Vascular Risk Factors Aggravate the Progression of Alzheimer's Disease

Abstract

Purpose:

To explore the correlation of vascular risk factors for Alzheimer’s disease (AD) in Chinese population.

Methods:

A total of 123 outpatients with probable AD followed up for 3 years were investigated. Severity of cognitive impairment and functional ability was assessed using Mini-Mental State Examination (MMSE) and modified activities of daily living (ADLs), respectively. The incidence of vascular risk factors was studied in patients with AD.

Results:

Univariate analysis showed significance difference in MMSE and ADL scores between patients with and without vascular risk factors (P < .05). Multiple regression analysis showed age, education, hyperhomocysteinemia, and hypertension were significant variables associated with annual MMSE, while there were no significant correlations between annual MMSE and sex, initial MMSE, diabetes, and so on.

Conclusions:

Vascular risk factors are common comorbidities in patients with AD in China, with younger, better educated ones showing faster cognitive decline. Hypertension and hyperhomocysteinemia may also aggravate the progression, and it is important to prevent and treat patients with AD.

Introduction

Alzheimer’s disease (AD) is a progressive neurodegenerative disorder characterized by irreversible cognitive deterioration. It has become a serious, harmful health problem leading to death and represents a significant economic burden to the family and society, as the life expectancy in the general population is increasing. ¹ More and more evidences suggest vascular risk factors, such as hypertension, diabetes, hypercholesterolemia, atrial fibrillation, and so on, are related to an increased risk and play an important role in the progression of AD. ^2,3 However, it remains unclear how such vascular factors play a role in the attack and progression of the disease itself. Although there have been some studies valuing the effect of vascular risk factors on incidence of patients with AD and rate of cognitive decline, the results show disagreement. ^{4 –8} Some studies showed that hypertension, diabetes, hyperlipidemia, and atrial fibrillation are associated with a greater rate of cognitive decline, but others did not show a significant influence of vascular risk factors on the progression of AD. Such contradictory results may be mainly due to differences in assessment methods of disease severity and duration time of vascular risk factors as well as the characteristics of patients itself. According to vascular hypothesis for AD, dysfunction of the neurovascular unit contributes to the pathogenesis of AD, but it is difficult to state definitive conclusions. More prospective studies on patients with AD having longer follow-up period are needed to continue studies in different regions and ethnic backgrounds. China shows a huge prevalence of AD among its aging population. ⁹ Because of the differences in race, economic level, and lifestyles, vascular risk factors’ profile and their effects on the progression of AD may differ from the Western countries. According to the population-based study in Chongqing, China, independent predictors like age, low educational level, everyday drinking, hypertension, diabetes mellitus, and prior stroke were more frequent in the patients with AD. ¹⁰ Although physical inactivity, smoking, and depression have been suggested to be increasingly important risk factors in the US population, ¹¹ some studies proposed that prevalence of dementia subtypes in China is comparable with that in Western countries. ⁹ The purpose of this study was to determine whether sociodemographic factors, including common vascular risk factors, contribute to cognitive decline in Chinese patients with AD.

Patients and Methods

Patients

We enrolled 123 consecutive outpatients (46 men and 77 women) with AD visiting the Memory Clinic of our hospital from January to April 2009 at baseline. All patients and their caregivers provided informed consent.

Eligible patients had mild to moderate AD, scored 10 to 24 on the Chinese version of the Mini-Mental State Examination (MMSE) at baseline inclusive, and met National Institute of Neurological and Communicative Disorders and Stroke and Alzheimer’s Disease and Related Disorders Association (NINCDS-ADRDA) criteria for probable AD. Patients underwent detailed general physical and extensive laboratory tests and brain magnetic resonance imaging examination and a set of neuropsychological tests. Preffers Outpatient Disability questionnaire was used to evaluate the social viability function. Fuld Object Memory Evaluation was used to evaluate delay memory function. Rapid Verbal Retreve was used to evaluate language fluency. Block Design in Wechsler Intelligence Scale for Children (WISC) was used to evaluate visuospatial function. Digit span in WISC was used to evaluate immediate memory function. Additional inclusion criterion was Hachinski ischemic scores of no more than 4 for each patient with AD. The cognition of patients was evaluated with MMSE, and the functional ability in basic and instrumental activities was evaluated using modified activities of daily living (ADLs) once in every 6 months.

