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Original Investigation |

Plasma Total Cholesterol Level as a Risk Factor for Alzheimer Disease:  The Framingham Study FREE

Zaldy Sy Tan, MD, MPH; Sudha Seshadri, MD; Alexa Beiser, PhD; Peter W. F. Wilson, MD; Douglas P. Kiel, MD, MPH; Michael Tocco, BA; Ralph B. D'Agostino, PhD; Philip A. Wolf, MD
[+] Author Affiliations

From the Division on Aging, Harvard Medical School (Drs Tan and Kiel), the Departments of Neurology (Drs Seshadri and Wolf and Mr Tocco) and Medicine (Dr Wilson), Boston University School of Medicine, the Department of Epidemiology and Biostatistics, Boston University School of Public Health (Dr Beiser), the Hebrew Rehabilitation Center for Aged Research and Training Institute (Drs Tan and Kiel), and the Department of Mathematics and Statistics, Boston University (Dr D'Agostino), Boston, Mass. The authors have no relevant financial interest in this article.

From the Division on Aging, Harvard Medical School (Drs Tan and Kiel), the Departments of Neurology (Drs Seshadri and Wolf and Mr Tocco) and Medicine (Dr Wilson), Boston University School of Medicine, the Department of Epidemiology and Biostatistics, Boston University School of Public Health (Dr Beiser), the Hebrew Rehabilitation Center for Aged Research and Training Institute (Drs Tan and Kiel), and the Department of Mathematics and Statistics, Boston University (Dr D'Agostino), Boston, Mass. The authors have no relevant financial interest in this article.


Arch Intern Med. 2003;163(9):1053-1057. doi:10.1001/archinte.163.9.1053.
Text Size: A A A
Published online

Background  Previous studies examining the association of plasma cholesterol levels with the risk for development of Alzheimer disease (AD) have been inconclusive. We examined the impact of baseline and lifetime plasma total cholesterol levels averaged across many years on the risk for AD in a large, population-based cohort.

Methods  Five thousand two hundred nine subjects from the Framingham Study original cohort underwent biennial evaluation for cardiovascular risk factors since 1950, with estimations of serum total cholesterol levels at 19 of these 25 biennial examinations. The study sample consisted of 1026 subjects from this cohort who were alive and free of stroke and dementia at examination cycle 20 (1988-1989) and had undergone apolipoprotein E (APOE) genotyping. The main outcome measure was incident AD diagnosed using standard criteria, according to average total cholesterol levels across biennial examination cycles 1 to 15 and baseline total cholesterol level measured at the 20th biennial examination cycle.

Results  Alzheimer disease developed in 77 subjects from 1992 to 2000. After adjustment for age, sex, APOE genotype, smoking, body mass index (calculated as weight in kilograms divided by the square of height in meters), coronary heart disease, and diabetes, we found no significant association between the risk for incident AD and average cholesterol level at biennial examination cycles 1 to 15 (hazard ratio per 10-mg/dL [0.3-mmol/L] rise, 0.95; 95% confidence interval, 0.87-1.04) or baseline total cholesterol level at examination 20 (hazard ratio, 0.97; 95% confidence interval, 0.90-1.05).

Conclusion  In this large, population-based cohort, baseline and long-term average serum total cholesterol levels were not associated with the risk for incident AD.

THE APOLIPOPROTEIN E (APOE) ϵ4 allele is a cholesterol transport protein that is a well-established risk factor for late-onset Alzheimer disease (AD).1 The presence of an APOE ϵ4 allele increases the lifetime risk for development of AD and is also associated with an earlier age of onset. However, it is an incomplete predictor of disease susceptibility, as AD does not develop in all subjects with the APOE ϵ4 allele and not all patients with AD have the ϵ4 allele.

