Prospective study of alcohol consumption and risk of dementia in older adults.

Abstract

Alcohol consumption has been associated with complex changes in cerebral vasculature and structure in older adults. How alcohol consumption affects the incidence of dementia is less clear.
To determine the prospective relationship of alcohol consumption and risk of dementia among older adults.
Nested case-control study of 373 cases with incident dementia and 373 controls who were among 5888 adults aged 65 years and older who participated in the Cardiovascular Health Study, a prospective, population-based cohort study in 4 US communities. The controls were frequency-matched on age, death before 1999, and their attendance of a 1998-1999 clinic. Participants in this study underwent magnetic resonance imaging (MRI) of the brain and cognitive testing between 1992 and 1994 and were followed up until 1999.
Odds of incident dementia, ascertained by detailed neurological and neuropsychological examinations according to average alcohol consumption, assessed by self-reported intake of beer, wine, and liquor at 2 visits prior to the date of the MRI.
Compared with abstention, the adjusted odds for dementia among those whose weekly alcohol consumption was less than 1 drink were 0.65 (95% confidence interval [CI], 0.41-1.02); 1 to 6 drinks, 0.46 (95% CI, 0.27-0.77); 7 to 13 drinks, 0.69 (95% CI, 0.37-1.31); and 14 or more drinks, 1.22 (95% CI, 0.60-2.49; P for quadratic term =.001). A trend toward greater odds of dementia associated with heavier alcohol consumption was most apparent among men and participants with an apolipoprotein E epsilon4 allele. We found generally similar relationships of alcohol use with Alzheimer disease and vascular dementia.
Compared with abstention, consumption of 1 to 6 drinks weekly is associated with a lower risk of incident dementia among older adults.

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. 2003;289(11):1405-1413 (doi:10.1001/jama.289.11.1405) JAMA
Kenneth J. Mukamal; Lewis H. Kuller; Annette L. Fitzpatrick; et al.


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ORIGINAL CONTRIBUTION
Prospective Study of Alcohol Consumption
and Risk of Dementia in Older Adults
Kenneth J. Mukamal, MD, MPH
Lewis H. Kuller, MD, DrPH
Annette L. Fitzpatrick, PhD
W. T. Longstreth, Jr, MD, MPH
Murray A. Mittleman, MD, DrPH
David S. Siscovick, MD, MPH
D
more than 360000 new cases in the
UnitedStatesannually,1withanational
annual cost of caring for such patients
of more than $50 billion.2This burden
has spurred a search for modifiable fac-
tors that cause or prevent dementia.
Atherosclerotic vascular disease may
be 1 such risk factor for vascular and
nonvasculardementia.3Becausemoder-
ate alcohol consumption is associated
with a lower risk of cardiovascular dis-
ease in the elderly,4such consumption
might be expected to lower risk of de-
mentia. However, even moderate alco-
hol consumption may have effects that
increasedementiarisk.Bloodalcohollev-
els as low as 0.02% impair driving abil-
ity,5andmoderatealcoholuseisassoci-
ated with a greater risk of cerebral
hemorrhage.6Inananalysisofsubclini-
cal abnormalities of the brain seen on
magneticresonanceimaging(MRI)stud-
iesamongCardiovascularHealthStudy
(CHS) participants, moderate alcohol
consumptionwasassociatedwithgreater
brain atrophy but fewer silent infarcts
and less white matter disease, associa-
tionsthatmightinfluenceriskofdemen-
tia in opposite directions.7
Previousstudiesofalcoholconsump-
tionandcognitivedecline8-20ordemen-
tia21-25have reported conflicting re-
EMENTIA IMPOSES A TREMEN-
dous burden on patients,
caregivers, and society. Alz-
heimer disease alone causes
sults. However, to our knowledge, no
previous study has addressed the risk
of confirmed dementia in a large co-
hort of adults with repeated measures
of alcohol use.
