. Relationship between categorical variables was tested by x2-test, Fisher’s exact test; continuous variables were tested by the t-test. Multiple logistic regression analysis was performed to assess the independent correlated factors for AD and VD.
3. Results 3.1. General characteristics and demographic results A total number of 1436 patients, mean age = 72.7 6.9 years (range: 65–108), 34.2% male, were examined. General characteristics and demographic results according to groups
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Table 1 General characteristics and demographic properties of the study population, n (%) AD
VD
NCS
203 140 (69) 73.3 7.9
73 44 (60.3) 73.1 6.3
1160 703 (60.6) 71.3 6.5
72 (35.5)
21 (28.8)
244 21.0)
Living conditions Alone With family Nursing home
105 (51.7) 94 (46.3) 4 (2.0)
35 (47.9) 35 (47.9) 3 (4.3)
628 (54.1) 478 (41.3) 54 (4.7)
Family history of dementia Smoker (>10 packs/year)** Alcohol consumption Depression** Cerebrovascular disease Hypertension Diabetes mellitus Cardiovascular disease
34 21 5 61 15 143 48 75
7 12 8 35 7 54 15 20
78 95 16 229 89 874 285 244
Number Female* Age** (mean S.D.) Education** Illiterate
* **
(16.7) (10.3) (2.5) (30.0) (7.4) (70.4) (23.6) (36.9)
(9.6) (16.4) (11.6) (47.9) (9.6) (74.0) (20.5) (27.4)
(6.7) (8.2) (1.4) (19.7) (7.7) (75.3) (24.6) (21.0)
p = 0.024, AD vs. NCS. p 0.001, AD vs. NCS.
which are AD group (203 patients, 14.1%), VD group (73 patients, 5.1%) and NCS group (1160 patients, 80.8%) are given in Table 1. The mean age of AD patients was 73.3 7.9 years, and 69% were female. The GDS2 revealed that 60% were mild (stage 3 of GDS2), 30% were moderate (stage 4 of GDS2) and 10% were severe stage (stage 6 of GDS2) of dementia. The primary reason for admission was memory complaints in only 57 (28.1%) of AD patients. Eleven patients (5.4%) had fecal and 94 (46.3%) had urinary incontinence. Thirtyseven (18.2%) AD patients suffered from insomnia, 17 (8.0%) had agitation, 9 (4.4%) had hallucination, 13 (6.4%) had anxiety, 66 (32.5%) described frequent crying, and 67 (33.0%) had reluctance. Poly-pharmacy (using four and more drugs) was present in 107 (52.7%) of AD patients. The score of IADL scale was significantly lower in AD than in the NCS group (13.5 3.5 versus 14.3 2.9, p = 0.001). 3.2. Associated factors of AD Thirty-three possibly related factors including age, sex, family history of AD (up to second degree relatives), level of education, body mass index (BMI), hypertension (HT), diabetes mellitus (DM), thyroid diseases, coronary heart disease (CHD), smoking, alcohol consumption, intake of nonsteroidal anti-inflammatory drugs (NSAID) or vitamins, anemia, high levels of CRP or ESR, TC, LDL-C, HDL-C, TG, Lp-a, APO-A, APO-B, vitamin B12 or folate deficiency, elevated levels of ferritin, serum iron, homocysteine, history of cerebrovascular events, congestive heart failure, depression, score of MNA and zinc levels were examined in these patients.
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The above-mentioned possibly associated factors and demographic properties between the AD group (n = 203) and NCS group (n = 1160) were compared. Female sex and advanced age were significantly associated with AD. AD frequency was significantly higher in female patients (16.6 and 12.1%, respectively, p = 0.024). Mean age was significantly higher in AD group (73.3 7.9 versus 71.3 6.5 years, p < 0.001). Family history of AD was positive in 16.7% of AD patients and in 6.7% of the NCS group, but this difference was not significant. AD was diagnosed in 72 (22.8%) of illiterate patients, and in 16 (13.0%) of university graduated patients. Significant correlation of AD with smoking and alcohol consumption could not be detected. In the patients with AD, 10.3% were smokers (>10 packs/year), and in 15.3% of the normal group were smokers (NS). Evaluation of alcohol consumption demonstrated that 2.5% of the AD and 2.1% of the normal group were heavy drinkers (NS). The relationship between dementia and intake of NSAIDs was evaluated. AD was diagnosed in 13.1% of the patients using one NSAID regularly, in 6.7% of the patients using two NSAIDs regularly, and in 16% of the patients never using NSAIDs. Although frequency of AD in patients using two NSAIDs regularly seemed to be lower, this was not statistically significant. When only the two groups, two NSAIDs using group and none NSAID using group, were compared, AD was significantly less frequent in two NSAIDs using group ( p = 0.03). Vascular diseases and risk factors including history of evident stroke, hypertension, diabetes mellitus, documented coronary artery disease, and BMI were examined and no significant difference was detected between the AD and NCS groups (Table 1). Among the co-existing diseases, congestive heart failure, depression and anemia were significantly more frequent in AD group; malnutrition, hyperthyroidism and hypothyroidism were not different between the groups. Congestive heart failure was present in 14.3% of AD and in 7.3% of NCS patients ( p = 0.001). Depression was diagnosed in 30.0% of AD patients and in 19.7% of the NCS group ( p = 0.001). Anemia (Hb < 13 g/dl for men and <12 g/dl for women) was significantly more frequent in AD (15.3% in AD, 8.5% in NCS, p = 