Alzheimer's disease is the most common cause of dementia, or Major NeuroCognitive Disorder (MNCD). It affects over 747 000 Canadians, and for every person who's living with Alzheimer's is a family and a care partner, often more than one who are affected as well.
Alzheimer's disease has no cure, and the medications that we currently prescribe increase a chemical called acetylcholine, which can help with some Alzheimer’s symptoms. Their effects are modest at best, and even on medication, progression of the dementia is inevitable. You can learn more about current dementia medications, here.
In this article, I’ll talk about some of the new treatments that could be available in the future. There are a lot of compounds being studied, and some of them could be on the market in a few years.
- Click on the video to watch me talk about how Alzheimer's affects the brain and what some of these new treatments are all about, or keep reading.
Let's start by taking a look at what Alzheimer's disease is and how it affects the brain.
Alzheimer’s Disease and the Brain
Like many diseases, one of the challenges with coming up with treatments for Alzheimer's is that we're still gaining an understanding of what it actually does to the brain.
You've probably heard about plaques and tangles. People living with Alzheimer's have amyloid plaques in the brain. These are made up of proteins: amyloid beta peptides also known as amyloid beta 42 because they contain 42 amino acids (amino acids are the building blocks of protein).
The tangles are composed of a protein called Tau which has been hyper phosphorylated, also known as p-tau. Non-phosphorylated tau is important for stable neuron function, but when it gets phosphorylated it can clump together into neurofibrillary tangles. Investigative Alzheimer’s therapies have targeted these proteins to see if we can remove that we can alleviate some of the plaques and tangles. The abnormal amyloid proteins could be over produced or could be under removed by the brain so any therapy that attacks amyloid might be helpful.
Changes to blood vessels also play a part. Those who have vascular changes in the brain have a more severe form of dementia but also have more amyloid and more neurodegenerative brain changes. These plaques and tangles and blood vessel changes disrupt the normal brain architecture.
Other abnormal protein deposits found in the brains of those with Alzheimer's can include amyloid beta and Alpha- synuclein also known as Lewy bodies.
The parts of the brain that are affected include the hippocampus (there are two of these little seahorse shaped lobes of the brain near the temporal and parietal lobes). In people with Alzheimer's, the hippocampus shrinks, and the cells show changes called sclerosis and gliosis. These changes are also seen in other types of dementia like frontotemporal dementia and vascular dementia.
All of these mechanisms lead to the symptoms of dementia: memory impairment, language difficulties, a decrease in reasoning and perceptual skills and overall, more difficulty managing day-to-day life.
The role of Genetics in Alzheimer’s disease
Many people want to know about the role of genetics as well. Genetic factors are actually a small part of Alzheimer's disease. The strongest genetic connection seems to be with early onset dementia, that is Alzheimer’s disease onset before the age of 60. Two genes that affect amyloid precursor protein are named presenilin-1 and presenilin-2. Mutations in these genes will increase the deposition of amyloid in the brain and will cause an early onset of Alzheimer's in many cases.
In later onset Alzheimer disease, which is much more common, we have a less clear understanding of the role of genetics. You might have heard of apolipoprotein E 4 (ApoE4). Some people who have mutations in genes that code for these proteins are more likely to get Alzheimer's. So, if you're reading a study about Alzheimer's treatment you might see that they comment on the participants’ ApoE4 allele status. We still don't know enough about this though, to know how much of a risk factor this is for Alzheimer's and what we would do to reduce the risk in people who do have mutations in the gene. If you’re worried about your Alzheimer’s disease risk, getting your ApoE4 status checked is not likely to be helpful.
Another way to look at it is that people who have a first degree relative with Alzheimer's probably have a higher risk of developing Alzheimer's and if you have a first degree relative with Alzheimer’s disease of early onset, that risk would be increased again.
It's probably also worthwhile to mention here that there are other things that seem to affect Alzheimer's risk. This includes the things that we know affect risk of stroke and heart attack like high blood pressure, stroke, diabetes, high cholesterol, obesity, sedentary lifestyle and head injury. Many medications have been linked to a higher risk of Alzheimer's disease, but these links are not completely clear. Medications like benzodiazepines, anticholinergic medications, and even proton pump inhibitors have been studied to see their effects on dementia.
Knowing all of that what are some of the new treatments for Alzheimer's that are coming down the pipeline?
Here are 7 treatments that are under investigation as a treatment for Alzheimer's Disease:
1. BACE Inhibitors
|HOW THEY WORK||Interfere with the production of amyloid precursor protein and reduce the amount of amyloid in the brain.|
|THE EVIDENCE SO FAR||Results were very promising in mammals. Human trials resulted in 80-90% less amyloid beta in human trials, but that didn’t translate into improved mental function and the side effects included worsening of cognition and function.|
|CHANCES OF SUCCESS||50%|
2. ABAD Inhibitors
|HOW THEY WORK||ABAD interacts with the amyloid protein to cause toxic effects on the brain cell mitochondria. Inhibitors of the ABAD could neutralize the amyloid from wreaking its havoc on the mitochondria and preventing cell death.|
|THE EVIDENCE SO FAR||So far, animal studies are promising but no human trials.|
|CHANCES OF SUCCESS||30%|
3. Methylene Blue
|TARGET||Amyloid and Tau|
|HOW THEY WORK||Protects the mitochondria (the brain cell powerhouse) from oxidative stress and reduces cell death. May also inhibit ABAD.|
|THE EVIDENCE SO FAR||In vitro and animal studies showed decreased tau accumulation and an initial human study showed improved blood flow to the brain and improved cognitive performance. More studies are ongoing. |
Side effects can include interactions a=with other common medications (SSRI’s) and at higher doses can increase blood pressure and cause heart rhythm disturbances.