To address the relationship of alco-
hol consumption and risk of dementia
further, we performed a nested case-
control study of alcohol consumption
and risk of incident dementia in the
CHS, a prospective, population-based
studyofadultsaged65yearsandolder
in the United States.26,27
METHODS
Study Population and Design
Cardiovascular Health Study partici-
pants include 5888 men and women
aged 65 years or older who were
randomly selected from Medicare-
AuthorAffiliations: DivisionsofGeneralMedicineand
Primary Care (Dr Mukamal) and Cardiology (Dr
Mittleman),BethIsraelDeaconessMedicalCenter,Bos-
ton, Mass; Department of Epidemiology, University
of Pittsburgh, Pittsburgh, Pa (Dr Kuller); Depart-
ments of Epidemiology (Drs Fitzpatrick, Longstreth,
and Siscovick), Biostatistics (Dr Fitzpatrick), Neurol-
ogy (Dr Longstreth), and Medicine (Dr Siscovick),
University of Washington, Seattle; and Department
ofEpidemiology,HarvardSchoolofPublicHealth,Bos-
ton, Mass (Dr Mittleman).
Corresponding Author and Reprints: Kenneth J.
Mukamal, MD, MPH, Division of General Medicine
andPrimaryCare,BethIsraelDeaconessMedicalCen-
ter, 330 Brookline Ave, RO-114, Boston, MA 02215
(e-mail: kmukamal@caregroup.harvard.edu).
Context Alcohol consumption has been associated with complex changes in cere-
bral vasculature and structure in older adults. How alcohol consumption affects the
incidence of dementia is less clear.
Objective Todeterminetheprospectiverelationshipofalcoholconsumptionandrisk
of dementia among older adults.
Design, Setting, and Participants Nested case-control study of 373 cases with
incident dementia and 373 controls who were among 5888 adults aged 65 years and
older who participated in the Cardiovascular Health Study, a prospective, population-
based cohort study in 4 US communities. The controls were frequency-matched on
age, death before 1999, and their attendance of a 1998-1999 clinic. Participants in
this study underwent magnetic resonance imaging (MRI) of the brain and cognitive
testing between 1992 and 1994 and were followed up until 1999.
MainOutcomeMeasures Oddsofincidentdementia,ascertainedbydetailedneu-
rologicalandneuropsychologicalexaminationsaccordingtoaveragealcoholconsump-
tion, assessed by self-reported intake of beer, wine, and liquor at 2 visits prior to the
date of the MRI.
Results Compared with abstention, the adjusted odds for dementia among those
whose weekly alcohol consumption was less than 1 drink were 0.65 (95% confidence
interval [CI], 0.41-1.02); 1 to 6 drinks, 0.46 (95% CI, 0.27-0.77); 7 to 13 drinks, 0.69
(95% CI, 0.37-1.31); and 14 or more drinks, 1.22 (95% CI, 0.60-2.49; P for qua-
dratic term=.001). A trend toward greater odds of dementia associated with heavier
alcohol consumption was most apparent among men and participants with an apoli-
poprotein E ?4 allele. We found generally similar relationships of alcohol use with Alz-
heimer disease and vascular dementia.
Conclusions Compared with abstention, consumption of 1 to 6 drinks weekly is as-
sociated with a lower risk of incident dementia among older adults.
JAMA. 2003;289:1405-1413
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eligibility lists in 4 communities in the
United States (Forsyth County, North
Carolina; Sacramento County, Califor-
nia;WashingtonCounty,Maryland;and
Allegheny County, Pennsylvania). Par-
ticipants were not institutionalized or
wheelchair-dependent, did not require
aproxyforconsent,werenotundertreat-
ment for cancer, and were expected to
remainintheirrespectiveregionsforat
least3years.In1989and1990,5201par-
ticipants were recruited; in 1992 and
1993, an additional 687 black partici-
pants were recruited. The institutional
review board at each participating cen-
ter approved the study, and each par-
ticipant gave informed consent.
The CHS study design and objec-
tives have been published.27The base-
line examination included standard-
ized medical history questionnaires,
physical examination, and laboratory
examination. Follow-up contact oc-
curredevery6months,alternatingbe-
tweentelephonecallsandclinicvisits.
