Vascular risk factors, alcohol intake, and cognitive decline

The Journal of Nutrition, Health & Aging©Volume 12, Number 6, 2008

376

Introduction

At present, there is no curative treatment for dementia andAlzheimer’s disease (AD), or therapeutical approach to preventthe conversion of mild cognitive impairment (MCI) todementia. In the past years, extensive research has increasedour knowledge of the aetiology of AD, other dementingdisorders, and predementia syndromes and several hypotheseshave already emerged from the epidemiological research.Epidemiological evidence supported the hypothesis thatmodifiable vascular and lifestyle-related factors are associatedto the development of dementia and predementia syndromes inlate life, opening new avenues for the prevention of thesediseases (1).

The aim of this article was to examine the possible role ofvascular and lifestyle-related factors in cognitive decline,reviewing current epidemiological evidence with a focus on thefindings from the Italian Longitudinal Study on Aging (ILSA),a large, population-based, prospective study with a sample of5,632 subjects 65-84 years old, independent or institutionalized,randomly selected from the demographic rolls of eight Italianmunicipalities after stratification for age and gender (2). Specialattention was paid to the possible role of metabolic syndrome(MetS) and alcohol consumption in predementia and dementiasyndromes.

Vascular risk factors, metabolic syndromes, and cognitive decline

In older subjects, particularly over age 85 years, theprevalence of vascular factors and other medical conditions that

impair cognition increases substantially including chroniccardiovascular, respiratory, and metabolic diseases, and severesensory deficits (3). Evidence of overlap between degenerativeand vascular disorders is emerging from pathologic andepidemiological studies. Various genetic and non geneticfactors known to increase the risk of vascular disease, includingapolipoprotein E (APOE) and angiotensin I converting enzyme1 (ACE1) genotypes, total cholesterol, lipoprotein(a) [Lp(a)],diabetes mellitus, atrial fibrillation, hypertension, obesity,serum APOE levels, and C-reactive protein levels aninflammation, have been evaluated as risk factors for AD andVaD, and cognitive decline (4). Recent evidence frompopulation-based studies and case series suggests thatcerebrovascular disease (CVD) and vascular risk factors maycontribute to the heterogeneity of MCI (2, 3, 5-7). Because suchvascular risk factors may be modifiable, identification andsubsequent management of these possible risk factors may helpto prevent, and reduce conversion rates of MCI to dementia (3).Apart from the association between AD and vascular riskfactors, dietary fatty acids appeared to have a role inpredementia and dementia syndromes (8, 9).

Recently, based on the data from Cardiovascular RiskFactors, Ageing and Incidence of Dementia (CAIDE) study, arisk score including easily measurable variables associated withthe risk of dementia later in life has recently developed (10).The CAIDE Dementia Risk Score has already been validated ina large population (N=9831) and provides a quantitativeestimation of the probability of becoming demented, but itcannot definitely state whether a person will develop dementia.Among the variables associated with the risk of dementia later

VASCULAR RISK FACTORS, ALCOHOL INTAKE, AND COGNITIVE DECLINE


F. PANZA1, C. CAPURSO2, A. D’INTRONO1, A.M. COLACICCO1, V. FRISARDI1, A. SANTAMATO3, M. RANIERI4, P. FIORE3, G. VENDEMIALE2, D. SERIPA5, A. PILOTTO6, A. CAPURSO1, V. SOLFRIZZI1

1. Department of Geriatrics, Center for Aging Brain, Memory Unit, University of Bari, Bari, Italy; 2. Department of Geriatrics, University of Foggia, Foggia, Italy; 3. Department ofPhysical Medicine and Rehabilitation, University of Foggia, Foggia, Italy; 4. Department of Neurological and Psychiatric Sciences, University of Bari, Bari, Italy; 5. Laboratory of

Gerontology & Geriatrics, Department of Research, IRCCS Casa Sollievo della Sofferenza, San Giovanni Rotondo (FG), Italy; 6. Geriatric Unit, Department of Medical Sciences, IRCCSCasa Sollievo della Sofferenza, San Giovanni Rotondo (FG), Italy. Corresponding Author: Francesco Panza, MD, PhD, Department of Geriatrics, Center for Aging Brain, Memory Unit

University of Bari, Policlinico, Piazza Giulio Cesare, 11, 70124 Bari - Italy, Phone: + 39-080-5473685; Fax : + 39-080-5478860; E-mail: [email protected]

