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Original Contribution |

Atorvastatin for the Treatment of Mild to Moderate Alzheimer Disease:  Preliminary Results FREE

D. Larry Sparks, PhD; Marwan N. Sabbagh, MD; Donald J. Connor, PhD, PhD; Jean Lopez, MSN, CNRN; Lenore J. Launer, PhD; Patrick Browne, MD; Dawn Wasser, BS; Sherry Johnson-Traver; Jeff Lochhead, BS; Chuck Ziolwolski, MS
[+] Author Affiliations

Author Affiliations: Sun Health Research Institute, Sun City, Ariz (Drs Sparks, Sabbagh, and Connor, Mss Lopez and Johnson-Traver, and Messrs Lochhead and Ziolwolski); National Institute on Aging, Bethesda, Md (Dr Launer); and Departments of Cardiology (Dr Browne) and Pharmacy (Ms Wasser), Walter O. Boswell Hospital, Sun City.


Arch Neurol. 2005;62(5):753-757. doi:10.1001/archneur.62.5.753.
Text Size: A A A
Published online

Background  Laboratory evidence of cholesterol-induced production of amyloid β as a putative neurotoxin precipitating Alzheimer disease, along with epidemiological evidence, suggests that cholesterol-lowering statin drugs may favorably influence the progression of the disorder.

Objective  To determine if treatment with atorvastatin calcium affects the cognitive and/or behavioral decline in patients with mild to moderate Alzheimer disease.

Design  Pilot intention-to-treat, proof-of-concept, double-blind, placebo-controlled, randomized (1:1) trial with a 1-year exposure to once-daily atorvastatin calcium (80 mg; two 40-mg tablets) or placebo using last observation carried forward analysis of covariance as the primary method of statistical assessment.

Participants  Individuals with mild to moderate Alzheimer disease (Mini-Mental State Examination score of 12-28) were recruited. Of the 98 participants providing informed consent, 71 were eligible for randomization, 67 were randomized, and 63 subjects completed the 3-month visit and were considered evaluable.

Main Outcome Measures  The primary outcome measures were change in Alzheimer's Disease Assessment Scale–cognitive subscale and the Clinical Global Impression of Change Scale scores. The secondary outcome measures included scores on the Mini-Mental State Examination, Geriatric Depression Scale, the Neuropsychiatric Inventory Scale, and the Alzheimer’s Disease Cooperative Study–Activities of Daily Living Inventory. The tertiary outcome measures included total cholesterol, low-density lipoprotein cholesterol, and very low-density lipoprotein cholesterol levels.

Results  Atorvastatin reduced circulating cholesterol levels and produced a positive signal on each of the clinical outcome measures compared with placebo. This beneficial effect reached significance for the Geriatric Depression Scale and the Alzheimer's Disease Assessment Scale–cognitive subscale at 6 months and was significant at the level of a trend for the Alzheimer's Disease Assessment Scale–cognitive subscale, Clinical Global Impression of Change Scale, and Neuropsychiatric Inventory Scale at 12 months assessed by analysis of covariance with last observation carried forward.

Conclusion  Atorvastatin treatment may be of some clinical benefit and could be established as an effective therapy for Alzheimer disease if the current findings are substantiated by a much larger multicenter trial.

Figures in this Article

Alzheimer disease (AD) is characterized clinically by progressive deterioration of cognitive and noncognitive abilities, culminating in profound dementia. The antemortem diagnosis of AD is confirmed by the neuropathologic presence of neurofibrillary tangles and senile plaques in sufficient numbers to meet diagnostic criteria set by convention.1

The first hint of a relationship between cholesterol and AD stemmed from observations of enhanced prevalence of amyloid β–containing senile plaques among subjects without dementia with coronary artery disease compared with individuals without dementia and heart disease.2,3 Although not a consistent finding, it has been proposed that previously elevated circulating cholesterol levels increase the risk of AD 3-fold.4 A more recent study indicates chronically elevated cholesterol levels in midlife increase later risk of AD.5 The cholesterol-AD relationship gained support with evidence of increased brain amyloid β levels in cholesterol-fed New Zealand White rabbits as the best small-animal model of human coronary artery disease.6,7 A potential benefit for cholesterol-lowering therapy in AD was clear once significant reductions in brain amyloid β levels were identified after removing cholesterol from the diet of animals previously fed a cholesterol-enriched diet.7 More recently, some, but not all, epidemiological studies suggest that prior statin use in treating risk of coronary artery disease may reduce the risk of AD later in life.810

