African Americans and Hispanic Americans experience a higher incidence and prevalence of dementia than white Americans while also experiencing more environmental, metabolic, and nutritional factors potentially promoting such disparities. Greater exposure to air, water, and soil pollutants, including toxic metals associated with neurodegeneration, accrues in both minorities, as does worse dental care than Whites exposing them to periodontitis, raising dementia risk. Hispanic Americans experience greater occupational exposure to herbicides and pesticides, and have a higher rate of developing non-alcoholic fatty liver disease (NAFLD), predisposing to dementia. African Americans have a greater likelihood of both vitamin D deficiency and magnesium deficiency, increasing neuroinflammation and dementia risk. Both have greater air pollution exposure, a known dementia risk. Nutritional changes, including greater nut consumption and reduced sugar drink consumption, improved dental care, and reduced toxicant exposure, may help reduce this higher risk of dementia among African Americans and Hispanic Americans.

Journal of Internal MedicineEarly View Letter to the Editor The Hispanic American longevity paradox: Sofrito and beyond Jaime Uribarri, Jaime Uribarri orcid.org/0000-0001-9826-1134 Department of Medicine, Icahn School of Medicine at Mount Sinai, One Gustave Levy Place, New York, New York, 10029 USA Contribution: Conceptualization (equal), Formal analysis (equal), Writing - original draft (lead)Search for more papers by this authorLorena Drago, Lorena Drago Hispanic Foodways, LLC, Greenwood Lake, New York, USA Contribution: Conceptualization (supporting), Formal analysis (supporting), Methodology (equal), Writing - review & editing (supporting)Search for more papers by this authorArnold R. Eiser, Corresponding Author Arnold R. Eiser [email protected] orcid.org/0000-0003-3906-5509 Penn Center for Public Health, Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania, USA Correspondence: Arnold R. Eiser, Penn Center for Public Health, Perelman School of Medicine, University of Pennsylvania, 610 209-8016, 3620 Hamilton Walk, Philadelphia, PA 19104, USA. Email: [email protected] Contribution: Conceptualization, Formal analysis, Project administration, Writing - review & editingSearch for more papers by this author Jaime Uribarri, Jaime Uribarri orcid.org/0000-0001-9826-1134 Department of Medicine, Icahn School of Medicine at Mount Sinai, One Gustave Levy Place, New York, New York, 10029 USA Contribution: Conceptualization (equal), Formal analysis (equal), Writing - original draft (lead)Search for more papers by this authorLorena Drago, Lorena Drago Hispanic Foodways, LLC, Greenwood Lake, New York, USA Contribution: Conceptualization (supporting), Formal analysis (supporting), Methodology (equal), Writing - review & editing (supporting)Search for more papers by this authorArnold R. Eiser, Corresponding Author Arnold R. Eiser [email protected] orcid.org/0000-0003-3906-5509 Penn Center for Public Health, Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania, USA Correspondence: Arnold R. Eiser, Penn Center for Public Health, Perelman School of Medicine, University of Pennsylvania, 610 209-8016, 3620 Hamilton Walk, Philadelphia, PA 19104, USA. Email: [email protected] Contribution: Conceptualization, Formal analysis, Project administration, Writing - review & editingSearch for more papers by this author First published: 05 March 2023 https://doi.org/10.1111/joim.13623Read the full textAboutPDF ToolsRequest permissionExport citationAdd to favoritesTrack citation ShareShare Give accessShare full text accessShare full-text accessPlease review our Terms and Conditions of Use and check box below to share full-text version of article.I have read and accept the Wiley Online Library Terms and Conditions of UseShareable LinkUse the link below to share a full-text version of this article with your friends and colleagues. Learn more.Copy URL Share a linkShare onEmailFacebookTwitterLinkedInRedditWechat No abstract is available for this article. References 1Johnson CO, Boon-Dooley AS, Decleene NK, Henny KF, Blacker BF, Anderson JA, et al. Life expectancy for White, Black and Hispanic Race/Ethnicity in US States: trends and disparities, 1990 to 2019. Ann Intern Med. 2022; 175: 1057–64. 2McDonald JA, Paulozzi LJ. Parsing the paradox: Hispanic mortality in the US by detailed cause of death. J Immigr Minor Health. 2019; 21(2): 237–45. 3Lozano-Castellón J, de Alvarenga JF, Vallverdú-Queralt A, Lamuela-Raventós RM. Cooking with extra-virgin olive oil: a mixture of food components to prevent oxidation and degradation. Trends Food Sci Technol. 2022; 123: 28–36. 4Desai G. Schleske-Santos M. Nazario CM, Rosario-Rosado RV, Mansilla-Rivera I, Ramírez-Marrero F, et al. Onion and garlic intake and breast cancer, a case-control study in Puerto Rico. Nutr Cancer. 2019; 72: 791–800. 5Urquiza-Salvat N, Pascual-Geler M, Lopez-Guarnido O, Rodrigo L, Martinez-Burgos A, Cozar JM, et al. Adherence to Mediterranean diet and risk of prostate cancer. Aging Male. 2019; 22: 102–8. 6Figueira N, Curtain F, Beck E, Grafenauer S. Consumer understanding and culinary use of legumes in Australia. Nutrients. 2019; 11(7): 1575. https://doi.org/10.3390/nu11071575 7Ofori-Asenso R, Mohsenepour MA, Nouri M, Faghih S, Liew D, Mazidi M, et al. Association of spicy chilli food consumption with cardiovascular and all-cause mortality: a meta-analysis of prospective cohort studies. Angiology. 2021; 72: 625–32. 8Juul F, Vaidean G, Lin Y, Deierlein AL, Parekh N. Ultra-processed foods and incident cardiovascular disease in the Framingham Offspring Study. J Am Coll Cardiol. 2021; 77: 1520–31. Early ViewOnline Version of Record before inclusion in an issue ReferencesRelatedInformation

