“Some people don’t like change, but you need to embrace change if the alternative is disaster.” (Elon Musk)
The 21st-century is facing an increasing rate of chronic diseases such as cardiovascular and respiratory diseases, cancer, type-2 diabetes but also neurodegenerative diseases, and in particular Alzheimer’s disease (AD). This event represents a worldwide challenge affecting the global economy and the rise of healthcare costs . Indeed, besides their comorbidity with aging, chronic diseases lead to disabilities while negatively impacting life quality [2,3]. Thus, promoting more effective preventing measures would be needed to reduce the worsening of conditions and clinical interventions .
However, to foster healthcare innovation, this system should shift from a reactive to a proactive approach, in the perspective of preventive, predictive, proactive, and participatory (P4) medicine [5,6]. Hence, a P4 approach would dramatically reduce the rate of chronic diseases by implementing disruptive technologies and a patient-centric approach to promoting healthy longevity.
In this regard, in a previous article, I described how artificial intelligence (AI) has been widely implemented to detect specific biomarkers and diagnose early-onset AD. Particularly, the focus has been on reporting recent scientific evidence about how AI can empower physicians in improving AD therapies while identifying even several AD subtypes, concluding that investing in AI technologies is needed in our century to fight diseases that were untreatable so far.
Continuing this short article series on Alzheimer’s disease (AD) and innovative treatments, in today’s article I will discuss the latest advances in the treatment of AD in which gene therapies, vaccines, or virtual reality have been implemented to cure and counteract disease progression. Moreover, the threat of underpopulation and abruptly decreased fertility rates, well-known topics, will be discussed about age-reversal, health longevity, and exponential technologies.
Gene therapy in dementia
For decades, healthcare providers and scientists have had to face two big life-threatening diseases that affect the worldwide population; cancer and dementia. So far, no therapies have been found to cure these diseases. However, a recent study, published in Nature Communications, did find an innovative gene therapy method able to explain a relevant regulatory process to maintain the genome healthy, thus potentially helpful in protecting against cancer and dementia. The research took place at the University of Sheffield and it has discovered that when body cells are trying to read DNA to build proteins, they can make mistakes causing genome damage, and consequently the rise of certain diseases . Hence, while exploring how cells try to fix this DNA damage, three proteins called USP11, KEAP1, and SETX were found in charge to keep a healthy genome. Understanding how cells can protect themselves from possible “mistakes”, and how to modify the behavior of these proteins, leads to the prevention of disease occurrence while promoting health. These findings are promising and will stimulate scientists to further establish novel diagnostic tests and target treatments in the context of dementia and cancer. 
Moreover, the possibility to reverse the progression of neurological disorders seems possible with the discovery of novel gene therapy. Researchers from the University of California San Diego School of Medicine have launched a first-in-human Phase I clinical trial to investigate how safe and effective a newly discovered gene therapy approach is to release specific proteins into target brain areas in patients suffering from AD and MCI . These proteins are called brain-derived neurotrophic factors (BDNF), in charge of supporting the survival of already existing neurons to promote the growth and differentiation of new neurons and synapses . Thus, the role of BDNF is crucial when considering certain diseases such as AD. In addition, these proteins are generated in the entorhinal cortex and hippocampus that are central brain regions dedicated to memory functioning, but also the primary areas that are progressively damaged in AD, thus leading to memory loss. Indeed, AD patients show a decreased amount of BDNF. However, these specific growth factors cannot easily pass the blood-brain barrier due to their size. Hence, scientists are planning to implement a gene therapy in which a harmless adeno-associated virus (AAV2) is modified to transport these BDNF genes, successively precisely injected into damaged brain regions while restoring and growing surrounding cells. This project (clinical trial) lasting three years will involve twelve patients diagnosed with AD or MCI. When compared to a control group, patients will receive the AAV2-BDNF treatment to test the effects of this outstanding gene therapy over previous methods (e.g., nerve growth factor trials, NGF). And as Mark Tuszynski, professor of neuroscience and director of the Translational Neuroscience Institute (UC San Diego School of Medicine) said: “BDNF gene therapy has the potential, unlike other AD therapies currently under development, to rebuild brain circuits, slow cell loss, and stimulate cell function. We are looking forward to observing the effects of this new effort in patients with AD and MCI” .