We tested the cholesterol-lowering medication atorvastatin calcium for positive effects on cognitive and noncognitive deterioration in mild to moderate AD. This investigator-initiated clinical evaluation began in 1999 as a proof-of-concept trial evaluating atorvastatin for clinical benefit. We used tests of clinical efficacy (Clinical Global Impression of Change scale11 [CGIC]) and cognitive function (Alzheimer's Disease Assessment Scale–cognitive subscale12 [ADAS-cog]) as primary outcomes and measures of global function (Mini-Mental State Examination [MMSE]), psychiatric symptoms (Neuropsychiatric Inventory Caregiver Distress Scale13 [NPI]), activity of daily living (Alzheimer’s Disease Cooperative Study–Activities of Daily Living Inventory14,15 [ADCS-ADL]), and depression severity (Geriatric Depression Scale16 [GDS]) as secondary outcome indexes. Tertiary outcome measures included total and fractionated cholesterol levels.

The study was initiated as an intention-to-treat investigation using a double-blind, placebo-controlled, randomized (1:1) design testing atorvastatin calcium (80 mg/d) compared with placebo for clinical benefit in treating mild to moderate AD for a 1-year period. As an intention-to-treat study, early withdrawals were anticipated and any subject completing the 3-month visit was considered evaluable. Written informed consent was obtained from participants and the participant’s legally authorized representative or caregiver using an institutional review board–approved informed consent form.

We recruited 97 individuals with probable or possible AD (National Institute of Neurological and Communicative Disorders and Stroke–the Alzheimer’s Disease and Related Disorders Associations’ [NINCDS/ADRDA] criteria)17 for this single-site study. Individuals 51 years and older with mild to moderate impairment (MMSE score, 12-28) meeting all preestablished criteria were eligible to participate in the trial. A single dose of atorvastatin calcium (80 mg/d) without dose titration was used. Because active treatment was expected to reduce circulating cholesterol levels, all investigators were blinded to both treatment group and cholesterol profiles after randomization. Only the special physician safety monitor (P.B.), who was not involved in any other aspect of the trial, viewed quarterly cholesterol levels to ensure patient safety. Blood-borne markers of liver dysfunction and altered muscle physiologic features were also monitored quarterly by the safety monitor as indicators of possible adverse events known to accompany administration of statins. Subjects were ineligible if they were already taking a cholesterol-lowering medication or being administered an investigational treatment for AD.

Atorvastatin calcium tablets (40 mg) and identical placebo tablets were supplied in bulk (single lot numbers for each, respectively) by Pfizer Pharmaceuticals, Inc (Ann Arbor, Mich). Active drug or placebo was packaged in bottles of 200 tablets (3-month supply) and provided to participants at the baseline, 3-, 6-, and 9-month visits.

Randomization was performed in blocks of 10 (5 active medication and 5 placebo) using the Excel spreadsheet random-number generator. The randomization schedule was inspected to ensure there was no duplication of random sequences and that there were 5 individuals assigned to each treatment group (D.W.). Bottles of study medication (as 3-month supplies) were coded at the pharmacy.

To participate, an individual 51 years or older, with a diagnosis of probable or possible AD according to NINCDS-ADRDA and Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition (DSM-IV) criteria for dementia and at least a ninth-grade education, was required to provide informed consent. It was necessary for the participant to be accompanied by an appropriate caregiver who could aid in administration of medication and make assessments, be of good general health as evidenced by physical, neurological, and clinical laboratory examinations, and speak English fluently. Participants were required to score 4 or less on the modified Hachinski Ischemia Scale18 and 20 or less on the GDS.

Participants were allowed to continue the use of stable doses of medications for the treatment of nonexcluded medical conditions for 4 weeks prior to screening; this included the use of 400 IU or lower of vitamin E. Patients currently taking cholinesterase inhibitors were required to have taken a stable dose for at least 3 months. No study subject was using memantine or allowed to initiate cholinesterase inhibitor use after trial entrance and continue participation.