Cognitive testing included the 30-
point Mini-Mental State Examination
at baseline and the 100-point Modi-
fied Mini-Mental State Examination
(3MSE) and the Digital-Symbol Sub-
stitutionTestinallsubsequentyears.28,29
MRI Examination
A total of 3660 CHS participants com-
pleted an MRI examination between
1992 and 1994. Those who completed
an MRI examination were generally
healthierthanthoseparticipantswhodid
not,30andwerelesslikelytoabstainfrom
alcohol (48% vs 54%; P?.001).
Determination of Dementia
Of the 3660 participants who com-
pletedanMRI,3608completeda3MSE
at the same clinical visit and were eli-
gible for the CHS cognition study
(FIGURE). We determined their subse-
quent risk of dementia using the CHS
Cognition Study protocol.31,32Investi-
gators performed a multistage screen-
ing process on all eligible partici-
pants, whether or not they were still
alive, beginning in 1999. When a par-
ticipantdiedbeforethattime,determi-
nation of dementia was made using
availablemedicalrecords,previousCHS
testing, and Informant Questionnaire
on the Cognitive Decline of the El-
derly(IQCODE)questionnaires33sent
to each participant’s personal physi-
cian and proxy respondent. Investiga-
torsobtainedsimilarinformationfrom
participantswhowerealivebutdidnot
complete the full screening process.
The first stage of the screening pro-
cess identified participants at particu-
lar risk of dementia for intensive
subsequent evaluation. Low-risk par-
ticipantswerealivein1999andhadno
history of stroke or dementia, 3MSE
scoresof80orabovethroughout1997-
1999,andnodeclinein3MSEscorefrom
1992-1994to1999greaterthan5points,
consistentwithpreviousstudiesofcog-
nitivedeclineinCHS.34At3ofthe4CHS
sites (n=2681), high-risk participants
and all black participants (because of
their smaller sample size and higher
underlying risk35) then underwent fur-
ther evaluation in a second stage; low-
risk participants (n=1492) were con-
sidered not to have dementia. At the
Pittsburghsite,allparticipants(n=927),
irrespective of risk status, were further
evaluated in a second stage.
Inthesecondstage,participantsun-
derwent a full neuropsychiatric bat-
tery. At the Pittsburgh site, all avail-
able participants underwent further
neurological testing in a third stage;
at the other 3 sites, participants with
abnormal tests of memory or of any
2 other domains underwent further
evaluation.
In the third stage, neurologists per-
formed detailed neurological examina-
tions, reviewed previously collected
information, and classified participants
as having no cognitive impairment,
mild cognitive impairment, or demen-
tia.31Neurologists completed the Uni-
fied Parkinson’s Disease Rating Scale,36
and the Hachinski Ischemic Scale.37
They diagnosed dementia based on a
progressive or static cognitive deficit of
Figure. Flow of Participants Through the Cardiovascular Health Study Cognition Study
2116 Assessed for Dementia or MCI
5888 Participants in CHS Cohort
3608 Completed MRI and Mini-Mental
State Examination and Entered CHS
Cognition Study
927 Did Not Have Risk Screening (Pittsburgh Site)
2681 Had Risk Screening (3 Sites)
1189 High Risk or Minority Race1492 Screened Negative
1386 Did Not Complete MRI
277 Had
Contraindications
to MRI
466 Unable to Complete
597 Refused
46 Technical or Other
Problems
3660 Completed MRI Between 1992 and 1994
52 Did Not Complete Mini-Mental
State Examination
5046 Completed 1992-1994 Visit
842 Did Not Complete 1992-1994
Visit
411 Deceased
244 Did Not Attend
187 Not Recruited for MRI
(Reasons Unknown)
107 Excluded
373 Cases of Incident
Dementia
373 Controls Matched on Age,
Death, and 1999 Clinic Visit
577 Had MCI6 Unknown227 Had Prevalent
Dementia
480 Had Incident
Dementia
826 Cognitively
Healthy
Low-risk Cardiovascular Health Study (CHS) participants were alive in 1999 and had no history of stroke or
dementia, Modified Mini-Mental State Examination (3MSE) scores of 80 or higher throughout 1997-1999 and
a decline of no more than 5 points in 3MSE score from 1992-1994 to 1999. Excluded participants with inci-
dent dementia died within 2 years of having undergone a magnetic resonance imaging of the brain (MRI) had
a 3MSE score at onset of screening lower than 80 or had no follow-up cognitive testing performed after their
MRI. MCI indicates mild cognitive impairment.