Objective: To determine the frequency with which suspected pathogenic factors, including metals and metabolites that might contribute to Alzheimer's disease (AD), may be found in patients with cognitive impairment through commonly available blood tests. Methods: A variety of serum studies, including metals, ammonia, homocysteine, vitamin B12, folate, thyroid tests, metabolic products, and inflammatory markers, were measured in two cohorts: one meeting mild cognitive impairment (MCI) criteria and the other meeting mild-to-moderate dementia (DE) criteria. Medications these patients received were reviewed. Results: Metal abnormalities were detected in over half the subjects, including evidence of mercury, lead, and arsenic elevation as well as instances of excessive essential metals, iron (Fe), and copper. Some metal aberration was detected in 64% of the DE group and 66% of the MCI group. Females were more likely to have elevated copper, consistent with hormonal effects on copper excretion. Homocysteinemia was the most common abnormality, detected in 71% with DE and 67% with MCI, while methylmalonic acid was not elevated. Slight hyperammonemia was moderately common (38%) suggesting a hepatic factor in this subset. Findings of moderate insulin resistance were present in nearly half (44% DE, 52% MCI). Sixty of 65 (92%) had at least one abnormal biomarker and 60% had two or more. The most common drug taken by the total cohort was proton pump inhibitors at 22% DE and 38% MCI. Conclusions: This study suggests that both toxic metals and excessive vital metals such as copper and iron, as well as common metabolic and hepatic factors are detectable at both stages of MCI and DE. There appears to be a multiplicity of provocative factors leading to DE. Individualized interventions based on these parameters may be a means to reduce cognitive decline leading to DE. A more comprehensive prospective study of these environmental and metabolic factors with corrective early interventions appears warranted.

Recent political events have called the public's attention to the diagnosis of mild cognitive impairment (MCI) in older people with concerns about cognitive function. Perhaps, it is time for the medical community to reflect on the potential of formally screening and offering interventions for mild cognitive impairment as a means to reduce the prevalence of dementia. Up to 40% with mild cognitive impairment may progress to dementia but could benefit from screening that is currently only done in 25% of annual Medicare exams. What types of interventions might be considered if mild cognitive impairment is present? A number of conditions that promote mild cognitive impairment can be potentially remedied when identified at an early stage. These include normal pressure hydrocephalus, thyroid disorders, insulin resistance, hepatic dysfunction with hyperammonemia, gut dysbiosis, oral dysbiosis, and environmental toxin exposure including metals1Eiser AR Fulop T. Alzheimer's Disease Is a Multi-Organ Disorder: It May Already Be Preventable.J Alzheimer's Dis. 2023; 91: 1277-1281https://doi.org/10.3233/JAD-221078Google Scholar,2Lyon AC Lippa CF Eiser AR. Metabolic and Environmental Biomarkers in Mild Cognitive Impairment and Dementia: An Exploratory Study.J Integr Compl Med. 2024; https://doi.org/10.1089/jicm.2023.0583Google Scholar as well as nutritional deficiencies including vitamin D, thiamine, pyridoxine, vitamin B12 and folate, magnesium, zinc, and selenium.3Pereira ME Souza JV Galiciolli MEA Effects of Selenium Supplementation in Patients with Mild Cognitive Impairment or Alzheimer's Disease: A Systematic Review and Meta-Analysis.Nutrients. 2022; 14 (Aug 5): 3205https://doi.org/10.3390/nu14153205Google Scholar For some with mild cognitive impairment, vital nutrients provision appears to make the difference between improvement or progression to dementia4Chang J. Liu M. Liu C. et al.Effects of vitamins and polyunsaturated fatty acids on cognitive function in older adults with mild cognitive impairment: a meta-analysis of randomized controlled trials.Eur J Nutr. 2024; https://doi.org/10.1007/s00394-024-03324-yGoogle Scholar. The brain is heavily dependent on both the detoxifying and generative capabilities of the liver. Supplementation with docosahexaenoic acid (DHA), especially if there is evidence of hyperammonemia should be considered. NAFLD (non-alcoholic fatty liver disease), increasingly common today, is a risk factor for cognitive impairment.5Wernberg CW. Grønkjær LL. Jacobsen G et al.The prevalence and risk factors for cognitive impairment in obesity and NAFLD.Hepatol Commun. 