Abstract: Since the therapeutic options currently available have demonstrated limited efficacy, the search forpreventive strategies for cognitive decline and dementia is mandatory. A possible role of vascular and lifestyle-related factors was recently proposed for age-related changes of cognitive function, predementia syndromes, andcognitive decline of degenerative (Alzheimer’s disease, AD) or vascular origin. At present, cumulative evidencesuggested that vascular risk factors may be important in the development of mild cognitive impairment (MCI),dementia, and AD. Among vascular-related factors, metabolic syndrome has been associated with the risk ofcognitive decline and overall dementia. Moderate alcohol drinking has been proposed as a protective factoragainst MCI and dementia in several longitudinal studies, but contrasting findings also exist. However, in mostcases, these were only observational studies, and results are awaited from large multicenter randomized clinicaltrials in older persons. At present, vascular risk factor management, lifestyle changes, and drugs could beemployed together to delay the onset of dementia syndromes.

Key words: Alcohol, metabolic syndrome, vascular risk factors, predementia syndromes, dementia, Alzheimer’sdisease, vascular dementia, mild cognitive impairment.

Received April 29, 2008Accepted for publication May 5, 2008

in life, we found some vascular factors [blood pressure, bodymass index (BMI), and total cholesterol] and some lifestyle-related factors (education and physical activity). It shouldtherefore be used mainly to target preventive measures to thosemost at risk and not to label individuals as being demented ornon-demented in the future (11).

MetS is defined as a cluster of abdominal obesity, impairedfasting glucose, hypertension, low high-density lipoprotein(HDL) and/or high triglycerides, firstly described about 40years ago (12, 13). Most of the MetS components have beenshown to be independent risk factors for coronary artery disease(CAD) and stroke, and MetS itself was already evidenced to bean independent risk factor for CAD, CAD mortality, and fataland non-fatal stroke (14-16). In particular, MetS increases therisk of both clinical stroke and silent brain infarction by 2–4times (15, 16). As seen above, several individual componentsof MetS have been linked to risk of developing dementia andMCI (2, 3, 17). However, few studies have looked at thecomponents of MetS as a whole. MetS has also been previouslyshown to increase the risk of cognitive decline in differentethnic groups (18-21), overall dementia (22), AD in bothpopulation-based and case-control studies (23, 24), and frontal-subcortical syndrome (25). However, the association betweenMetS and accelerated cognitive decline seems to disappear atthe age 85 and older (26). Recent findings from the ILSAsuggested that the prevalence of MetS according to the criteriaof the Third Adults Treatment Panel of the National CholesterolEducation Program (ATP-III) was around 31.5% in men, and59.8% in women among the Italian elderly (27). Although,there were evidence of a link between MetS and VaD from theHonolulu-Asia Aging Study (HAAS) (22) and Braziliancommunity-dwelling elderly (25), these studies did not usestandard criteria for MetS and VaD. In fact, in the HAAS aclustering of 7 metabolic cardiovascular risk factors (randompostload glucose, diastolic and systolic blood pressures, BMI,subscapular skinfold thickness, random triglycerides, and totalcholesterol) increases the risk of dementia, and in particular forVaD, but not for AD (22). However, this clustering ofcardiovascular risk factors did not identifies a MetS diagnosisaccording to current criteria. More recently, in Braziliancommunity-dwelling elderly, frontal-subcortical syndrome wasstrongly associated with MetS diagnosed adapting ATP IIIcriteria , independently of age, gender or presence of stroke(25). In this recent study, Met.S was also significantlyassociated with lower cognitive, executive, and neuromotorfunctions, and depressive symptoms (25). However, at present,there is no clear consensus in the diagnosis of frontal-subcortical syndrome, arbitrary defined by presence of at leastone frontal release reflex plus presence of three or more of thefollowing four criteria: cognitive impairment, late-onsetdepression, lower limbs neuromotor dysfunction, and urgencyincontinence (28). It is also unclear whether the MetS has ahigher predictive value for developing dementia than the sumof its individual components (17). The mechanisms of vascularfactors in the development of dementia syndromes are still

under investigation. Nonetheless, vascular risk factors maydirectly induce Alzheimer’s pathology, or lead toarteriosclerosis, impaired brain blood flow and metabolism, andneuronal dysfunction. Vascular risk factors may also inducesmall and large vessel CVD and infarcts, leading to anincreased risk of development of clinically overt AD (10).