Another interesting research, recently published in the journal Redox Biology  discovered that a drug, CMS121, is effective in modifying how brain cells metabolize lipids. Indeed, in a previous study, a drug developed in the lab of Salk Professor David Schubert has been able to slow aging while reversing memory loss in a mouse model of inherited AD . Pamela Maher, the senior scientist at the Salk Institute, studied a particular chemical called fisetin, which can restore memory and even prevent AD in mouse models. Different variants of this chemical have been indeed synthesized, in which CMS121 was found to be effective in improving memory while delaying the rate of degeneration. The study did prove that when tested on a battery of memory and behavioral tasks, mice with AD who received the new drug treatment were able to equally perform when compared to healthy control mice, whereas untreated mice did show a decreased performance . Furthermore, the study did find that CMS121 was able to decrease the levels of fatty acid synthetase (FASN), which produced a consequent decrease in lipid peroxidation. Concerning this, post-mortem samples of AD patients showed higher levels of FASN in comparison to age-matched healthy controls, suggesting that targeting FASN proteins could become a possible AD treatment, stimulating further research to continue with clinical trials, and in which FASN and lipid peroxidation would be the target factor in treating AD .
Other innovative treatments in AD
AD becomes a considerable healthcare, financial, and social burden, not only in the US but also in some countries such as UAE, Saudi Arabia, Kuwait, and Qatar, estimated to increase in the coming years. Besides, a shift toward the increasing aging population is also predicted. Indeed, by 2050 the population over the age of 65 is predicted to be more than double. Longevity is also accompanied by the increasing rate of chronic diseases, in which AD plays a relevant role. In addition to outstanding gene therapies to treat AD, other innovative treatments have been recently proposed .
The new Aviv Clinics in Dubai is paving the way for a novel cognitive regeneration solution that uses hyperbaric oxygen therapy (HBOT) to reverse the effect of biological aging by improving cognitive abilities. The HBOT is a non-invasive method that consists of the administration of 100% pure oxygen in a pressurized environment to restore organ functioning and tissue repair. Moreover, the Aviv Medical Program comprehends a series of assessments to evaluate a patient's health, physical, cognitive status, and overall well-being; a program that did show beneficial effects even in AD patients. Hence, this method could be implemented to reverse those activation factors observed at the earlier stages of AD and dementia, while preventing further memory loss and structural brain damage. Recently published, the study from Aviv Clinics did find the capability of HBOT to regulate blood flow, blood vessels, and overall brain and body functionality in patients, by mimicking the state of hypoxia effectively changing the structure of brain vessels, and thus suggesting this approach as a drug-free and non-invasive solution to treat the cognitive and physical decline in aging .
Nevertheless, although the results from the Tel Aviv research look promising, large-scale studies are needed to better confirm these data and the effectiveness of this approach in improving memory and thinking in patients . Indeed, “if we consider that the number of people with dementia in the UK is approaching one million, it is hard to see how hyperbaric oxygen could ever be available on this scale”, said Tom Dening, professor of dementia research at University Nottingham, and so to further develop this method into an established treatment the way is still long.
It is well-known that treatment options are very limited, and the majority of existing medications are neuropharmacological in nature. Biogen’s aducanumab became the first new Alzheimer’s therapy FDA approved by the US in nearly 20 years, although still debated is the efficacy of this treatment in patients . Indeed, Aduhelm was able to decrease the number of plaques in AD patients, but the absence of strong evidence to establish the effectiveness of the treatment was missing, particularly due to the discontinued clinical trial in 2019 and the lack of considerable cognitive improvements in patients.
The majority of approaches so far presented were mostly focused on delaying disease progression, instead of targeting the source cursing the disease itself, leading to the hope that today’s medicine can reverse AD pathology. In respect to the P4 of Health, personalized and precision medicine is becoming the new trend of disrupted and innovative healthcare. Indeed, a clinical trial implementing a personalized approach, targeting the key drivers of AD was the first to show improvements in patients. These findings published in medRxiv  demonstrated that 21 of 25 study participants improved their cognition after undergoing the personalized treatment. However, more trials are needed to reinforce these results on a larger dataset. Moreover, Dr. Dale Bredesen, co-author of the study and neurodegenerative disease expert, mentioned that a single treatment modality to cure AD patients is a kind of “blind approach” that mostly fails to even target the primary drivers of an individual's cognitive deterioration . Lastly, to generate this personalized approach, the research team was also aimed at identifying the primary factors of AD, from pathogens, toxins to vascular diseases, and while investigating those individual variables that may be the cause behind the several AD subtypes .