The underlying pathophysiology that explains the relationship between APOE ϵ4 and AD remains speculative, but may involve an APOE ϵ4–mediated increase in serum cholesterol levels. Cholesterol has been linked to the development of AD by studies showing an association between lipoprotein(a) levels and AD2 and between low-density lipoprotein receptor–related protein and AD3 and by epidemiological studies implicating cardiovascular risk factors in the development of dementia.4 Recently, several studies have suggested that the use of 3-hydroxy-3-methylglutaryl coenzyme A reductase inhibitors (statins) to lower cholesterol levels reduces the risk for AD.5,6 These studies are observational, and results from randomized, clinical trials are not yet available.

Several observational epidemiological studies examining the association between cholesterol and AD have yielded conflicting results.79 Possible explanations for the heterogeneity of results from these studies may be the use of single rather than cumulative, time-averaged cholesterol levels,7,9 the restriction of the study population to men,8 and the brief follow-up in some studies.7,9 The Framingham Heart Study data provide an opportunity to examine the association between lifetime cholesterol levels and the risk for development of AD in a large population-based cohort of men and women during a 25-year follow-up.

STUDY POPULATION

The Framingham Study is a longitudinal population-based cohort study of 5209 participants (2336 men and 2873 women) who have undergone evaluation for cardiovascular risk factors since 1948. In 1975, at the start of the 14th biennial examination cycle, 3330 subjects from the original cohort were still alive. Of these, 2828 (85%) attended the 14th biennial examination. Of the 2123 subjects undergoing testing using a standardized neuropsychological test battery10 administered during cycles 14 and 15, 2082 were judged to be cognitively intact. An additional 529 subjects who were not administered the neuropsychological test battery for logistic reasons had normal results of the Folstein Mini-Mental State Examination11 performed between 1982 and 1983.12 This yielded 2611 subjects (1061 men and 1550 women; mean ± SD age, 66 ± 7.4 years; age range, 54-85 years) who were cognitively intact at examination cycle 14. Subjects suspected of having cognitive impairment on neuropsychological testing underwent evaluation by a neurologist, and 41 subjects who were diagnosed as having dementia or cognitive impairment were excluded.

At examination cycle 20, 1229 subjects were alive and free of dementia. Of these, 203 subjects were excluded due to prevalent stroke (n = 75) or lack of APOE data (n = 128). The remaining 1026 subjects (646 women and 380 men) constituted our study sample. Baseline characteristics of subjects at examination cycle 20 are presented in Table 1 and Table 2.

Table Graphic Jump LocationTable 1. Baseline Subject Characteristics and Cholesterol Levels at Examination Cycle 20 (1988-1989)*
Table Graphic Jump LocationTable 2. Age- and Sex-Adjusted Hazard Ratios of AD in Relation to Cholesterol Measurements
CHOLESTEROL LEVELS

During the 40 years of follow-up (examination cycles 1-20), nonfasting cholesterol levels in the Framingham Study subjects were measured at 19 examinations.13 Nonenzymatic laboratory methods were used until the 20th biennial examination.14 Plasma cholesterol level was determined according to the Abell-Kendall method, and high-density lipoprotein cholesterol (HDL-C) level was measured after precipitation of plasma with a combination of heparin-manganese.15,16 Previous studies have shown that in comparing fasting and nonfasting cholesterol measurements, a 6% increase would be found in one third of the population; no change, in one third; and a 7% decrease, in one third, for a negligible population net difference attributable to fasting status.17

We used the following 3 different measures of total cholesterol level: the mean of the total cholesterol measurements obtained at or before the 15th examination cycle (mean TC1-15) as an estimate of time-averaged cholesterol level in subjects undergoing total cholesterol level estimates at 4 or more examination cycles by cycle 15; the total cholesterol level measured at examination cycle 20 (TC20) as an estimate of baseline cholesterol level; and the change in cholesterol levels between examination cycles 15 and 20 (ΔTC15-20) as a measure of change in cholesterol levels, excluding subjects taking medications to lower lipid levels (n = 83). The ΔTC15-20 was taken as an absolute difference between the cholesterol levels in the 2 examination cycles and treated continuously in the regression. In addition, we examined the relation of HDL-C levels at the 20th biennial examination to the risk for incident AD.