Alcohol consumption and cognitive decline

Among lifestyle factors related to diet, several studies haveassessed alcohol consumption and cognitive function amongolder adults, but with inconsistent results (1) (Table 1). Launerand colleagues showed in the Zutphen Elderly Study that menwith CAD or diabetes and low-to-moderate alcohol intake had asignificantly lower risk of poor cognitive function compared toabstainers (29). In the Framingham Heart Study the associationbetween alcohol consumption and cognitive performance wasanalyzed separately for men and women, since the researchersexpected a different alcohol-cognition relationship for male andfemale drinkers (30). Some have claimed there is a J or Ushaped relation between alcohol drinking and cognitiveimpairment (29, 31, 32); that is, light to moderate alcoholdrinking might have a protective effect compared with totalabstention and heavy drinking.

Moreover, epidemiological studies have recently reported anassociation between wine consumption and the incidence ofAD. Particularly, red wine was investigated in the PAQUIDstudy, in which the relative risk for dementia and AD among318 subjects who drank three or four glasses of wine each dayin comparison with 971 total abstainers were 0.21 and 0.25,respectively. Among the 922 older subjects who drank no morethan one or two glasses of wine each day respect to theabstainers the relative risk for AD was reduced significantly(0.55) (33). More recently, the relation between alcoholconsumption and risk of dementia (AD, VaD, or otherdementia) was examined in the Rotterdam Study. The findingsof this study, with an average follow-up of 6 years, suggestedthat light-to-moderate alcohol consumption is associated with areduced risk of dementia in individuals aged 55 years or older;this effect seems to be unchanged by the source of alcohol (34)(Table 1). In the Rotterdam study, the protective effect ofalcohol drinking was found mainly for VaD, and the authorssuggested that moderate alcohol intake might protect againstdementia via a reduction in vascular risk factors (34). In anested case-control study on 373 cases with incident dementiaand 373 controls who were among 5,888 adults aged 65 yearsand older, and participated in the Cardiovascular Health Study(CHS), the adjusted odds ratio for dementia among whoseweekly alcohol consumption was less than 1 drink were 0.65,compared with abstention; 1 to 6 drinks, 0.46; 7 to 13 drinks,0.69; and 14 or more drinks (35). In the Copenhagen City HeartStudy, the risk of developing dementia was significantly loweramong occasional wine drinkers, in weekly drinkers and, butnot significantly, in daily drinkers. An increased risk for beerand for spirits was found in occasional, weekly, and dailydrinkers (36).

THE JOURNAL OF NUTRITION, HEALTH & AGING©


377



378

Tabl

e 1

Prin

cipa

l stu

dies

on

the

rela

tions

hips

am

ong

alco

hol c

onsu

mpt

ion

and

dem

entia

, vas

cula

r dem

entia

(VaD

), A

lzhe

imer

’s d

iseas

e (A

D),

and

mild

cog

nitiv

eim

pairm

ent (

MCI

)

Ref

eren

ceSe

tting

and

stud

y de

sign

Subj

ects

M

etho

dsR

esul

ts a

nd c

oncl

usio

ns

Laun

er e

t al.,

199

6 Cr

oss-

sect

iona

l and

489

men

MM

SE, e

valu

atio

n of

alc

ohol

A

fter a

djus

tmen

t for

age

, edu

catio

n, a

nd sm

okin

g sta

tus,

men

with

CV

D/d

iabe

tes a

nd lo

w-to

-mod

erat

e a

lcoh

ol(2

9)

long

itudi

nal,

popu

latio

n-ag

ed 6

9-89

yea

rsin

take

and

smok

ing

habi

tsin

take

had

a si

gnifi

cant

ly lo

wer

risk

for p

oor c

ogni

tive

func

tion

than

abs

tain

ers.

Alc

ohol

inta

ke w

as n

ot a

ssoc

iate

d w

ith

base

d (3

yea

rs)

cogn

itive

dec

line

Org

ogoz

o et

al.