Pathological Examination

The presence of hypertension and diabetes was defined according to the diagnosis and subsequent treatment by a physician at hospital or according to a relative report of previous and ongoing treatment for the respective conditions. Each diagnosis was based on the clinical guidelines published by Chinese Medical Association. Hypercholesterolemia was defined as plasma cholesterol level of more than 5.2 mmol/L and hyperhomocysteinemia was defined as plasma homocysteine of more than 15 μmol/L. Carotid atherosclerostic plaques were defined as intima–media thickness of more than 1.3 mm. The progression of cognitive impairment was evaluated on the basis of the MMSE changes each year between initial and final evaluations.

Treatments

All patients enrolled were continuously or intermittently treated with cholinesterase inhibitors and/or N-methyl-d-aspartate receptor antagonist (memantine hydrochloride).

Follow-Up Information

After the final evaluation (January to April 2012), 84 patients had followed up for 3 years. The follow-up data of the remaining 39 patients were not available due to various complications like stroke, depression, myocardial infarction, or any cause leading to death, affecting clinical course. The study protocol was approved by the ethics committee.

Statistic Analysis

Values are expressed as means ± standard deviation or constituent ratio. The relationship between with vascular risk factors and without vascular risk factors was analyzed by univariate analysis, including t test for association in independent normally distributed continuous data and chi-square test for categorical data. In addition, multiple regression analysis was performed to determine the influence of sociodemographic factors on the annual MMSE. Independent variables included age, sex, education, initial MMSE scores, and vascular risk factors including hypertension, diabetes, hypercholesterolemia, hyperhomocysteinemia, and carotid atherosclerostic plaque. The dependent variable was annual MMSE. A P value <.05 was considered to be statistically significance. The statistical analyses were performed by SPSS version 13.0 for Windows. (SPSS Inc.Chicago,USA)

Results

The mean age of overall patients enrolled was 72.3 ± 8.6 years. In all, 46 (37.4%) were men and 77 (62.6%) were women. The education level was illiteracy, 22.8% (28 patients); primary school, 43.1% (53 patients); and middle school and above, 34.1% (42 patients). The courses of disease were 3.6 ± 3.1 years. The mean MMSE and ADL scores at initial evaluation were 20.6 ± 3.1 and 36.4 ± 4.2, respectively (Table 1). Thirty-nine patients did not finish the follow-up process, and they did not show any difference with reference to age, gender, education levels, courses, and MMSE and ADL score at baseline in patients followed up for 3 years.

Table 1.

Clinical and Demographic Characteristics of Patients With AD at Initial Evaluation.

	Patients With AD
No.	123
Mean age ± SD, year	72.3 ± 8.6
Sex (male), n (%)	46 (37.4)
Mean course ± SD, year	3.6 ± 3.1
Education
Illiteracy, n (%)	28 (22.8)
Primary school, n (%)	53 (43.1)
Middle school and above, n (%)	42 (34.1)
MMSE score at initial evaluation	20.6 ± 3.1
ADL score at initial evaluation	36.4 ± 4.2

Abbreviations: MMSE, Mini-Mental State Examination; ADL, activity of daily living; AD, Alzheimer’s disease; SD, standard deviation.

As shown in Table 2, the incidence of vascular risk factors was hypertension, 38.2% (47 patients); diabetes, 28.5% (35 patients); and hypercholesterolemia, 22.7% (28 patients); hyperhomocysteinemia, 34.2% (42 patients); and carotid atherosclerostic plaque, 42.2% (52 patients), and only 32.5% (40 patients) without any vascular risk factors. Most patients with vascular factors were medically followed up. The drugs used were calcium channel blockers, angiotensin-converting enzyme inhibitors, angiotensin receptor blockers for hypertension, oral hypoglycemic drugs for diabetes, statins for hypercholesterolemia, and folic acid and vitamin B12 for hyperhomocysteinemia.

Table 2.

Vascular Risk Factors for Patients With AD at Initial Evaluation.