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sufficient severity to affect a partici-
pant’s activities of daily living, and his-
tory of normal intellectual function
before the onset of cognitive abnor-
malities. Participants were required to
have impairments in 2 cognitive
domains, which did not necessarily
include memory.
Inthefourthstage,aneurologistwith
extensive experience in dementia re-
viewed all subjects diagnosed by local
neurologists as free of dementia to en-
sure that no cases were missed. An ad-
judicationcommitteeofstudyneurolo-
gists or psychiatrists from the 4 CHS
clinics then reviewed cases classified as
possibledementiainthethirdandfourth
stages,confirmedthediagnoses,andes-
tablished types of dementia. The classi-
fication of dementia type was done af-
terreviewofthe1992-1994MRIresults
although the diagnosis of dementia per
se was not affected by the results of the
MRI.Theadjudicationcommitteebased
itsclassificationsoncriteriafromtheDi-
agnostic and Statistical Manual of Men-
tal Disorders, Fourth Edition,38National
Institute of Neurological and Commu-
nicativeDiseasesandStroke-Alzheimer
Disease and Related Disorders Associa-
tion,39State of California Alzheimer’s
DiseaseDiagnosticandTreatmentCen-
ters,40and National Institute of Neuro-
logicalDiseasesandStroke-Association
Internationale pour la Recherche et
ll’Enseignement en Neurosciences.41
Finally, to ensure that all partici-
pantswithincidentdementiawerefree
of dementia at the start of follow-up,
we excluded subjects who died within
2 years of undergoing an MRI, had a
3MSE score of less than 80 at the time
of their MRI, or had no follow-up test-
ingperformedafterundergoinganMRI.
Based on results from the Pittsburgh
site, in which all participants (rather
than just high-risk participants) un-
derwentfullevaluation,ouroveralles-
timates of dementia are approxi-
mately 9% lower than if we had fully
evaluated all participants.31
Alcohol Consumption
At yearly visits, participants were in-
dividually asked the usual number
of 12-oz cans or bottles of beer, 6-oz
glassesofwine,andshotsofliquorthat
they drank at a time and the usual fre-
quency with which they consumed
those beverages. In primary analyses,
weaveragedalcoholconsumptionfrom
thebaselinequestionnaireandtheques-
tionnaire from the annual clinic visit
closest to the date of the MRI exami-
nation.Insecondaryanalyses,weused
alcoholconsumptiondeterminedfrom
these 2 assessments individually.
At baseline, participants reported
whether they changed their pattern of
consumption during the past 5 years
and whether they ever regularly con-
sumed 5 or more drinks daily. Partici-
pantswhoreportedabstentionatbase-
linebutrespondedyestoeitherofthese
questions were classified as former
drinkers. Participants who reported
some alcohol consumption at baseline
butabstentionatthetimeofMRIwere
classified as quitters separate from
former drinkers.
AsinpreviousCHSanalyses,7wecat-
egorized participants according to
weekly alcohol consumption for pri-
maryanalysesasfollows:none,former,
quitter,lessthan1drink,1to6drinks,
7 to 13 drinks, and 14 or more drinks
weekly. For logistic regression analy-
ses,weusedabstainerswithoutformer
use as the reference category, to mini-
mize the inclusion of sick quitters.42
Weperformedadditionalanalysesthat
incorporated alcohol consumption
(in drinks per week) as a continuous
variable, performing log transforma-
tion because of the skewed distribu-
tion of alcohol consumption in CHS.
When these analyses included non-
drinkers, we added 0.01 drinks per
week to all observations to allow log
transformation.
