Feature Article: July-August 2024 – New and Cutting Edge Breakthroughs in Dementia and Alzheimer’s Disease

Jeff Morris

There has been a lot in the news recently about new developments in Alzheimer’s disease, from biomarkers for early detection to new and innovative treatments. And there are lectures dealing with AD at the upcoming AMMG conference. Here is a run down on some of the latest findings.

Elsewhere in this same issue of the eJournal, you’ll find several updates on Alzheimer’s. One new study that is not yet peer reviewed found that replacing one serving of processed red meat per day with healthier foods was linked to a 20% drop in dementia risk. Another group of researchers is focused on the amyloid beta (Aβ) monomer — tiny protein fragments that are the building blocks of the larger, more notorious amyloid plaques. They say even before these plaques form, Aβ monomers can cause significant damage on their own.

Another study focuses on the molecule miR-519a-3p, a microRNA directly linked to the expression of the cellular prion protein (PrPC), which is deregulated in people suffering from some neurodegenerative diseases such as Alzheimer’s. In yet another study, a modified version of the neuropeptide CART not only suppresses appetite, but protects the brain by reducing the pathogenicity of the tau protein, which is associated with Alzheimer’s disease. And researchers have examined a change in the way Alzheimer’s disease is identified, detecting the presence of amyloid plaques with a simple blood test which would be easier and more accurate than a lumbar puncture.

Another new study, published in Frontiers in Neuroscience on Sept. 5, finds that outdoor nighttime light exposure may be associated with higher prevalence of Alzheimer’s disease. And a new drug, Kisunla, has been approved by the FDA to slow the progression of Alzheimer’s disease in its early stages, becoming the third treatment approved by the FDA that targets the underlying causes of Alzheimer’s disease. It is designed to slow cognitive decline, giving individuals more time to maintain their independence.

One of the presenters at the upcoming AMMG conference, Mark Gordon, M.D., says there has been a paradigm shift in identifying the mechanisms of Alzheimer’s disease. “It becomes clear that neuroinflammation is not just a byproduct but a key driver in the onset and progression of Alzheimer’s disease,” says Dr. Gordon. “By fueling the production and spread of Aβ and Tau, chronic inflammation triggers a cascade of neurodegenerative processes that underlie cognitive decline in AD patients.”

Dr. Gordon says the role of microglia and astrocytes as central mediators in the precipitation of neuroinflammation leading to AD has been obscured by the misdirection and focus on the APOE4 genes. “These glial cells, when activated by neuroinflammatory triggers such as infections or injury, release cytokines and chemokines, creating a feedback loop that exacerbates inflammation. This persistent inflammatory environment directly promotes the misfolding and aggregation of amyloid-beta (Aβ) proteins. Aβ plaques further activate microglia, which, in turn, perpetuate astrocyte activation and inflammation. This interaction disrupts neuronal homeostasis, leading to synaptic damage and neuronal death. Over time, this chronic inflammation drives the pathological phosphorylation of Tau, leading to neurofibrillary tangles (NFTs), which further contribute to neurodegeneration.”

According to Dr. Gordon, the molecular signaling mechanisms that link neuroinflammation to Alzheimer’s pathology are based upon the activation of the nuclear factor kappa-light-chain-enhancer of activated B cells (NF-κB), a master regulator of inflammation. This pathway is upregulated in AD, increasing the expression of pro-inflammatory cytokines such as IL-1β and TNF-α. These cytokines not only exacerbate amyloid plaque deposition but also promote Tau hyperphosphorylation, facilitating the spread of toxic Tau throughout the brain. Moreover, neuroinflammation compromises the blood-brain barrier (BBB), allowing peripheral immune cells to infiltrate the CNS, further amplifying the inflammatory cycle and driving AD progression.

Finally, says Dr. Gordon, the persistence of neuroinflammation leads to the denigration of important neurochemical pathways leading to the loss of neurotransmitters, neurosteroids, and enzyme systems that produce serotonin, melatonin, and glutathione, to name a few. “Understanding that the causation is fundamentally due to chronic neuroinflammation, gives us a direction for mitigation,” says Dr. Gordon. “Stopping the pro-inflammatory cascade using neurosteroids and select nutraceutical products can halt the progression of the disease and give time to reverse the damage.”

Dr. Gordon will be presenting Alzheimer’s Disease: A Hormonal Approach to Treatment. “This presentation will provide the science supporting how neuroinflammation can be combated by replenishment of many of the hormones that we fail/need to address in the course of Age Management Medicine,” he says.

