Month: June 2023

A new study revealed that abnormalities in the eye blood vessels could aid in the early detection of Alzheimer’s. The team identified an aberration in the blood-retinal barrier, which stops hazardous compounds from entering the retinal tissue, by comparing the retinal blood vessels of Alzheimer’s patients, people with mild cognitive impairment, and healthy volunteers.

According to a study by Cedars-Sinai researchers published in the journal Alzheimer’s & Dementia, anomalies in the blood vessels in the eye play a significant role in the development of Alzheimer’s. These modifications correspond to brain changes, opening a new avenue for early disease detection.

Maya Koronyo-Hamaoui, the senior author, stated that this research offers fresh insight into the vascular abnormalities linked to Alzheimer’s disease, particularly in the retina, the layer of nerve tissue in the back of the eye. Additionally, it highlights the damage that Alzheimer’s does to the blood vessels in the retina, opening up a novel, noninvasive route to early detection and disease progression monitoring.

The Research Findings

Researchers evaluated the blood vessels in the retinas of 27 donors with normal cognition, 10 with MCI (mild cognitive impairment), and 24 with Alzheimer’s.

They discovered one of the earliest symptoms of Alzheimer’s disease in participants with Alzheimer’s and MCI: the breakdown of the blood-retinal barrier, composed of closely bound cells that keep hazardous substances from penetrating the retinal tissue.

The researchers observed a loss of up to 70% in that barrier in Alzheimer’s patients, implying that toxic substances can flow through and penetrate the retinal tissue.

Damage to the blood-retinal barrier has been linked to different types of vascular illness in the brain as well as the condition known as cerebral amyloid angiopathy (CAA), which involves the amyloid proteins buildup in small blood vessels.

According to Koronyo-Hamaoui, post-mortem brain tissue samples are the only current means to identify CAA in patients. With further research and the development of enhanced retinal imaging technology, vascular and blood-retinal barrier impairment may provide the first opportunity to diagnose CAA in living individuals.

The study also discovered that amyloid beta 40 protein deposits built up in the retinal arteries of people with Alzheimer’s, stiffening the arteries, interfering with blood flow, and preventing the vessels from removing dangerous compounds from the retina. Further research is required to identify whether the deposits only accumulate as a result of blood vessel injury or actually contribute to the damages.

Rich in blood vessels, retinal and brain tissues require enough blood flow for optimal function. The restriction of blood supply, which may occur due to the damage, means these cells do not receive the oxygen and nutrients they require. Advanced retinal imaging is under development, but the Food and Drug Administration has not yet given it the go-ahead. It would allow noninvasive examination of blood vessels and protein buildup in living patients.

What did the researchers conclude?

Keith L. Black, MD, chair of the Department of Neurosurgery and the Ruth and Lawrence Harvey Chair in Neuroscience at Cedars-Sinai, stated that the retina had received extensive attention since it is a central nervous system window and an anatomical extension of the brain. This research contributes to current advances in sophisticated retinal imaging and the development of other retinal biomarkers to enhance the science of Alzheimer’s early detection.

According to the findings, blood vessel damage plays a significant role in the progression of Alzheimer’s. Therefore, Koronyo-Hamaoui urges people to do everything they can to maintain a healthy circulatory system, particularly blood vessels in the retina and brain, to help stave off dementia and CAA.

Controlling hypertension, eating a low-sugar diet, limiting alcohol use, and quitting smoking all assist in preventing chronic inflammation and blood vessel damage.

