Vascular risk factors and progression of Alzheimer disease

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By Douglas J Lanska MD MS MSPH

Article under review: Helzner EP, Luchsinger JA, Scarmeas N, et al. Contribution of vascular risk factors to the progression in Alzheimer disease. Arch Neurol 2009;66(3):343-8.

Background: Vascular risk factors have been associated with higher risks of vascular dementia, Alzheimer disease, and mixed dementia. However, few studies have assessed the contribution of vascular risk factors to the progression of Alzheimer disease.

Purpose: To assess the contribution of pre-diagnosis vascular risk factors to the progression of Alzheimer disease.

Methods: A subgroup of 156 individuals with incident Alzheimer disease from 2 population-based cohorts of Medicare enrollees in portions of Manhattan was studied. The sample of cases included was about one third (37%) of the 417 individuals with incident Alzheimer disease in the original cohorts over the study period. Subjects were excluded if lipid assessments were not available before a diagnosis of dementia was made (98 individuals) or if post-diagnosis follow-up data was not available (163 individuals). Diagnosis of dementia was made using criteria from the DSM-IIIR (Diagnostic and Statistical Manual of Mental Disorders, Third Edition Revised), and diagnosis of probable or possible Alzheimer disease was made using criteria from the NINCRS/ADRDA (National Institute of Neurological and Communicative Disorders and Stroke/Alzheimer Disease and Related Disorders Association). The outcome measure was the change from diagnosis in a composite score of cognitive function derived from different psychometric instruments assessing 5 cognitive domains (memory, abstract reasoning, visual-spatial function, language, and "executive speed," which assessed phonemic and category fluency). Separate statistical models were developed for each vascular variable (heart disease, stroke, diabetes, hypertension, smoking, and pre-diagnosis lipid concentration), and a separate multivariate model assessed the independent contributions of the vascular variables after adjustment for age, race/ethnicity, and years of education.

Results: Higher total cholesterol and low-density lipoprotein (LDL) cholesterol and a history of diabetes mellitus were associated with a faster rate of cognitive decline. Histories of heart disease and stroke were associated with cognitive decline only in apolipoprotein E epsilon4 gene carriers. High-density lipoprotein (HDL) cholesterol and triglyceride levels were not associated with cognitive decline. In the final multivariable model, which included HDL and LDL cholesterol concentrations and a history of diabetes, only higher LDL cholesterol was independently associated with a faster rate of cognitive decline. In supplementary analyses, the use of lipid-lowering agents was not associated with the rate of cognitive decline. Statistical models stratifying by the use of lipid-lowering agents produced similar results.

Conclusions and commentary: Higher pre-diagnosis levels of total and LDL cholesterol and a history of diabetes were associated with faster rates of cognitive decline in patients with incident Alzheimer disease. A history of heart disease or stroke predicted faster rates of cognitive decline only in apolipoprotein E epsilon4 gene carriers. Curiously, smoking and atrial fibrillation were not included in the models.

A number of studies have examined individual vascular risk factors as possible prognostic factors for the rate of progression of Alzheimer disease. However, few other studies have explored the independent contributions of multiple vascular risk factors to the progression of Alzheimer disease. Unfortunately, the methodology and results of the few available studies are inconsistent, making a meaningful synthesis difficult.

Regan and colleagues studied 167 people with probable Alzheimer disease but without significant vascular disease (including having a Hachinski ischemic score greater than 4) who completed 18 months of follow-up (Regan et al 2006). This group represented about three fourths of the initial study group of 224 people, but most of those who did not complete follow-up had died, without there being any significant difference in vascular risk factors between those who completed follow-up and those who did not. Regan and colleagues used several measures of cognition, behavioral and psychological symptoms, and functional abilities. In this study, during 18 months of follow-up, only stroke during the study period was an independent predictor of cognitive decline, while other vascular risk factors had no significant effect on rate of decline (including Hachinski ischemic score, diabetes, history of myocardial infarction, history of atrial fibrillation, body mass index, history of hypertension, blood pressure, Framingham risk score, cholesterol level, and smoking).

Mielke and colleagues studied a sample of 135 individuals with incident Alzheimer disease identified in a population-based sample of elderly persons who were followed with in-home visits for an average of 3 years (Mielke et al 2007). Atrial fibrillation, systolic hypertension, and angina were associated with more rapid decline in both the Mini-Mental State Examination and the Clinical Dementia Rating Sum of Boxes score, while histories of coronary artery bypass graft surgery, diabetes, and use of antihypertensive medications were associated with a slower rate of decline.

One important distinction between the study by Helzner and colleagues in 2009 and the earlier studies by Regan and colleagues in 2006 and Mielke and colleagues in 2007 is that Helzner and colleagues included cases of possible Alzheimer disease with a much wider range of vascular disease at baseline - including twice the frequency of prevalent stroke at baseline and much higher (2 to 3 times higher) frequency of hypertension (although the definitions of hypertension varied also).

  Regan et al 2006 Mielke et al 2007 Helzner et al 2009
Diabetes 12% 19% 16%
Hypertension* 27% 36% 72%
Heart disease# ? ? 18%
Ever angina ? 10% ?
Myocardial infarction 5% 16% ?
Atrial fibrillation 7% 7% ?
Stroke 8% 7% 15%
Current smoker 14% 2% ?

*Hypertension status in the papers by Regan and colleagues and Mielke and colleagues was based on current use of antihypertensive medications, whereas in the paper by Helzner and colleagues it was based on a self report of a history of hypertension.

#Heart disease in the paper by Helzner and colleagues was defined as a history of myocardial infarction, congestive heart failure, or angina pectoris at any time prior to the diagnosis of Alzheimer disease. Corresponding information according to this definition is not available for the other papers.

Collectively, these studies suggest that vascular risk factors may impact the rate of progression of Alzheimer disease, but further work is clearly needed to understand the degree to which this is true, for which risk factors, and under what specific circumstances. The hope is to identify relatively modifiable factors that can ameliorate progression of dementia.

Certainly, it would not be surprising if vascular risk factors might accelerate the progression of dementia in patients with Alzheimer disease, since (1) they certainly have a bearing on the rate of progression of vascular dementia, and (2) having 2 relatively independent processes (vascular disease and Alzheimer disease) would be expected to result in greater collective damage to brain tissue.

For such studies, cases of possible and probable Alzheimer disease are likely to differ in the degree to which vascular risk factors impact on progression; therefore, future studies should examine this by separating such groups in the analysis.