Long

itudi

nal,

popu

latio

n-37

77 su

bjec

ts ag

ed

Dia

gnos

is of

dem

entia

and

AD

;In

the

318

mod

erat

e dr

inke

rs, a

s com

pare

d to

the

971

non-

drin

kers

, and

afte

r adj

ustin

g fo

r pos

sible

con

foun

ders

, the

19

97 (3

3)ba

sed

(3 y

ears

)65

and

ove

r ev

alua

tion

of a

lcoh

ol in

take

odds

ratio

s wer

e re

spec

tivel

y 0.

19 fo

r inc

iden

t dem

entia

and

0.2

8 fo

r AD

. Am

ong

the

922

mild

drin

kers

resp

ect t

o th

e ab

stain

ers t

he re

lativ

e ris

k fo

r AD

was

redu

ced

signi

fican

tlyEl

ias e

t al.

1999

(30)

Cros

s-se

ctio

nal a

nd

1786

subj

ects

aged

Ei

ght c

ogni

tive

tests

of v

erba

lW

omen

who

dra

nk m

oder

atel

y (2

-4 d

rinks

/day

) sho

wed

supe

rior p

erfo

rman

ce in

man

y co

gniti

ve d

omai

ns re

lativ

e to

lo

ngitu

dina

l, po

pula

tion-

55-8

8 ye

ars

mem

ory,

lear

ning

, visu

alab

stain

ers.

For m

en, s

uper

ior p

erfo

rman

ce w

as fo

und

with

in th

e ra

nge

of 4

-8 d

rinks

/day

, alth

ough

few

er si

gnifi

cant

ba

sed

(24

year

s)or

gani

zatio

n an

d m

emor

y, a

ttent

ion,

re

latio

ns w

ere

obse

rved

. The

se re

sults

wer

e co

nfirm

ed b

y pr

ospe

ctiv

e an

alys

es o

f 24-

year

drin

king

hist

ory

abstr

act r

easo

ning

, and

con

cept

fo

rmat

ion;