VRF	n (%)
Hypertension	47 (38.2)
Diabetes	35 (28.5)
Hypercholesterolemia	28 (22.7)
Hyperhomocysteinemia	42 (34.2)
Carotid atherosclerostic plaque	52 (42.2)

Abbreviations: AD, Alzheimer's disease; VRF, vascular risk factor.

No significant difference in age, sex, education levels, and initial MMSE scores was found between patients having AD with and without vascular risk factors. But the scores of MMSE and ADLs were significantly different at initial and final evaluation (P < .05). The MMSE scores of patients with vascular risk factors were lower than that of patients without vascular risk factors whether at initial evaluation or at final evaluation. The ADL scores of patients with vascular risk factors were higher than that of patients without vascular risk factors whether at initial evaluation or at final evaluation (Table 3). Multiple regression analysis showed that age, education, and hypertension and hyperhomocysteinemia, but not diabetes, hypercholesterolemia, and carotid atherosclerostic plaque, were significant variables associated with AD progression. Younger, more educated patients with hypertension or hyperhomocysteinemia showed greater decline in annual MMSE scores (Table 4).

Table 3.

Characteristics of Patients With and Without VRF at Initial and Final Evaluations.

Variables	With VRF	Without VRF	P
Mean age ± SD, year	70.3 ± 6.8	69.8 ± 7.1	>.05
Sex (male), n (%)	30 (42.2)	16 (40.0)	>.05
Education
Illiteracy, n (%)	16 (57.1)	12 (42.9)	>.05
Primary school, n (%)	37 (69.8)	16 (30.2)
Middle school and above, n (%)	30 (71.4)	12 (29.6)
Course, mean ± SD, year	3.7 ± 3.5	3.6 ± 4.1
MMSE score
At initial evaluation (n = 123)	20.1 ± 3.3	21.2 ± 4.5	<.05
At final evaluation (n = 84)	14.2 ± 5.3	16.8 ± 3.1	<.05
ADL score
At initial evaluation (n = 123)	41.3 ± 5.8	35.3 ± 4.8	<.01
At final evaluation (n = 84)	68.8 ± 6.9	52.3 ± 6.8	<.01

Abbreviations: MMSE, Mini-Mental State Examination; ADL, activity of daily living; VRF, vascular risk factor; SD, standard deviation.

Table 4.

Effects of Variables on Annual MMSE Score Change (n = 84).

Variables	β	t Value	P Value
Age, year	.384	4.538	.001a
Male	−.032	−0.360	.65
Education	−.283	−3.376	.038b
Initial MMSE score	−.023	−0.178	.772
Hypertension	−.185	−2.368	.041b
Diabetes	−.194	−2.295	.073
Hypercholesterolemia	−.096	−1.046	.295
Hyperhomocysteinemia	−.165	−2.412	.043b
Carotid atherosclerostic plaque	.039	−0.164	.805

Abbreviations: β, standardized regression coefficient; MMSE, Mini-Mental State Examination.

^a P < .01.

^b P < .05.

Discussions

Alzheimer’s disease, characterized by progressive cognition decline, is the most common form of dementia, followed by vascular dementia, affecting the aging population. ¹ According to a number of study reports, the observed change in MMSE was used to estimate the rate of cognitive decline. ^{12 –14} Age at onset and education level have been shown to affect the progression of cognitive deterioration. ¹⁵ There is evidence in support of the view that vascular risk factors and disorders may be involved in AD. ^{4 –8} The view that AD is a neurodegenerative or vascular disorder was disputed. ^16,17 In accordance with those studies, we confirmed that vascular risk factors, including hypertension, diabetes, hypercholesterolemia, hyperhomocystinemia, and carotid atherosclerotic plaques, are common comorbidities in patient with AD. About 67.5% of patients with AD also had vascular risk factors. Moreover, we further confirmed that younger and more educated patients with AD have faster cognitive deterioration. In addition, we found that hypertension or hyperhomocysteinemia can aggravate the progression of AD, but diabetes, hypercholesterolemia, and carotid atherosclerostic plaque were not associated with faster cognitive deterioration.