0.003). Association between AD and malnutrition was assessed by the MNA score which was not significantly different between the AD and NCS groups. Examination of laboratory results revealed that serum iron, ferritin, zinc levels and nonspecific markers of inflammation including CRP and ESR were not significantly different between the AD and NCS groups. High levels of CRP were detected in 32.5% of AD and 28.4% of NCS group (NS). High levels of ESR were shown in 45.8% of AD and 39.8% of NCS patients (NS). Comparison of lipid and lipoprotein levels between groups revealed no significant differences. High levels of TC were detected in 38.4% of AD and 38.4% of NCS group (NS). TG levels were high in 17.7% of AD and 16.2% of NCS patients (NS). LDL-C was high in 31.5% of AD and 45.9% of NCS group (NS). HDL-C was low in 13.3% of AD and this was not significantly different from the NCS group. 18.7% of AD group and 14.1% of NCS group had high levels of Lp-a (NS). Also, high APO-A levels were not associated with AD (45.3% in AD and 47.7% in NCS, NS). Finally, APO-B was normal in the AD group, and in every patient except one in the NCS group (NS). When the relationship between vitamin B12 level and cognitive functions were examined, it was found that 6.9% of AD patients and 13.9% of NCS patients had vitamin
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Table 2 Associated factors of AD Parameter
Univariate analysis
Female sex Age Education level Depression Two NSAIDs intake Multivitamin intake Heart failure Anemia
Logistic regression analysis
p
OR
95% CI
p
0.024 <0.001 0.001 0.001 0.030 0.006 0.001 0.003
1.5 1.2
0.98–1.96 1.07–2.11
0.031 0.019
1.4
1.13–2.27
0.008
1.2
0.98–3.16
0.024
Notes: Univariate analysis was performed by comparing AD and NCS groups. Logistic regression was performed for AD and NCS by including the variables age, gender, education level, body mass index, hypertension, smoking, family history of dementia, intake of vitamins and NSAIDs, ESR, Lp-a, congestive heart failure, MNA score, and depression. Statistical results of only independently associated factors determined by logistic regression analysis are shown in this table.
B12 levels lower than 160 pg/dl (NS). Only 2 AD patients (1.0%) and 10 NCS patients (0.9%) had folic acid deficiency (NS). High homocysteine levels were observed in 84 AD patients (41.4%) and in 481 of NCS group (41.5%) (NS). The statistical data of associated factors for AD versus NCS are detailed in Table 2. 3.3. Associated factors of VD Seventy-three (3.8%) patients (mean age = 73.1 6.3 years, 60.3% female) were diagnosed as having VD. Statistical results of the comparison between VD and NCS groups are presented in Table 3. Gender, age, education level, anemia, stroke, congestive heart failure, intake of vitamin supplements and NSAID were not significantly associated with VD. LDL-C, coronary heart disease, smoking, alcohol consumption, and depression were found significantly associated with VD. Some vascular risk factors such as hypertension, diabetes mellitus and history of evident stroke were not found related to VD. Table 3 Associated factors of VD Parameter
Univariate analysis
Logistic regression analysis
p
OR
95% CI
p
Depression LDL-C Smoking Alcohol CHD
0.0001 0.017 0.002 0.007 0.017
1.2 1.4
1.13–2.27 1.08–3.02
<0.001 0.024
Notes: Univariate analysis was performed by comparing VD and NCS groups. Logistic regression analysis was performed for VD and NCS groups, including the variables age, gender, education level, smoking, alcohol consumption, hypertension, LDL-C, HDL-C, Lp-a, vitamin B12, CHD, and depression. Statistical results of only independently associated factors determined by logistic regression analysis are shown in this table.
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LDL-C levels were high in 45.9% of VD and in 31.9% of NCS ( p = 0.017). Coronary heart disease was present in 27.4% of VD and in 21.0% of NCS ( p = 0.017). 16.4% of VD patients and 8.2% of NCS patients were smokers (>10 packs/year) ( p = 0.002). Alcohol consumption was present in 11.6% of VD and in 1.4% of NCS group ( p = 0.007). Finally, depression was diagnosed in 47.9% of VD and in 19.7% of NCS patients ( p < 0.001). 3.4. Results of logistic regression analysis To determine the independent associated factors of AD, logistic regression analysis was performed with the variables age, gender, education level, BMI, hypertension, smoking, family history of dementia, intake of vitamins and NSAIDs, ESR, Lp-a, CHD, MNA score, and depression. It was found that independently associated factors of AD were female sex (OR = 1.5, 95% CI = 0.09–0.98, p = 0.031), age (OR = 1.2, 95% CI = 1.07–2.11, p = 0.019), vitamin intake (OR = 1.2, 95% CI = 0.23–0.90, p = 0.024), and depression (OR = 1.4, 95% CI = 1.13–2.27, p = 0.008) (Table 2). Logistic regression analysis to determine the independent associated factors of VD was performed with the variables age, gender, education level, smoking, alcohol consumption, hypertension, LDL-C, HDL-C, Lp-a, vitamin B12, coronary heart disease, and depression. It was determined that LDL-C (OR = 1.4, 95% CI = 1.08–3.02, p = 0.024) and depression (OR = 1.2, 95% CI = 2.16–5.84, p < 0.001) were independent associated factors of VD (Table 3).