The eJournal reached out to Dharma Singh Khalsa, M.D., President/Medical Director of the Alzheimer’s Research and Prevention Foundation and Prevention Editor, Journal of Alzheimer’s Disease, for his input. Dr. Khalsa took issue with conventional Alzheimer’s organizations, and said their approach can be typified by the most recent edition of The Lancet. The writers in The Lancet state, “The potential for prevention is high and, overall, nearly half of dementias could theoretically be prevented by eliminating 14 risk factors.”¹

“That is a breakthrough thought, especially coming from such a conventional journal,” says Dr. Khalsa. “On investigation, however, their risk factor list and interventions are behind the times.” He says many risk factors well-known to Age Management physicians such as chronic stress, get only a brief mention. “Moreover,” he says, “hormone replacement therapy is not considered and new approaches such as peptide therapy, while not necessarily shown to prevent Alzheimer’s, does improve exercise tolerance and lack of exercise is a clear risk factor for cognitive decline.” 

Similarly, Dr. Khalsa says, the concept of mind/body interactions such as meditation, and yoga, well proven to not only decrease stress but also improve cognition, are strikingly absent.² And multiple risk factors that are mentioned, such as the treatment of depression, smoking cessation, and especially hypertension, are all amenable to mind/body therapies such as Kirtan Kriya meditation, “which the Alzheimer’s Research and Prevention Foundation has studied for two decades,” says Dr. Khalsa. “All of the research of this work can be discovered at www.alzheimersprevention.org/research.” 

Dr. Khalsa notes that Kirtan Kriya has no side effects and is fast, affordable, and easy to do on a regular basis as shown by a very high compliance rate.²  

Other Alzheimer’s risk factors such as weight control, are also helped by yoga, says Dr. Khalsa, along with following a Mediterranean diet rich in vegetables, fruit and some fish and whole grains if tolerated but little red meat and minimal alcohol consumption.³ “Following this type of regime reverses brain aging by 12 years,” he says. Moreover, following this diet or a similar plan called DASH, delays neurodegeneration as well as helps prevent cardiovascular disease, a clear risk factor for Alzheimer’s disease.⁴ Indeed, the more “Medi” the diet, the less brain pathology. As stated in The Lancet, “a high diet quality relative to low diet quality was associated with lower dementia risk.”¹

Yet, Dr. Khalsa points out, they are equivocal about following any type of diet and, of note, do not endorse the use of any vitamins, minerals, brain specific nutrients or even Omega-3 rich fish oil, well known to Age Management practitioners to be an integral part of any Alzheimer’s prevention plan. 

“Beyond that,” says Dr. Khalsa, “proven risk reduction provided by supportive community environments may be considered applicable to mind/body therapies, as people of all ages do yoga class in a congenial setting.”² 

Dr. Khalsa says Kirtan Kriya has also been shown to increase cerebral blood flow in anatomical brain areas significant for memory including the dendate gyrus, hippocampus, posterior cingulate gyrus, frontal lobes and prefrontal cortex, which sends reciprocal fibers to the amygdala.²

“Perhaps most significantly,” says Dr. Khalsa, “especially since The Lancet does NOT endorse the use of hormone replacement therapy in women, which research suggests may be beneficial⁵, is the crucial finding of a research study accomplished at UCLA called The Pink Brain Project.⁶ In this  study, menopausal women at high risk for developing Alzheimer’s disease secondary to mild cognitive impairment (MCI) and cardiovascular issues, were divided into a control group doing Memory Enhancement Training (MET), considered the ‘gold standard,’ and a second group that practiced a special form of yoga called Kundalini and also Kirtan Kriya memory meditation.

“The results were significant in that the yoga and meditation group had benefits comprising enhanced cognition and mood compared to the control group.⁶ Similar to previous research on Kirtan Kriya, inflammatory markers such as cytokines were diminished and telomerase was increased and telomere length increased.”⁷

Furthermore, notes Dr. Khalsa, in research accomplished at The University of Pennsylvania, subjects with various forms of cognitive decline including early Alzheimer’s, showed strong increases in cerebral blood flow the very first time they practiced Kirtan Kriya and very significant changes after partaking in an 8 week program of at home practice. Their memory loss was also reversed.⁸  

Dr. Khalsa points out that also left out of The Lancet was any mention of the proven benefits of psychological well-being (PWB), one of the features of which, purpose in life, has been revealed to dramatically decrease the incidence of Alzheimer’s disease. “Also unmentioned is Spiritual Fitness, a new concept in medicine combining multiple facets of spirituality such as religious attendance, prayer, meditation, being in nature, selfless service and more,”⁹ he says. “Although the development of Spiritual fitness does not necessarily require belonging to a specific religion, not unlike physical fitness it requires an action such as the above to develop its attributes: Patience, Awareness of something greater than ones’ self, compassion, or empathy, and living a life committed to spiritual growth and wellbeing.” 