2023; 7 (Jul): e00203https://doi.org/10.1097/HC9.0000000000000203Google Scholar There are several research studies noting significant improvements when mild cognitive impairment patients are given omega 3 fatty acids with DHA. They find improvements in memory, arithmetic skills, other executive functions, and even preservation of hippocampal volume6Zhang YP Miao R Li Q et al.Effects of DHA Supplementation on Hippocampal Volume and Cognitive Function in Older Adults with Mild Cognitive Impairment: A 12-Month Randomized, Double-Blind, Placebo-Controlled Trial.J Alzheimers Dis. 2017; 55: 497-507https://doi.org/10.3233/JAD-160439Google Scholar,7Bo Y. Zhang X. Wang et al.The n-3 Polyunsaturated Fatty Acids Supplementation Improved the Cognitive Function in the Chinese Elderly with Mild Cognitive Impairment: A Double-Blind Randomized Controlled Trial.Nutrients. 2017; 9 (Jan 10): 54https://doi.org/10.3390/nu9010054Google Scholar. Have these studies been largely ignored because they are performed in and reported from other countries?. Systematic review and metanalysis of probiotics in mild cognitive impairment and Alzheimer's disease revealed significantly improve cognitive function in mild cognitive impairment but not in Alzheimer's disease. Lactobacillus acidophilus, Bifidobacterium bifidum, B. longum, and L. rhamnosus were species that are most associated with improved cognitive outcomes8Zhu G Zhao J Zhang H et al.Probiotics for Mild Cognitive Impairment and Alzheimer's Disease: A Systematic Review and Meta-Analysis.Foods. 2021; 10: 1672https://doi.org/10.3390/foods10071672Google Scholar. Mechanism for improved cognitive function likely includes reduction of ammonia and an increase in the metabolome, butyrate.9Shen TC Albenberg L Bittinger K et al.Engineering the gut microbiota to treat hyperammonemia.J Clin Invest. 2015; 125 (Jul 1): 2841-2850https://doi.org/10.1172/JCI79214Google Scholar Some interventions may be applied broadly to the mild cognitive impairment population include exercise10Zhang Y Zhang X Lin S. Irisin: A bridge between exercise and neurological diseases.Heliyon. 2022; 8 (Dec 15): e12352https://doi.org/10.1016/j.heliyon.2022.e12352Google Scholar, both aerobic and resistance types, and brain-body exercises11Zou L. Loprinzi P.D. Yeung et al.The beneficial effects of mind-body exercises for people with mild cognitive impairment: a systematic review with meta-analysis.Arch Phys Med Rehabil. 2019; 100 (Aug): 1556-1573https://doi.org/10.1016/j.apmr.2019.03.009Google Scholar as they have demonstrated efficacy for better cognitive outcomes in mild cognitive impairment while the same is not so in dementia. Prevention appears more effective at the mild cognitive impairment stage once again. The mechanism whereby exercise may improve cognition in mild cognitive impairment appears to be by reducing microglial activation, enhancing release of such neuronal growth factors as brain derived neurotrophic factor (BDNF) and irisin as well as reducing inflammatory cytokines13García-Casares N. Gallego Fuentes P. Barbancho M.Á. et al.M. Alzheimer's Disease, Mild Cognitive Impairment and Mediterranean Diet. A Systematic Review and Dose-Response Meta-Analysis.J. Clin. Med. 2021; 10: 4642https://doi.org/10.3390/jcm10204642Google Scholar. A meta-analysis suggests that mind-body exercises (tai chi, qigong, yoga) appears to be beneficial for improving cognitive functions (cognitive processing speed, short-term memory, visual-spatial ability, attention, global cognitive function) among those with mild cognitive impairment. Low-impact mind-body exercises may be suitable for mild cognitive impairment patients with low exercise intolerance12Nascimento CMC Pereira J R Pires de Andrade L. Physical exercise in MCI elderly promotes reduction of pro-inflammatory cytokines and improvements on cognition and BDNF peripheral levels.Curr Alzheimer Res. 2014; 11: 799-805https://doi.org/10.2174/156720501108140910122849Google Scholar. Cognitive exercises alone appear to lack efficacy because they do not stimulate brain biochemistry. Adherence to a Mediterranean diet is one of the best known means of reducing dementia risk.11Zou L. Loprinzi P.D. Yeung et al.The beneficial effects of mind-body exercises for people with mild cognitive impairment: a systematic review with meta-analysis.Arch Phys Med Rehabil. 2019; 100 (Aug): 1556-1573https://doi.org/10.1016/j.apmr.2019.03.009Google Scholar In addition specific food items appear to have efficacy regarding maintaining cognition. While nuts in general are thought to contain substances needed for brain health, the walnut has the most evidence supporting this contention14Theodore L.E. Kellow N.J. McNeil et al.Nut consumption for cognitive performance: a systematic review.Adv Nutr. 2021; 12: 777-779https://doi.org/10.1093/advances/nmaa153Google Scholar. Berry consumption with its constituent anthocyanins appears to increase BDNF and maintain robust brain perfusion contributing to hippocampal well-being and thus preservation of cognition.15Kent K. Yousefi M. do Rosario V.A. et al.Anthocyanin intake is associated with improved memory in older adults with mild cognitive impairment.Nutr Res. 2022; 104 (Aug): 36-43https://doi.org/10.1016/j.nutres.2022.04.003Google Scholar The benefits of fish consumption have already been alluded to since DHA is a component of fish oil. Of course there is the caveat to avoid the neurotoxin methylmercury that may contaminate fish from some sources. Moreover there are medications that appear to promote dementia especially those that reduce gastric acidity that could be discontinued in mild cognitive impairment patients in order to help prevent progression. Protein pump inhibitors (PPI) and histamine-2 blockers (H2) both are in this category suggesting lack of stomach acidity is contributory. In a prospective cohort study in Germany, PPI usage promoted the development of dementia with a hazard ratio of 1.4416Gomm W. von Holt K. Thomé et al.Association of proton pump inhibitors with risk of dementia: a pharmacoepidemiological claims data analysis.JAMA Neurol. 