4. Discussion The progression of dementia is accompanied by increased morbidity, mortality, and care problems. Therefore, clinicians should be aware of the risk factors of dementia for early diagnosis. The interference of genetic and environmental factors may lead to variability in risk factors in different countries. Every country should determine the risk factors in their own elderly people. Evidence about risk factors in AD is inconsistent in the literature (Kim et al., 2005; Mielke and Zandi, 2006; Yip et al., 2006). Therefore, we examined wellknown and novel risk factors in our geriatric medicine outpatient setting. This study found that independent correlates are female sex, advanced age, depression and intake of vitamin supplements for AD; and depression and LDL-C for VD. Some limitations of the study should be considered. One limitation is the lack of information about apolipoprotein-E4, which is a well-known risk factor for AD. Moreover, another risk factor, namely the temporal lobe and hippocampal atrophy, could not be measured volumetrically, because of the large number of patients. Another limitation is that, as this is a cross-sectional study, we cannot determine causality, and the exact roles of the independently associated factors. Longitudinal follow-up of normal subjects having these risk factors would give more information. Novel risk factors examined in this study were malnutrition, BMI, thyroid diseases, heart failure, and anemia. Evidence about the role of these risk factors is inadequate. This justifies our research on the possible risk factors, and adds new information to the literature. We found that MNA score and BMI were not correlated with AD and VD which suggests
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that nutritional status is not a determinant factor for dementia. However, we cannot make an assumption about its role in the progression of the disease and morbidity since this is not a longitudinal study. Hypothyroidism was not found to be a risk factor in this study. Hypothyroidism is not accepted as a risk factor, but is a reversible cause of cognitive decline, which should be screened before diagnosis of dementia. Although univariate analysis showed a relationship between AD and anemia, multivariate analysis revealed no independent correlation. Studies concerning anemia in AD are inadequate. It can be put forward that decreased oxygenation of the brain in anemia may lead to cognitive decline, but there is not enough evidence to support this hypothesis. Although heart failure was more frequent in AD, multivariate analysis showed no correlation. However, heart failure may trigger AD by leading to hypoxemia. Further studies with longitudinal follow-up should be carried out to demonstrate these relationships. In this study, patients with AD or VD were evaluated in the same setting and were compared to NCS groups, because of the increasing evidence about the hypothesis that AD and VD are the different clinical presentations of the same disease originating from the shared risk factors (Launer, 2002). Some risk factors for VD have been proposed previously and some of these risk factors are identical to the AD risk factors (Pansari et al., 2002). Our results revealed that a shared independent correlate of VD and AD was depression. Depression accompanies AD in 10–25%, especially in the early stages (Kumor and Cummings, 2001; Souder and Beck, 2004; Cankurtaran et al., 2005). Although the Mirage study put forward depression as a risk factor for AD, some studies could not obtain the same result (Wetherell et al., 1999; Green et al., 2003). Recently, depression has been thought to originate from vascular pathologies and the term vascular depression is being raised. The vascular depression hypothesis postulates that cerebrovascular disease predisposes or precipitates depression in some elder subjects (Alexopoulos et al., 1997). In the light of these studies, our result describing the depression as a correlate for both AD and VD, gains a certain importance. Vascular risk factors are recently being implied in the pathogenesis of AD. Since postmortem studies showed vascular changes in AD patients’ brains, neuroimaging studies detected vascular pathologies such as white matter lesions and lacunar infarcts in AD patients, the role of vascular risk factors has gained importance in AD (Launer, 2002; Pansari et al., 2002). It has been postulated that hypertension, diabetes mellitus, dyslipidemia (Reitz et al., 2004), and homocysteine (Seshadri et al., 2002) are risk factors for AD as well as VD (Morris et al., 2000). However, in our study we could not find a relationship between AD and any of the vascular risk factors. On the other hand, among the vascular risk factors, only LDL-C was found to be an independent correlate of VD. We feel that this result is due to the cross-sectional approach of the study. Advanced age is one of the major risk factors of AD (Yip et al., 2006). It is known that the incidence of AD increases directly in proportion to age (Fratiglioni et al., 2000). The results of the present study are in agreement with the literature. Since age is a nonmodifiable risk factor, determining other risk factors in the geriatric population, and assessment of cognitive function in the elderly at each visit for any reason is of great importance for diagnosing AD at early stages. Female sex, which is another nonmodifiable major risk factor (Yip et al., 2006) was also found as an independent correlate of AD in this study. It has been put forward that this may be due to the earlier mortality of men
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or lower education level of women (Scinto, 2000). However, the results of our regression analysis showed that female sex was related with AD independently from age and education level. There is evidence about the positive effects of vitamin E on cognitive function (Klatte et al., 2003). Vitamin B12 deficiency is not only a cause of reversible cognitive dysfunction but also a risk for AD (Eastley et al., 2000). Therefore, our results suggesting that vitamin supplement intake increases AD risk 1.2-fold was unexpected. However, there are some studies suggesting that vitamin E does not play a major role in cognitive function (Israel et al., 1994), and vitamins A, C, and E supplementation do not reduce the risk of AD (Luchsinger et al., 2003). It can be concluded that our findings may support these negative results about the role of vitamins in cognitive function. However, it is not clear that the vitamin E intake started before the beginning of the dementia process id not effective. Therefore, a safe conclusion cannot be reached on this issue. Moreover, doses of vitamin E were not standard, since they were 20–200 IU and it is not certain that they were consumed regularly. Longitudinal studies may ascertain the real relationship. For the assessment of cognitive function of elderly people, memory complaints alone are not usually sufficient, because as it is demonstrated by our study only a little percent of AD patients applying to the clinic with these complaints. Therefore, for every geriatric patient admitted for any reason, the cognitive assessment should be performed, risk factors should be determined and patients at high risk should be evaluated further and closer. The role of geriatric medicine is of great importance to achieve this goal. Following on from the results of this study, future research is needed to evaluate the independent effects of these associated factors in prospectively designed, cohort studies.