Individuals with a neurological or psychiatric disease other than AD, including suspected Parkinson disease or dementia with Lewy bodies,19 significant systemic illness, organ failure, myocardial infarction, cardiac or thromboembolic vascular disease, major depression according to DSM-IV criteria, or currently using anticholinergic medications, were excluded from participation. Individuals with a history of head injury, significant liver disease and/or elevated transaminase levels, allergy to statin medications, or screen cholesterol levels below 90 mg/dL (2.3 mmol/L) were also excluded from participation.

At screening, the baseline MMSE20 was administered to ensure eligibility; if within established criteria (score 12-28), the modified Hachinski Ischemia Scale score (≤4) and the baseline GDS score (<20)16 were established to exclude individuals with significant vascular risk factors or clinical depression, respectively. At this visit, blood was drawn for testing (experimental and safety monitoring) and the baseline ADAS-cog12 was administered (by individuals blinded to CGIC performance).

At the randomization visit, no more than 14 days after the screening visit, the baseline CGIC11 (performed by a single individual blind to all other assessment information), NPI,13 and ADCS-ADL14,15 were administered.

The ADAS-cog, MMSE, and CGIC were readministered at the 3-, 6-, 9-, and 12-month visits, and the NPI and ADCS-ADL were readministered at the 6- and 12-month visits. The GDS was readministered at the participant’s exit visit (12-month or early termination).

Fasting cholesterol (total, low-density lipoprotein, high-density lipoprotein, and very low-density lipoprotein), liver function, and creatinine phosphokinase (to monitor muscle derangements and rhabdomyolysis) tests were performed using standard, approved methods in the Clinical Laboratory Improvement Amendments–certified and accredited Clinical Chemistry Laboratory at Walter O. Boswell Hospital, Sun City, Ariz. Any individual exhibiting a greater than 3-fold increase in liver function test results or a 10-fold increase in creatinine phosphokinase level, both higher than the upper limits of normal, was considered to have experienced an adverse event requiring discontinuation of study medication without possibility of resuming trial participation.

The initial statistical evaluation was to determine if there were differences in the mean value for any index between the atorvastatin and placebo groups prior to randomization (2-tailed independent t tests) (Table 1).

Table Graphic Jump LocationTable 1. Prerandomization Values for Each Index Among Individuals Providing Evaluable Data*

Thereafter, we used a statistical approach routinely used in intention-to-treat AD trials21,22 by performing analysis of covariance considering last observation carried forward data using baseline observations as a covariant to compare differences of least squares means between the groups (SAS Version 6.12; SAS Institute Inc, Cary, NC). Screen and quarterly visit values were evaluated for the ADAS-cog, MMSE, and cholesterol. Change in CGIC scores from baseline at quarterly visits was evaluated. Baseline and semiannual visit scores were compared for the NPI and ADCS-ADL. Screening and exit scores were compared for the GDS. Significance was based on 2-tailed evaluations.

SUBJECT POPULATION AND STUDY ATTRITION

We obtained 98 informed consents (Figure 1). Fifteen individuals withdrew prior to screening primarily to participate in other treatment trials. There were 12 screen failures, leaving 71 individuals eligible for randomization; 4 withdrew prior to the baseline visit. Sixty-seven individuals were blindly randomized (1:1) to receive either 80 mg of atorvastatin calcium or placebo. Sixty-three individuals were considered evaluable by completing the 3-month visit, 32 individuals receiving atorvastatin and 31 individuals receiving placebo. All but 6 individuals were taking cholinesterase inhibitors, 3 in the atorvastatin group and 3 in the placebo group. A total of 56 individuals completed the 6-month visit, 29 receiving active medication and 27 receiving placebo. Forty-eight individuals completed the 9-month visit, 26 receiving atorvastatin and 22 receiving placebo. Forty-six individuals completed the 1-year study, 25 receiving atorvastatin and 21 receiving placebo.

Place holder to copy figure label and caption
Figure 1.

Flow of subjects providing informed consent for participation in the Alzheimer’s Disease Cholesterol-Lowering Treatment trial and staging of attrition.

