epidemiological evidence suggests that drugs which counteract inflammation might have efficacy for the prevention and treatment of alzheimer s disease , but up to now clinical trials have failed to show any clear - cut benefits for nonsteroidal anti - inflammatory drugs ( nsaids ) , hydroxychloroquine , anti - leprosy agents or prednisone ( endoh et al 1999 ; aisen et al 2000 ; van gool et al 2001 ; adapt et al 2007 ) . in the case of prednisone , however , it may be that much higher doses might be effective where lower doses were not . in the largest clinical trial to date , patients were given prednisone starting at 20 mg per day for one month , followed by one year at 10 mg daily and then tapering off over another 4 months ( aisen et al 2000 ) . by contrast , in a series of 16 nondemented patients aged 25 to 82 who were given prednisolone 3060 mg per day for at least month for treatment of various conditions , there was significant reduction in cerebrospinal fluid amyloid beta peptides in 15 out of 16 patients , up to about a 50% decline for patients receiving 50 and 60 mg of prednisolone ( tokuda et al 2002 ) . if amyloid is indeed a cause of alzheimer s disease ( hardy 2006 ) , the above data suggests high dose steroids could suppress alzheimer s disease by reducing amyloid . along the same lines , there is a report of a patient where two single doses of dexamethasone 4 mg completely suppressed amyloid angiopathy , reversed white matter changes on brain imaging , and restored cognitive function ( harkness et al 2004 ) . in that patient , 8 mg of dexamethasone would correspond to 80 mg of prednisone , or four times the starting dose of prednisone used in the alzheimer s disease clinical trial but given in a single dose . if the above line of reasoning is on the right track , it is important to note that high dose corticosteroids are already used clinically for treatment of primary systemic amyloidosis , in amounts orders of magnitude greater than those used in the alzheimer s disease trial . for example , in one recently published study of a regimen combining dexamethasone and interferon , patients were given several days of dexamethasone in an amount of 40 mg per day , which would be equivalent to 400 mg of prednisone daily ( dhodapkar et al 2004 ) . even if amyloid is only a marker , not a cause , for alzheimer s disease ( lee 2006 ) , high - dose corticosteroids could have beneficial effects by reducing inflammatory cytokines , which have been strongly linked to alzheimer s disease pathogenesis ( town and nikolic 2005 ; cagnin et al 2006 ; galimberti et al 2006 ; mcgeer et al 2006 ; rota et al 2006 ) . finally , there is a case report of a 64-year - old man with multiple myeloma who had a temporary remission of alzheimer s disease while receiving chemotherapy with vincristine , carmustine , melphalan , cyclophosphamide , and prednisone ( keimowitz 1997 ) . obviously megadose steroids or cytotoxic chemotherapy as a treatment for alzheimer s disease would be hard to justify , but if one can knock down amyloid production , inflammation or both with corticosteroids alone , there should be at least some therapeutic effects . the key is delivering high enough doses of corticosteroids to have efficacy without devastating or killing patients with steroid - induced side effects in the process . building on several case reports of patients with central nervous system lupus erythematosus and multiple sclerosis who responded to intrathecal prednisolone , dexamethasone , or triamcinalone after failing oral and intravenous steroids ( funauchi et al 2003 ; hellwig et al 2004 , 2006 ) , this paper proposes that a similar therapeutic strategy could be pursued for patients with alzheimer s disease . studies in rhesus monkeys and pigs indicate that that intrathecal steroids maximize biodistribution within the brain and minimize it within the rest of the body ( marynick et al 1976 ; koszdin et al 2000 ) . a short pulse of high dose intrathecal methylprednisolone , dexamethasone or triamcinalone will result in detectable slowing of alzheimer s disease as assessed by neuropsychological testing , cerebrospinal fluid studies and functional brain imaging . it is further predicted that this route of administration will minimize the risk of steroid - induced side effects , which include diabetes , cataracts , glaucoma , poor wound healing , myopathy , increased susceptibility to infection , osteoporosis and altered fat distribution , based on the premise that the bioavailability of steroids would be almost exclusively within the central nervous system . steroid - induced dementia that remits once steroids are stopped has been described in case reports ( varney 1997 ; sacks and shulman 2005 ) , but memantine , a noncompetitive antagonist of n - methyl - d - aspartate glutamate receptors , should reduce or eliminate this risk . memantine , which acts by protecting against excitoxic neuronal