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Israel, L., Melac, M., Milinkevitch, D., Dubos, G., 1994. Drug therapy and memory training programs: a doubleblind randomized trial of general practice patients with age-associated memory impairment. Int. Psychogeriatr. 6, 155–170. Kim, K.Y., Wood, B.E., Wilson, M.I., 2005. Risk factors for Alzheimer’s disease: an overview for clinical practitioners. Consult. Pharm. 20, 224–230. Klatte, E.T., Scharre, D.W., Nagaraja, H.N., Davis, R.A., Beversdorf, D.Q., 2003. Combination therapy of donepezil and vitamin E in Alzheimer disease. Alzheimer Dis. Assoc. Disord. 17, 113–116. Kumor, A., Cummings, J.L., 2001. Depression in neurodegenerative disorders and related conditions. In: Gauthier, S., Cummings, J.L. (Eds.), Alzheimer’s Disease and Related Disorders, Annual 2001. Martin Denitz, London, pp. 123–141. Launer, L., 2002. Demonstrating the case that Alzheimer disease is a vascular disease; epidemiologic evidence. Aging Res. Rev. 1, 61–67. Lawton, M.P., Broody, E.M., 1969. Assessment of older people: self-maintaining and instrumental activities of daily living. Gerontologist 9, 179–186. Luchsinger, J.A., Tang, M.X., Shea, S., Mayeux, R., 2003. Antioxidant vitamin intake and risk of Alzheimer disease. Arch. Neurol. 60, 203–208. Mahoney, F.I., Barthel, D.W., 1965. Functional evaluation: the Barthel index. Md. State Med. J. 14, 61–65. McKhann, G., Drachman, D., Folstein, M., Katzman, R., Price, D., Stadlan, E.M., 1984. Clinical diagnosis of Alzheimer’s disease: report of the NINCDS-ADRDA Work Group under the auspices of Department of Health and Human Services Task Force on Alzheimer’s Disease. Neurology 34, 939–944. Mielke, M.M., Zandi, P.P., 2006. Hematologic risk factors of vascular disease and their relation to dementia. Dement. Geriatr. Cogn. Disord. 21, 335–352. Morris, M.C., Scherr, P.A., Hebert, L.E., Bennett, D.A., Wilson, R.S., Glynn, R.J., Evans, D.A., 2000. The cross sectional association between blood presssure and Alzheimer’s disease in a biracial community population of older people. J. Gerontol. A: Biol. Sci. Med. Sci. 55, M130–M136. Pansari, K., Gupta, A., Thomas, P., 2002. Alzheimer’s disease and vascular factors. Facts and theories. Int. J. Clin. Pract. 56, 197–203. Reisberg, B., Ferris, S.H., De Leon, M.J., Crook, T., 1982. The Global Deterioration Scale for assessment of primary degenerative dementia. Am. J. Psychiatry 139, 1136–1139. Reitz, C., Tang, M.X., Luchsinger, J., Mayeux, R., 2004. Relation between plasma lipids to Alzheimer’s disease and vascular dementia. Arch. Neurol. 61, 705–714. Scalco, M.Z., Van Reekum, R., 2006. Prevention of Alzheimer disease. Can. Fam. Physician 52, 200–207. Scinto, F.M., 2000. Early Diagnosis of Alzheimer’s Disease. Humana Press, New Jersey. Seshadri, S., Beiser, A., Selhub, J., Jacques, P.F., Rosenberg, I.H., D’Agostino, R.B., Wilson, P.W., Wolf, P.A., 2002. Plasma homocysteine as a risk factor for dementia and Alzheimer’s disease. N. Engl. J. Med. 346, 476– 483. Soto, M.E., Andrieu, S., Gillette-Guyonnet, S., Cantet, C., Nourhashemi, F., Vellas, B., 2006. Risk factors for functional decline and institutionalisation among community-dwelling older adults with mild to severe Alzheimer’s disease: one year of follow-up. Age Ageing 35, 308–310. Souder, E., Beck, C., 2004. Overview of Alzheimer’s disease. Nurs. Clin. North Am. 39, 545–559. Stahelin, H.B., Monsch, A.U., Spiegel, R., 1997. Early diagnosis of dementia via a two-step screening and diagnostic procedure. Int. Psychogeriatr. 9, 123–130. Stern, Y., 2006. Cognitive reserve and Alzheimer disease. Alzheimer Dis. Assoc. Disord. 20, 112–117. Wetherell, J.E., Gatz, M., Johansson, B., Pedersen, N.L., 1999. History of depression and other psychiatric illness as risk factors for Alzheimer’s disease in a twin sample. Alzheimer Dis. Assoc. Disord. 13, 47–52. Yesavage, J.A., Brink, T.L., Rose, T.L., Lum, O., Huang, V., Adey, M., Leirer, V.O., 1982–1983. Development and validation of a geriatric depression screening scale. A preliminary report. J. Psychiatr. Res. 17, 37–49. Yip, A.G., Brayne, C., Matthews, F.E., MRC Cognitive Function and Ageing Study, 2006. Risk factors for incident dementia in England and Wales: the Medical Research Council Cognitive Function and Ageing Study. A population-based nested case-control study. Age Ageing 35, 154–160.