References

1. Shi, H., Koronyo, Y., Fuchs, D.T., Sheyn, J., Jallow, O., Mandalia, K., Graham, S.L., Gupta, V.K., Mirzaei, M., Kramerov, A.A. and Ljubimov, A.V., 2023. Retinal arterial Aβ40 deposition is linked with tight junction loss and cerebral amyloid angiopathy in MCI and AD patients. Alzheimer’s & Dementia.
2. Study: Blood Vessel Damage could be an Alzheimer’s Driver. Cedars Sinai. https://www.cedars-sinai.org/newsroom/study-blood-vessel-damage-could-be-an-alzheimers-driver. Published Online: 19th May, 2023. Accessed: 2nd June, 2023.
3. Blood Vessel in the Eye May Drive Alzheimer’s Disease. Technology Networks. https://www.technologynetworks.com/neuroscience/news/blood-vessel-damage-in-the-eye-may-drive-alzheimers-disease-373622. Published Online: 22nd May, 2023. Accessed: 2nd June, 2023.
4. Eye Blood Vessel Changes: A New Window into Alzheimer’s Diagnosis. Neuroscience. https://neurosciencenews.com/alzheimers-eye-blood-vessels-23289/. Published Online: 19th May, 2023. Accessed: 2nd June, 2023.

A recent study demonstrates that menthol inhalation enhances cognitive function in animal models of Alzheimer’s. Researchers discovered that inhaling menthol reduced interleukin-1-beta levels, a protein that induces inflammation. The findings imply that some inhaled substances may help treat Alzheimer’s.

Repetitive brief exposure to methanol can affect the immune system and stave off the cognitive deterioration that occurs in people with Alzheimer’s disease, according to a recent mouse study published in Frontiers in Immunology.

Researchers discovered that when mice sniffed this chemical, their levels of interleukin-1-beta reduced. This protein has a role in the inflammatory response.

Additionally, researchers improved cognitive function in the mice with Alzheimer’s-like symptoms by inhibiting this protein with a medication used to treat autoimmune diseases.

These results highlight the potential for scents and immune modulators to treat this neurodegenerative condition.

The discovery is intriguing because it demonstrates how we might influence the brain’s olfactory (smell) pathways. Furthermore, there is no need for the implanting deep brain stimulator electrode or a vagal nerve stimulator system. The research shows that by administering a disease-modifying medication through the nose, the mouse Alzheimer’s brain can be “accessed” and favorably impacted at the cellular level.

Why inhaling menthol might be beneficial

According to the study, immune cells called regulatory T cells (T-regs), which have immunosuppressive activity, play a crucial role in modulating cognitive performance in mice designed to acquire Alzheimer’s. Intriguingly, the effectiveness of menthol inhalation and T-reg blocking in reducing cognitive impairment was equal.

The specifics of their signaling could shed light on the underlying mechanisms since the researchers conclude that T-reg blocking and olfaction appear to be mediated by the same cytokines. It is well known that T-regs release the cytokine IL-17 in proinflammatory circumstances, which starts with the onset of cognitive and synaptic impairments in the early stages of Alzheimer’s. Interestingly, the researcher did not investigate IL-17 as a possible mechanistic relationship in the study.

The connection of the brain, smell, & immune system

Complex connections between different types of nerve cells, immune cells, and neural stem cells are essential for maintaining the brain’s functional equilibrium. Numerous research have examined the odors’ immunomodulatory and neurological effects in this intricate web of interactions. Previous studies have also demonstrated a connection between the loss of scent and the onset of Alzheimer’s initial symptoms.

Menthol reduces inflammation in the region of the brain linked with memory. It appears to have immunomodulatory effects in the prefrontal cortex, a memory-related area that malfunctions in Alzheimer’s patients.

Researchers also found that limiting the activity of T regulatory cells (a type of immune cell with immunosuppressive activity) also improved the cognitive capacity of mice with Alzheimer’s and even generated a clear benefit in the cognitive ability of young, healthy mice.

Both Treg cell blockage and menthol exposure resulted in a drop in IL-1, a protein that may be responsible for cognitive deterioration in mice. Furthermore, blocking this protein with a medicine used to treat some inflammatory diseases increased the cognitive capacity of both healthy and Alzheimer’s mice.

More specifically, menthol inhalation reduced the cytokine (inflammatory chemicals) quantity in this region in the mice Alzheimer’s model compared to the control group. The outcome was less brain inflammation. This result can be due to at least one of the ways through which the mice exposed to menthol displayed enhanced cognitive function.