eva

luat

ion

of w

eekl

y al

coho

l int

ake

Ruite

nber

g et

al.,

Long

itudi

nal,

popu

latio

n-5,

395

subj

ects

aged

D

iagn

osis

of A

D, V

aD, o

r oth

erLi

ght-t

o-m

oder

ate

drin

king

(one

to th

ree

drin

ks p

er d

ay) w

as si

gnifi

cant

ly a

ssoc

iate

d w

ith a

low

er ri

sk o

f any

dem

entia

20

02 (3

4)ba

sed

study

(6 y

ears

)55

and

old

erde

men

tia; e

valu

atio

n of

alc

ohol

an

d V

aD. N

o ev

iden

ce th

at th

e re

latio

n be

twee

n al

coho

l and

dem

entia

var

ied

by ty

pe o

f alc

ohol

ic b

ever

age

was

foun

din

take

Muk

amal

et a

l.,

Nes

ted

case

-con

trol o

f a37

3 ca

ses w

ith

Dia

gnos

is of

inci

dent

dem

entia

Com

pare

d w

ith a

bste

ntio

n, c

onsu

mpt

ion

of 1

to 6

drin

ks w

eekl

y is

asso

ciat

ed w

ith a

low

er ri

sk o

f inc

iden

t dem

entia

20

03 (3

5)lo

ngitu

dina

l, po

pula

tion-

inci

dent

dem

entia

(A

D a

nd V

aD),

aver

age

alco

hol

amon

g ol

der a

dults

. A tr

end

tow

ard

grea

ter o

dds o

f dem

entia

ass

ocia

ted

with

hea

vier

alc

ohol

con

sum

ptio

n w

as m

ost

base

d stu

dyan

d 37

3 co

ntro

ls co

nsum

ptio

n, a

nd m

agne

tic

appa

rent

am

ong

men

and

par

ticip

ants

with

an

APO

E ε4

alle

le, w

ith si

mila

r rel

atio

nshi

ps o

f alc

ohol

use

with

AD

and

re

sona

nce

imag

ing

findi

ngs

VaD

Luch

sing

er e

t al.,

Long

itudi

nal,

popu

latio

n-90

8 su

bjec

ts ag

ed

Dia

gnos

is of

inci

dent

dem

entia

Afte

r adj

ustin

g fo

r age

, sex

, APO

E ε4

stat

us, e

duca

tion,

and

oth

er a

lcoh

olic

bev

erag

es, o

nly

inta

ke o

f up

to th

ree

daily

20

04 (3

8)ba

sed

study

(4 y

ears

)65

yea

rs a

nd o

lder

(AD

and

dem

entia

ass

ocia

ted

with

se

rvin

gs o

f win

e w

as a

ssoc

iate

d w

ith a

low

er ri

sk o

f AD

. Stra

tifie

d an

alys

es b

y th

e A

POE-

epsil

on 4

alle

le re

veal

ed th

at

strok

e) a

nd a

lcoh

ol in

take

th

e as

soci

atio

n be

twee

n w

ine

cons

umpt

ion

and

low

er ri

sk o

f AD

was

con

fined

to su

bjec

ts w

ithou

t the

APO

E ε4

alle

le

Antti

la e

t al.,

200

4Lo

ngitu

dina

l, po

pula

tion-

1464

men

and

wom

enD

iagn

osis

of in

cide

nt d

emen

tia a

ndA

lcoh

ol d

rinki

ng in

mid

dle

age

show

ed a

U sh

aped

rela

tion

with

risk

of M

CI in

old

age

. Onl

y th

e ca

rrier

s of A

POE ε4

(4

1)ba

sed

study

(23

year

s)ag

ed 6

5-79

yea

rsM

CI, a

nd su

bjec

ts cl

assif

ied

as

had

an in

crea

sed

risk

of d

emen

tia w

ith in

crea

sing

alco

hol c

onsu

mpt

ion

thos

e w

ho n

ever

dra

nk a

lcoh

ol,

thos

e w

ho d

rank

“in

frequ

ently

” (le

ss th

an o

nce

a m

onth

), an

d th

ose

who

dra

nk “

frequ

ently

” (s

ever

al ti

mes

a m

onth

)Es

pela

nd e

t al.,

Long

itudi

nal,

popu

latio

n-4,

451

com

mun

ity-

Dia

gnos

is of

inci

dent

MCI

and

Mod

erat

e al

coho

l int

ake

was

ass

ocia

ted

with

an

appr

oxim

atel

y 50

per

cent

redu

ced

risk

of c

ombi

ned

prob

able

dem

entia

20

05 (4

2)ba

sed

study

(4.2

yea

rs)

dwel

ling

wom

en a

ged

dem

entia

, and

ann

ual m

odifi

edan

d/or

MCI

. Sig

nific

ant d

eclin

e in

glo

bal c

ogni

tion

was

less

com

mon

am

ong

wom

en w

ho re

porte

d al

coho

l int

ake

at

65–7

9 ye

ars

Min

i-Men

tal S

tate

Exa

min

atio

n.

base

line,

also

afte

r adj

ustm

ent f

or b

oth

dem

ogra

phic

/soci

al a

nd c

linic

al fa

ctor

sSu

bjec

ts cl

assif

ied

as a

bsta

iner

s, <

1 dr

ink/

day,

and

> 1

drin

k/da

y

Solfr

izzi

et a

l.,Lo

ngitu

dina

l, po

pula

tion-

1,44

5 m

en a

nd

Dia

gnos

is of

inci

dent

MCI

and

In p

atie

nts w

ith M

CI u

p to

1 d

rink/

day

of a

lcoh

ol o

r win

e m

ay d

ecre

ase

the

rate

of p

rogr

essio

n to

dem

entia

. No

2007

(40)

base

d stu

dy (3

.5 y

ears

)w

omen

age

d 65

-84

prog

ress

ion

from

MCI

to d

emen

tia;

signi

fican

t ass

ocia

tions

wer

e fo

und

betw

een

any

leve

ls of

drin

king

and

the

inci

denc

e of

MCI

in n

on-c

ogni

tivel

y ye

ars

subj

ects

clas

sifie

d as

abs

tain

ers,

impa

ired

indi

vidu

als v

s abs

tain

ers

< 1

drin

k/da

y, 1

-2 d

rink/

day,

and

>

2 dr

ink/

day

Mel

hig

et a

l., 2

007

Long

itudi

nal,

popu

latio

n-1,

462

wom

en a

ged

Dia

gnos

is of

dem

entia

; eva

luat

ion

Win

e w

as p

rote

ctiv

e fo

r dem

entia

, and

the

asso

ciat

ion

was

stro

nges

t am

ong

wom

en w

ho c

onsu

med

win

e on

ly. I

n (3

9)ba

sed

study

(34

year

s)38

–60

year

sof

alc

ohol

inta

ke

cont

rast,

con

sum

ptio

n of

spiri

ts at

bas

elin

e w

as a

ssoc

iate

d w

ith sl

ight

ly in

crea

sed

risk

of d

emen

tia

MM

SE: M

ini-m

enta

l Sta

te E

xam

inat

ion;