Risk factors and type of dementia: Vascular or Alzheimer? Mustafa Cankurtaran a,*, Burcu Balam Yavuz a, Eylem Sahin Cankurtaran b, Meltem Halil a, Zekeriya Ulger a, Servet Ariogul a a
Hacettepe University, Faculty of Medicine, Department of Internal Medicine, Division of Geriatric Medicine, 06100 Sihhiye, Ankara, Turkey b Ankara Oncology Hospital, Department of Psychiatry, Kurtulus 06100, Ankara, Turkey Received 27 March 2007; received in revised form 22 June 2007; accepted 25 June 2007 Available online 10 August 2007
Abstract The most efficient strategy for combating Alzheimer’s disease (AD) is to prevent the onset of clinically significant symptoms. Determining the clinical characteristics, risk factors, and indices of cognitive reserve would help in achieving this goal. The aim of this study was to determine the risk factors for AD and vascular dementia (VD) in the elderly and to highlight the importance of risk factor modification in the early diagnosis. Consecutive 1436 patients (mean age = 72.7 6.9 years, 34.2% male) were enrolled in the study. After a comprehensive geriatric and cognitive assessment, patients were grouped as AD group (n = 203), VD group (n = 73) and normal cognitive status (NCS) group (n = 1160). Thirty-three possibly related factors including demographic characteristics, coexisting diseases and laboratory parameters were examined. The results revealed that female sex, advanced age, depression, and intake of vitamin supplements were independent related factors for AD; whereas depression and low-density lipoprotein-cholesterol (LDL-C) were independent related factors for VD. For every geriatric patient admitted for any reason, cognitive assessment should be performed, risk factors should be determined and the patients at high risk should be followed up carefully. # 2007 Elsevier Ireland Ltd. All rights reserved. Keywords: AD; Senile dementia; Risk factors; VD; Vascular factors
* Corresponding author. Tel.: +90 312 3053 071; fax: +90 312 3051 538. E-mail address: [email protected] (M. Cankurtaran). 0167-4943/$ – see front matter # 2007 Elsevier Ireland Ltd. All rights reserved. doi:10.1016/j.archger.2007.06.005
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1. Introduction In view of the present demographic evolution, AD is becoming increasingly common in older people (Fratiglioni et al., 2000). If left untreated, patients rapidly progress to the stage with marked severity, increased costs of caring, and result in severe morbidity together with caregiver burden. Besides, it is clear that treatments for AD have substantial limitations, including the inability to delay progression of the disease. Therefore, the most efficient strategy for combating AD is to prevent, or at least delay, the onset of clinically significant symptoms (Scalco and Van Reekum, 2006). Achieving this goal is feasible by determining the risk factors for the disease. A better knowledge of the natural history of the disease, such as the risk factors is useful for planning the medical strategies for the care and the follow-up of patients (Soto et al., 2006). Risk factors for AD which were examined in previous studies include advanced age, genetics, family history of dementia, female sex, low level of education, head trauma, smoking, apolipoprotein e-4 allele (Apo-E4), alcohol intake, diet rich in fat, systolic hypertension, cerebrovascular events, depression, dyslipidemia, vascular risk factors, homocysteine, neurotoxic agents, oxidative stress, inflammation, and infections. Among these risk factors, only age, female sex, family history, and genetics are definite risk factors (Souder and Beck, 2004; Kim et al., 2005; Mielke and Zandi, 2006; Scalco and Van Reekum, 2006; Yip et al., 2006). The combination of clinical characterization, risk factor determination, and indices of cognitive reserve would provide a more complete picture of the status of a patient, and may help the early diagnosis (Stern, 2006). The aim of this study is to determine the risk factors for AD and VD. Recently, by getting evidence about the role of vascular risk factors in AD, the question ‘‘Are AD and VD different manifestations of the same disease?’’ is raised (Launer, 2002; Pansari et al., 2002). Therefore, the other aim is to point out the shared risk factors of AD and VD. Determining individual risk of developing AD enables frequent follow-ups and early diagnosis; as well as planning specific strategies to delay the onset of clinically evident cognitive dysfunction (Soto et al., 2006). We aimed at giving evidence of risk factors determined in a geriatric medicine outpatient setting, in order to highlight the role of geriatric medicine in the early diagnosis of dementia and risk factor modification.
2. Subjects and methods 2.1. Subjects and cognitive status assessment This study was conducted over 2 years by evaluating 1436 patients admitted to our geriatric medicine outpatient clinic. Patients underwent comprehensive geriatric assessments including the Geriatric Depression Scale (GDS1) (Yesavage et al., 1982–1983), the MiniNutritional Assessment (MNA) scale (Cohendy et al., 2001), the Activities of Daily Living (ADL) scale (Mahoney and Barthel, 1965), and the Instrumental ADL scale (Lawton and Broody, 1969). Depression diagnosis was made after performing the GDS1 and clinical evaluation. For cognitive assessment, the Mini Mental State Examination (MMSE) (Folstein et al., 1975), and the clock drawing test (CDT) were performed (Stahelin et al., 1997).
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Patients had to meet the DSM-IV criteria and the NINCDS-ADRDA criteria (McKhann et al., 1984) for the diagnosis of AD. The patients had to get the score of 7 and over from Hachinski Ischemic Score (HIS) (Hachinski et al., 1975) and had to meet the DSM-IV (APA, 1994) VD criteria, as well as the NINCDS-ADRDA criteria for VD diagnosis. The patients with dementia underwent cranial magnetic resonance (MR) neuroimaging and/or computerized tomography (CT). No infarct was detected in the AD patients. The Global Detoriation Scale (GDS2) was used to determine the stage of dementia (Reisberg et al., 1982). After this assessment, the subjects were grouped as AD group (n = 203), VD group (n = 73) and NCS group (n = 1160). Patients with mild cognitive impairment, other types of dementia, and mixed dementia were not included in the study. 2.2. Laboratory examinations A blood sample of 30 ml was obtained from each patient after a 12 h fasting. Total blood count, fasting plasma glucose, hepatic and renal function tests, albumin, serum electrolytes, vitamin B12 and folic acid levels, homocysteine, free T3, free T4, thyroid stimulating hormone (TSH), total cholesterol (TC), triglycerides (TG), LDL-C, highdensity lipoprotein cholesterol (HDL-C), lipoprotein-a (Lp-a), apolipoprotein-A (APO-A), apolipoprotein-B (APO-B), C-reactive protein (CRP), serum iron, serum iron binding capacity, ferritin levels, erythrocyte sedimentation rate (ESR) were determined. The normal ranges for various tests were considered as follows: 15 mmol/l and lower for homocysteine, 160 pg/ml and over for vitamin B12, 3 ng/ml and over for folic acid, 15 ng/ ml and over for ferritin, 0.0–0.8 mg/dl for CRP, 0.35–4.94 mIU/ml for TSH, 2.62– 5.69 pmol/l for free T3, 9–19.04 pg/ml for free T4, 12 g/dl hemoglobin for female and 13 g/dl in male, 200 mg/dl and lower for TC, 200 mg/dl and lower for TG, 130 mg/dl and lower for LDL-C, 40 mg/dl and over for HDL-C, 20 mm/h and lower for ESR, 30 mg/dl and lower for Lp-a, 115–210 mg/dl for APO-A and 55–135 mg/dl for APO-B. 2.3. Statistical analysis The statistical package for social sciences (SPSS) for Windows Version 10.0 was used for the statistical analysis. Data are presented as mean S.D. for normally distributed variables and as median (minimum–maximum) for skew distributed continuous variables. Categorical variables are shown as frequencies. Relationship between categorical variables was tested by x2-test, Fisher’s exact test; continuous variables were tested by the t-test. Multiple logistic regression analysis was performed to assess the independent correlated factors for AD and VD.