Graphic Jump Location
PRERANDOMIZATION COMPARISON OF GROUP DIFFERENCES

There was no significant difference in the mean entrance values for any demographic, clinical, or chemical index between individuals later randomized into the atorvastatin and placebo groups (Table 1), although performance on the NPI in the placebo group was somewhat more impaired at the start of the trial. There was no difference in the entrance Hachinski Ischemia Scale score (mean ± SD, atorvastatin = 2.44 ± 0.25; placebo = 2.52 ± 0.23) between the 2 groups.

BLOOD TESTING RESULTS

Consistent with results in individuals with normal cognition, atorvastatin treatment produced significant decreases in total cholesterol (Figure 2A), low-density lipoprotein cholesterol, and very low-density lipoprotein cholesterol levels (not shown) among the individuals with mild to moderate AD compared with placebo (P<.01). These significant decreases relative to placebo (P<.002) in total cholesterol (40%), low-density lipoprotein cholesterol (54%), and very low-density lipoprotein cholesterol (30%) levels were detected at the 3-month visit and persisted to 12 months.

Place holder to copy figure label and caption

Figure 2. Course of the effect of atorvastatin calcium vs placebo at screen/baseline and at each quarterly visit. A, Mean ± SEM circulating total cholesterol levels from evaluable individuals (N = 63) at screen and all visits. B, Alzheimer’s Disease Assessment Scale–cognitive subscale12 (ADAS-cog) data from all evaluable individuals (N = 63). Mean ± SEM scores for screen and quarterly visits. C, Clinical Global Impression of Change Scale11 (CGIC) mean ± SEM data for all individuals receiving study medication in the placebo and treatment groups at each visit. D, Mini-Mental State Examination20 (MMSE) data from all evaluable individuals (N = 63). Mean ± SEM scores for screen and all visits. E, Neuropsychiatric Inventory Caregiver Distress Scale13 (NPI) (10-item) mean ± SEM scores from all evaluable individuals (N = 63) for visits while receiving study medications. F, Geriatric Depression Scale16 (GPS) mean ± SEM scores for individuals taking study medication at screen and at exit or 1 year. Observed means at each point (±SEM) for each treatment group are presented with corresponding significance by analysis of covariance with last observation carried forward.

Graphic Jump Location
PRIMARY CLINICAL OUTCOME MEASURES

Both the atorvastatin and placebo groups showed deterioration on the ADAS-cog at 3 months; the placebo population continued to deteriorate approximately 1 point per quarter thereafter (Figure 2B). Performance on the ADAS-cog in the atorvastatin population was approximately 3.5 points superior to the placebo group at 6 months and 12 months. Difference in ADAS-cog scores between the groups was significant at 6 months (P<.003) and all but significant at 12 months (P = .055) (Table 2). A trend for a difference on the CGIC between the atorvastatin and placebo groups was achieved at both 9 (P = .058) (Figure 2C) and 12 months (P = .07) (Table 2).

Table Graphic Jump LocationTable 2. Significance of Difference After 12 Months of Atorvastatin Treatment Compared With Placebo for Each Clinical Instrument*
SECONDARY CLINICAL OUTCOME MEASURES

Although performance on the MMSE in the atorvastatin group showed limited improvement after the 3-month visit (Figure 2D), the difference between the groups was not significant (P>.10) (Table 2). There was a trend for a significant difference in NPI scores between the groups (Figure 2E) at 6 months (P = .08) and 12 months (P = .07) (Table 2). Atorvastatin produced significant benefit on the GDS (P<.04) (Table 2) because there was deterioration in the placebo group and improvement in the atorvastatin group (Figure 2F). Differences in performance on the ADCS-ADL between the treatment and placebo groups did not achieve significance (P>.23) (Table 2).

We have found that daily administration of 80 mg of atorvastatin calcium significantly reduces circulating cholesterol levels and may have a positive effect on the progressive deterioration of cognitive function and behavior anticipated in mild to moderate AD. As a pilot proof-of-concept study, significant differences were not expected, but benefits identified tend to support the trial’s rationale based on the hypothesis that excess brain cholesterol-promoting amyloid β production and subsequently the symptoms of AD come from the blood because of increased circulating levels. Although the data may seem to support a cholesterol-lowering mechanism, we must acknowledge that other physiologic effects of atorvastatin (ie, anti-inflammatory, vascular, or pleiotropic) could contribute to or produce the apparent beneficial effect.