APOE GENOTYPES

We determined APOE genotypes using an isoelectric focusing of plasma and confirmed the findings by subsequent genotyping.18,19 Participants were dichotomized into one group consisting of persons with APOEϵ2/ϵ2, ϵ2/ϵ3, or ϵ3/ϵ3 genotypes, and the other consisting of those with APOE ϵ2/ϵ4, ϵ3/ϵ4, or ϵ4/ϵ4 genotypes.

CASE ASCERTAINMENT

Beginning at examination cycle 17 (1982), the Mini-Mental State Examination was administered biennially to the cohort. A Mini-Mental State Examination score below the education-specific cutoff score, a decline of 3 or more points between consecutive biennial examinations, or a decline of more than 5 points compared with any previous examination prompted more in-depth testing.20 For each subject with possible dementia, neurological and neuropsychological examinations were performed. Subjects with mild cognitive impairment (Clinical Dementia Rating21 scale score, 0.5) underwent reassessment at least biennially for progression to moderate or severe dementia. A panel consisting of 2 neurologists and a neuropsychologist reviewed all subjects designated as having significant dementia (Clinical Dementia Rating scale score, ≥1) by the examining neurologists. We used data from the neurologist's examination, neuropsychological test performance, Framingham Study records, hospital medical records, information from primary care physicians, computed tomographic and magnetic resonance imaging records, and autopsy confirmation when available. All subjects identified as having dementia satisfied the criteria of the Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition,22 had dementia severity of at least 1 on the Clinical Dementia Rating scale, and exhibited symptoms of dementia for a period of at least 6 months. All subjects identified as having AD met the criteria of the National Institute of Neurological and Communicative Disorders and Stroke and the Alzheimer's Disease and Related Disorders Association23 for definite, probable, or possible AD.

All subjects who were alive and free of dementia and stroke and who attended examination cycle 20 (1988-1989) were followed up longitudinally from examination 20 onward for the development of dementia. Therefore, at least a 10-year interval occurred from the last measurement of cholesterol level at examination 15 to the start of longitudinal follow-up that began at examination 20. This 10-year interval and the baseline screening of all subjects for dementia in 1976 to 1978 significantly increased the probability of effectively screening out subjects with subclinical dementia at the time of estimation of cholesterol level.

DEFINITION OF ADDITIONAL RISK FACTORS

Risk factors that could potentially confound the relationship between cholesterol level and AD were defined using data collected at the 20th biennial examination. Educational status was dichotomized at the level of high school completion. Cigarette smoking was defined as a lifetime smoking exposure of at least 5 pack-years. Diabetes mellitus was defined as a recorded casual blood glucose level of at least 200 mg/dL (≥11.1 mmol/L), a previous diagnosis of diabetes mellitus, or use of a hypoglycemic agent, including insulin. Systolic blood pressure and body mass index (calculated as weight in kilograms divided by the square of height in meters) were treated as continuous variables. Coronary heart disease was defined to include angina pectoris, myocardial infarction, and coronary insufficiency.24

STATISTICAL ANALYSIS

We used Cox proportional hazards regression analyses to examine the association between each of the various measures of total cholesterol and HDL-C levels and the subsequent development of incident AD, with and without adjustment for potential confounders (age, sex, APOE genotype, coronary heart disease, smoking, therapy to lower lipid levels, diabetes, and body mass index).

From 1992 to 2000, AD developed in 77 subjects. The baseline characteristics of the subjects are presented in Table 1. We found no significant association between the risk for incident AD (Table 2) and mean TC1-15 or TC20. Adjusting for potential confounders did not change this lack of association between the dependent and independent variables (Table 3) (hazard ratios [HR] per 10-mg/dL [0.3-mmol/L] rise in serum total cholesterol level, 0.95 and 0.97, respectively; 95% confidence intervals [CIs] 0.87-1.04 and 0.90-1.05, respectively).

