1624 J Neurol Neurosurg Psychiatry: first published as 10.1136/jnnp.2005.063388 on 16 November 2005. Downloaded from PAPER Lipid lowering agents are associated with a slower cognitive decline in Alzheimer’s disease I Masse, R Bordet, D Deplanque, A Al Khedr, F Richard, C Libersa, F Pasquier ............................................................................................................................... See Editorial Commentary, p 1611 J Neurol Neurosurg Psychiatry 2005;76:1624–1629. doi: 10.1136/jnnp.2005.063388 Background: Data from epidemiological studies and animal models imply that disturbances in cholesterol metabolism are linked to Alzheimer’s disease susceptibility. Lipid lowering agents (LLAs) may have implications for the prevention of Alzheimer’s disease. Objective: To investigate whether LLAs are associated with a slower cognitive decline in Alzheimer’s disease. Methods: An observational study in 342 Alzheimer patients followed in a memory clinic for 34.8 months (mean age 73.5 years, mini-mental state examination score (MMSE) 21.3 at entry); 129 were dyslipaemic See end of article for authors’ affiliations treated with LLAs (47% with statins), 105 were untreated dyslipaemic, and 108 were normolipaemic. The ....................... rate of cognitive decline was calculated as the difference between the first and last MMSE score, divided by the time between the measurements, expressed by year. Patients were divided into slow and fast decliners Correspondence to: Professor according to their annual rate of decline (lower or higher than the median annual rate of decline in the Florence Pasquier, total population). Department of Neurology, Results: Patients treated with LLAs had a slower decline on the MMSE (1.5 point/year, p = 0.0102) than University Hospital, 59037 Lille, France; pasquier@ patients with untreated dyslipaemia (2.4 points/year), or normolipaemic patients (2.6 points/year). Patients chru-lille.fr with a slower decline were more likely to be treated with LLAs. Logistic regression analysis, with low annual cognitive decline as the dependent variable, showed that the independent variable LLA (treated with or not) was Received 19 January 2005 positively associated with the probability of lower cognitive decline (odds ratio = 0.45, p = 0.002). In revised form 30 May 2005 Conclusions: LLAs may slow cognitive decline in Alzheimer’s disease and have a neuroprotective effect. Accepted 19 July 2005 This should be confirmed by placebo controlled randomised trials in patients with Alzheimer’s disease and ....................... no dyslipaemia. copyright. aised plasma concentrations of cholesterol have been have an inhibiting effect on b-amyloid production in cultured implicated as a risk factor for Alzheimer’s disease,1–5 and cells.20 21 Besides having a preventive effect against the Rlow serum concentrations of high density lipoprotein occurrence of dementia, lipid lowering agents (LLAs) may cholesterol are associated with cognitive impairment and also have an effect on Alzheimer’s disease progression, dementia.6 In vitro studies suggest that cholesterol favours because of additional properties: the so called pleiotropic the formation of b-amyloid (Ab) in the brain,78a hallmark of effects.22 These include endothelial protection through Alzheimer’s disease. In transgenic animal models of actions on the nitric oxide synthase system, as well as Alzheimer’s disease, hypercholesterolaemia accelerates the antioxidant, anti-inflammatory, and antiplatelet effects. development of Alzheimer amyloid pathology.910Cholesterol- Statins in therapeutically relevant doses interfere with CNS fed rabbits develop extracellular deposits of b-amyloid, and cholesterol metabolism, but do not seem to be associated http://jnnp.bmj.com/ when they are placed subsequently on a control diet, a with significantly altered CSF alteration of Ab in non- significant reduction in identifiable b-amyloid immunoreac- demented elderly subjects.23 Some epidemiological studies tivity is observed.11 A strong association of late life high have provided evidence of a lower prevalence of diagnosed density lipoprotein (HDL) cholesterol levels with the number Alzheimer’s disease and vascular dementia in patients with of neuritic plaques and neurofibrillary tangles in a population hypercholesterolaemia treated with statins24–26 or other based necropsy series also support the view that cholesterol LLAs,26 although this was not confirmed in a recent study.27 plays a role in the formation of Alzheimer’s disease A randomised trial with pravastatin in non-demented pathology.12 A recent study showed that disease progression patients (mean (SD) MMSE = 28.0 (1.6)) did not show on September 30, 2021 by guest. Protected in the no-APOE epsilon4 allele/high cholesterol subgroup was significant effect on cognitive function or disability.28 greater than in the normal cholesterol subgroups with or Our aim in the present study was to investigate whether