2016; 73 (Apr): 410-416https://doi.org/10.1001/jamaneurol.2015.4791Google Scholar while a similar study in Taiwan17.Chen L.-Y. Lin H.-J. Wu W.-T. et al.Clinical Use of Acid Suppressants and Risk of Dementia in the Elderly: A Pharmaco-Epidemiological Cohort Study.Int. J. Environ. Res. Public Health. 2020; 17: 8271https://doi.org/10.3390/ijerph17218271Google Scholar found the same rate for PPIs and hazard ratio of 1.82 for H2 blockers for the occurrence of dementia. Anticholinergic agents (AC) have been known to impair cognitive function. A study using fluorodeoxyglucose F 18–positron emission tomographic scans demonstrated that along with cognitive impairment, AC users experienced both cortical atrophy and thinning of the temporal lobe.18Risacher SL McDonald BC Tallman EF et al.Association Between Anticholinergic Medication Use and Cognition, Brain Metabolism, and Brain Atrophy in Cognitively Normal Older Adults.JAMA Neurol. 2016; 73: 721-732https://doi.org/10.1001/jamaneurol.2016.0580Google Scholar Long-term usage of the benzodiazepines, commonly used anxiolytics, have been found to cause cognitive impairment in a considerable subset of chronic users.19Zetsen SPG Schellekens AFA Paling EP et al.Cognitive Functioning in Long-Term Benzodiazepine Users.Eur Addict Res. 2022; 28: 377-381https://doi.org/10.1159/000525988Google Scholar This effect was particularly noted in women and may be mediated by reduced BDNF and enhanced tau phosphorylation. Discontinuation of the above mentioned medications and some others during a period of MCI may help to avoid the progression to dementia. Clinical research is needed to evaluate this potential intervention. It is time for the medical community to address the rising pandemic of mild cognitive impairment and establish greater preventive measures regarding dementia in those suffering with mild cognitive impairment. The US Preventive Task Force hold tremendous influence over clinical practice in the USA. Their last published analysis of this matter recommended against screening for mild cognitive impairment. Their review of the relevant research appeared limited and important information on the subject that had been researched in other countries was not considered. Moreover the authors of the report are experts in health policy, health services research, and family medicine. None have expertise in the neurosciences or neurology. This decision-making process needs examination as well. Finally it is important to note that in a large prospective, population based study by Mayo Clinic, researchers find that individuals with mild cognitive impairment had twice the hazard ratio for mortality than those with normal cognition with a median follow-up of 5.8 years21Vassilaki M Cha RH Aakre JA et al.Mortality in mild cognitive impairment varies by subtype, sex, and lifestyle factors: the Mayo Clinic Study of Aging.J Alzheimers Dis. 2015; 45: 1237-1245https://doi.org/10.3233/JAD-143078Google Scholar. Ignoring MCI imperils human lives as well as human brain function. More research is needed but it is time to take the initiative to diagnose and intervene with mild cognitive impairment to reduce human suffering. [20Owens DK Davidson KW etal Krist AH Screening for Cognitive Impairment in Older Adults: US Preventive Services Task Force Recommendation Statement.JAMA. 2020; 323 (Feb 25): 757-763https://doi.org/10.1001/jama.2020.0435Google Scholar] Arnold R. Eiser: Conceptualization, Methodology, Writing – original draft, Writing – review & editing. None

In this commentary, we offer an overview of the several environmental and metabolic factors that have been identified as contributing to the development of Alzheimer's disease (AD). Many of these factors involve extracranial organ systems including immune system dysfunction accompanied by neuroinflammation (inflammaging), gastrointestinal dysbiosis, insulin resistance, and hepatic dysfunction. A variety of microbial factors including mouth flora, viruses, and fungi appear to play a significant role. There is a role for the colonic microbiome becoming dysbiotic and producing toxic metabolites. Declining hepatic function contributes diminished neuronal precursors and reduces toxin elimination. Environmental toxins especially metals play an important role in impairing the blood-brain barrier and acting synergistically with biotoxins and other toxic chemicals. Prevention and treatment of AD appears to require measuring several of these biomarkers and implementing corrective actions regarding such toxicants and correcting metabolic dysfunction at early or preclinical stages of this disorder.

