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Statin therapy in Alzheimer's disease
Reflection and Reaction
Statin therapy in Alzheimer’s disease Statin therapy is a widely used treatment for hypercholesterolaemia and reduces the risk of stroke and adverse cardiovascular outcomes. In the past decade, epidemiological, clinical, and experimental evidence has accumulated that links cholesterol to the development of Alzheimer’s disease (AD), and a recent study showed that statin therapy might be of benefit in treating AD.1 The association between cholesterol and AD is not surprising: the brain is the most cholesterol-rich organ, and cholesterol has roles in many brain functions. In experimental studies, disturbances in cholesterol homoeostasis have been associated with all the major neuropathological features of AD. Furthermore, epidemiological data indicate that high serum cholesterol concentrations at midlife increase the risk of AD later in life.2 The role of cholesterol later in life or closer to dementia onset is less clear; cholesterol concentrations commonly decline during ageing and the decline seems to be more rapid among people who develop AD. Finally, some but not all observational studies have shown an association between statin use and a low risk of AD. Sparks and co-workers1 recently published preliminary results from the Alzheimer’s Disease CholesterolLowering Treatment trial, which is a pilot proof-ofconcept, double-blind, placebo-controlled, randomised study on the effects of statin treatment in AD.1 Individuals with mild-to-moderate AD (MMSE 12–28) and normal cholesterol concentration were randomly assigned to treatment with placebo or atorvastatin (80 mg/day) for 1 year while continuing to take cholinesterase inhibitors. Of 67 patients, 63 completed the 3 month visit and could be assessed. Trends toward benefits of atorvastatin were seen in each of the clinical outcome measures over the course of the study. The benefit was significant for depressive symptoms (the Geriatric Depression Scale) and for cognitive function (ADAS-cog) at 6 months, and there were trends for improvements in cognitive function, clinical efficacy, and psychiatric symptoms at 12 months. A significant effect on depressive symptoms remained at 12 months. The results of this small pilot study can be taken as a sign that statins may have a positive effect on cognition and behaviour in patients with AD. However, the results should be interpreted with caution, and larger multicentre trials are needed to assess the long-term http://neurology.thelancet.com Vol 4 September 2005
effects of statins in patients with AD, including both beneficial and adverse effects. Furthermore, it will be interesting to investigate whether ApoE genotype (Sparks and co-workers found a high frequency of the 4 allele), severity of cognitive impairment, and other characteristics affect the outcomes of statin treatment. An earlier, 26 week, randomised study in 44 patients with AD found a smaller reduction in MMSE score in patients given simvastatin (80 mg/day) than in those given placebo.3 Simvastatin lowered the concentration of amyloid- peptide in the CSF of patients with mild AD. In a small, 1 year, open-label study in patients with AD, a lower dose of simvastatin (20 mg/day) affected brain cholesterol metabolism and favoured the nonamyloidogenic pathway, but had no effect on CSF amyloid- concentrations.4 Relative benefit of lipophilic statins (eg, simvastatin, lovastatin; which cross the blood–brain barrier more effectively) and hydrophilic statins (eg, pravastatin, fluvastatin, rosuvastatin, atorvastin) is a matter of debate. Sparks and co-workers selected a hydrophilic statin because increased brain cholesterol promoting amyloid production may be due to high peripheral cholesterol concentrations, and they suggested that lipophilic statins may exacerbate degeneration in AD by inhibiting normal neuronal cholesterol synthesis. Cholesterol may indeed have a dual role in the pathogenesis of AD: increased concentrations of cellular cholesterol may increase amyloid- production, but oligomeric amyloid may decrease cellular cholesterol, and finally, low cholesterol concentrations in the brain may promote neurodegeneration. Thus, a low concentration of cellular cholesterol may prevent AD, but may increase AD pathology when cognitive impairment is already clinically manifest.5 Contradictory results of experimental, clinical, and epidemiological studies could be caused by differences in timing between the beginning of AD changes in the brain and initiation, duration, and type of statin treatment. The main open question in the “peripheral-cholesterollowering theory” is how serum cholesterol affects brain cholesterol? Central and peripheral cholesterol pools are separate—almost all cholesterol in the brain is synthesised locally. However, side-chain oxidised cholesterol metabolites such as hydroxycholesterols do 521
Reflection and Reaction
