With the underlying cause of Alzheimer’s disease (AD) developing from dementia remaining undiscovered, the availability of treatments is slim, and a cure is non-existent. The key features of AD are well known but still go without a full explanation. Over time, many assumptions have been made about certain components that contribute to the development of AD. A newer target of research, as discussed throughout this chapter, is the gut microbiome and its relationship to the central nervous system. As with all studies, there are limitations that come about in studies of the gut microbiota in relation to Alzheimer’s disease.

We will now outline some key limitations in the general study of Alzheimer’s disease and move forward to discuss the limitations of studying the microbiome’s contribution to the disorder.

General Limitations in the Study of Alzheimer’s Disease

Mice models are the most commonly used organism for studies regarding Alzheimer’s because, although the disease does not occur naturally in mice, when they are genetically modified, their brain model has very similar features to a human AD brain. These models have led to many breakthroughs in AD discovery, but none have fully replicated the human form of the disease. This is the key limitation in studying Alzheimer’s. There is no organism whose AD brain exactly resembles a human AD brain. Although there are animals that show signs of dementia such as plaque build-up in the brain, there are no ethical means in which to use these animals as models, especially when scientists have very well-known and highly developed methods for resembling AD in mice.

One may wonder why human models are not used in studies regarding AD, as humans would be the ones to receive treatment. The reasons for this mainly stem from the ethics behind studies using individuals with dementia or Alzheimer’s disease. Due to memory loss being a large result of AD and dementia, consent from the patient would be a difficult thing to achieve for these studies. This is a large reason why AD patients used for studies, including studies looking at gut microbiota, are diagnosed with very mild dementia. By using participants with a mild case of Alzheimer’s, the results may provide a very different meaning than, for example, the gut microbiota of someone diagnosed with severe AD. Although using these mild cases helps give an idea of something such as gut composition, there still may be missing pieces.

Now let’s move on and discuss the limitations present in the form of study our chapter is focusing on:

Limitations in Gut Microbiota Studies of Alzheimer’s Disease

The limitation that is probably most prevalent when using bacterial quantification from gut microbiota samples in AD patients is the varying medication use between patients. Medication use can have a large effect on gut composition, and individuals with Alzheimer’s disease and dementia most often must be on medications for the treatment of many different symptoms resulting from the disease. The differing effect that medications may have on individuals’ gut composition, along with the general differences in the specific medications being taken, can make coming to conclusions about the gut microbiota of AD patients challenging.

Another important limitation regarding the study of gut microbiota of AD patients is the underlying reasons someone may have a given amount of certain taxa found in their microbiota. Someone’s age, gender, ethnicity, other health conditions, and many other factors can act as roadblocks in this specific type of clinical study. Although the correlation between gut composition and neurodegenerative disease is a proven and well-backed up theory, there are many extraneous variables that must be ruled out in these studies.

Future Directions in Alzheimer’s Studies

Alzheimer’s studies have come a long way and researchers have made an immense amount of progress over the years. There are still many missing pieces to the underlying causation and potential cures for Alzheimer’s disease. The main questions still remain: What causes Alzheimer’s disease? How can it be cured?

Here are just a few directions that are being taken today and moving forward in order to progress in Alzheimer’s studies and uncover more information:

Discovery of New Biomarkers

• We have already discussed how important biomarkers are in relation to quantities correlating with plaque and p-tau presence in the brain
• New biomarkers can allow early diagnosis without the patient showing symptoms
• This is very important, as treatments done on post-symptomatic patients are consistently unsuccessful

Treatment of Asymptomatic Patients

• This type of treatment may allow the early prevention of neurodegeneration
• This may not act as a complete cure but may allow a prolonged duration of time before serious effects of AD set in for the patient
• These types of treatments have been in the works for years, and have allowed steps in the direction of a better quality of life for the patient

Targeting Plaques in the Brain

• Newer studies are taking steps to attempt the destruction of plaques that build up in the brain as a result of AD
• This is done through taking specific drugs that call in immune cells to work against the building up of these plaques
• There is a protein, Fyn, that causes destruction in the brain when paired with the plaques
• A new drug, Saracatinib, is being used in treatments to turn off this specific protein, therefore preventing its destructive action

Tau Tangling Prevention

• There are studies being conducted which prevent p-tau’s hallmark formation of “tangles” in the brain
• The slowing down or complete prevention of these accumulations of tangles being formed can help preserve the parts of the brain that are involved in memory

Considering Insulin Resistance

• Insulin levels and changes in the brain have been thought to have ties to AD
• Keeping this in mind while looking at patients’ alternate health concerns and general health is key to research progression

There are many more prevalent and hopeful treatment plans and clinical trials being undergone consistently to move forward in the search for an Alzheimer’s disease cure. Through collective research and creativity, we can only be hopeful that a dependable cure for this terrible disease can become available soon.