without epsilon4.13 In addition, hypercholesterolaemia is LLAs are associated with a slower cognitive decline in associated with increased microglial activation and leucocyte patients with Alzheimer’s disease in an observational study. infiltration.14 Activated microglial cells are concentrated in amyloid plaques. Such accumulation of activated microglia may contribute to neurodegeneration through the production METHODS An observational study was carried out from the compu- of cytokines and free radicals. terised database of the University outpatients memory clinic Relations between cholesterol and Alzheimer’s disease of Lille, France. This multidisciplinary memory clinic was raised the hope that cholesterol lowering strategy might influence the progression of Alzheimer’s disease.15 16 Vascular risk factors are known to be risk factors for Alzheimer’s Abbreviations: AChEI, acetylcholinesterase inhibitor; DRS, dementia 17 18 19 rating scale; HDL, high density lipoprotein; LLA, lipid lowering agent; disease, including stroke. Statins (b-hydroxy-b-methyl- MMSE, mini-mental state examination score; NSAID, non-steroidal anti- glutaryl-CoA reductase inhibitors), which can reduce intra- inflammatory drug; PROSPER, prospective study of pravastatin in elderly cellular cholesterol levels and prevent coronary heart disease, at risk; SSRI, selective serotonin reuptake inhibitor www.jnnp.com Alzheimer’s disease and lipid lowering agents 1625 J Neurol Neurosurg Psychiatry: first published as 10.1136/jnnp.2005.063388 on 16 November 2005. Downloaded from Table 1 Characteristics of patients according to treatment with lipid lowering agents and lipaemic status Patients with Patients with Total population dyslipaemia treated untreated Normolipaemic (n = 342) with LLAs (n = 129) dyslipaemia (n = 105) patients (n = 108) p Value Men 110 (32.2) 46 (35.7) 25 (23.8) 39 (36.1) 0.088 Age (years) at the end of the study 76.5 (7.5) 75.3 (7.1) 76.9 (7.3) 77.5 (8.0) 0.065 Arterial hypertension 197 (57.6) 72 (55.8) 59 (56.2) 66 (61.1) 0.783 Diabetes mellitus 56 (16.4) 25 (19.4) 12 (11.4) 19 (17.6) 0.241 Dyslipaemia 234 (68.4) 129 (100) 105 (100) 0 ,0.0001 Hypercholesterolaemia 213 (62.3) 124 (96.1) 89 (84.8) 0 ,0.0001 Hypertriglyceridaemia 76 (22.2) 32 (24.8) 44 (41.9) 0 ,0.0001 Small vascular lesions on imaging 85 (24.9) 27 (24.8) 22 (21) 36 (33.3) 0.048 Duration of disease at entry 35.8 (89.8) 32.9 (24) 47.4 (111.2) 27.9 (113.1) 0.258 MMSE score at entry 21.3 (5.1) 22.2 (5.1) 21 (5.1) 20.5 (5.1) 0.034 DRS score at entry 112 (19.2), NA = 37 116.4 (16.2), NA = 11 109.7 (21.8), NA = 9 108.6 (19.1), NA = 17 0.006 AChEI at entry: 279 (81.6) 104 (80.6) 87 (82.9) 88 (81.5%) 0.908 Treatment with AChEI (end of follow up) 229 (67.0), NA = 23 90 (69.8), NA = 7 63 (60.0), NA = 15 78 (72.2), NA = 1 0.012 Total duration of AChEIs (months) 21.8 (16), NA = 10 23.3 (16.8) NA = 4 22.5 (16.7), NA = 3 19.4 (14), NA = 3 0.237 Antidepressant (SSRI) 158 (46.2) 57 (44.2) 57 (54.3) 44 (40.7) 0.118 Follow up duration (months) 34.8 (18.9) 37.1 (21.5) 35.5 (18) 31.3 (16) 0.053 Delay between first and last MMSE scores 30.9 (17.7) 33.6 (20) 31.6 (16.2) 27.1 (15.3) 0.017 (months) Annual decline on MMSE score 2.1 (2.8) 1.5 (2.5) 2.4 (2.6) 2.6 (3.3) 0.010 Follow up duration (months) 34.8 (18.9) 37.1 (21.5) 35.5 (18) 31.3 (16) 0.053 Death 35 (10.2) 13 (10.1) 11 (10.5) 11 (10.2) 0.995 Values are n (%). AChEI, acetyl choline esterase inhibitor; DRS, dementia rating scale26; LLA, lipid lowering agent; MMSE, mini-mental state examination; NA, not available; SSRI, selective serotonin reuptake inhibitor. opened in 1992. From the start, all patients are assessed with drugs. Diabetes mellitus was defined as fasting serum glucose a comprehensive standardised clinical examination con- level >6.0 mmol/l or current use of antidiabetic drugs. Drug ducted by a senior staff neurologist, a psychiatrist, a prescriptions were collected according to the following neuropsychologist, a speech therapist, and a nurse. They classification: non-steroidal anti-inflammatory drugs have cerebral imaging and laboratory investigation including (NSAIDs), antidepressants, fibrates, statins, and acetylcholi- fasting plasma total cholesterol and triglycerides. A standar- nesterase inhibitors (AChEI). For AChEIs and LLAs, the copyright. dised file is completed, which includes demographic data, compound, dosage, and duration of treatment were noted. comprehensive personal and family history, especially vas- When patients took consecutively LLAs of two different cular risk factors, mini-mental state examination (MMSE),29 pharmacological classes, both treatments were taken into and previous and current treatments. During confrontation account. Homogeneity of corticoid and postmenopausal meetings with all the staff, a consensual diagnosis is given for hormone therapy prescriptions was controlled between each patient according to the current diagnostic criteria.30–33 groups, because these might be confounding factors.