alzheimer 's disease ( ad ) , the most common form of dementia affecting populations aged over 65 years worldwide , is sporadic , genetically non - obvious , and rarely inherited ( 1 ) .
the main well - known pathological features of the disease include the abnormal extracellular deposition of misfolded amyloid- ( a ) senile plaques in brain parenchyma and cerebral vessels , the intracellular accumulation of hyperphosphorylated tau (  ) in neurofibrillary tangles ( nfts ) , chronic neuroinflammation , neuronal loss and severe brain atrophy as well as progressive loss of memory ( 2,3 ) .
consequently , in the last 30 years , the deregulation of a metabolism ( oligomerization , aggregation and plaque formation ) has been the major target for therapeutic intervention ( 4 ) , and only marginal effects have been registered ( 57 ) , suggesting the need for preventive / curative treatments or alternative solutions .
therefore , although the causes of ad remain unknown and cures or universally effective treatments , are not available , most experts have highlighted a broad constellation of contributing risk factors . among these risk factors ,
alcohol consumption , associated with extensive cognitive problems ( 8) , including alcoholic dementia ( 9 ) , has been targeted .
similar features have been denoted between the effects of alcohol on cognition , brain disorder and brain biochemistry with the biological effects of ad , suggesting that the use of alcohol may constitute a risk for aggravating or developing ad ( 10 ) . in line with this view
, ad patients with a habitual drinking history have shown cognitive improvement during the clinical course of abstinence ( 11 ) .
by contrast , this effect was not observed in patients consuming high amounts of alcohol prior to diagnosis of ad ( 11 ) . in line with these data , there is another emerging body of literature that contends alcohol consumption , particularly red wine , may rather serve as a protective factor for cognitive decline ( 12,13 ) .
several epidemiological studies have shown that low or moderate wine consumption can be effective in retarding age - related cognitive decline ( 14 ) , possibly linked to polyphenols present in beverages . however , the studies promoting the benefits of alcohol on ad exclusively focus on moderate alcohol consumption ( 12 ) , the restriction of alcohol to only an elderly population ( 13 ) , and broad classification of cognitive decline ( 15 ) .
relevant issues remained regarding the protection , the aggravating or detrimental effects of alcohol consumption or whether protective effects are simply influenced by the quantity and/or frequency of drinking . despite the limiting factors identified regarding the beneficial effects of alcohol consumption ( 16 ) , a single - target therapeutic strategy appears to produce only suboptimal results and a broader neuroprotective approach , at least theoretically , appears more appealing ( 17 ) .
thus , the aim of the present review was to discuss the association between alcohol consumption and ad .
heavy alcohol consumption impairs cognitive performance with immediate and long - term effects on the brain anatomy and neuropsychological functioning ( 1821 ) .
cognitive impairment is related to clinical dementia as it accelerates shrinkage and atrophy of the brain , leading to critical determinant of neurodegenerative changes and cognitive decline in aging ( 22 )
. however , these morphological changes induced by alcohol consumption may be reversible unlike ad or aging ( 23 ) , as atrophy decreases , with cognitive improvement after abstinence from alcohol ( 24,25 ) .
other data showed that morphological changes in the brain are associated with the loss of a number of nerve cells occurring in the white matter , which largely comprises nerve fibers that connect neurons ( 26 ) and/or cortical cholinergic neurons ( 24 ) , known to be affected in ad .
this link renders plausible that alcohol use may be linked to ad as the cholinergic system plays an important role in memory .
this role is confirmed and its deficits are well established in ad ( 27 ) .
chronic alcohol use causes degeneration of cholinergic neurons ( 28 ) , or decreases receptors of cholinergic system in ad . these may aggravate the reduction of cholinergic neurons already present in ad patients
however , the improvement of cognitive function in alcoholics after abstention from alcohol suggests that cognitive deficits may reflect neurochemical alterations rather than neuronal loss ( 24,28 ) .
therefore , without appearing as an accelerator of ad process , alcohol may induce its effects on the cholinergic system , independently from the cholinergic deficits caused by ad ( 29,30 ) .
however , alcohol - related brain damage appears to differ in young and older alcohol consumers ( 24 ) , although data suggest that alcohol abuse may accelerate aging - related changes in the brain at any age and that older adults may be more vulnerable to the effects of alcohol ( 8) .
apart from cholinergic deficit , another negative effect of heavy alcohol consumption on cognitive function may be attributed to nutritional deficiency or vascular change ( 31,32 ) , which consist of damage that may be relatively irreversible even after abstinence from heavy alcohol consumption ( 11 ) . therefore , despite the above evidence showing cognitive detrimental effects of heavy alcohol consumption , to the best of our knowledge , no study has established a clear association between alcohol consumption and ad ( 33 ) .
