AD:

• progressive, neurodegenerative, above 60 years of age
• memory complaints, deterioration of ADLs

What should be done in the future:

• studying more diverse populations
• more diverse methods
• examining drinking habits across the whole lifetime
• take into account gender and genetic subtypes

What do you expect? (Hypotheses)
1: Alcohol in general: when considered together, there is a general benefit of moderate alcohol consumption
2: Wine: as a rich source of polyphenols, would be protective and would delay the onset of Alzheimer’s disease, wine most effective
3: Beer & liquor would not differ in term of their effectiveness.

Taking into account the aforementioned research on AD and its limitations, the current research proposal deals with the following research question: Does moderate alcohol consumption prevent the development of AD?

looking into more alcoholic beverages in addition to wine ie. wine, beer, hard liquor ie. vodka

Why is that problem important:

• one of the most predominant causes of death (6th leading cause of death in US)
• the most common dementia type among older individuals
• Without advances in therapy, the number of symptomatic cases in the United States is predicted to rise to 13.2 million by 2050
• since there is currently no cure for AD and major pharmaceutical companies withdraw from further reasearch on the development of the cure, the only alternative for managing AD is prevention based on life style factors, including alcohol consumption

research design: randomized control trial, double blind, 104 weeks (two years), clinical trial

Proposals for treatments that could slow down the progression of AD and easing the symptoms, mostly focusing on drugs ie. Donepezil

Main characteristics of AD and their basic biological underpinnings: amyloid, tangles, inflammation, loss of neuronal connections, cell death, neurotransmitter/cholinergic deficiency, neuronal mitochondrial damage

recently, the focus shifted towards early prevention of AD

• amyloid B aggregation research
• incorporation of lifestyle factors: physical activity, cognitive training
• when it comes to diet, small links to meditterean diet but not strong enough for recommendation (also vitamin B12 and folic acid supplements) → proposing consumption of antioxidants ie. Vitamin E and beta carotene --> antioxidant therapy
• speculations that Other antioxidants ie. Polyphenols might be beneficial -> found in wine (reduce inflammation and improve waste removal (glymphatic system)
• neuroprotective effects in both in vitro and in vivo preclinical models of AD
• resveratrol

the above-mentioned questions could not be decisively answered due to the following research limitations:

• mixing diverse populations into one study ie. Classifying non-drinkers as people who have given up alcohol consumption due to health reasons (previous alcoholics) and lifetime non-drinkers
• not considering major confounders ie. tabacco use, stress
• The benefits are described based on memory and other cognitive tests, so the biological processes are not well described
• Commenges et al. (2000) have shown that a diet rich in flavonoids was associated with a lower risk of dementia. In addition, the association with wine consumption disappeared after controlling for diet and may indicate that wine is a marker of a healthier diet.

remaining questions:

• why and how does moderate wine consumption benefit the brain?
• is there a causal link?
• only wine consumption or also other alcoholic beverages?

still inconclusive results concerning dietary recommendations for AD prevention, also controversive since current research proposes that moderate alcohol consumption could be beneficial

The main element favoring wine lies in its flavonoid content and its antioxidant activity

inhibit reactive oxygen species (ROS)-mediated cell death

most of the studies use rat or mice AD models but there are fewer human clinical trials, limited clinical trial evidence

pharmacokinetics in a smaller sample of randomly chosen participants

5 fl oz of table wine at around 12 percent alcohol, 12 ounces beer, 1.5 ounces hard liquor

biomarker analysis at baseline, after 6, 12 months and after two years

MRI) to measure rate of whole-brain and regional atrophy at baseline, after 6 months, 12 months, after 2 years

Screening comprises of medical history, physical exam, neurological exam, and a MMSE.

• reduced fluorodeoxyglucose (FDG) PET measurements of the cerebral metabolic rate for glucose (CMRgl) in brain regions preferentially affected by AD
• structural MRI measurements of brain shrinkage (i.e., hippocampal, entorhinal cortex and whole brain volume loss, ventricular enlargement and gray matter loss and cortical thinning in regions preferentially affected by AD
• PET measurements of fibrillar Aβ burden (using 11C-labeled Pittsburgh Compound-B
• CSF analytes (i.e., low CSF Aβ42 levels, high t- or p-tau levels, or a combination of low Aβ42 and high t-tau or p-tau levels)
• neurogranin as biomarker