CV

D: c

ereb

rova

scul

ar d

iseas

e; A

D: A

POE:

apo

lipop

rote

in E

A trend toward greater odds for dementia associated withheavier alcohol consumption was most apparent among menand participants bearing an APOE ε4 allele, with similarrelationships of alcohol use with AD and VaD (35). Thefindings from the CHS were consistent with the PAQUIDStudy (33) and the Rotterdam Study (34), but suggested ahigher risk of dementia with consumption greater than 2 drinksper day. The results of the CHS were also consistent with thoseof the Epidemiology of Vascular Aging Study which found thatalcohol intake was associated with a lower risk of cognitivedeterioration among subjects without an APOE ε4 allele, but ahigher risk in APOE ε4 carriers (37). Surprisingly, theRotterdam Study found that the lower risk of dementiaassociated with alcohol use was more consistent amongindividuals with an APOE ε4 allele (34), but no significantinteraction was detected. In the Washington Heights Inwood-Columbia Aging Project, with 908 subjects aged 65 years andolder, consumption of up to three servings of wine daily isassociated with a lower risk of AD in elderly individualswithout the APOE ε4 allele (38). Finally, in the ProspectivePopulation Study of Women in Goteborg, Sweden, in a 34-yearfollow-up, wine was protective for dementia, and theassociation was strongest among women who consumed wineonly. In contrast, consumption of spirits at baseline wasassociated with slightly increased risk of dementia (39) (Table1).

Very recently, we evaluated the impact of alcoholconsumption on the incidence of MCI in 1,445 non–cognitivelyimpaired individuals and on its progression to dementia in 121patients with MCI, aged 65 to 84 years, participating in theILSA, with a 3.5-year follow-up. Patients with MCI whoconsumed up to 1 drink/day had a reduction in the rate ofprogression to dementia in comparison with patients with MCIwho never consumed alcohol. Overall, vs non-drinkers, patientswith MCI who consumed 1.0 to 14.9 g of alcohol/day, derivedmostly from wine, had a decrease in the rate of progression todementia of about 85 percent. Moderate intake of alcoholderiving from wine, in drinks controlled for the intake ofalcohol deriving from other sources within each level of totalintake, was also associated with a significantly lower rate ofprogression to dementia. No significant associations werefound between any levels of drinking and the incidence of MCIin non–cognitively impaired individuals vs abstainers (40).

To the best of our knowledge, only two other studies haveexamined the effect of alcohol consumption on the risk for theincidence of MCI (41, 42) (Table 1). After an average follow-up of 23 years, non-drinkers and frequent drinkers were bothmore than twice as likely to have MCI in old age thanoccasional drinkers (41). However, the APOE genotype seemedto modify the relationship, such that the risk of old agedementia increased with increasing midlife alcoholconsumption only among carriers of the APOE ε4 allele (41).In our report on ILSA sample, we failed to confirm thesefindings, but we note that the alcohol consumption reportedwas a midlife determination (39). Probably, a follow-up period

longer than 3.5 years would have revealed that a moderatealcohol consumption might influence the incidence of MCI. Onthe other hand, our findings are consistent with those obtainedin the Women’s Health Initiative Memory Study with a 4.2year-follow-up, which found that moderate alcohol intake wasassociated with an approximately 50 percent reduced risk ofcombined probable dementia and MCI (42). However, afteradjusting for demographic and socioeconomic factors, andbaseline Modified Mini Mental State Examination (3MSE), thesignificance disappeared (42). Currently, ours is the first studyin which alcohol consumption was associated with the rate ofpro progression of MCI to dementia, in fact, up to 1 drink/dayof alcohol or wine may decrease the rate of progression todementia in patients with MCI (38). It is also possible thatmoderate lifestyles in general, which obviously vary accordingto different cultural environments, protect from cognitiveimpairment. Thus, it may not be the direct effect of alcohol orspecific substances in alcoholic drinks that provide theprotection, but moderate alcohol drinking may be an indicatorof a complex set of favorable social and lifestyle factors. Aprotective effect of alcohol on cognitive function in moderatedrinkers may be due to a relatively poor health status amongabstainers or because cognitive status influences alcoholconsumption and overall health status.