Other Covariates
We defined diabetes as having a fast-
ing blood sugar level of at least 126
mg/dL (?6.9 mmol/L) or were receiv-
ing medication for diabetes. We di-
chotomized educational attainment
(completion of ?high school vs
?vocational school or college), in-
come(?$16000vs?$16000peryear),
and marital status (married vs wid-
owed, divorced, separated, or never
married). We assessed leisure-time
physical activity as a weighted sum of
kilocaloriesexpendedinspecificphysi-
cal activities.43Apolipoprotein E
(APOE) genotype testing was per-
formedaspreviouslydescribed44;ofthe
664 participants who agreed to be
tested,171testedpositiveforAPOE?4
positive(9APOE?4/?4,147?3/?4,and
15 ?2/?4). We assessed depression us-
ing the Center for Epidemiological
Studies Depression (CES-D) Scale.45
We quantified MRI results in a stan-
dardized, reliable manner, as previ-
ously described.30,46For 3 participants
with missing values for body mass in-
dex or physical activity, we assigned
mean values of these variables; analy-
ses that deleted these individuals gave
identicalresultsandarenotshown.Un-
lessotherwisenoted,covariateswereas-
sessed at the onset of follow-up.
Statistical Methods
We used a nested case-control ap-
proach to assess the relative odds of in-
cident dementia according to alcohol
consumption.Wefrequency-matchedall
participantswithincidentdementiatoan
equalnumberofparticipantswithoutde-
mentia on the basis of age (in 5-year
increments),deathbeforetheendoffol-
low-upin1999,andcompletionofaCHS
clinic visit in 1998-1999. We used lo-
gistic regression to control for poten-
tiallyconfoundingfactorsandincluded
the matching variables in all models.47
Other factors included were race, sex,
educational attainment, income level,
physicalactivity,diabetes,bodymassin-
dex, use of hormone replacement
therapy, total cholesterol, atrial fibrilla-
tion, APOE ?4 status (1 or 2 alleles vs
none), former smoking, current smok-
ing, history of congestive heart failure,
history of stroke, and history of tran-
sient ischemic attack. Because high-
densitylipoproteincholesterol(HDL-C),
fibrinogen, and MRI results are plau-
sible mediators of the effect of alcohol
consumptiononvasculardiseaseandde-
mentia, those factors were entered into
the model in sensitivity analyses.
ALCOHOL USE AND DEMENTIA IN OLDER ADULTS
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To explore possible effect modifica-
tion, we repeated adjusted analyses
withinstrataofsex,APOE?4genotype,
andage.Becauseofthesmallernumber
ofparticipantsinstratifiedanalyses,we
performed stepwise logistic regression
(with entry and stay P values of .20) to
generate a more parsimonious model,
forcing alcohol consumption, sex, and
the matching variables into the model.
This model yielded results very similar
to the full model when used on the en-
tire cohort and included race, APOE ?4
status,diabetes,andhistoryofstroke.In
beverage-specific analyses, we used the
full model and simultaneously con-
trolled for use of the other 2 beverages
(assessedcategorically).Fortestsoflin-
eartrend,wetreatedthecategoriesofal-
coholconsumptionascontinuousvari-
able,excludingformerdrinkers.Fortests
of quadratic trend, we squared the lin-
ear trend variable after centering it on
medianconsumption.WeusedSASsta-
tistical software version 8 (SAS Insti-
tute Inc, Cary, NC) for all analyses.
RESULTS
Wehavepreviouslyreportedthechar-
acteristicsofCHSparticipantsaccord-
ingtoalcoholconsumption.7Wedocu-
mented 373 cases of dementia during
follow-up, including 258 with Alzhei-
merdiseasealone,44withvascularde-
mentia alone, 54 with Alzheimer dis-
easeandvasculardementia,and17with
othertypesofdementia.TABLE1dem-
onstrates characteristics of cases and
controls. As expected, lower baseline
3MSE scores, previous stroke, diabe-
tes, and a genotype that included an
APOE ?4 allele were more common
amongcasesthancontrols.Medianfol-
low-up time was 6.0 years for controls
and 6.1 years for cases. Age-adjusted
rates of incident dementia were 56 per
1000 among black participants and 36
per 1000 among white participants.31
TABLE 2 demonstrates the associa-
tion of average alcohol consumption
with incident dementia. In logistic re-
gressionmodelsadjustingforpotential
confounders,thelowestoddsratio(OR)
fordementiaoccurredamongindividu-
als consuming 1 to 6 drinks per week
and the highest OR occurred among
thoseconsuming14ormoredrinksper
week(Pforquadraticterm=.001;Table
2). Participants who consumed 1 to 6
drinks per week had a 54% lower odds
of experiencing dementia than did ab-
stainers(95%confidenceinterval[CI],
23%-73%).