cross the blood–brain barrier. Interestingly, there is net uptake of 27-hydroxycholesterol by the brain from the circulation,6 which might be a missing link between hypercholesterolaemia and AD. Cholesterol-lowering statins have several other actions including anti-inflammatory, antioxidative, antithrombogenic, and immunological effects, and improvement of endothelial function that may produce or contribute to the observed trends. The roles of these additional effects in AD need to be further assessed Large clinical trials are needed to provide additional information about the potential benefit of statin therapy in the treatment of AD. Two such studies are ongoing: the Cholesterol Lowering Agent to Slow Progression (CLASP) of AD, in which about 400 patients will be randomly assigned to simvastatin (20 mg/day, titrated to 40 mg/day) or placebo for 18 months, and the Lipitor’s Effect in AD (LEAD) study, in which around 600 patients are assigned to donepezil (10 mg/day) plus either atorvastatin (80 mg/day) or placebo for 72 weeks. AD is a complex and multifactorial disease in which a long preclinical phase is an opportunity for intervention. Available drugs have mainly symptomatic effects. Delaying of the disease process would be of great clinical and public-health importance. Statins may be useful both in the prevention or delaying of onset, in treating
the symptoms, and in slowing the progression. Finally, the optimum approach may consist of a combination of statins with other treatments. To date, we do not have enough evidence to recommend statins for AD treatment. However, the evidence available highlights the importance of identifying and treating high cholesterol concentrations among both cognitively intact and cognitively impaired individuals. Miia Kivipelto, Alina Solomon, Bengt Winblad Karolinska University Hospital, Huddinge, Stockholm, Sweden [email protected] MK and BW have been consultants or advisory-board members for Pfizer (MK, BW), Merz, Lundbeck, Novartis, Janssen (BW). AS has no conflicts of interest. 1
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Sparks DL, Sabbagh MN, Connor DJ, et al. Atorvastatin for the treatment of mild to moderate Alzheimer disease: preliminary results. Arch Neurol 2005; 62: 753–57. Kivipelto M, Helkala E-L, Laakso MP, et al. Midlife vascular risk factors and Alzheimer’s disease in later life: longitudinal population based study. BMJ 2001; 322: 1447–51. Simons M, Schwarzler F, Lutjohann D, et al. Treatment with simvastatin in normocholesterolemic patients with Alzheimer’s disease: a 26-week randomized, placebo-controlled, double-blind trial. Ann Neurol 2002; 52: 346–50. Höglund K, Thelen KM, Syversen S, et al. The effect of simvastatin treatment on the amyloid precursor protein and brain cholesterol metabolism in patients with Alzheimer’s disease. Dement Geriatr Cogn Disord 2005; 19: 256–65. Michikawa M. The role of cholesterol in pathogenesis of Alzheimer’s disease: dual metabolic interaction between amyloid -protein and cholesterol. Mol Neurobiol 2003; 27: 1–11. Heverin M, Meaney S, Lutjohann D, Diczfalusy U, Wahren J, Björkhem I. Crossing the barrier: net flux of 27-hydroxycholesterol into the human brain. J Lipid Res 2005; 46: 1047–52.
CSF testing for multiple sclerosis New diagnostic criteria for multiple sclerosis (MS) were published in 2001 by McDonald and colleagues.1 These criteria take account of the clinical features, brain and spinal-cord MRI findings, CSF findings, and visual evoked-potential studies. The McDonald criteria define rigorous MRI requirements but do not define an optimum CSF test for the diagnosis of MS. CSF testing should be optimised, because, in the McDonald criteria, a positive CSF study is an essential diagnostic criterion in patients who have objective clinical evidence of only one lesion and only a few MRI lesions, and it is a mandatory criterion for the diagnosis of primary progressive MS.1 The rationale underpinning the use of CSF testing is the determination of whether there is synthesis of immunoglobulin G (IgG) in the CNS compartment (intrathecal synthesis). This indicates expansion of B cells in the CNS and is a characteristic feature of MS. In 522
the McDonald criteria, a positive CSF study is defined as one showing either oligoclonal IgG bands or a high IgG index, which are two different indicators of intrathecal IgG synthesis. These indicators differ in sensitivity and specificity, and there are also differences in the techniques of CSF analysis. To assess and recommend the type of CSF analysis that is optimum for a diagnosis of MS, the Consortium of Multiple Sclerosis Clinics commissioned a study group that included individuals who had considerable expertise in CSF analysis, the diagnosis and management of patients with MS, or both. The result is a recently published helpful consensus statement recommending a standard of CSF analysis in the diagnosis of MS.2 The consensus group recommend that the gold standard should be qualititative assessment of paired CSF and serum samples for the detection of http://neurology.thelancet.com Vol 4 September 2005