Table Graphic Jump LocationTable 3. Multivariate Adjusted Hazard Ratios of AD in Relation to Cholesterol Measurements*

We also examined the relationship of HDL-C level measured at examination 20 and the risk for AD. No significant association was noted in this cohort (HR, 1.10; 95% CI, 0.93-1.31). Likewise, among subjects not receiving medication to lower lipid levels, the ΔTC15-20 was not significantly associated with AD risk (HR, 1.01; 95% CI, 0.92-1.11).

Epidemiological studies suggest that atherosclerosis is associated with an increased risk for Alzheimer dementia.4,25 Critical coronary artery disease has been associated with a 3- to 10-fold increased risk for cerebral β-amyloid plaques, the neuropathologic hallmark of AD, relative to control subjects free of coronary heart disease.26 Similarly, an in vivo animal study showed a graded hippocampal accumulation of immunolabeled β-amyloid with increasing duration of feeding with a high-cholesterol diet.27 A human postmortem study showed that subjects with neuropathologically diagnosed AD had significantly elevated levels of low-density lipoprotein cholesterol, apolipoprotein B, and brain β-amyloid and significantly lower levels of HDL-C compared with controls.28

A cholesterol-AD link is further suggested by recent epidemiological studies that demonstrate an association between the use of certain agents that lower cholesterol levels (statins) and a decreased risk for dementia.5,6 This observation appears to support earlier tissue culture studies that show complete inhibition of β-amyloid formation in hippocampal cell cultures treated with lovastatin and methyl-β-cyclodextrin, suggesting that β-amyloid formation is a cholesterol-dependent process.29 However, the observed protective effect of statins in the epidemiological studies was independent of the presence or absence of hyperlipidemia and was not seen in subjects treated with nonstatin agents to lower lipid levels.

Previous prospective epidemiological studies exploring the relationship between serum cholesterol levels and the risk for AD have yielded varying results. A study of survivors of the Finnish cohort of the Seven Countries Study found that a high serum total cholesterol level (mean level, >251 mg/dL [>6.5 mmol/L]) at 40 to 59 years of age predicted AD in later life.8 The Finnish and Framingham Study cohorts are both white populations comparable in age and were studied during a similar period. Some differences between the 2 studies are the inclusion of subjects with prevalent dementia and the lack of women in the Finnish cohort. However, in our study population, the inclusion of subjects with prevalent dementia did not change our results (data not presented), and we did not find a sex-specific effect. Other possible explanations include the varying case definitions of dementia in the 2 studies (Diagnostic and Statistical Manual of Mental Disorders, Revised Third Edition, in the Finnish cohort and Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition in the Framingham cohort), the use of fasting rather than nonfasting plasma cholesterol levels in the Finnish cohort, and ethnic variations within white populations. Mean plasma cholesterol levels in Finnish populations are higher than in other ethnic white populations.30

Romas et al9 found that subjects with the lowest (<177 mg/dL [<4.6 mmol/L]) baseline total cholesterol level had an increased risk for incident dementia after 2.5 years of follow-up. This inverse relationship between cholesterol levels and incident AD may be accounted for by the short follow-up. When the follow-up is short, subjects with subclinical dementia at the start of the study may be erroneously classified as cognitively intact. This is important because, even in the early stages, dementia may cause a decrease in food intake, weight, and plasma cholesterol levels.31 Moreover, since cholesterol levels decline with age, the age of the subject at the time of cholesterol level determination can be a significant factor, when using single rather than time-averaged cholesterol levels.32 Older subjects are more likely to have low plasma cholesterol levels and also a greater risk for development of AD. This may explain why the association observed by Romas et al9 was no longer significant after adjustment for age.