more consistently , recent genetical study on a japanese population provided evidence that the mitochondrial aldehyde dehydrogenase 2 ( aldh2 * 2 , metabolizes acetaldehyde into acetate , protecting against oxidative stress and playing an important role in the development of ad ) , and two functional single - nucleotide polymorphisms ( snps ) of the dopamine--hydroxylase ( dbh ) gene , involved in the pathophysiology of alcoholism and whose activity is reduced in the neocortex of ad ) , did not modify the risk for developing ad , suggesting that the polymorphism of the aldh2 and dbh genes were not associated with ad ( 34 ) . nevertheless , future studies must be undertaken on other populations worldwide .
low - to - moderate alcohol intake is considered to protect against neurodegeneration pathology ( 13,15 ) , dementia ( 3539 ) and cognitive deterioration ( 4043 ) . of the biologic mechanisms
suggested to explain such potential beneficial effects on the brain , there are mainly the antioxidant properties of wine flavonoids ( 44 ) , the effects against a ( 45 ) and the prevention of ischemia or stroke by alcohol ( 46 ) .
specifically , polyphenols , members of a large family of plant - derived compounds , are molecules containing one or more phenolic group .
there are thousands of polyphenols that have been identified thus far including , bioflavonoids ( anthocyanins , flavanols , favanols , favones , flavanones , isofavones and proanthocyanins ) , coumestans , ligans and stilbenoids ( 47 ) .
polyphenolics are in general antioxidant molecules that reduce the in vitro process aggregation of a , reducing the neuronal death of cortical neurons preventing neurodegeneration ( 48 ) .
the morin for example , a specific flavonoid described in red wine exhibited significant effects in preventing aggregation of a ( 49 ) . in agreement with these data ,
red wine cabernet sauvignon significantly reduced the number of a plaque - induced neuropathology and attenuated a spatial memory decrease in an adult tg2576 mouse model of ad ( 50 ) .
resveratrol is known to protect against cardiovascular diseases ( which are risk factors for developing ad ) and various types of cancer , together with the promotion of the antiaging effect , the modulation of pathomechanisms of debilitating neurological disorder such as strokes , ischemia and huntington 's disease , as well as protection against neuronal degeneration ( 14,51 ) .
other natural molecules including fulvic acid , altered the aggregation mechanism of  proteins , a critical protein involved in the stabilization of microtubule and axonal transport , found to be involved in ad pathogenesis ( 52 ) .
however , whatever the facts around the benefits that may follow the potential benefits of low - to - moderate consumption of alcohol , the importance of drinking patterns and specific beverages consumed remain elusive . the operational definition of low or moderate drinking which may vary greatly across studies ( 53 ) and the concept of a moderate drinker , which may also be imprecise , comprising a wide range measure that may include those consuming less than one drink a day ( 54 ) .
red wine consumption appears to promote far more protective effects than the consumption of other ethanol containing beverages ( 55 ) .
this is in keeping with variations that may be introduced by consumers who sometimes associate the consumption of tobacco , or the possible toxicity effects of chronic exposure of the liver to alcohol ( 56 ) , which can also contribute to brain alteration in regions involved in memory ( 57 ) . taken together , the data provide insufficient evidence to suggest abstainers should initiate alcohol consumption to protect against dementia or ad .
based on the abovementioned research data , no relationship between alcohol consumption and ad exists . in addition , although low - to - moderate consumption of alcohol may protect against ad , leading to benefits on neurodegeneration , a , oxidative stress and  neurofibrilary tangle formation suggest bias regarding the definition of low - to - moderate consumption as well as the variability of beverages containing alcohol . in addition , the absence of studies on the possible side effects of chronic exposure to alcohol on peripheral organs such as liver , and kidney lead to the necessity to delineate global and standard protocols for advanced studies .
these studies render the benefits associated with low - to - moderate alcohol consumption against ad .
however , the results should be considered as controversial and insufficient to suggest abstainers that initiate alcohol consumption in a preventive manner against ad .
 alzheimer 's disease ( ad ) is a neurodegenerative disease characterized by dense deposition of amyloid- ( a ) protein in the brain , failure of the memory and dementia . at present 
 , there is no cure for ad and current treatments only provide a temporary reduction of symptoms . 
 thus , there is a need for effective preventive / curative strategic approaches . 
 accordingly , epidemiological studies have reported a reduction in the prevalence of ad in individuals ingesting low amounts of alcohol , while a moderate consumption of ethanol may protect against a. these data are conflicting with other observations that assigned detrimental effects of heavy alcohol use on brain function , which are apparently similar to those observed in ad . 
 these discrepancies questioned whether or not alcohol is a protective agent against the development of ad , whether the probable protective effects are influenced by the quantity and/or frequency of drinking . 
 these issues are addressed in this review with the aim to suggest the real risk of alcohol for developing or preventing ad . 