3. Results 3.1. General characteristics and demographic results A total number of 1436 patients, mean age = 72.7 6.9 years (range: 65–108), 34.2% male, were examined. General characteristics and demographic results according to groups
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Table 1 General characteristics and demographic properties of the study population, n (%) AD
VD
NCS
203 140 (69) 73.3 7.9
73 44 (60.3) 73.1 6.3
1160 703 (60.6) 71.3 6.5
72 (35.5)
21 (28.8)
244 21.0)
Living conditions Alone With family Nursing home
105 (51.7) 94 (46.3) 4 (2.0)
35 (47.9) 35 (47.9) 3 (4.3)
628 (54.1) 478 (41.3) 54 (4.7)
Family history of dementia Smoker (>10 packs/year)** Alcohol consumption Depression** Cerebrovascular disease Hypertension Diabetes mellitus Cardiovascular disease
34 21 5 61 15 143 48 75
7 12 8 35 7 54 15 20
78 95 16 229 89 874 285 244
Number Female* Age** (mean S.D.) Education** Illiterate
* **
(16.7) (10.3) (2.5) (30.0) (7.4) (70.4) (23.6) (36.9)
(9.6) (16.4) (11.6) (47.9) (9.6) (74.0) (20.5) (27.4)
(6.7) (8.2) (1.4) (19.7) (7.7) (75.3) (24.6) (21.0)
p = 0.024, AD vs. NCS. p 0.001, AD vs. NCS.
which are AD group (203 patients, 14.1%), VD group (73 patients, 5.1%) and NCS group (1160 patients, 80.8%) are given in Table 1. The mean age of AD patients was 73.3 7.9 years, and 69% were female. The GDS2 revealed that 60% were mild (stage 3 of GDS2), 30% were moderate (stage 4 of GDS2) and 10% were severe stage (stage 6 of GDS2) of dementia. The primary reason for admission was memory complaints in only 57 (28.1%) of AD patients. Eleven patients (5.4%) had fecal and 94 (46.3%) had urinary incontinence. Thirtyseven (18.2%) AD patients suffered from insomnia, 17 (8.0%) had agitation, 9 (4.4%) had hallucination, 13 (6.4%) had anxiety, 66 (32.5%) described frequent crying, and 67 (33.0%) had reluctance. Poly-pharmacy (using four and more drugs) was present in 107 (52.7%) of AD patients. The score of IADL scale was significantly lower in AD than in the NCS group (13.5 3.5 versus 14.3 2.9, p = 0.001). 3.2. Associated factors of AD Thirty-three possibly related factors including age, sex, family history of AD (up to second degree relatives), level of education, body mass index (BMI), hypertension (HT), diabetes mellitus (DM), thyroid diseases, coronary heart disease (CHD), smoking, alcohol consumption, intake of nonsteroidal anti-inflammatory drugs (NSAID) or vitamins, anemia, high levels of CRP or ESR, TC, LDL-C, HDL-C, TG, Lp-a, APO-A, APO-B, vitamin B12 or folate deficiency, elevated levels of ferritin, serum iron, homocysteine, history of cerebrovascular events, congestive heart failure, depression, score of MNA and zinc levels were examined in these patients.
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The above-mentioned possibly associated factors and demographic properties between the AD group (n = 203) and NCS group (n = 1160) were compared. Female sex and advanced age were significantly associated with AD. AD frequency was significantly higher in female patients (16.6 and 12.1%, respectively, p = 0.024). Mean age was significantly higher in AD group (73.3 7.9 versus 71.3 6.5 years, p < 0.001). Family history of AD was positive in 16.7% of AD patients and in 6.7% of the NCS group, but this difference was not significant. AD was diagnosed in 72 (22.8%) of illiterate patients, and in 16 (13.0%) of university graduated patients. Significant correlation of AD with smoking and alcohol consumption could not be detected. In the patients with AD, 10.3% were smokers (>10 packs/year), and in 15.3% of the normal group were smokers (NS). Evaluation of alcohol consumption demonstrated that 2.5% of the AD and 2.1% of the normal group were heavy drinkers (NS). The relationship between dementia and intake of NSAIDs was evaluated. AD was diagnosed in 13.1% of the patients using one NSAID regularly, in 6.7% of the patients using two NSAIDs regularly, and in 16% of the patients never using NSAIDs. Although frequency of AD in patients using two NSAIDs regularly seemed to be lower, this was not statistically significant. When only the two groups, two NSAIDs using group and none NSAID using group, were compared, AD was significantly less frequent in two NSAIDs using group ( p = 0.03). Vascular diseases and risk factors including history of evident stroke, hypertension, diabetes mellitus, documented coronary artery disease, and BMI were examined and no significant difference was detected between the AD and NCS groups (Table 1). Among the co-existing diseases, congestive heart failure, depression and anemia were significantly more frequent in AD group; malnutrition, hyperthyroidism and hypothyroidism were not different between the groups. Congestive heart failure was present in 14.3% of AD and in 7.3% of NCS patients ( p = 0.001). Depression was diagnosed in 30.0% of AD patients and in 19.7% of the NCS group ( p = 0.001). Anemia (Hb < 13 g/dl for men and <12 g/dl for women) was significantly more frequent in AD (15.3% in AD, 8.5% in NCS, p = 0.003). Association between AD and malnutrition was assessed by the MNA score which was not significantly different between the AD and NCS groups. Examination of laboratory results revealed that serum iron, ferritin, zinc levels and nonspecific markers of inflammation including CRP and ESR were not significantly different between the AD and NCS groups. High levels of CRP were detected in 32.5% of AD and 28.4% of NCS group (NS). High levels of ESR were shown in 45.8% of AD and 39.8% of NCS patients (NS). Comparison of lipid and lipoprotein levels between groups revealed no significant differences. High levels of TC were detected in 38.4% of AD and 38.4% of NCS group (NS). TG levels were high in 17.7% of AD and 16.2% of NCS patients (NS). LDL-C was high in 31.5% of AD and 45.9% of NCS group (NS). HDL-C was low in 13.3% of AD and this was not significantly different from the NCS group. 