Statin therapy in Alzheimer’s disease Statin therapy is a widely used treatment for hypercholesterolaemia and reduces the risk of stroke and adverse cardiovascular outcomes. In the past decade, epidemiological, clinical, and experimental evidence has accumulated that links cholesterol to the development of Alzheimer’s disease (AD), and a recent study showed that statin therapy might be of benefit in treating AD.1 The association between cholesterol and AD is not surprising: the brain is the most cholesterol-rich organ, and cholesterol has roles in many brain functions. In experimental studies, disturbances in cholesterol homoeostasis have been associated with all the major neuropathological features of AD. Furthermore, epidemiological data indicate that high serum cholesterol concentrations at midlife increase the risk of AD later in life.2 The role of cholesterol later in life or closer to dementia onset is less clear; cholesterol concentrations commonly decline during ageing and the decline seems to be more rapid among people who develop AD. Finally, some but not all observational studies have shown an association between statin use and a low risk of AD. Sparks and co-workers1 recently published preliminary results from the Alzheimer’s Disease CholesterolLowering Treatment trial, which is a pilot proof-ofconcept, double-blind, placebo-controlled, randomised study on the effects of statin treatment in AD.1 Individuals with mild-to-moderate AD (MMSE 12–28) and normal cholesterol concentration were randomly assigned to treatment with placebo or atorvastatin (80 mg/day) for 1 year while continuing to take cholinesterase inhibitors. Of 67 patients, 63 completed the 3 month visit and could be assessed. Trends toward benefits of atorvastatin were seen in each of the clinical outcome measures over the course of the study. The benefit was significant for depressive symptoms (the Geriatric Depression Scale) and for cognitive function (ADAS-cog) at 6 months, and there were trends for improvements in cognitive function, clinical efficacy, and psychiatric symptoms at 12 months. A significant effect on depressive symptoms remained at 12 months. The results of this small pilot study can be taken as a sign that statins may have a positive effect on cognition and behaviour in patients with AD. However, the results should be interpreted with caution, and larger multicentre trials are needed to assess the long-term http://neurology.thelancet.com Vol 4 September 2005
effects of statins in patients with AD, including both beneficial and adverse effects. Furthermore, it will be interesting to investigate whether ApoE genotype (Sparks and co-workers found a high frequency of the 4 allele), severity of cognitive impairment, and other characteristics affect the outcomes of statin treatment. An earlier, 26 week, randomised study in 44 patients with AD found a smaller reduction in MMSE score in patients given simvastatin (80 mg/day) than in those given placebo.3 Simvastatin lowered the concentration of amyloid- peptide in the CSF of patients with mild AD. In a small, 1 year, open-label study in patients with AD, a lower dose of simvastatin (20 mg/day) affected brain cholesterol metabolism and favoured the nonamyloidogenic pathway, but had no effect on CSF amyloid- concentrations.4 Relative benefit of lipophilic statins (eg, simvastatin, lovastatin; which cross the blood–brain barrier more effectively) and hydrophilic statins (eg, pravastatin, fluvastatin, rosuvastatin, atorvastin) is a matter of debate. Sparks and co-workers selected a hydrophilic statin because increased brain cholesterol promoting amyloid production may be due to high peripheral cholesterol concentrations, and they suggested that lipophilic statins may exacerbate degeneration in AD by inhibiting normal neuronal cholesterol synthesis. Cholesterol may indeed have a dual role in the pathogenesis of AD: increased concentrations of cellular cholesterol may increase amyloid- production, but oligomeric amyloid may decrease cellular cholesterol, and finally, low cholesterol concentrations in the brain may promote neurodegeneration. Thus, a low concentration of cellular cholesterol may prevent AD, but may increase AD pathology when cognitive impairment is already clinically manifest.5 Contradictory results of experimental, clinical, and epidemiological studies could be caused by differences in timing between the beginning of AD changes in the brain and initiation, duration, and type of statin treatment. The main open question in the “peripheral-cholesterollowering theory” is how serum cholesterol affects brain cholesterol? Central and peripheral cholesterol pools are separate—almost all cholesterol in the brain is synthesised locally. However, side-chain oxidised cholesterol metabolites such as hydroxycholesterols do 521
Reflection and Reaction
