Connecting some more dots in Alzheimer's disease

Lane Simonian

This recent study on Alzheimer's disease has made some breakthrough connections:

"The study may also help connect the dots between loss of neurons and the well-documented accumulation of amyloid-β and tau proteins in Alzheimer’s disease. The pattern of mutations the team found suggests that they are caused by reactive oxygen species (ROS), chemicals that can oxidize and damage DNA. Both amyloid-β and tau can induce the production of ROS, and ROS have been found to be increased in the brains of people with Alzheimer’s...

They not only found more mutations in those with Alzheimer’s, but differences in the pattern of mutations compared with normally aging brains. These changes — switches in certain bases or “letters” that make up DNA — were of a kind known to be induced by ROS, unlike mutations in normally aging brains. The team also found direct evidence of increased oxidation in the neurons of people with Alzheimer’s."

If amyloid-beta and misfolded tau proteins were the only cause of oxidative stress in Alzheimer's disease, removing them would cure the disease.  But many other factors cause damage to the brain via oxidation, including environmental toxins, mental stress, an unhealthy diet (high in sugar and other carbohydrates, salt, high fructose corn syrup, etc.), and genetic mutations.  These factors contribute to the formation of misfolded amyloid and tau proteins, and neuroinflammation (in part through DNA damage) which then can add to that stress.  But intervening at this point does very little in terms of slowing down the progression of the disease.

Crushed

FWIW connect the dots is a terrible analogy
Connect these dots and what do you have? 

X                                     X

  

 X                                      X

(hint you can have a square a circle   or a very large number of regular polygons)
The dots don't have a pattern its imposed by the viewer 

And that is always a problem with science and medicine in alzheimer's
  

Donr

Lane, thank you for posting. Found the information that you posted was interesting.

Lane Simonian

Thank you, Don.  It is always good to know when information is of use to people.

Larrytherunner

Lane, you often comment or quote from studies but don't give a web address so we can look it up ourselves. Further I don't think understanding the pathology of Alzheimer's is so simple as you think it is.

ButterflyWings

Larry this may be the source article. Lane can correct me if not. 

Interesting premise. I would rather read and consider potential new insights, than not.

https://www.eurekalert.org/news-releases/950232

Crushed

Somatic genomic changes in single Alzheimer’s disease neurons

https://www.nature.com/articles/s41586-022-04640-1

Nature volume 604, pages 714–722 (2022)Cite this article

Abstract

Dementia in Alzheimer’s disease progresses alongside neurodegeneration1,2,3,4, but the specific events that cause neuronal dysfunction and death remain poorly understood. During normal ageing, neurons progressively accumulate somatic mutations5 at rates similar to those of dividing cells6,7 which suggests that genetic factors, environmental exposures or disease states might influence this accumulation5. Here we analysed single-cell whole-genome sequencing data from 319 neurons from the prefrontal cortex and hippocampus of individuals with Alzheimer’s disease and neurotypical control individuals. We found that somatic DNA alterations increase in individuals with Alzheimer’s disease, with distinct molecular patterns. Normal neurons accumulate mutations primarily in an age-related pattern (signature A), which closely resembles ‘clock-like’ mutational signatures that have been previously described in healthy and cancerous cells6,7,8,9,10. In neurons affected by Alzheimer’s disease, additional DNA alterations are driven by distinct processes (signature C) that highlight C>A and other specific nucleotide changes. These changes potentially implicate nucleotide oxidation4,11, which we show is increased in Alzheimer’s-disease-affected neurons in situ. Expressed genes exhibit signature-specific damage, and mutations show a transcriptional strand bias, which suggests that transcription-coupled nucleotide excision repair has a role in the generation of mutations. The alterations in Alzheimer’s disease affect coding exons and are predicted to create dysfunctional genetic knockout cells and proteostatic stress. Our results suggest that known pathogenic mechanisms in Alzheimer’s disease may lead to genomic damage to neurons that can progressively impair function. The aberrant accumulation of DNA alterations in neurodegeneration provides insight into the cascade of molecular and cellular events that occurs in the development of Alzheimer’s disease.
 Science daily had an explanation by the lead author "

As we age, neurons are known to accumulate somatic mutations. In AD neurons, however, we see more mutations and DNA alterations," said lead author Michael B. Miller, MD, PhD, of the Department of Pathology at the Brigham. "Our results suggest that AD neurons experience genomic damage that causes immense stress on cells and creates dysfunction among them. These findings may explain why many brain cells die during AD."

The team conducted its study using single-cell whole genome sequencing of 319 hippocampal and prefrontal cortex neurons of patients with or without AD to determine the link between the number and type of somatic mutations and AD. To better understand the genomic changes that occur in AD neurons, researchers sequenced tissue DNA and discovered a greater number of mutations termed somatic single-nucleotide variants (sSNVs) in patients with AD. Theorizing that the large number of mutations is the result of increased DNA oxidation, researchers then measured 8-Oxoguanine, an indicator of oxidative stress and DNA damage, and found that AD neurons were in fact more oxidized.

Crushed note.  This is good science but it is only correlation  

Ultimately, the discovery of accumulating DNA alterations in AD neurons provides researchers with a window into molecular and cellular events in AD pathogenesis. "Our findings suggest that the sheer number of oxidative lesions and somatic mutations we observed in AD neurons may contribute to its pathology," said Miller.

The authors acknowledge two main study limitations. First, two groups were primarily studied: patients with no neurologic disease and those with advanced AD based on the Braak staging system. In the future, researchers are eager to study the neurons of individuals with intermediate-stage AD. Second, while single-cell, whole-genome sequencing was feasible for the preliminary studies, the authors note that there are advanced methods that allow for an in-depth analysis of each strand of DNA that should be explored in the future.