cell death , is already a mainstay of treatment for alzheimer s disease , with disease modifying activity that is maximized when given alongside cholinesterase inhibitors ( tariot et al 2004 ) . corticosteroids down - regulate glutamate transporter protein in microglia ( jacobsson et al 2006 ) , which in turn increases excitoxicity , so memantine which blocks glutamate excitotoxicty would seem to be ideal for preventing this problem . these agents improve learning and memory by increasing synaptic levels of acetylcholine , and cholinesterase inhibitors produce symptomatic improvement not only for alzheimer s disease but vascular , multiple sclerosis , parkinsonian , and lewy body dementias and delirium . they in essence boost cognitive reserve to cope with cognitive impairment no matter what the etiology , which would presumably include the minority of patients who have cognitive impairment specifically from steroids . thus , by doing all pulse dose steroid regimens alongside both cholinesterase inhibitors and memantine , it is predicted that there will be no worsening of dementia but rather additive effects on top of the benefits of cholinesterase inhibitors and memantine have on their own . a protocol is outlined here based on regimens described for central nervous system lupus and multiple sclerosis , to be used as a starting point for designing future clinical trials . investigators should follow all recommended guidelines for research involving human subjects , such as institutional review board approval and informed consent . after obtaining a baseline positron emission tomography ( pet ) scan and neuropsychological tests , patients with early alzheimer s disease already taking a cholinesterase inhibitor and memantine would be given six intrathecal injections of 10 mg of dexamethasone , 100 mg of prednisolone , or 40 mg triamcinalone . intrathecal injections can be done in the office with a bedside spinal tap or under fluoroscopic guidance , if desired . patients should be followed for at least one year in the initial study , repeating pet scans , cerebrospinal fluid studies , and neuropsychological testing at the end of the study . pet scanning has emerged as an important modality for studying alzheimer s disease and its response to treatment ( alexander et al 2002 ) . alongside functional brain imaging , cerebrospinal fluid should be assayed for amyloid peptide and other alzheimer s disease biomarkers , such as neural thread protein ( chong et al 1992 ; mrak and griffin 2005 ) . it would be predicted that levels of these biomarkers should fall over time , if steroids indeed have efficacy for halting dementia progression . studies should focus on patients with the earliest signs of cognitive impairment so that they can be followed for longer periods of time . also , there may be a window of opportunity for use of steroids only earlier in the disease process . many of the inflammatory cytokines peak with mild cognitive impairment and early alzheimer s disease and are actually declining by the late stages ( galimberti et al 2006 ) . validation of the proposed hypothesis could be an important step towards the ultimate aim of curing alzheimer s disease . pulse dosed intrathecal corticosteroids might become part of a future multi - agent regimen for halting alzheimer s disease progression , along - side cholinesterase inhibitors , memantine , and other drugs currently under investigation . given that activated microglia are thought to play a role in the pathogenesis of other neurodegnerative diseases such as parkinson s disease , amyotrophic lateral sclerosis and hiv dementia ( wojtera et al 2005 ) , success of intrathecal corticosteroids for alzheimer s disease would encourage trials for these other disorders . for all these reasons , i am presenting this idea here for maximum exposure to the widest possible interested audience .
anti - inflammatory drugs for treatment and prevention of alzheimer s disease have to date proved disappointing , including a large study of low - dose prednisone , but higher dose steroids significantly reduced amyloid secretion in a small series of nondemented patients . 
 in addition , there is a case report of a patient with amyloid angiopathy who had complete remission from two doses of dexamethasone , and very high dose steroids are already used for systemic amyloidosis . 
 this paper presents the hypothesis that pulse - dosed intrathecal methylprednisolone or dexamethasone will produce detectable slowing of alzheimer s progression , additive to that obtained with cholinesterase inhibitors and memantine . 
 a protocol based on treatment regimens for multiple sclerosis and central nervous system lupus is outlined , to serve as a basis for formulating clinical trials . 
 ultimately intrathecal corticosteroids might become part of a multi - agent regimen for alzheimer s disease and also have application for other neurodegenerative disorders .