cross the blood–brain barrier. Interestingly, there is net uptake of 27-hydroxycholesterol by the brain from the circulation,6 which might be a missing link between hypercholesterolaemia and AD. Cholesterol-lowering statins have several other actions including anti-inflammatory, antioxidative, antithrombogenic, and immunological effects, and improvement of endothelial function that may produce or contribute to the observed trends. The roles of these additional effects in AD need to be further assessed Large clinical trials are needed to provide additional information about the potential benefit of statin therapy in the treatment of AD. Two such studies are ongoing: the Cholesterol Lowering Agent to Slow Progression (CLASP) of AD, in which about 400 patients will be randomly assigned to simvastatin (20 mg/day, titrated to 40 mg/day) or placebo for 18 months, and the Lipitor’s Effect in AD (LEAD) study, in which around 600 patients are assigned to donepezil (10 mg/day) plus either atorvastatin (80 mg/day) or placebo for 72 weeks. AD is a complex and multifactorial disease in which a long preclinical phase is an opportunity for intervention. Available drugs have mainly symptomatic effects. Delaying of the disease process would be of great clinical and public-health importance. Statins may be useful both in the prevention or delaying of onset, in treating
the symptoms, and in slowing the progression. Finally, the optimum approach may consist of a combination of statins with other treatments. To date, we do not have enough evidence to recommend statins for AD treatment. However, the evidence available highlights the importance of identifying and treating high cholesterol concentrations among both cognitively intact and cognitively impaired individuals. Miia Kivipelto, Alina Solomon, Bengt Winblad Karolinska University Hospital, Huddinge, Stockholm, Sweden [email protected] MK and BW have been consultants or advisory-board members for Pfizer (MK, BW), Merz, Lundbeck, Novartis, Janssen (BW). AS has no conflicts of interest. 1
2
3
4
5
6
Sparks DL, Sabbagh MN, Connor DJ, et al. Atorvastatin for the treatment of mild to moderate Alzheimer disease: preliminary results. Arch Neurol 2005; 62: 753–57. Kivipelto M, Helkala E-L, Laakso MP, et al. Midlife vascular risk factors and Alzheimer’s disease in later life: longitudinal population based study. BMJ 2001; 322: 1447–51. Simons M, Schwarzler F, Lutjohann D, et al. Treatment with simvastatin in normocholesterolemic patients with Alzheimer’s disease: a 26-week randomized, placebo-controlled, double-blind trial. Ann Neurol 2002; 52: 346–50. Höglund K, Thelen KM, Syversen S, et al. The effect of simvastatin treatment on the amyloid precursor protein and brain cholesterol metabolism in patients with Alzheimer’s disease. Dement Geriatr Cogn Disord 2005; 19: 256–65. Michikawa M. The role of cholesterol in pathogenesis of Alzheimer’s disease: dual metabolic interaction between amyloid -protein and cholesterol. Mol Neurobiol 2003; 27: 1–11. Heverin M, Meaney S, Lutjohann D, Diczfalusy U, Wahren J, Björkhem I. Crossing the barrier: net flux of 27-hydroxycholesterol into the human brain. J Lipid Res 2005; 46: 1047–52.
CSF testing for multiple sclerosis New diagnostic criteria for multiple sclerosis (MS) were published in 2001 by McDonald and colleagues.1 These criteria take account of the clinical features, brain and spinal-cord MRI findings, CSF findings, and visual evoked-potential studies. The McDonald criteria define rigorous MRI requirements but do not define an optimum CSF test for the diagnosis of MS. CSF testing should be optimised, because, in the McDonald criteria, a positive CSF study is an essential diagnostic criterion in patients who have objective clinical evidence of only one lesion and only a few MRI lesions, and it is a mandatory criterion for the diagnosis of primary progressive MS.1 The rationale underpinning the use of CSF testing is the determination of whether there is synthesis of immunoglobulin G (IgG) in the CNS compartment (intrathecal synthesis). This indicates expansion of B cells in the CNS and is a characteristic feature of MS. In 522
the McDonald criteria, a positive CSF study is defined as one showing either oligoclonal IgG bands or a high IgG index, which are two different indicators of intrathecal IgG synthesis. These indicators differ in sensitivity and specificity, and there are also differences in the techniques of CSF analysis. To assess and recommend the type of CSF analysis that is optimum for a diagnosis of MS, the Consortium of Multiple Sclerosis Clinics commissioned a study group that included individuals who had considerable expertise in CSF analysis, the diagnosis and management of patients with MS, or both. The result is a recently published helpful consensus statement recommending a standard of CSF analysis in the diagnosis of MS.2 The consensus group recommend that the gold standard should be qualititative assessment of paired CSF and serum samples for the detection of http://neurology.thelancet.com Vol 4 September 2005