Treatment of vascular risk factors in patients with a diagnosis of Alzheimer�s disease: a systematic review

Valenti et al. BMC Medicine 2014, 12:160 http://www.biomedcentral.com/1741-7015/12/160 Vascular risk factors and Alzheimer’s Disease RESEARCH ARTICLE Open Access Treatment of vascular risk factors in patients with a diagnosis of Alzheimer’s disease: a systematic review Raffaella Valenti1, Leonardo Pantoni2 and Hugh S Markus3* Abstract Background: Increasing evidence suggests vascular risk factors (VRF) play a role in the pathogenesis of Alzheimer’s disease (AD). Epidemiological studies have found associations between VRF and risk of AD. Treating VRF in patients with AD offers a potential treatment option but ineffective treatments should be avoided in this group who are frequently on multiple medications and in whom compliance may be challenging. Methods: Studies containing information on the treatment of VRF in patients with a diagnosis of AD were identified using a defined search strategy. Randomised controlled trials and observational studies were included. Results: The pre-specified search strategy retrieved 11,992 abstract articles, and 25 papers including those identified on review of reference lists and reviews met the inclusion criteria. Of these, 11 were randomised controlled trials (RCTs) and 14 observational studies. Observational studies suggested that a VRF package and treatment of hypertension and statin therapy may be associated with improved outcome but these studies suffered from potential bias. The few RCTs performed were mostly small with short duration follow-up, and do not provide clear evidence either way. Conclusions: Observational data raises the possibility that treating VRF could alter the rate of decline in AD. However RCT data are not yet available to support this hypothesis and to alter clinical practice. RCTs in larger numbers of individuals with longer follow-up, ideally in the early stages of AD, are required to address this potentially important treatment question. Keywords: Alzheimer’s disease, Cholesterol, Dementia, Diabetes mellitus, Hypertension, Progression, Smoking, Statin, Treatment, Vascular risk factors Background Dementia is a common disorder with major medical, economic and societal costs. The most frequent cause of dementia is Alzheimer’s disease (AD). Key neuropathological hallmarks of the AD brain are diffuse and neuritic extracellular amyloid plaques - often surrounded by dystrophic neurites - and intracellular neurofibrillary tangles. Although the aetiological mechanisms underlying these neuropathological changes remain unclear, the disease is thought to be multifactorial, resulting from complex interactions between genetic, lifestyle and * Correspondence: 3 Department of Clinical Neurosciences, University of Cambridge, Cambridge, UK Full list of author information is available at the end of the article environmental factors [1]. By 2050 it is estimated that the number of patients with AD worldwide will quadruple from the current number of 36 million [2]. Although AD is thought to be primarily a neurodegenerative disease, several experimental and clinical observations have suggested that vascular factors may play a role in disease pathogenesis and progression [3-5]. Prospective cohort studies have reported associations between vascular risk factors (VRF) and dementia including hypertension [6] and diabetes mellitus (DM) [7]. Case-control studies have linked a wide range of VRF with disease risk, including hypertension, DM, high cholesterol, atrial fibrillation, smoking, obesity and low physical activity. Not only have VRF been associated with disease risk, but it has also been suggested that their presence © 2014 Valenti et al.; licensee BioMed Central Ltd. This is an Open Access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/4.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly credited. The Creative Commons Public Domain Dedication waiver (http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated. Valenti et al. BMC Medicine 2014, 12:160 http://www.biomedcentral.com/1741-7015/12/160 accelerates disease progression [8]. This implies that control of VRF could have an impact on disease progression in the individual patient with AD, and may offer a useful secondary prevention treatment strategy [5]. Furthermore, it has been suggested that some drugs used to treat VRF, such as statins, may have specific pleotrophic protective effects in AD. Before implementing the widespread treatment of VRF as part of routine clinical care in AD, it is important to show that their treatment really does reduce disease progression and impact on quality of life. To assess this we performed a systematic review to determine whether treatment of VRF is associated with improved clinical outcome in patients with already diagnosed AD. We included both randomised controlled trials (RCTs) and observational studies. Methods Studies containing information on the treatment of VRF in patients with a diagnosis of AD were identified using a defined search strategy. RCTs and observational studies were included. Pre-specified search strategy PubMed, MEDLINE, Embase, CENTRAL (Cochrane Library), DARE (Database of Abstracts of Reviews of Effects) and BIOSIS databases (conference abstract or proceedings) were searched between 1 January 1966 and 22 March 2014. Search terms were (dementia OR "Alzheimer's Disease" OR Alzheimer OR "demented patients" OR "cognitive decline progression" OR "post-dementia cognitive change" OR "complications in dementia") AND (vascular risk factor OR predictors OR hypertension OR diabetes mellitus OR diabetes OR smoking OR hyperlipidaemia OR hypercholesterolaemia OR cholesterol OR "alcohol intake" OR overweight OR obesity) AND (treatment OR therapy OR control OR contribution OR antihypertensives OR hypoglycemic agents OR insulin treatment OR "smoking cessation" OR "alcohol intake reduction" OR "hypolipidemic agents" OR statins OR diet OR "weight loss" OR exercise OR "physical activity"). The search was limited to articles on humans, in English and Italian languages, and full papers. Abstracts were reviewed and articles potentially meeting inclusion criteria identified. References lists and reviews were hand searched. To exclude duplicate papers, Reference Manager 12 was used. Articles were included if they fulfilled the following criteria: five patients or more; AD dementia (according to diagnostic criteria); VRFs (hypertension, DM, hyperlipidaemia, smoking, overweight and no exercise) defined according to reported criteria; AD progression with outcome measures (for example, Mini Mental Score Page 2 of 11 Examination (MMSE) for cognition, Activities of Daily Living (ADL) and Modified Rankin Scale for disability); studies with a mixture of dementia types where it was possible to separate out the data on the AD pat (...truncated)