Finally, although the results clearly hold promise, this was a pilot proof-of-concept trial with a small number of participants. We believe that we provide evidence for proof of concept, and establishment of similar benefit of atorvastatin in a multicenter trial investigating the effect in a much larger population may provide proof of therapy. Two such studies are ongoing.

Correspondence: D. Larry Sparks, PhD, Sun Health Research Institute, 10515 W Santa Fe Dr, Sun City, AZ 85351 (larry.sparks@sunhealth.org).

Accepted for Publication: November 22, 2004.

Author Contributions:Study concept and design: Sparks and Connor. Acquisition of data: Sabbagh, Connor, Lopez, Browne, Wasser, Johnson-Traver, Lochhead, and Ziolwolski. Analysis and interpretation of data: Sparks and Launer. Drafting of the manuscript: Sparks and Connor. Critical revision of the manuscript for important intellectual content: Sparks, Sabbagh, Lopez, Launer, Browne, Wasser, Johnson-Traver, Lochhead, and Ziolwolski. Statistical analysis: Launer. Obtained funding: Sparks. Administrative, technical, and material support: Sparks, Sabbagh, Connor, Lopez, Browne, Wasser, Johnson-Traver, Lochhead, and Ziolwolski. Study supervision: Sparks.

Funding/Support: This study was supported by the Institute for the Study of Aging, the Estee Lauder Charitable Trust, and Pfizer Inc, New York, NY.

Acknowledgment: We thank the Institute for the Study of Aging and the Estee Lauder Charitable Trust for making this study possible by providing initial funding. We thank Pfizer Inc for provision of additional funding and study medication.

Newell  KLHyman  BTGrowdon  JHHedley-Whyte  ET Application of the National Institute on Aging (NIA)-Reagan Institute criteria for the neuropathological diagnosis of Alzheimer's disease. J Neuropathol Exp Neurol 1999;581147- 1155
PubMed Link to Article
Sparks  DLHunsaker  JCScheff  SW  et al.  Cortical senile plaques in coronary artery disease, aging and Alzheimer's disease. Neurobiol Aging 1990;11601- 607
PubMed Link to Article
Sparks  DLLiu  HScheff  SWCoyne  CMHunsaker  JC  III Temporal sequence of plaque formation in the cerebral cortex of non-demented individuals. J Neuropathol Exp Neurol 1993;52135- 142
PubMed Link to Article
Notkola  I-LSulkava  RPekkanen  J  et al.  Serum total cholesterol, apolipoprotein E epsilon4 allele, and Alzheimer's disease. Neuroepidemiology 1998;1714- 20
PubMed Link to Article
Kivipelto  MHelkala  E-LHallikainen  M  et al.  Midlife vascular risk factors and Alzheimer’s disease in later life. BMJ 2001;3221447- 1451
PubMed Link to Article
Sparks  DLScheff  SWHunsaker  JC  III  et al.  Induction of Alzheimer-like β-amyloid immunoreactivity in the brains of rabbits with dietary cholesterol. Exp Neurol 1994;12688- 94
PubMed Link to Article
Sparks  DL Intraneuronal β-amyloid immunoreactivity in the CNS. Neurobiol Aging 1996;17291- 299
PubMed Link to Article
Rockwood  KKirkland  SHogan  DB  et al.  Use of lipid-lowering agents, indication bias, and the risk of dementia in community-dwelling elderly people. Arch Neurol 2002;59223- 227
PubMed Link to Article
Jick  HZornberg  GLJick  SSSeshadri  SDrachman  DA Statins and the risk of dementia. Lancet 2000;3561627- 1631
PubMed Link to Article
Wolozin  BKellman  WRuosseau  PCelesia  GSiegel  G Decreased prevalence of Alzheimer disease associated with 3-hydroxy-3-methyglutaryl coenzyme A reductase inhibitors. Arch Neurol 2000;571439- 1443
PubMed Link to Article
Schneider  LSOlin  JTDoody  RS  et al.  Validity and reliability of the Alzheimer's Disease Cooperative Study-Clinical Global Impression of Change. Alzheimer Dis Assoc Disord 1997;11S22- S32
PubMed Link to Article
Rosen  WGMohs  RCDavis  KL A new rating scale for Alzheimer's disease. Am J Psychiatry 1984;1411356- 1364
PubMed
Kaufer  DICummings  JLCristine  EL Assessing the impact of neuropsychiatric symptoms in Alzheimer's disease. J Am Geriatr Soc 1998;46210- 215
PubMed
Galasko  DCorey-Bloom  JThal  LJ Monitoring progression in Alzheimer's disease. J Am Geriatr Soc 1991;39932- 941
PubMed
Galasko  DBennett  DSano  M  et al.  An inventory to assess activities of daily living for clinical trials in Alzheimer's disease. Alzheimer Dis Assoc Disord 1997;11S33- S39
PubMed Link to Article
Yesavage  JA Geriatric Depression Scale. Psychopharmacol Bull 1988;24709- 711
PubMed
McKhann  GDrachman  DFolstein  M Clinical diagnosis of Alzheimer's disease. Neurology 1984;34939- 944
PubMed Link to Article
Rosen  WGTerry  RDFuld  PAKatzman  RPeck  A Pathological verification of ischemic score in differentiation of dementias. Ann Neurol 1980;7486- 488
Link to Article
McKeith  IGGalasko  DKosaka  K  et al.  Consensus guidelines for the clinical and pathologic diagnosis of dementia with Lewy bodies (DLB): report of the consortium on DLB international workshop. Neurology 1996;471113- 1124
PubMed Link to Article
Folstein  MFFolstein  SEMcHugh  PR “Mini-Mental State.” J Psychiatr Res 1975;12189- 198
PubMed Link to Article
Aisen  PSSchafer  KAGrundman  M  et al.  Effects of rofecoxib or naproxen vs placebo on Alzheimer disease progression. JAMA 2003;2892819- 2826
PubMed Link to Article
Aisen  P Randomized pilot study of nimesulide treatment in Alzheimer's disease. Neurology 2002;581050- 1054
PubMed Link to Article