We describe important settings where environmental exposure leads to disease disparities. Lead exposure in urban settings disproportionately impacts the urban Black poor. Native Americans have been forcibly relocated to areas of the West that have arsenic-contaminated groundwater or exposure to radionuclides near mines and nuclear development. Latino farm workers are disproportionately exposed to pesticides and herbicides. These chemicals are associated with cancer, neuropsychiatric disorders, renal failure, and respiratory disorders. The rural poor, both white and of color, are disproportionately impacted by hydraulic fracturing, exposing residents to volatile organic compounds such as toluene and benzene and heavy metals such as lead and arsenic. The urban and rural poor are both exposed to air pollution that significantly impact health. Short- and long-term ambient air pollution exposure has been associated with all-cause cardiovascular disease, stroke, blood pressure, and ischemic heart disease. Cancer due to air pollution has disproportionately impacted poor communities like "Cancer Alley" where numerous industrial sources are geographically clustered. Understanding local environmental hazards and available resources to address them can enhance the quality of medical care.

Journal of Integrative and Complementary MedicineVol. 28, No. 12 CommentaryNeurocovid, Neuroinflammation, and Nuclear Factor-κB: The Role for MicronutrientsAida Adlimoghaddam, Benedict C. Albensi, and Arnold R. EiserAida AdlimoghaddamDivision of Neurodegenerative Disorders, St. Boniface Hospital Albrechtsen Research Centre, Department of Pharmacology and Therapeutics, Max Rady College of Medicine, University of Manitoba, Winnipeg, Manitoba, Canada.Search for more papers by this author, Benedict C. AlbensiDivision of Neurodegenerative Disorders, St. Boniface Hospital Albrechtsen Research Centre, Department of Pharmacology and Therapeutics, Max Rady College of Medicine, University of Manitoba, Winnipeg, Manitoba, Canada.Department of Pharmaceutical Sciences, College of Pharmacy, Nova Southeastern University, Fort Lauderdale, FL, USA.Search for more papers by this author, and Arnold R. EiserAddress correspondence to: Arnold R. Eiser, MD, MACP, Penn Center for Public Health, Perelman School of Medicine, University of Pennsylvania, 3620 Hamilton Walk, Philadelphia, PA 19104, USA E-mail Address: Arnold.Eiser@Pennmedicine.upenn.eduhttps://orcid.org/0000-0003-3906-5509Penn Center for Public Health, Perelman School of Medicine, University of Pennsylvania, Philadelphia, USA.Search for more papers by this authorPublished Online:7 Dec 2022https://doi.org/10.1089/jicm.2022.0736AboutSectionsView articleView Full TextPDF/EPUB Permissions & CitationsPermissionsDownload CitationsTrack CitationsAdd to favorites Back To Publication ShareShare onFacebookTwitterLinked InRedditEmail View articleFiguresReferencesRelatedDetails Volume 28Issue 12Dec 2022 InformationCopyright 2022, Mary Ann Liebert, Inc., publishersTo cite this article:Aida Adlimoghaddam, Benedict C. Albensi, and Arnold R. Eiser.Neurocovid, Neuroinflammation, and Nuclear Factor-κB: The Role for Micronutrients.Journal of Integrative and Complementary Medicine.Dec 2022.916-918.http://doi.org/10.1089/jicm.2022.0736Published in Volume: 28 Issue 12: December 7, 2022Online Ahead of Print:October 26, 2022KeywordsneurocovidCOVID-19NF-kBvitamin DmagnesiumseleniumPDF download

Alzheimer's disease (AD) is the most common form of dementia and aging is the most common risk factor for developing the disease. The etiology of AD is not known but AD may be considered as a clinical syndrome with multiple causal pathways contributing to it. The amyloid cascade hypothesis, claiming that excess production or reduced clearance of amyloid-beta (Aβ) and its aggregation into amyloid plaques, was accepted for a long time as the main cause of AD. However, many studies showed that Aβ is a frequent consequence of many challenges/pathologic processes occurring in the brain for decades. A key factor, sustained by experimental data, is that low-grade infection leading to production and deposition of Aβ, which has antimicrobial activity, precedes the development of clinically apparent AD. This infection is chronic, low grade, largely clinically silent for decades because of a nearly efficient antimicrobial immune response in the brain. A chronic inflammatory state is induced that results in neurodegeneration. Interventions that appear to prevent, retard or mitigate the development of AD also appear to modify the disease. In this review, we conceptualize further that the changes in the brain antimicrobial immune response during aging and especially in AD sufferers serve as a foundation that could lead to improved treatment strategies for preventing or decreasing the progression of AD in a disease-modifying treatment.