A few weeks ago, Brigham and Women’s Hospital announced the beginning of the first clinical trial on humans of a nasal vaccine for AD, developed to prevent and slow the progression of the pathology. Although the small sample size of this clinical trial, in which 16 patients between ages 60 to 85 manifesting AD symptoms will receive two doses of a vaccine, the study has been developed over several years of research and in which the activation of the immune system to decrease and remove the amount of beta-amyloid plaques was proposed . This vaccine is aimed to spray a drug called Protollin along the nasal cavity to further stimulate immune cells. Indeed, this procedure is getting more attention as a potential intervention to treat AD while removing the accumulation of plaques that are responsible for deteriorating cognitive functions in patients. However, it is also true that the capability of this treatment would be more efficacious if implemented in the earlier stages of the disease, and before initiating larger clinical trials, the safety and the proper dosage of this vaccine should be confirmed .
Moreover, memory and attentional complaints, as well as, learning, reasoning, and comprehension are visible features characterizing disease progression in AD. However, cognitive decline is the result of progressive structural damage due to volume loss, beta-amyloid accumulation, and impaired neural oscillations. To this, it has been found that virtual reality (VR) would be able to stimulate a unique brain oscillation that could enhance learning. A recent study by Safaryan and Mehta (2021)  did show that when rats were running in VR, their neural activities were uniquely responding to the VR space, potentially able to influence learning, and this speculating on the possible transfer when treating memory decline in AD. Indeed, cognitive functions are related to the activity of different brain waves that oscillate at different frequencies. Among these, theta oscillations are famous for being related to memory and related to the hippocampus, a memory center, found to stimulate memory, learning, and neuroplasticity. Hippocampal theta waves are particularly important because they play a relevant role in recalling things associated with locations, and also in space navigation; abilities that are going to progressively decline in AD due to the gradual hippocampal atrophy . To investigate the behavior of theta oscillations, in the experiment rats were left running in VR, and their theta waves were recorded both in the virtual and real space. What has been observed was that while rats were running in VR, a particular brain pattern emerged. Indeed, peculiar oscillations half as slow as normal theta waves were detected in the CA1 cell layer, primarily in interneurons . However, these oscillations tended to disappear once the rats were not moving anymore. The authors called these waves as “eta band.” Moreover, another interesting finding was that theta oscillations were enhanced in VR when compared to the real environment, probably because in VR the hippocampus processes information differently . Indeed, in VR sensory inputs are way different than in the real world, and thus stimulating much more theta and eta oscillations. These findings have a great implication when it comes to learning, suggesting that eta oscillations may separate the activity inside the hippocampus into “parallel streams of information processing” said the authors. This process would consequently influence the way we learn and memorize information into VR, potentially enhanced, speculating on the possibility to translate this approach to treat AD, dementia, and other memory disorders [18, 19].
Vaccines and gene therapy to reverse aging and solve underpopulation
A demographic statistic from the Lancet forecasted that the global population will peak at 9.7 billion by 2064, followed by a considerable decrease to 8.8 billion by 2100. Not surprisingly, this is the result of a better standard of living and decreased reproductivity rates that consequently would determine a worldwide underpopulation. What does this all mean? Well, fewer people mean fewer workers, and besides demographic changes toward the increasing aging population would affect the part of the population capable of working .
Although this does not sound like an exciting prediction of the future, “the world’s biggest problems are the world’s biggest business opportunities.” Indeed, speculations on age-reversal and healthy longevity have been made. The dilemma about underpopulation is characterized by a decreased fertility rate, needed to replace the population at each generation. However, when compared to 70 years ago, today the situation looks very different with a dramatic drop in the reproductivity rate, even below the replacement level in several countries. The empowerment of women, declining child mortality, and raised childhood costs are the major reason for explaining this event. Besides, the Covid-19 pandemic accelerated this trend, in which people feel less secure about their finances, and similarly when it’s about childcare. “Earth is going to face a massive population collapse over the next 20 to 30 years… this would be the civilization’s way of dying with a whimper”, said Elon Musk, interviewed for the launch of the $100M XPRIZE Carbon Removal this year.