|CHANCES OF SUCCESS||40%|
4. ISRIB (Integrated Stress Response Inhibitor)
|TARGET||“The Integrated Stress Response” – inflammation and maladaptive immune responses|
|HOW THEY WORK||Intravenous infusion of this small molecule reduces levels of proteins that activate the integrated stress response (like ATF4 protein)|
|THE EVIDENCE SO FAR||Animal studies in mice have been variable but a recent study showed improvement in some memory performance measures. No human data yet.|
|CHANCES OF SUCCESS||25%|
|TARGET||Mitochondria of brain cells|
|HOW THEY WORK||Protects the mitochondria (the brain cell powerhouse) from oxidative stress and reduces effect of Amyloid on the cell. |
Examples are Vitamin C, Vitamin E, Coenzyme Q, MitoQ, SS31, Resveratrol
|THE EVIDENCE SO FAR||A recent study of over 7500 older men followed for 7 years showed no prevention of dementia. Studies of resveratrol have shown it to be well tolerated and to have some neuromodulator effect haven’t demonstrated cognitive changes. |
Souvenaid® (uridine monophosphate, docosahexaenoic acid, eicosapentaenoic acid, choline, phospholipids, folic acid, vitamins B12, B6, C, and E, and selenium) has a very small effect on memory scores but there’s no data on whether they prevent dementia or preserve day to day function.
|CHANCES OF SUCCESS||50%|
6. Intranasal Insulin
|TARGET||Insulin dysregulation in the brain|
|HOW THEY WORK||Insulin reduces amyloid formation and toxicity|
|THE EVIDENCE SO FAR||There have been small studies that show promise, and a meta-analysis of 293 patients with MCI or AD showed improvement on memory tests and more importantly, seemed to stabilize functional status|
|CHANCES OF SUCCESS||50%|
|TARGET||Amyloid and Tau|
|HOW THEY WORK||Essentially a vaccine against tau and/or amyloid. Injections of anti-tau antibodies or anti-amyloid antibodies are given intravenously every week.|
|THE EVIDENCE SO FAR||Antibodies to amyloid beta have been studied in mice, delaying functional decline, and reducing tau levels. |
Human trials have been mixed. Earlier studies of amyloid beta antibodies unfortunately caused brain inflammation and had to be scrapped.
More recently though, modified, new and improved Amyloid beta antibody compounds are being studied. Examples are aducanumab, gantenerumab, and BAN2401, and a small molecule oral agent, ALZ-801. ALZ801 is a small molecule, so has fewer side effects and obviously more convenient.
A recent trial of aducanumab demonstrated reduction of amyloid plaques by 50% and some stabilization of memory tests.
|CHANCES OF SUCCESS||70%|
Other proposed treatments
This list is exceedingly long including such things as ketogenic diets, ketone beverages, n-acetyl cysteine, coconut oil, curcumin and turmeric, gingko biloba and on and on. None of these compounds have strong, large scale studies to back up their use in Alzheimer’s disease or other types of dementia.
The Bottom Line
- Alzheimer’s disease has no cure, and currently available treatments are focussed on modulating brain chemistry to try to alleviate symptoms
- Future treatments for Alzheimer’s disease target abnormal proteins like Amyloid and Hyperphosphorylated Tau, which form brain plaques and neurofibrillary tangles.
- The most promising treatment is immunotherapy treatments like aducanumab, which is an antibody to amyloid. Right now, intravenous infusions seem like the likely route of delivery, but an oral form is also being studied.
See the links below to read more in depth about some of these scientific studies.
Antioxidants: Association of Antioxidant Supplement Use and Dementia in the Prevention of Alzheimer’s Disease by Vitamin E and Selenium Trial (PREADViSE) | Dementia and Cognitive Impairment | JAMA Neurology | JAMA Network
ISRIB: Small molecule cognitive enhancer reverses age-related memory decline in mice
Immunotherapy: Crenezumab, and Aducanumab, gantenerumab, BAN2401, and ALZ-801-the first wave of amyloid-targeting drugs for Alzheimer's disease with potential for near term approval
Insulin: Long-acting intranasal insulin detemir improves cognition for adults with mild cognitive impairment or early-stage Alzheimer's disease dementia
Methylene Blue: Methylene blue and Alzheimer's disease
Amyloid-Binding Alcohol Dehydrogenase (ABAD) Inhibitors: Amyloid-Binding Alcohol Dehydrogenase (ABAD) Inhibitors for the Treatment of Alzheimer's Disease
BACE inhibitors: Investigational BACE inhibitors for the treatment of Alzheimer's disease
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