We are grateful to the scientists who developed the coronavirus disease 2019 (COVID-19) vaccines and to the companies that brought them to market. Such gratitude does not obviate the adverse developments in the pharmaceutical industry-Federal Drug Administration (FDA) relationship that impact US health care, its patients, and burgeoning health care costs. The latest and most flagrant example is the approval of aducanumab in the treatment of Alzheimer's disease (AD) by the FDA, despite the advice of its own nervous system drug advisory panel against approval: 10 no, 0 yes, and 1 abstention.1Terry M. Fallout continues as third FDA panel member resigns over Aduhelm approval. Available at:https://www.biospace.com/article/3rd-fda-alzheimer-s-advisory-panel-member-resigns-over-biogen-approval/. Accessed June 17, 2021.Google Scholar Moreover, 3 members of the panel, all experts in the field, have resigned from the panel, citing this egregious decision and a process that can readily ignore their advice even when unanimous. Furthermore, an independent scholarly think tank, the Institute for Clinical and Economic Review, also concluded that the drug's risks, including brain microhemorrhages, outweigh its questionable intermediate endpoint benefit.2Lin GA, Whittington MD, Synnott PG, et al. Aducanumab for Alzheimer's disease: effectiveness and value; Draft Evidence Report. Institute for Clinical and Economic Review. Available at:https://icer.org/assessment/alzheimersdisease-2021/. Accessed June 17, 2021.Google Scholar Because its clinical benefit remains in doubt, it may only add cost to the health care system. The lack of efficacy and the serious nature of side effects did little to deter the decision-making when the world of commerce, financial interests, and consumerism predominate over healthcare ethics and scientific objectivity. One needs to consider why this is so. First, the theory behind development of this drug is simply wrong or merely outdated. Aducanumab is the latest in a generation of monoclonal antibodies directed against β-amyloid. Its proposed therapeutic efficacy is based on an archaic understanding of the pathogenesis of AD, one that has amyloid as the central causative factor. Although β-amyloid certainly accompanies this disease, the evidence that it is causative has been receding in the rearview window as neuroscience research has unearthed a complex web of multiorgan dysfunction in the aging body accounting for it.3Eiser AR Fulop T. Extra-cranial factors in the development of Alzheimer's disease.Brain Res. 2020; 748147076Crossref Scopus (6) Google Scholar Moreover, β-amyloid has significant antimicrobial activity,4Li F Hearn M Bennett LE. The role of microbial infection in the pathogenesis of Alzheimer's disease and the opportunity for protection by anti-microbial peptides.Crit Rev Microbiol. 2021; 47: 240-253Crossref PubMed Scopus (12) Google Scholar a fact that goes with the rising importance of immunological dysfunction termed “inflammaging” and chronic low-grade infection in the aging human, leading to dementia.5Gritsenko A Green JP Brough D Lopez-Castejon G. Mechanisms of NLRP3 priming in inflammaging and age-related diseases.Cytokine Growth Factor Rev. 2020; 55: 15-25Crossref PubMed Scopus (59) Google Scholar So, the key brain components in AD are not the amyloid deposits but an activated “angry” microglial cell. Instead, hyperphosphorylated tau protein accumulates, lipid and protein peroxidation, metal toxicity, gut microbiome dysbiosis, impaired mitochondrial function, hormonal disruption, chronic infection, and subtle liver dysfunction all contribute to the development of AD. So why the persistent pursuit of this dead-end in AD clinical research? Because a pharmaceutical company can charge a great deal for a monoclonal antibody, and company executives and stockholders can profit mightily; so why change course? With the way the FDA let the opioid manufacturers have their way, maybe yet another questionable drug may get through. The companies and their lobbyists have substantial influence within the DC Beltway, so this situation is unlikely to change in the future. Ironically, there is accumulating evidence from neuroscience and case-control studies that much can be done to prevent AD and possibly reverse early stages of the disorder that is cost-effective and readily available.6Eiser AR. Preserving Brain Health in a Toxic Age: New Insights from Neuroscience, Integrative Medicine, and Public Health. Lanham, MD: Rowman & Littlefield; 2021.Google Scholar These include vigorous exercise with sweating; low inflammatory diets like the Mediterranean diet or the keto diet;7Cunnane SC Courchesne-Loyer A Vandenberghe C et al.Can ketones help rescue brain fuel supply in later life? Implications for cognitive health during aging and the treatment of Alzheimer's disease.Front Mol Neurosci. 2016; 9: 53Crossref PubMed Scopus (139) Google Scholar use of spices including turmeric, rosemary, and oregano; the regular consumption of green tea, blueberries, and extra virgin olive oil;8D'Angelo S Current evidence on the effect of dietary polyphenols intake on brain health.Curr Nutr Food Sci. 2020; 16: 1170-1182Crossref Scopus (24) Google Scholar stress reduction, including meditation; and much more. But these therapeutic strategies are not going to be evaluated in a manner that would garnish a practice guideline because no institution will spend the hundreds of millions of dollars for such a trial. Furthermore, these self-care strategies are harder to evaluate than a single drug is, given human individuality and variability. Moreover, in this epoch, many institutional review boards (IRBs) that approve research studies are likely to be a for-profit company (in approximately 70% of clinical research studies9Kaplan S. In clinical trials, for-profit review boards are taking over for hospitals. Should they? Available at:https://www.statnews.com/2016/07/06/institutional-review-boards-commercial-irbs/. Accessed June 17, 2021.Google Scholar). Thus, with profitability so front and center even in the review processes of research, you can expect burgeoning health care costs with little substantive benefits with notable exceptions like the COVID-19 vaccines. Isn't it time that medical societies and other professional organizations demand an end to the coziness between Pharma and the FDA? If you think so, ask your medical society or professional organization to take a strong stand on this. We need a wide swath of them to articulate the urgent concern that the status quo is unacceptable and demand change. If physicians and other clinicians do not demand change, nothing will happen. Don't wait for the politicians to act because they aren't going to do so. It is the patients who primarily suffer from the lack of proper oversight of this powerful industry as questionable drugs reach the marketplace. But clinicians also suffer when placed in the untenable situation such approvals create. So, thank you, Biogen, for pushing your drug across the finish line. Perhaps, you have accomplished the nearly impossible. No, I don't mean stopping dementia in its tracks. I am referring to removing the blinders from our postmodern eyes so acclimated to moral relativism and revealing what is really going on in much of today's pharmaceutical industry-FDA nexus. Change may be simpler than it appears. Why not have the FDA advisory panel's decision be decisive? That one change would expedite an improved drug-approval process and remove the economic and political pressures from the decision to which FDA executives are currently subjected. Time to shift the power equation away from the corporate and FDA executives and back to the medical scientists with expertise and a measure of objectivity in their respective subject. Time to relocate our moral compass, isn't it?