Figures

Place holder to copy figure label and caption
Figure 1.

Flow of subjects providing informed consent for participation in the Alzheimer’s Disease Cholesterol-Lowering Treatment trial and staging of attrition.

Graphic Jump Location
Place holder to copy figure label and caption

Figure 2. Course of the effect of atorvastatin calcium vs placebo at screen/baseline and at each quarterly visit. A, Mean ± SEM circulating total cholesterol levels from evaluable individuals (N = 63) at screen and all visits. B, Alzheimer’s Disease Assessment Scale–cognitive subscale12 (ADAS-cog) data from all evaluable individuals (N = 63). Mean ± SEM scores for screen and quarterly visits. C, Clinical Global Impression of Change Scale11 (CGIC) mean ± SEM data for all individuals receiving study medication in the placebo and treatment groups at each visit. D, Mini-Mental State Examination20 (MMSE) data from all evaluable individuals (N = 63). Mean ± SEM scores for screen and all visits. E, Neuropsychiatric Inventory Caregiver Distress Scale13 (NPI) (10-item) mean ± SEM scores from all evaluable individuals (N = 63) for visits while receiving study medications. F, Geriatric Depression Scale16 (GPS) mean ± SEM scores for individuals taking study medication at screen and at exit or 1 year. Observed means at each point (±SEM) for each treatment group are presented with corresponding significance by analysis of covariance with last observation carried forward.

Graphic Jump Location

Tables

Table Graphic Jump LocationTable 1. Prerandomization Values for Each Index Among Individuals Providing Evaluable Data*
Table Graphic Jump LocationTable 2. Significance of Difference After 12 Months of Atorvastatin Treatment Compared With Placebo for Each Clinical Instrument*