The study demonstrates that inflammation is the driving force behind Alzheimer’s, and if medicines get developed to address this pathogenic component, Alzheimer’s progression may be postponed.

Are the conclusions applicable to humans?

We cannot predict how a human might be affected because this study only involved mice. Often, such research doesn’t correspond to a human. It is due to various genetic, anatomical, metabolic, and physiologic differences among the species.

Another drawback of the study is the lack of characterization of immune cells involved in the process alongside T-regs.

This area requires further research to help us understand how it might work in humans.

A Significant Advancement

One of the authors claims that this study is a significant advancement toward understanding the relationship between smell, the immune system, and the central nervous system. The findings suggest that odors and immune modulators may be crucial in preventing and treating Alzheimer’s and other central nervous system disorders.

References

1. Casares, N., Alfaro, M., Cuadrado-Tejedor, M., Lasarte-Cia, A., Navarro, F., Vivas, I., Espelosin, M., Cartas-Cejudo, P., Fernández-Irigoyen, J., Santamaría, E. and García-Osta, A., 2023. Improvement of cognitive function in wild-type and Alzheimer’s disease mouse models by the immunomodulatory properties of menthol inhalation or by depletion of T regulatory cells. Frontiers in Immunology, 14, p.2143.
2. Inhaling menthol improves cognitive function in Alzheimer’s disease. Cima Universidad de Navarra. https://cima.cun.es/en/news/news/cima-menthol-improves-cognitive-function-alzheimer. Published Online: 10th May, 2023. Accessed: 1st June, 2023.
3. Could inhaling menthol help improve memory in Alzheimer’s disease? Medical News Today. https://www.medicalnewstoday.com/articles/could-inhaling-menthol-help-improve-memory-in-alzheimers-disease. Published Online: 19th May, 2023. Accessed: 1st June, 2023.

Although there is yet no cure for Alzheimer’s, the field is at a critical crossroads, which is prompting further study. A single, magical “cure” for this complicated disease is unlikely to emerge. The recent historic approval of a drug to delay the progression of Alzheimer’s, together with a deeper understanding of the disease, is strengthening this notion of the scientific community.

A few medications aimed at removing the beta-amyloid protein, the hallmark of Alzheimer’s, have received approval from the FDA. However, the complexity of the disease demands the exploration of other possible treatment pathways as well.

Why is it challenging to treat Alzheimer’s?

The most prevalent type of dementia, Alzheimer’s disease (AD), causes severe cognitive and functional impairment that significantly affects everyday living. It becomes incapacitating and ultimately fatal as brain damage mounts.

The fact that the damage starts decades before the first symptoms arise is one of the disease’s most concerning characteristics. Studying it becomes exceedingly difficult as a result. Even when symptoms do manifest, each patient may experience them quite differently.

While many aspects of the disease onset are still unknown, the accumulation of specific proteins in the brain has been connected to the degeneration of neurons, the nerve cells that control memory, language, and behavior. Beta-amyloid proteins build up as plaques around neurons as the disease worsens, while tau proteins manifest as tangles inside neurons.

Team Amyloid faces a challenging path!

A good 30 years of research has concentrated on medications to eliminate beta-amyloid. However, even with a very promising drug, success requires the almost perfect execution of a clinical study. Nine beta-amyloid-targeting medicines have failed phase 3 trials in the past five years.

According to Dr. Sara Imarisio, Head of Strategic Initiatives at Alzheimer’s Research UK, many companies have been reluctant to invest in Alzheimer’s drugs because of the disease’s characteristic intricacies, which include a heterogeneous population (different rates of disease advancement and symptoms), challenges getting medications to cross the blood-brain barrier (BBB), and testing a drug in an elderly population with other concurrent illnesses.

In 2021, Biogen’s monoclonal antibody (mAb) Aduhelm, which works to remove beta-amyloid plaques, got accelerated approval from FDA. However, the medicine received criticism for its high price and disputed efficacy. It went underutilized since Medicare refused to pay for it outside of clinical studies.