It has become well known that the severity of illness and lethality in corona virus disease 2019 (COVID-19) infection is strongly associated with exuberant inflammatory cytokine activation. Many factors may go into determining one’s preinfection inflammatory status including genetic constitution, presence of obesity, air pollution, exercise, and even the sauna usage. None is probably more important than the role of nutrition in determining one’s inflammatory status. This hypothesis, based on the evidence presented below, indicates that the baseline inflammatory state of an individual in the absence of disease is significantly influenced by the content of one’s diet, specifically whether it contains proinflammatory or anti-inflammatory foodstuffs. Furthermore, the hypothesis suggests that the severity of illness that develops when one contracts COVID-19, that is, whether it be a mild-to-moderate upper respiratory viral illness or a fatal acute respiratory distress syndrome (ARDS) or myocarditis death is dependent on that inflammatory state. I will contrast the Japanese diet and the Mediterranean diet both known for its anti-inflammatory qualities with the Western diet, known for its proinflammatory properties as well as refer to laboratory studies addressing lethal viral infections and COVID-19 risk factors. The Mediterranean diet containing specific polyphenols, lipids, and peptides with anti-inflammatory, antithrombotic, and antioxidant properties has been suggested as offering benefit regarding COVID-19 infectious severity as well through similar mechanisms.

The development of Alzheimer's Disease (AD) likely involves dysfunction in more than one extra-cranial organ system. AD appears to depend on several functional organ impairments that develops frequently during aging: lack of normal hepatic synthesis, defective detoxification of ammonia, gut microbiome dysbiosis, the development of insulin resistance, diminished adrenal production of dehydroepiandrosterone, nutrient depletion, impaired immune processes with persistent chronic neuro-inflammation, and persistent infectious processes are important components of this system-wide disorder. By reviewing these abnormalities in different organ systems, this review intends to suggest that clinical research into the prevention of dementia needs to take this interplay of organ system dysfunction into account. The design of therapeutic interventions needs to address dysfunction in more than one system at a time. We have singled out one aberrant signaling pathway, NF-kB, that seems common to several of the dysfunctional organ systems and suggest some potential interventions that may be effective when combined with others. Clinical research may need to shift from single factor interventions to studies that include multiple simultaneous interventions that restore health in multiple impaired organ systems in the aging human in order to avert future epidemics of AD.