Most longitudinal studies have shown that the cognitive level is often inversely proportional to blood pressure values measured 15 or 20 years previously. ^18,19 A large number of epidemiological investigation research found that blood pressure is one of the important factors of cognitive function in the elderly patients. ^{20 –22} The elevation of blood pressure in the middle age is an important risk factor for cognitive function impairment and AD occurrence in the old age. ²³ Drug clinical trials also found, on the other hand, controlling blood pressure with antihypertensive medications can reduce the occurrence of cognitive impairment and slow down the progress of AD. ¹⁸ The evidence seems to support that high blood pressure promotes the occurrence of AD. Vascular changes linked to hypertension may induce chronic and episodic cerebral hypoperfusion, ischemia, and hypoxia, which are suspected to be some of the mechanisms that link cerebrovascular disorders to dementia. ^24,25 Experimental study demonstrates that chronic hypertension determined an impairment of the blood–brain barrier (BBB) permeability with deposition of β-amyloid (Aβ) in brain tissue. ²⁶

The AD was designated as type 3 diabetes. ²⁷ Diabetes is associated with an increased risk of AD. ²⁸ Many clinical epidemiological studies found that either type 1 or type 2 diabetes is closely related to the occurrence of dementia, including vascular dementia and AD. Our study showed slightly slower rate of cognitive decline in patients with AD having diabetes but not a statistically significant difference (Table 4). The result is not in line with the other study that suggested diabetes was associated with faster cognitive decline. ⁴ It may be affected by the severity of the disease and the treatment for diabetes. As reported by some studies, as long as the blood sugar levels are in control, whether by oral hypoglycemic drugs or by insulin treatment, it can slow down the cognitive decline and delay the occurrence of dementia. ^29,30 Diabetes may influence AD progression via an inflammatory mechanism or by contributing to amyloid plaque and neurofibrillary tangle formation. ³¹

Homocysteine is a new risk factor for atherosclerosis and cardiocerebrovascular disease, and its level is associated with the serum concentration of folate and vitamin B12. Some studies have found that high blood levels of homocysteine were related to dementia and AD. ^32,33 Homocysteine may cause cerebral ischemic lesion by directly or indirectly damaging vascular endothelial and blood coagulation system. It was also found that homocysteine can enhance the neurotoxic effects of Aβ in experimental models of AD. ^34,35

It is now widely recognized that substantial overlap exists among vascular risk factors and AD. Vascular hypothesis of AD have been further improved. ^36,37 Vascular risk factors lead to BBB dysfunction and cerebral blood flow reduction, initiating a cascade of events that precedes dementia. In the non-Aβ pathway, toxic accumulates and cerebral hypoperfusion induces early neuronal dysfunction. Vascular injury also reduces Aβ clearance at the BBB and increases the production of this peptide from the Aβ precursor protein, leading to Aβ accumulation. Thus, it has been suggested that AD and vascular disease may work synergistically to cause cognitive decline.

It should be noted that our study has some limitations. First, it remains flaw with the MMSE score changes as the evaluation index of cognitive deterioration. Second, we did not assess the duration of the existence of vascular risk factors and medications used to control the vascular risk factors, which may associate with the progression of the disease. Third, the number of cases was less and the follow-up time was shorter. In spite of these limitations, we can still conclude that hypertension and hyperhomocysteinemia, in addition to age and education levels, may speedup cognition. Our findings imply new strategies, namely vascular risk factors should be controlled, leading to the prevention of AD. At least till now, it remains controversial whether vascular risk factors are the predictor of AD or whether the disease processes that cause the progress of dementia. There is limited direct evidence to support the complex associations between vascular risk factors and AD pathogenesis, but the matter is far from resolved. On the other hand, the sample size in our study is not big enough, thus, the follow-up period is relatively shorter. Further prospective studies involving large sample and long-term study of evaluation (application) will be needed to determine whether control of hypertension or hyperhomocysteinemia may slow down the progression of AD.

In conclusion, our study demonstrates that vascular risk factors such as hypertension, diabetes, hypercholesterolemia, hyperhomocystinemia, and carotid atherosclerotic plaques are common comorbidities in patients with AD. Younger, more educated patients are more likely to have faster cognitive decline. In addition, hypertension and hyperhomocysteinemia may also aggravate the progression of AD. Our results suggest that it is the important to prevent and treat hypertension and hyperhomocysteinemia in patients with AD.