However, early this year, Leqembi (lecanemab), another amyloid-targeting antibody by the Japanese company Eisai in collaboration with Biogen, received accelerated approval by the FDA. In a clinical investigation, it decreased the loss of cognitive function by 27% over 18 months compared to a placebo. A full-fledged approval, allowing broader coverage by health insurance providers, is expected in July.

Getting the drug’s levels sufficiently elevated in the brain and across the BBB without sacrificing safety is the primary challenge for current beta-amyloid targeting medicines.

These medications cause the infiltration of disease-fighting cells, but that has the potential side effect of cerebral edema (ARIA-E), which can result in brain swelling. Drugs frequently struggle to attain adequate potency levels that offset the potentially harmful side effects because only a tiny portion of the initial dose of the injectable mAb can penetrate the BBB.

Companies like Roche and Voyager are developing “shuttle” technology to enhance drug distribution across the BBB. Conversely, oral small-molecule medications have a higher chance of crossing the BBB. Alzheon, a private US biotech company, is now conducting phase 3 studies for ALZ-801, an amyloid-targeting drug, that is expected to complete in mid-2024.

Alternative treatment options

While removing beta-amyloid has already demonstrated some significant (albeit minor) advantages, inhibiting some mechanisms that cause neuronal damage may be the optimal strategy for patients.
Let’s explore some of the alternative strategies attracting the most interest.

Enhancing Immunity

The topic receiving the most attention these days is improving the brain’s immune system, particularly microglia, immune cells that remove trash from around neurons.

Numerous companies are now investing in medications that target TREM2 to promote the proliferation of microglia since the increase in studies that have improved our understanding of the microglial receptor TREM2.
The mid-stage (phase 2) human trial for the injectable mAb AL002 from Alector/Abbvie will end in late 2023 or early 2024. DNL919, a mAb from Denali/Takeda, is undergoing a preliminary (phase 1) human trial expected to end in July 2023. Likewise, Vigil Neuroscience is developing a TREM2 targeting pill currently in the pre-clinical laboratory phases.

Clearing Tau Tangles

Although the attention on beta-amyloid has cast a shadow over the clearing of tau, the strategy is still sound. The scientific understanding of this strategy is developing, particularly concerning optimum binding domains, which may result in more efficacy in removing tau tangles.

Even though early tau-based strategies were unsuccessful, a few pharmaceutical companies are still developing medications that try to reduce and remove the proteins that accumulate in the brain.

Among the companies conducting phase 2 trials are Eli Lilly, whose oral LY3372689 trial will reach the end in June 2024, Janssen Research & Development, LLC, whose injectable mAb JNJ-63733657 will reach the end of the trial in late 2025, and Roche/UCB, whose injectable mAb bepranemab is due in 2025.

Fixing Metabolism

According to some experts, neurodegeneration can result from poor metabolism and abnormal lipid metabolism in the brain, and AD is best described as a neuro-metabolic illness.

T3D-959, an oral medication in a phase 2 trial, is the leading candidate from T3D Therapeutics. The once-daily pills try to control the transcription of genes linked to glucose energy and lipid metabolism to combat neurodegeneration.

Some other possible treatment alternatives

Reducing neuroInflammation (NLRP3)

Although research on the NLRP3 inflammasome target is still in its early phases, experts have developed an interest in it. Beta-amyloid and tau can activate inflammasomes, a multiprotein complex essential for triggering inflammatory reactions. It may contribute to persistent neuroinflammation development, which may cause neuronal degeneration and cognitive impairment. Although pre-clinical testing constitutes the majority of NLRP3 inhibitor research in AD, NLRP3 can lead to several other inflammatory illnesses, and some major pharmaceutical companies, including Roche, Novartis, and Novo Nordisk, have invested in NLRP3 inhibitors.

CRISPR/Gene Editing

Although it is still in the early preclinical stages, experts believe that gene-editing technology CRISPR has a potential miracle treatment for complex disorders.