18.7% of AD group and 14.1% of NCS group had high levels of Lp-a (NS). Also, high APO-A levels were not associated with AD (45.3% in AD and 47.7% in NCS, NS). Finally, APO-B was normal in the AD group, and in every patient except one in the NCS group (NS). When the relationship between vitamin B12 level and cognitive functions were examined, it was found that 6.9% of AD patients and 13.9% of NCS patients had vitamin
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Table 2 Associated factors of AD Parameter
Univariate analysis
Female sex Age Education level Depression Two NSAIDs intake Multivitamin intake Heart failure Anemia
Logistic regression analysis
p
OR
95% CI
p
0.024 <0.001 0.001 0.001 0.030 0.006 0.001 0.003
1.5 1.2
0.98–1.96 1.07–2.11
0.031 0.019
1.4
1.13–2.27
0.008
1.2
0.98–3.16
0.024
Notes: Univariate analysis was performed by comparing AD and NCS groups. Logistic regression was performed for AD and NCS by including the variables age, gender, education level, body mass index, hypertension, smoking, family history of dementia, intake of vitamins and NSAIDs, ESR, Lp-a, congestive heart failure, MNA score, and depression. Statistical results of only independently associated factors determined by logistic regression analysis are shown in this table.
B12 levels lower than 160 pg/dl (NS). Only 2 AD patients (1.0%) and 10 NCS patients (0.9%) had folic acid deficiency (NS). High homocysteine levels were observed in 84 AD patients (41.4%) and in 481 of NCS group (41.5%) (NS). The statistical data of associated factors for AD versus NCS are detailed in Table 2. 3.3. Associated factors of VD Seventy-three (3.8%) patients (mean age = 73.1 6.3 years, 60.3% female) were diagnosed as having VD. Statistical results of the comparison between VD and NCS groups are presented in Table 3. Gender, age, education level, anemia, stroke, congestive heart failure, intake of vitamin supplements and NSAID were not significantly associated with VD. LDL-C, coronary heart disease, smoking, alcohol consumption, and depression were found significantly associated with VD. Some vascular risk factors such as hypertension, diabetes mellitus and history of evident stroke were not found related to VD. Table 3 Associated factors of VD Parameter
Univariate analysis
Logistic regression analysis
p
OR
95% CI
p
Depression LDL-C Smoking Alcohol CHD
0.0001 0.017 0.002 0.007 0.017
1.2 1.4
1.13–2.27 1.08–3.02
<0.001 0.024
Notes: Univariate analysis was performed by comparing VD and NCS groups. Logistic regression analysis was performed for VD and NCS groups, including the variables age, gender, education level, smoking, alcohol consumption, hypertension, LDL-C, HDL-C, Lp-a, vitamin B12, CHD, and depression. Statistical results of only independently associated factors determined by logistic regression analysis are shown in this table.
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LDL-C levels were high in 45.9% of VD and in 31.9% of NCS ( p = 0.017). Coronary heart disease was present in 27.4% of VD and in 21.0% of NCS ( p = 0.017). 16.4% of VD patients and 8.2% of NCS patients were smokers (>10 packs/year) ( p = 0.002). Alcohol consumption was present in 11.6% of VD and in 1.4% of NCS group ( p = 0.007). Finally, depression was diagnosed in 47.9% of VD and in 19.7% of NCS patients ( p < 0.001). 3.4. Results of logistic regression analysis To determine the independent associated factors of AD, logistic regression analysis was performed with the variables age, gender, education level, BMI, hypertension, smoking, family history of dementia, intake of vitamins and NSAIDs, ESR, Lp-a, CHD, MNA score, and depression. It was found that independently associated factors of AD were female sex (OR = 1.5, 95% CI = 0.09–0.98, p = 0.031), age (OR = 1.2, 95% CI = 1.07–2.11, p = 0.019), vitamin intake (OR = 1.2, 95% CI = 0.23–0.90, p = 0.024), and depression (OR = 1.4, 95% CI = 1.13–2.27, p = 0.008) (Table 2). Logistic regression analysis to determine the independent associated factors of VD was performed with the variables age, gender, education level, smoking, alcohol consumption, hypertension, LDL-C, HDL-C, Lp-a, vitamin B12, coronary heart disease, and depression. It was determined that LDL-C (OR = 1.4, 95% CI = 1.08–3.02, p = 0.024) and depression (OR = 1.2, 95% CI = 2.16–5.84, p < 0.001) were independent associated factors of VD (Table 3).