"In the future, we are eager to elucidate how the observed mutations in AD neurons cause neuronal cell death and are dedicated to aiding in the discovery of novel treatments that target these pathways," Miller said.https://www.sciencedaily.com/releases/2022/04/220420112913.htm

That is the science as always the spoonful of science creates the swimming pool of speculation  
those are the dots folks are connecting in accordance with their own biases 

Lane Simonian

Thank you, Butterfly for posting the link and Crushed for posting the abstract and additional background information.

Larrytherunner

I am a follower of the concept that the robust immune system that evolved to protect us when we are young becomes overactive and off target when we grow old. Here is a great overview of immune system involvment in Alzheimers.

https://www.npr.org/sections/health-shots/2022/01/30/1076166807/how-a-hyperactive-cell-in-the-brain-might-trigger-alzheimers-disease

Crushed, if you could create a hyperlink, that would be great. I haven't been able to do it on my android phone.

Lane Simonian

I am almost onboard with your explanation of Alzheimer's disease, Larry, but not quite.

At worst, the relationship between oxidative stress and neuroinflammation is bi-directional.

Many neurological diseases, including Alzheimer's disease (AD) and amyotrophic lateral sclerosis (ALS), are now recognized to share atypical inflammatory reactions as a major pathological feature. Neuroinflammation can both be a cause, and a consequence, of chronic oxidative stress. Cytokine-stimulated microglia generate copious amounts of reactive oxygen and reactive nitrogen species, creating a stress upon ambient neurons. Conversely, oxidants can stimulate pro-inflammatory gene transcription in glia, leading to various inflammatory reactions.

https://pubmed.ncbi.nlm.nih.gov/15096698/#:~:text=Abstract,consequence%2C%20of%20chronic%20oxidative%20stress.

If you reduce oxidative stress, you substantially reduce neuroinflammation, but the reverse may not be true: many other factors in addition to cytokine-stimulated microglia can cause the formation of hydrogen peroxide (a reacive oxygen species) and peroxynitrite (a reactive nitrogen species).  Certain anti-inflammatory drugs are likely to have some impact on Alzheimer's disease, but certain anti-oxidant drugs (and natural products) are more likely to stall the progression of Alzheimer's for a much longer period of time.

Lane Simonian

These are the results from a recent clinical trial using aromatherapy to treat Alzheimer's disease (a preprint that has not been peer reviewed yet).

Effect of aromatherapy in patients with Alzheimer's disease: a randomised controlled clinical trial

Conclusion 

Aromatherapy improves sleep quality in patients with AD, alleviates psychobehavioural symptoms, and improves quality of life. This effect of aromatherapy is probably caused by regulating oxidative stress damage in the brain and inhibiting the expression of inflammatory factors to delay the deterioration of AD. In fact, the method of stimulating the olfactory nerve through scent exposure is easy to implement because of its low invasiveness and is suitable not only for patients with AD, but also for caregivers [31]. Our research confirms the effectiveness of aromatherapy as a non-pharmacological intervention for the treatment of patients with AD, and its potential as a valuable option is worthy of widespread application at healthcare facilities, communities, and homes in the future.

https://assets.researchsquare.com/files/rs-1392290/v1/e7cfb296-3325-4e7d-9653-f8117b8782cf.pdf?c=1650652974

Alzheimer's, Aromatherapy, and the Sense of Smell

Essential Oils to Prevent Cognitive Loss and Restore Memory

By Jean-Pierre Willem

• Cites multiple clinical studies to show how Alzheimer’s is critically bound with the sense of smell and how the loss of this sense is often the first symptom of onset

• Details how to use essential oils to stimulate memory, prevent cognitive loss, and counter the isolation, withdrawal, and depression of Alzheimer’s patients

• Reveals the striking results seen in several French hospitals and senior living homes where aromatherapy has been used as a therapy for Alzheimer’s

While there is still no known cure for Alzheimer’s, new research and trials from France reveal that it is possible to slow its progression, ameliorate some of its effects, and improve the quality of life for those suffering from this degenerative condition, using the sense of smell.

Citing years of clinical evidence, Jean-Pierre Willem, M.D., shows how Alzheimer’s is critically bound with the sense of smell. He explains how the olfactory system is connected to the limbic area of the brain, which holds the keys to memory and emotion and is the area of the brain most severely afflicted by Alzheimer’s. He reveals how one of the very first signs of Alzheimer’s is typically the loss of the sense of smell. Sharing the striking results seen in French hospitals and senior living homes where aromatherapy has been used as a therapy for Alzheimer’s for more than 10 years, Dr. Willem details how to use essential oils to stimulate memory, prevent cognitive loss, and counter the isolation, withdrawal, and depression these patients are likely to feel. He explains how essential oils make a direct connection with the cerebral structures involved in emotion and memory and make it possible for the patient to bring deeply buried memories back to the thinking surface. This allows the patient to recover a portion of their identity, which can become the foundation for additional healing, including regaining the ability to communicate and reducing behavioral issues. Tracing the evolutionary links between smell and taste, he also explores the effects of diet and nutrition on Alzheimer’s and other forms of dementia, explaining the benefits of raw foods, what foods to avoid, and what supplements can help.

Offering a hands-on and medication-free way to help those suffering from Alzheimer’s, this guide provides a way for Alzheimer’s patients and their families to recover the joy of living again.

Crushed

Lane Simonian wrote:

These are the results from a recent clinical trial using aromatherapy to treat Alzheimer's disease (a preprint that has not been peer reviewed yet).

NO they are not in any way shape or form TREATING Alzheimers disease  They are supposedly treating certain symptoms related to alzheimer's  Its a very small study and has no long term follow up