In our study, the 10-year interval between the last cholesterol level (examination 15) and the start of longitudinal follow-up for dementia (examination 20) significantly increased the probability of screening out subclinical dementia. We also used the average of multiple serial cholesterol levels estimated biennially for a 30-year period to achieve a more accurate reflection of lifetime cholesterol levels. Additional strengths of the present study are the ongoing surveillance for incident stroke in the Framingham cohort (thus reducing the chances that subjects with mixed or vascular dementia are inaccurately classified as having AD), long follow-up, and ability to control for multiple potential confounders. The primarily white American study population limits the applicability of our conclusions to other population groups.

The lack of association between TC20, mean TC1-15, or recent ΔTC15-20 and the risk for AD in the Framingham cohort supports the postulate that an alternative explanation exists for the observed association of statin use with a lower risk for AD. In addition to their lipid-lowering activity, statins have other putative beneficial effects, including capillary dilation, increased blood flow, blockage of macrophage and platelet activation, immunosupression, and anti-inflammatory actions. These mechanisms, independent of the lowering of lipid levels, are hypothesized to be responsible for some of the beneficial effect of statins on coronary artery disease, renal failure, stroke prevention, and cerebral infarct size reduction.3335 A similar mechanism may exist for the relationship between statin use and the risk for Alzheimer dementia. Inflammatory mechanisms involving complement, acute-phase reactants, cytokines, and proteases have been implicated in the pathogenesis of AD.36 Further studies are warranted to confirm the beneficial effect of statins in the risk for AD and to elucidate the mechanism by which they may exert this effect.

Despite plausible biological mechanisms and a remarkable convergence of data linking cholesterol levels to the pathophysiology of and the corresponding risk for AD, our study found that elevated serum total cholesterol level was not a significant risk factor for development of Alzheimer dementia.

Corresponding author and reprints: Philip A. Wolf, MD, Neurological Epidemiology and Genetics Division, Department of Neurology, Boston University School of Medicine, 715 Albany St, Room B-608, Boston, MA 02118 (e-mail: pawolf@bu.edu).

Box Section Ref ID

Accepted for publication July 31, 2002.

This study was supported by grants 5R01-AG08122-11 and 5R01-AG16495-02 from the National Institute of Aging, Bethesda, Md; grant 5R01-NS17950-19 from the National Institute of Neurological Disorders and Stroke, Bethesda; and contract N01-HC-38038 from the National Institutes of Health, Bethesda.