References

Newell  KLHyman  BTGrowdon  JHHedley-Whyte  ET Application of the National Institute on Aging (NIA)-Reagan Institute criteria for the neuropathological diagnosis of Alzheimer's disease. J Neuropathol Exp Neurol 1999;581147- 1155
PubMed Link to Article
Sparks  DLHunsaker  JCScheff  SW  et al.  Cortical senile plaques in coronary artery disease, aging and Alzheimer's disease. Neurobiol Aging 1990;11601- 607
PubMed Link to Article
Sparks  DLLiu  HScheff  SWCoyne  CMHunsaker  JC  III Temporal sequence of plaque formation in the cerebral cortex of non-demented individuals. J Neuropathol Exp Neurol 1993;52135- 142
PubMed Link to Article
Notkola  I-LSulkava  RPekkanen  J  et al.  Serum total cholesterol, apolipoprotein E epsilon4 allele, and Alzheimer's disease. Neuroepidemiology 1998;1714- 20
PubMed Link to Article
Kivipelto  MHelkala  E-LHallikainen  M  et al.  Midlife vascular risk factors and Alzheimer’s disease in later life. BMJ 2001;3221447- 1451
PubMed Link to Article
Sparks  DLScheff  SWHunsaker  JC  III  et al.  Induction of Alzheimer-like β-amyloid immunoreactivity in the brains of rabbits with dietary cholesterol. Exp Neurol 1994;12688- 94
PubMed Link to Article
Sparks  DL Intraneuronal β-amyloid immunoreactivity in the CNS. Neurobiol Aging 1996;17291- 299
PubMed Link to Article
Rockwood  KKirkland  SHogan  DB  et al.  Use of lipid-lowering agents, indication bias, and the risk of dementia in community-dwelling elderly people. Arch Neurol 2002;59223- 227
PubMed Link to Article
Jick  HZornberg  GLJick  SSSeshadri  SDrachman  DA Statins and the risk of dementia. Lancet 2000;3561627- 1631
PubMed Link to Article
Wolozin  BKellman  WRuosseau  PCelesia  GSiegel  G Decreased prevalence of Alzheimer disease associated with 3-hydroxy-3-methyglutaryl coenzyme A reductase inhibitors. Arch Neurol 2000;571439- 1443
PubMed Link to Article
Schneider  LSOlin  JTDoody  RS  et al.  Validity and reliability of the Alzheimer's Disease Cooperative Study-Clinical Global Impression of Change. Alzheimer Dis Assoc Disord 1997;11S22- S32
PubMed Link to Article
Rosen  WGMohs  RCDavis  KL A new rating scale for Alzheimer's disease. Am J Psychiatry 1984;1411356- 1364
PubMed
Kaufer  DICummings  JLCristine  EL Assessing the impact of neuropsychiatric symptoms in Alzheimer's disease. J Am Geriatr Soc 1998;46210- 215
PubMed
Galasko  DCorey-Bloom  JThal  LJ Monitoring progression in Alzheimer's disease. J Am Geriatr Soc 1991;39932- 941
PubMed
Galasko  DBennett  DSano  M  et al.  An inventory to assess activities of daily living for clinical trials in Alzheimer's disease. Alzheimer Dis Assoc Disord 1997;11S33- S39
PubMed Link to Article
Yesavage  JA Geriatric Depression Scale. Psychopharmacol Bull 1988;24709- 711
PubMed
McKhann  GDrachman  DFolstein  M Clinical diagnosis of Alzheimer's disease. Neurology 1984;34939- 944
PubMed Link to Article
Rosen  WGTerry  RDFuld  PAKatzman  RPeck  A Pathological verification of ischemic score in differentiation of dementias. Ann Neurol 1980;7486- 488
Link to Article
McKeith  IGGalasko  DKosaka  K  et al.  Consensus guidelines for the clinical and pathologic diagnosis of dementia with Lewy bodies (DLB): report of the consortium on DLB international workshop. Neurology 1996;471113- 1124
PubMed Link to Article
Folstein  MFFolstein  SEMcHugh  PR “Mini-Mental State.” J Psychiatr Res 1975;12189- 198
PubMed Link to Article
Aisen  PSSchafer  KAGrundman  M  et al.  Effects of rofecoxib or naproxen vs placebo on Alzheimer disease progression. JAMA 2003;2892819- 2826
PubMed Link to Article
Aisen  P Randomized pilot study of nimesulide treatment in Alzheimer's disease. Neurology 2002;581050- 1054
PubMed Link to Article

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