4. Discussion The progression of dementia is accompanied by increased morbidity, mortality, and care problems. Therefore, clinicians should be aware of the risk factors of dementia for early diagnosis. The interference of genetic and environmental factors may lead to variability in risk factors in different countries. Every country should determine the risk factors in their own elderly people. Evidence about risk factors in AD is inconsistent in the literature (Kim et al., 2005; Mielke and Zandi, 2006; Yip et al., 2006). Therefore, we examined wellknown and novel risk factors in our geriatric medicine outpatient setting. This study found that independent correlates are female sex, advanced age, depression and intake of vitamin supplements for AD; and depression and LDL-C for VD. Some limitations of the study should be considered. One limitation is the lack of information about apolipoprotein-E4, which is a well-known risk factor for AD. Moreover, another risk factor, namely the temporal lobe and hippocampal atrophy, could not be measured volumetrically, because of the large number of patients. Another limitation is that, as this is a cross-sectional study, we cannot determine causality, and the exact roles of the independently associated factors. Longitudinal follow-up of normal subjects having these risk factors would give more information. Novel risk factors examined in this study were malnutrition, BMI, thyroid diseases, heart failure, and anemia. Evidence about the role of these risk factors is inadequate. This justifies our research on the possible risk factors, and adds new information to the literature. We found that MNA score and BMI were not correlated with AD and VD which suggests
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that nutritional status is not a determinant factor for dementia. However, we cannot make an assumption about its role in the progression of the disease and morbidity since this is not a longitudinal study. Hypothyroidism was not found to be a risk factor in this study. Hypothyroidism is not accepted as a risk factor, but is a reversible cause of cognitive decline, which should be screened before diagnosis of dementia. Although univariate analysis showed a relationship between AD and anemia, multivariate analysis revealed no independent correlation. Studies concerning anemia in AD are inadequate. It can be put forward that decreased oxygenation of the brain in anemia may lead to cognitive decline, but there is not enough evidence to support this hypothesis. Although heart failure was more frequent in AD, multivariate analysis showed no correlation. However, heart failure may trigger AD by leading to hypoxemia. Further studies with longitudinal follow-up should be carried out to demonstrate these relationships. In this study, patients with AD or VD were evaluated in the same setting and were compared to NCS groups, because of the increasing evidence about the hypothesis that AD and VD are the different clinical presentations of the same disease originating from the shared risk factors (Launer, 2002). Some risk factors for VD have been proposed previously and some of these risk factors are identical to the AD risk factors (Pansari et al., 2002). Our results revealed that a shared independent correlate of VD and AD was depression. Depression accompanies AD in 10–25%, especially in the early stages (Kumor and Cummings, 2001; Souder and Beck, 2004; Cankurtaran et al., 2005). Although the Mirage study put forward depression as a risk factor for AD, some studies could not obtain the same result (Wetherell et al., 1999; Green et al., 2003). Recently, depression has been thought to originate from vascular pathologies and the term vascular depression is being raised. The vascular depression hypothesis postulates that cerebrovascular disease predisposes or precipitates depression in some elder subjects (Alexopoulos et al., 1997). In the light of these studies, our result describing the depression as a correlate for both AD and VD, gains a certain importance. Vascular risk factors are recently being implied in the pathogenesis of AD. Since postmortem studies showed vascular changes in AD patients’ brains, neuroimaging studies detected vascular pathologies such as white matter lesions and lacunar infarcts in AD patients, the role of vascular risk factors has gained importance in AD (Launer, 2002; Pansari et al., 2002). It has been postulated that hypertension, diabetes mellitus, dyslipidemia (Reitz et al., 2004), and homocysteine (Seshadri et al., 2002) are risk factors for AD as well as VD (Morris et al., 2000). However, in our study we could not find a relationship between AD and any of the vascular risk factors. On the other hand, among the vascular risk factors, only LDL-C was found to be an independent correlate of VD. We feel that this result is due to the cross-sectional approach of the study. Advanced age is one of the major risk factors of AD (Yip et al., 2006). It is known that the incidence of AD increases directly in proportion to age (Fratiglioni et al., 2000). The results of the present study are in agreement with the literature. Since age is a nonmodifiable risk factor, determining other risk factors in the geriatric population, and assessment of cognitive function in the elderly at each visit for any reason is of great importance for diagnosing AD at early stages. Female sex, which is another nonmodifiable major risk factor (Yip et al., 2006) was also found as an independent correlate of AD in this study. It has been put forward that this may be due to the earlier mortality of men
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or lower education level of women (Scinto, 2000). However, the results of our regression analysis showed that female sex was related with AD independently from age and education level. There is evidence about the positive effects of vitamin E on cognitive function (Klatte et al., 2003). Vitamin B12 deficiency is not only a cause of reversible cognitive dysfunction but also a risk for AD (Eastley et al., 2000). Therefore, our results suggesting that vitamin supplement intake increases AD risk 1.2-fold was unexpected. However, there are some studies suggesting that vitamin E does not play a major role in cognitive function (Israel et al., 1994), and vitamins A, C, and E supplementation do not reduce the risk of AD (Luchsinger et al., 2003). It can be concluded that our findings may support these negative results about the role of vitamins in cognitive function. However, it is not clear that the vitamin E intake started before the beginning of the dementia process id not effective. Therefore, a safe conclusion cannot be reached on this issue. Moreover, doses of vitamin E were not standard, since they were 20–200 IU and it is not certain that they were consumed regularly. Longitudinal studies may ascertain the real relationship. For the assessment of cognitive function of elderly people, memory complaints alone are not usually sufficient, because as it is demonstrated by our study only a little percent of AD patients applying to the clinic with these complaints. Therefore, for every geriatric patient admitted for any reason, the cognitive assessment should be performed, risk factors should be determined and patients at high risk should be evaluated further and closer. The role of geriatric medicine is of great importance to achieve this goal. Following on from the results of this study, future research is needed to evaluate the independent effects of these associated factors in prospectively designed, cohort studies.
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