Corder  EHSaunders  AMStrittmatter  WJ  et al.  Gene dose of apolipoprotein E type 4 allele and the risk of Alzheimer's disease in late onset families. Science. 1993;261921- 923
Mooser  VHelbecque  NMiklossy  JMarcovina  SMNicod  PAmouyel  P Interactions between apolipoprotein E and apolipoprotein(a) in patients with late-onset Alzheimer's disease. Ann Intern Med. 2000;132533- 537
Hyman  BTStrickland  DRebeck  GW Role of Low-density lipoprotein receptor–related protein in β-amyloid metabolism and Alzheimer disease. Arch Neurol. 2000;57646- 650
Hofman  AOtt  ABreteler  MMB  et al.  Atherosclerosis, apolipoprotein E, and prevalence of dementia and Alzheimer's disease in the Rotterdam Study. Lancet. 1997;349151- 154
Wolozin  BKellman  WRuosseau  PCelesia  GGSiegel  G Decreased prevalence of Alzheimer disease associated with 3-hydroxy-3-methylglutaryl coenzyme A reductase inhibitors. Arch Neurol. 2000;571439- 1443
Jick  HZornberg  GLJick  SSSeshadri  SDrachman  DA Statins and the risk of dementia. Lancet. 2000;3561627- 1631
Evans  RMEmsley  CLGao  S  et al.  Serum cholesterol, APOE genotype, and the risk of Alzheimer's disease: a population-based study of African Americans. Neurology. 2000;54240- 242
Notkola  ILSulkava  RPekkanen  J  et al.  Serum total cholesterol, apolipoprotein E ϵ4 allele, and Alzheimer's disease. Neuroepidemiology. 1998;1714- 20
Romas  SNTang  MXBerglund  LMayeux  R APOE genotype, plasma lipids, lipoproteins, and AD in community elderly. Neurology. 1999;53517- 521
Farmer  MEWhite  LRKittner  SJ  et al.  Neuropsychological test performance in Framingham: a descriptive study. Psychol Rep. 1987;60 ((3, pt 2)) 1023- 1040
Folstein  MEFolstein  SEMcHugh  PR "Mini-Mental State": a practical method for grading the cognitive state of patients for the clinician. J Psychiatr Res. 1975;12189- 198
Bachman  DLWolf  PALinn  RT  et al.  Incidence of dementia and probable Alzheimer's disease in a general population: the Framingham Study. Neurology. 1993;43515- 519
Wilson  PWFHoeg  JMD'Agostino  RB  et al.  Cumulative effects of high cholesterol levels, high blood pressure, and cigarette smoking on carotid stenosis. N Engl J Med. 1997;337516- 522
Abell  LLLevy  BBBrodie  BBKendall  FE A simplified method for the estimation of total cholesterol in serum and demonstration of its specificity. J Biol Chem. 1952;195357- 366
Lipid Research Clinics Program, Manual of Laboratory Operation.  Bethesda, Md National Institutes of Health1974;Publication NIH75-628.
Warnick  GRBenderson  JAlbers  JJ Dextran sulfate–Mg2+ precipitation procedure for quantitation of high-density–lipoprotein cholesterol. Clin Chem. 1982;281379- 1382
Cooper  GRMyers  GLSmith  SJSchlant  RC Blood lipid measurements: variations and practical utility. JAMA. 1992;2671652- 1660
Ordovas  JMLitwack-Klein  LWilson  PWSchaefer  MMShaefer  EJ Apolipoprotein E isoform phenotyping methodology and population frequency with identification of apoE1 and apoE5 isoforms. J Lipid Res. 1987;28371- 380