The mechanism by which low alcohol intake could beprotective against the progression of MCI to dementia oragainst dementia syndromes is, at present, unknown. Alcoholconsumption might protect from dementia by effects on thecerebral vasculature, supporting the observation that moderatealcohol intake might be protective against ischemic stroke (43).In fact, a light-to-moderate alcohol use is associated with alower prevalence of MRI-defined white matter lesions and sub-clinical infarcts (44), although MRI abnormalities, HDLcholesterol levels, and fibrinogen levels only marginallyinfluenced the association of alcohol consumption anddementia in the CHS (35). Furthermore, light-to-moderatealcohol intake has been reported to be associated with a lowerprevalence of vascular brain findings and, in APOE ε4 carriers,with hippocampal and amygdalar atrophy as assessed by MRI(44). Experimental studies found than ethanol initially increaseshippocampal acetylcholine release, which could conceivablyimprove memory performance (1). Moderate doses of alcoholmay increase prostacyclin concentrations, reduce the generationof thromboxane A2, and inhibit platelet function (1). It is alsoknown that alcohol is associated with increased levels of HDLcholesterol, its subfractions HDL2 and HDL3, and itsassociated apolipoproteins A-I and A-II (45, 46). Theassociation with HDL cholesterol is deemed to account for upto a half of the reduction in coronary events associated withmoderate alcohol consumption (1). Wine consumption mayexert a protective effect, either through alcohol intake itself,through the antioxidant effects of polyphenols richlyrepresented in red wine (47, 48), or through both. The lattereffects, of course, are independent of alcohol and, in fact, havebeen also associated with alcohol-free red wine (49). Processes



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that originate, modulate, or precipitate the deposition ofamyloid beta in the brain, such as oxidative stress, rather thanvascular processes, may better explain the development of AD,and the vascular effects of the alcohol component of alcoholicbeverages may not be enough to explain the protective effectsof the moderate intake of alcohol from dementia. The presencein wine of nonalcoholic components, such as particularantioxidants, could explain a differential effect of wine on theprogression to dementia. In fact, liquor has been shown to haveless antioxidant activity than wine (50).

Conclusions

Drugs currently used in the treatment of cognitiveimpairment and dementia have a very limited therapeutic value,overall on the management of psychiatric and behaviouralsymptoms, rather than cognitive symptoms. It results evidentthe necessity to potentially individualize new strategies able toprevent and to slow down the progression of predementia anddementia syndromes.

In the past few years, vascular and lifestyle-related factorsfor predementia and dementia syndromes have been an area ofintensive research. At present, cumulative evidence suggestedthe vascular risk factors may be important in the developmentof MCI, dementia, and AD. Also, MetS, defined as a cluster ofvascular risk factors, appeared to be a possible, independentrisk factor for cognitive decline and dementia. Moderatealcohol drinking has been proposed as a protective factoragainst MCI and dementia in several longitudinal studies, butcontrasting findings also exist. In fact, many of these studieswere limited by cross-sectional design, restriction by age orsex, or incomplete ascertainment. Whether, the divergentfindings can be explained by the drinking patterns has not beenextensively investigated. At present, there is no evidenceindicating that starting to drink at a later age would bebeneficial. It thus seems that from an epidemiologic point ofview, the way to curb the dementia epidemic is through strictattention to vascular risk factors. In fact, several studies haveconfirmed that good control of hypertension can preventdementia (both AD and VaD) and treatment with statins alsohas the same effect (51). Obviously, even rigid attention tothese risk factors will not be able to prevent dementiaaltogether. For one, the most important vascular risk factor isprobably age, which still cannot be manipulated. Secondly, thedata concerning the reduction of the incidence of dementiashould better be interpreted as delay in the onset rather thanprevention. However, because the prevalence of dementiadoubles every 5 years, delay in the onset of dementia by fiveyears is equivalent to a reduction of the prevalence by half inany given age group (52). Probably, at present, since severalimportant factors are already identified, vascular risk factormanagement, lifestyle changes, and drugs should be employedtogether to delay the onset of dementia syndromes.

Financial disclosure: none of the authors had any financial interest or support for thispaper.

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Vascular risk factors, alcohol intake, and cognitive decline

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