When talking about age-reversal and longevity, Peter Diamandis  highlights the importance of maintaining and increasing abundance for the global population. Indeed, reversing age does not mean to overpopulate, but to enhance health while benefitting from the number of resources available. As Diamandis says, the need is to increase our productive and healthy lifespan, which in turn have a tremendous economic value. Following this, researchers from Harvard, Oxford, and London Business School have lately shown how much health longevity can be extremely worthy in dollars. Thus, just considering delaying the aging process by one year, this is worth +$38 trillion to the global economy. What is it going to happen when if we extend our healthy lifespan by 10 or even 20 more years? A financial win!
Moreover, this event will be reinforced by exponential technologies that are going to disrupt the entire healthcare system, shifting the focus from sickness to health and prevention. Improving diagnostic tools, more advanced imaging techniques, the rising of CRISPR, gene therapy methods, and organ regeneration the possibility to promote health longevity is not a sci-fi story anymore . Contrary to past beliefs, aging represents an opportunity for innovation. AI and other exponential technologies will indeed support the process behind a healthy and productive life, in which longevity will become one of the main industries, a great business opportunity for the global economy .
In response to exponential technologies and the increasing aging population, can biological age be reversed? During life, our genome undergoes several chemical modifications determined by methyl groups that mark the DNA. Thus, different patterns of these modifications at the level of the body’s epigenome characterize the biological age independently of the chronological age, and in which the possibility to build epigenetic clocks would rely on the selection of DNA-methylation sites across the genome .
A small clinical trial that took place in California, was able to demonstrate that the body’s epigenetic clock can be reversed. Based on past humans and animal studies, the research of Fahy et al. (2019)  was indeed aimed to test the efficacy of growth hormone to regenerate tissues in the thymus gland, which plays a relevant role in the immune system. However, this gland shows a tendency to shrink throughout life while becoming occluded with fat.
In the Thymus Regeneration, Immunorestoration and Insulin Mitigation (TRIIM) trial, nine participants between the age of 51 and 65 years were treated with a combination of three drugs (a growth hormone and two medications for diabetes) for one year. Indeed, the administration of growth hormone can also cause diabetes. So, two anti-diabetic medications were included in the trial to prevent diabetes [21,22].
During the study period, blood samples have been acquired from participants and in which blood cells have been analyzed. Results did show that by measuring the individual genome, on average they gained 2.5 years of their biological age with a stronger and rejuvenated immune system [21,22]. Moreover, from a magnetic resonance imaging (MRI) scan, in seven participants the fat accumulated in the thymus, observed at the beginning of the TRIIM trial, was found to be replaced with regenerated thymus tissue. “I’d expected to see slowing down of the clock, but not a reversal,” said Steve Horvath, a geneticist at the University of California (LA). Nevertheless, although the published results  were promising, the lack of a control group and the small sample size were limiting factors to draw reliable conclusions. Hence, Intervene Immune is going to replicate the study but on larger sample size, including diversified ages, gender, and ethnicities. Fahy also commented that the three implemented medications would generate a different effect on biological aging. Consequently, researchers suggest that thymus regeneration might help reinforce the immune system in the aging population, but also in patients affected by infectious diseases and in cancer [21,22].
Furthermore, extended lifespan while removing mice senescent cells in vivo was found by researchers from the Shanghai Institute of Nutrition and Health (SINH), under the Chinese Academy of Sciences. They found that a polyphenolic extract from grape seed called procyanidin C1 would be capable of delaying, or even preventing, age-related pathologies, which in turn are caused by these senescent cells in mice models. However, further studies are needed to prove the validity and the safety of the method.
Similarly, a Japanese study from the Juntendo University developed a vaccine that eliminates senescent cells in aging. Indeed, these cells called “zombie cells”, release toxic chemicals responsible for chronic inflammations, hence leading to age-related diseases. In response to this, researchers did find a protein – glycoprotein nonmetastatic melanoma protein B (GPNMB) – in senescent cells of humans and mice, and in which by using an amino acid in GPNMB, a peptide vaccine enabled the clearance of senescent cells while releasing antibodies. Moreover, mice treated with this vaccine for “aging”, reduced the size of their arterial stiffening, when compared to unvaccinated mice . In addition, although fewer side effects, the vaccine found long-lasting benefits , and probably opened the door in the direction of vaccines for aging, while disrupting the healthcare system, the economy, and humanity worldwide.
“The aim of medicine is to prevent disease and prolong life, the ideal of medicine is to eliminate the need of a physician.” (William James Mayo)
“The future belongs to those who seize the opportunities created by innovation.” (Delos M. Cosgrove)
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