Welty  FKLahoz  CTucker  KLOrdovas  JMWilson  PWSchaefer  EJ Frequency of ApoB and ApoE gene mutations as causes of hypobetalipoproteinemia in the Framingham offspring population. Arterioscler Thromb Vasc Biol. 1998;181745- 1751
Cobb  JLWolf  PAAu  RWhite  RD'Agostino  RB The effect of education on the incidence of dementia and Alzheimer's disease in the Framingham Study. Neurology. 1995;451707- 1712
Berg  L Clinical Dementia Rating (CDR). Psychopharmacol Bull. 1988;24637- 639
American Psychiatric Association, Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition.  Washington, DC American Psychiatric Association1994;
McKhann  GDrachman  DFolstein  MKatzman  RPrice  DStadlan  EM Clinical diagnosis of Alzheimer's disease: report of the NINCDS-ADRDA work group under the auspices of Department of Health and Human Services Task Force on Alzheimer's disease. Neurology. 1984;34939- 944
Cupples  LAD'Agostino  RB Some risk factors related to the annual incidence of cardiovascular disease and death using pooled repeated biennial measurements. Kannel  WBWolf  PAGarrison  RJThe Framingham Study An Epidemiological Investigation of Cardiovascular Disease Bethesda, Md National Heart, Lung and Blood Institute1987;NIH publication 87-2703, section 34.
Wilson  PWShaefer  EJLarson  MGOrdova  JM Apolipoprotein E alleles and risk of coronary disease: a meta-analysis. Aterioscler Thromb Vasc Biol. 1996;161250- 1255
Sparks  DLLiu  HScheff  SWCoyne  CMHunsaker III  JC Temporal sequence of plaque formation in the cerebral cortex of non-demented individuals. J Neuropathol Exp Neurol. 1993;52135- 142
Sparks  DLScheff  SWHunsacker III  JCLiu  HLanders  TGross  DR Induction of Alzheimer-like beta-amyloid immunoreactivity in the brains of rabbits with dietary cholesterol. Exp Neurol. 1994;12688- 94
Kuo  YMEmmerling  MRBisgaier  CL  et al.  Elevated low-density lipoprotein in Alzheimer's disease correlates with brain Aβ 1-42 levels. Biochem Biophys Res Commun. 1998;252711- 715
Simons  MKeller  PDeStrooper  BBeyreuther  KDotti  CGSimons  K Cholesterol depletion inhibits the generation of β-amyloid in hippocampal neurons. Proc Natl Acad Sci U S A. 1998;956460- 6464
Hallman  DMBoerwinkle  ESaha  N  et al.  The apolipoprotein E polymorphism: a comparison of allele frequencies and effects in nine populations. Am J Hum Genet. 1991;49338- 349
Shatenstein  BKergoat  MJNadon  S Anthropometric changes over 5 years in elderly Canadians by age, gender and cognitive status. J Gerontol A Biol Sci Med Sci. 2001;56M483- M488
Wilson  PWAnderson  KMHarris  TKannel  WBCastelli  WP Determinants of change in total cholesterol and HDL-C with age: the Framingham Study. J Gerontol. 1994;49M252- M257
Davignon  JLaaksonen  R Low-density lipoprotein–independent effects of statins. Curr Opin Lipidol. 1999;10543- 559
Maron  DJFazio  SLinton  MF Current perspectives on statins. Circulation. 2000;101207- 213
Hess  DCDemchuk  AMBrass  LMYatsu  FM HMG-CoA reductase inhibitors (statins): a promising approach to stroke prevention. Neurology. 2000;54790- 796
McGeer  EGMcGeer  PL The importance of inflammatory mechanisms in Alzheimer disease. Exp Gerontol. 1998;33371- 378