Martin Kampmann’s lab at the University of California, San Francisco, is investigating how CRISPR-Cas9 can reprogram immune cells in the brain, a concept comparable to immunomodulation targeting TREM2.

References

1. FDA Grants Accelerated Approval for Alzheimer’s Disease Treatment. FDA News Release. https://www.fda.gov/news-events/press-announcements/fda-grants-accelerated-approval-alzheimers-disease-treatment. Published Online: 6th Jan, 2023. Accessed: 8th May, 2023.
2. Kim, C.K., Lee, Y.R., Ong, L., Gold, M., Kalali, A. and Sarkar, J., 2022. Alzheimer’s disease: Key insights from two decades of clinical trial failures. Journal of Alzheimer’s Disease, 87(1), pp.83-100. https://content.iospress.com/articles/journal-of-alzheimers-disease/jad215699.
3. FDA grants accelerated approval for ADUHELM™ as the first and only Alzheimer’s disease treatment to address a defining pathology of the disease. Biogen Press Release. https://investors.biogen.com/news-releases/news-release-details/fda-grants-accelerated-approval-aduhelmtm-first-and-only. Published Online: 7th June, 2021. Accessed: 8th May, 2023.
4. FDA Has Granted Accelerated Approval For Leqembi. Alzheimer’s Research Association. https://www.alzra.org/blog/fda-has-granted-accelerated-approval-for-leqembi/. Published Online: 26th Jan, 2023. Accessed: 8th May, 2023.
5. Brainshuttle. Roche. https://www.roche.com/stories/brain-shuttle-in-research-technologies/. Accesses: 8th May, 2023.
6. A Phase 2 study to evaluate efficacy and safety of AL002 in participants with early Alzheimer’s disease (INVOKE-2). ClinicalTrials.gov. https://clinicaltrials.gov/ct2/show/NCT04592874. Last Update Posted: 25 July, 2022. Accessed: 8th May, 2023.
7. A study to evaluate the safety, tolerability, pharmacokinetics, and pharmacodynamics of DNL919 in healthy participants. https://clinicaltrials.gov/ct2/show/NCT05450549. Last Update Posted: 16th September, 2022. Accessed: 8th May, 2023.
8. Pipeline. Vigil – Neuro. https://www.vigilneuro.com/pipeline. Accessed: 8th May, 2023.
9. A Study of LY3372689 to study the safety, tolerability, and efficacy in participants with Alzheimer’s disease. ClinicalTrial.gov. https://clinicaltrials.gov/ct2/show/NCT05063539. Last Update Posted: 24th March, 2023. Accessed: 9th May, 2023.
10. A study of JNJ-63733657 in participants with early Alzheimer’s disease (Autonomy). ClinicalTrials.gov. https://clinicaltrials.gov/ct2/show/NCT04619420. Last Update Posted: 13th April, 2023. Accessed: 9th May, 2023.
11. A study to test the efficacy, safety, tolerability of Bepranemab (UCB0107) in patients with mild cognitive impairment or mild Alzheimer’s disease (AD). ClinicalTrials.gov. https://clinicaltrials.gov/ct2/show/NCT04867616. Last Update Posted: 17th Feb, 2023. Accessed: 9th May, 2023.
12. Clinical study evaluating efficacy and safety of T3D-959 in Mild-to-moderate AD Subjects. ClinicalTrials.gov. https://clinicaltrials.gov/ct2/show/NCT04251182. Last Updated Post: 21st Feb, 2023. Accessed: 9th May, 2023.
13. Liang, T., Zhang, Y., Wu, S., Chen, Q. and Wang, L., 2022. The role of NLRP3 inflammasome in Alzheimer’s disease and potential therapeutic targets. Frontiers in Pharmacology, 13.
14. Fernando, S. Alzheimer’s disease: an illness that needs a long overdue cocktail. Freethink. https://www.freethink.com/health/alzheimers-cocktail. Published Online: 23rd April, 2023. Accessed: 8th May, 2023.