“Spiritual Fitness leads one to develop peace of mind, sorely lacking today, Universal love, what philosopher Stephen Post, Ph.D., considers to be the ultimate reality, and enlightenment, a state in which one is enjoys a state of divine well-being; calm, and restful alertness, and a desire to share your knowledge with others in hopes of making the world a better place,” says Dr. Khalsa. 

Therefore, he says, according to research, spiritual activity is associated with better cognitive function with aging.¹⁰ “And new evidence does suggest that the risk of dementia may be reduced thus increasing the number of healthy years of life,” adds Dr. Khalsa. “It’s never too early and it’s never too late. Unfortunately, in spite of The Lancet’s in depth report, they’re still behind the times.”

In another presentation at the AMMG Salt Lake City conference, Syed A. Asad, M.D., will delve into the forefront of Alzheimer’s research and clinical practice. His session, Alzheimer’s: A Journey from Prevention to Effective Intervention, is designed to equip attendees with the latest insights into preventive strategies and cutting-edge interventions that are transforming patient outcomes. In addition to his private practice, Universal Neurological Care in Jacksonville, FL, Dr. Asad, who is board certified in traumatic brain injury by the  American Board of Psychiatry and Neurology, is a consultant and neurological specialist for the Jacksonville Jaguars. He will provide a comprehensive understanding of emerging risk factors, innovative diagnostic tools, and groundbreaking therapeutic approaches to Alzheimer’s disease.  

Another AMMG conference presentation will be Reversing Mild to Moderate Cognitive Decline, a lecture by Edwin N. Lee, M.D., Assistant Professor of Internal Medicine at the University of Central Florida College of Medicine. Dr. Lee will discuss two cases of dementia that were reversed, one using bioidentical hormones, vitamin D and a peptide, and the other using therapeutic plasma exchange, stem cells, exosomes and peptides.

For more information on the upcoming conference, go to agemed.org.

    References:

1. Livingston G, Dementia prevention, intervention, and care: 2024 report of The Lancet Standing Commission July 2024. Published online July 31, 2024. http://doi.org /10.1016/s0140-6736(24)01296-0.
2. Khalsa, DS, Stress, Meditation, and Alzheimer’s Disease Prevention: Where the Evidence Stands. Journal of Alzheimer’s Disease 48 (2015) 1-12 doi: 10.3233/JAD-142766. 
3. Shannon OM, Ranson JM, Gregory S, et al. Mediterranean diet adherence is associated with lower dementia risk BMC Med 2023; 1-81. 
4. Agarwal P, Leurgans SF, Agrawal  S, et al. Association of Mediterranean-DASH intervention for neurodegenerative delay and Mediterranean diets with Alzheimer’s pathology. Neurology2023; 100: e2259-68.  
5. Morrison JH, Brinton RD, chmidt PJ, Gore AC. Estrogen, menopause, and the aging brain: how basic neuroscience can inform hormone therapy in woman. J Neurosci.2006: 26: 10332-48.
6. Grzenda, A., Siddarth, P., Milillo, M.M.. Aguilar-Faustino, Y,. Khalsa, Dharma S,. Lavretsky, H. Cognitive and immunological effects of yoga compared to memory training in older women at risk for alzheimer’s disease. Transl Psychiatry 14, 96 (2024). https://doi.org/10.1038/s41398-024-02807-0.
7. Innes KE, Selfe TK, Khalsa DS. Effects of meditation versus music listening on perceived stress, mood, sleep, and quality of life in adults with early memory loss: A pilot randomized controlled trial. J Alzheimer’s Dis. 2016; 52::1277-98.  
8. Newberg AB, Wintering N, Khalsa DS, Roggenkamp H, Waldman MR. Meditation effects on cognitive function and cerebral blood flow in subjects with memory loss: a preliminary study. J Alzheimers Dis. 2010;20(2):517-26. doi: 10.3233/JAD-2010-1391. PMID: 20164557.
9. Khalsa, DS, Newberg AB Spiritual Fitness: A New Dimension in Alzheimer’s disease prevention. : Journal of Alzheimer’s Disease 1 (2021) 1–15 DOI 10.3233/JAD-201433.      

10. Lung A, Lam L, spiritual Activity is associated with better cognitive function in old age. E Asian Arch Psychiatry. 2013 Sep;(3):102-7.