Figures

Tables

Table Graphic Jump LocationTable 1. Baseline Subject Characteristics and Cholesterol Levels at Examination Cycle 20 (1988-1989)*
Table Graphic Jump LocationTable 2. Age- and Sex-Adjusted Hazard Ratios of AD in Relation to Cholesterol Measurements
Table Graphic Jump LocationTable 3. Multivariate Adjusted Hazard Ratios of AD in Relation to Cholesterol Measurements*

References

Corder  EHSaunders  AMStrittmatter  WJ  et al.  Gene dose of apolipoprotein E type 4 allele and the risk of Alzheimer's disease in late onset families. Science. 1993;261921- 923
Mooser  VHelbecque  NMiklossy  JMarcovina  SMNicod  PAmouyel  P Interactions between apolipoprotein E and apolipoprotein(a) in patients with late-onset Alzheimer's disease. Ann Intern Med. 2000;132533- 537
Hyman  BTStrickland  DRebeck  GW Role of Low-density lipoprotein receptor–related protein in β-amyloid metabolism and Alzheimer disease. Arch Neurol. 2000;57646- 650
Hofman  AOtt  ABreteler  MMB  et al.  Atherosclerosis, apolipoprotein E, and prevalence of dementia and Alzheimer's disease in the Rotterdam Study. Lancet. 1997;349151- 154
Wolozin  BKellman  WRuosseau  PCelesia  GGSiegel  G Decreased prevalence of Alzheimer disease associated with 3-hydroxy-3-methylglutaryl coenzyme A reductase inhibitors. Arch Neurol. 2000;571439- 1443
Jick  HZornberg  GLJick  SSSeshadri  SDrachman  DA Statins and the risk of dementia. Lancet. 2000;3561627- 1631
Evans  RMEmsley  CLGao  S  et al.  Serum cholesterol, APOE genotype, and the risk of Alzheimer's disease: a population-based study of African Americans. Neurology. 2000;54240- 242
Notkola  ILSulkava  RPekkanen  J  et al.  Serum total cholesterol, apolipoprotein E ϵ4 allele, and Alzheimer's disease. Neuroepidemiology. 1998;1714- 20
Romas  SNTang  MXBerglund  LMayeux  R APOE genotype, plasma lipids, lipoproteins, and AD in community elderly. Neurology. 1999;53517- 521
Farmer  MEWhite  LRKittner  SJ  et al.  Neuropsychological test performance in Framingham: a descriptive study. Psychol Rep. 1987;60 ((3, pt 2)) 1023- 1040
Folstein  MEFolstein  SEMcHugh  PR "Mini-Mental State": a practical method for grading the cognitive state of patients for the clinician. J Psychiatr Res. 1975;12189- 198
Bachman  DLWolf  PALinn  RT  et al.  Incidence of dementia and probable Alzheimer's disease in a general population: the Framingham Study. Neurology. 1993;43515- 519
Wilson  PWFHoeg  JMD'Agostino  RB  et al.  Cumulative effects of high cholesterol levels, high blood pressure, and cigarette smoking on carotid stenosis. N Engl J Med. 1997;337516- 522
Abell  LLLevy  BBBrodie  BBKendall  FE A simplified method for the estimation of total cholesterol in serum and demonstration of its specificity. J Biol Chem. 1952;195357- 366
Lipid Research Clinics Program, Manual of Laboratory Operation.  Bethesda, Md National Institutes of Health1974;Publication NIH75-628.
Warnick  GRBenderson  JAlbers  JJ Dextran sulfate–Mg2+ precipitation procedure for quantitation of high-density–lipoprotein cholesterol. Clin Chem. 1982;281379- 1382
Cooper  GRMyers  GLSmith  SJSchlant  RC Blood lipid measurements: variations and practical utility. JAMA. 1992;2671652- 1660
Ordovas  JMLitwack-Klein  LWilson  PWSchaefer  MMShaefer  EJ Apolipoprotein E isoform phenotyping methodology and population frequency with identification of apoE1 and apoE5 isoforms. J Lipid Res. 1987;28371- 380
Welty  FKLahoz  CTucker  KLOrdovas  JMWilson  PWSchaefer  EJ Frequency of ApoB and ApoE gene mutations as causes of hypobetalipoproteinemia in the Framingham offspring population. Arterioscler Thromb Vasc Biol. 1998;181745- 1751
Cobb  JLWolf  PAAu  RWhite  RD'Agostino  RB The effect of education on the incidence of dementia and Alzheimer's disease in the Framingham Study. Neurology. 1995;451707- 1712
Berg  L Clinical Dementia Rating (CDR). Psychopharmacol Bull. 1988;24637- 639
American Psychiatric Association, Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition.  Washington, DC American Psychiatric Association1994;
McKhann  GDrachman  DFolstein  MKatzman  RPrice  DStadlan  EM Clinical diagnosis of Alzheimer's disease: report of the NINCDS-ADRDA work group under the auspices of Department of Health and Human Services Task Force on Alzheimer's disease. Neurology. 1984;34939- 944
Cupples  LAD'Agostino  RB Some risk factors related to the annual incidence of cardiovascular disease and death using pooled repeated biennial measurements. Kannel  WBWolf  PAGarrison  RJThe Framingham Study An Epidemiological Investigation of Cardiovascular Disease Bethesda, Md National Heart, Lung and Blood Institute1987;NIH publication 87-2703, section 34.
Wilson  PWShaefer  EJLarson  MGOrdova  JM Apolipoprotein E alleles and risk of coronary disease: a meta-analysis. Aterioscler Thromb Vasc Biol. 1996;161250- 1255
Sparks  DLLiu  HScheff  SWCoyne  CMHunsaker III  JC Temporal sequence of plaque formation in the cerebral cortex of non-demented individuals. J Neuropathol Exp Neurol. 1993;52135- 142
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