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
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©
The Journal of Nutrition, Health & Aging©Volume 12, Number 6, 2008
377
VASCULAR RISK FACTORS, ALCOHOL INTAKE, AND COGNITIVE DECLINE
The Journal of Nutrition, Health & Aging©Volume 12, Number 6, 2008
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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