Sensitivity Analyses
Toensureourfindingswererobust,we
performed several sensitivity analy-
Table 1. Characteristics of Cardiovascular Health Study Participants*
Characteristics
Incident Dementia
P
Value†No (n = 373)Yes (n = 373)
Demographics
Age, mean (SD), y
Women
Black
Married
Current smoker
Former smoker
Body mass index, mean (SD)
Some vocational school or college
Income ?$16 000‡
Died before 1999
Attended 1999 CHS clinic visit
Baseline MMSE score, mean (SD)§
Use of estrogen replacement
Prevalence of
Stroke
Transient ischemic attack
Hypertension
Diabetes
Congestive heart failure
Atrial fibrillation
Coronary heart disease
APOE ?4 genotype?
Energy expended in leisure physical activities,
mean (SD), kcal
Cholesterol, mean (SD), mg/dL
HDL, mean (SD), mg/dL
Triglycerides, mean (SD), mg/dL
Fibrinogen, mean (SD), mg/dL
Creatinine, mean (SD), mg/dL
Average number of alcoholic drinks
consumed per week
None
?1
1-6
7-13
?14
Former drinker
Quitter
Abbreviations: APOE, apolipoprotein E; CHS, Cardiovascular Health Study; HDL-C, high-density lipoprotein choles-
terol; MMSE, Mini-Mental State Examination.
SIconversionfactors:ToconvertcholesterolandHDL-Cfrommg/dLtommol/L,multiplyby0.0589;creatininetommol/L,
multiply by 88.4; fibrinogen to µmol/L, multiply by 0.0294; and triglycerides to mmol/L, multiply by 0.0113.
*Data are presented as No. (%) unless otherwise indicated. Mean values and SDs are shown for continuous variables.
Cases and controls were matched on age, vital status, and clinic visit status.
†P values are derived from exact tests for binary variables and t tests for continuous variables.
‡Data on income were available for 357 cases and 354 controls.
§Baseline MMSE is on a 30-point scale.
?APOE ?4 genotype was missing for 82 participants.
77.5 (5.2)
213 (57.1)
33 (8.9)
255 (68.4)
32 (8.6)
185 (49.6)
26.2 (4.2)
202 (54.2)
226 (63.8)
117 (31.4)
147 (39.4)
28.4 (1.7)
22 (10.3)
77.8 (5.5)
223 (59.8)
48 (12.9)
232 (62.2)
31 (8.3)
161 (43.2)
26.1 (4.6)
177 (47.5)
209 (58.5)
108 (29.0)
147 (39.4)
27.7 (1.9)
21 (9.4)
.39
.50
.10
.09
?.99
.09
.67
.08
.17
.52
?.99
?.001
.75
16 (4.3)
18 (4.8)
221 (59.3)
40 (10.7)
20 (5.4)
15 (4.0)
86 (23.1)
64 (18.6)
1622 (1939)
29 (7.8)
16 (4.3)
233 (62.5)
60 (16.1)
19 (5.1)
13 (3.5)
98 (26.3)
107 (33.4)
1471 (1809)
.06
.86
.41
.04
?.99
.85
.35
?.001
.27
209.4 (44.1)
53.8 (14.4)
142.4 (80.0)
324.1 (76.2)
1.1 (0.3)
208.8 (38.4)
53.2 (13.5)
144.0 (84.4)
327.0 (61.9)
1.1 (0.3)
.86
.58
.79
.57
.32
123 (33.0)
73 (19.6)
72 (19.3)
32 (8.6)
18 (4.8)
22 (5.9)
33 (8.9)
151 (40.5)
53 (14.2)
33 (8.9)
25 (6.7)
24 (6.4)
35 (9.4)
52 (13.9)
?.001
ALCOHOL USE AND DEMENTIA IN OLDER ADULTS
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