In their review on Cardiovascular and Other Benefits of Sauna Bathing, Laukkanen et al1Laukkanen J.A. Laukkanen T. Kunutsor S.K. Cardiovascular and other health benefits of sauna bathing: a review of the evidence.Mayo Clin Proc. 2018; 93: 1111-1121Abstract Full Text Full Text PDF PubMed Scopus (72) Google Scholar observed that, in a previous population cohort study, they detected that frequent use of sauna bathing (4 to 7 times a week), showed a 66% reduction in dementia in Finnish men compared with those who had 1 session per week. Regarding a possible mechanism for such a dramatic effect, toxicologists have shown that sweating is a major means of excreting both organochlorine pesticides2Genuis S.J. Lane K. Birkholz D. Human elimination of organochlorine pesticides: blood, urine, and sweat study.BioMed Res Int. 2016; https://doi.org/10.1155/2016/1624643Crossref Scopus (39) Google Scholar and a variety of toxic metals including cadmium, lead, and aluminum.3Genuis S.J. Birkholz D. Rodushkin I. Beesoon S. Blood, urine, and sweat (BUS) study: monitoring and elimination of bioaccumulated toxic elements.Arch Environ Contam Toxicol. 2011; 61: 344-357Crossref PubMed Scopus (87) Google Scholar Surprisingly, substantially more of these toxic substances can be excreted via sweat than by urine, so increasing sweating became an effective means of enhancing excretion of toxic substances. Rea reported that the use of sauna therapy improved the condition of patients with confirmed exposure to mold (including stachybortrys), those who had mycotoxins (including ochratoxin) in their urine, and patients who had impaired neurocognitive testing or autonomic nervous system testing results and whose conditions were refractory to other treatments.4Rea W.J. A large case-series of successful treatment of patients exposed to mold and mycotoxin.Clin Ther. 2018; 40: 889-893Abstract Full Text Full Text PDF PubMed Scopus (7) Google Scholar In a review of the high prevalence of fatal dementia in Finland,5Eiser A.R. Why does Finland have the highest dementia mortality rate? Environmental factors may be generalizable.Brain Res. 2017; 1671: 14-17Crossref PubMed Scopus (13) Google Scholar I noted that the frequent presence of mold in residential buildings is one of the contributing factors there. Similar problems with moldy environments exist throughout the world and are certainly common in the United States and Canada, 2 other countries with very high rates of dementia. A prospective clinical trial of sauna therapy for patients with early dementia who test positive for mycotoxins, toxic metals, or organic toxins appears warranted and feasible. Although this type of therapy is one of several promising new approaches to preventing or treating dementia, it should not be overlooked simply because it is unconventional. In reply—Sauna Bathing and Healthy SweatingMayo Clinic ProceedingsVol. 94Issue 4PreviewWe thank Eiser and Brooks for their comments about the health benefits of sauna bathing. Regular sauna bathing has some beneficial effects on blood pressure, cardiometabolic biomarkers, arterial compliance, and cardiovascular function.1 Our prospective studies have shown that higher frequency and duration of sauna bathing are related to a lower risk of cardiovascular mortality, sudden cardiac death, stroke, hypertension, pulmonary diseases, and dementia.1-3 The feelings of relaxation and promotion of mental health and well-being associated with sauna sessions might be linked to the increased production of circulating levels of hormones such as endorphins. Full-Text PDF Effect of the Significant Loss of Salt in SweatMayo Clinic ProceedingsVol. 94Issue 4PreviewThe review article on the health benefits of sauna bathing in the August 2018 issue1 appeared comprehensive but failed to mention the effect of the significant loss of salt in sweat that occurs with this clearly beneficial event repeated on a regular basis. Wouldn't most— if not all—of these benefits occur simply as a result of regularly repeated substantial losses of salt from the body? Is this counter-balanced by the consumption of salt-preserved fish in Finland? Full-Text PDF Cardiovascular and Other Health Benefits of Sauna Bathing: A Review of the EvidenceMayo Clinic ProceedingsVol. 93Issue 8PreviewSauna bathing, an activity that has been a tradition in Finland for thousands of years and mainly used for the purposes of pleasure and relaxation, is becoming increasingly popular in many other populations. Emerging evidence suggests that beyond its use for pleasure, sauna bathing may be linked to several health benefits, which include reduction in the risk of vascular diseases such as high blood pressure, cardiovascular disease, and neurocognitive diseases; nonvascular conditions such as pulmonary diseases; mortality; as well as amelioration of conditions such as arthritis, headache, and flu. Full-Text PDF

Implantable cardioverter defibrillator (ICD) management complexities challenge the ethos of fully informed consent, particularly for the typically multimorbid elderly patient considering the device for primary prevention. The Heart Rhythm Society recommends providers include discussion on the potential need for later device deactivation or nonreplacement at the time of first implant, and to revisit this at appropriate intervals. The initial consent procedure could meet this standard by incorporating the future need to discuss further such issues when the recipient's clinical condition changes to such an extent that defibrillation would no longer be beneficial. At the time of obtaining consent, some patients may lack the will or capacity to make medically complex decisions when it would be necessary for healthcare surrogate decision-makers to contribute to this process. Ensuring an appropriate level of understanding and response may be enhanced by the use of information and decision aids. With improved communication regarding the nuances of ICD therapy, device eligible patients, and those close to them, will be empowered with a better understanding of the nature, benefits, and risks of ICD implantation, allowing them to make treatment decisions consistent with their values.

In recent years, advances in cardiac treatment have changed the outlook for many individuals with heart failure, notably when associated with a reduced left ventricular ejection fraction. The development of an array of evidence-based therapies has provided affected patients the expectation of a longer, more comfortable lifespan. Notwithstanding such progress, and the nascent potential of regenerative medicine, the finitude of human life is unavoidable, often manifest in a concluding phase characterized by a compression of illness and mortality in the burgeoning aged population. The progressive nature of heart failure and the existential vulnerability of this often frail clinical cohort, increasingly encountered across the continuum of medical practice, challenges internists and cardiologists to recalibrate the perception of optimal management. There is unequivocal evidence of the benefits of implantable cardioverter defibrillator (ICD) therapy for the primary or secondary prevention of sudden cardiac death in appropriately selected heart failure patients, especially those with underlying coronary artery disease. Acknowledging that mortality remains intrinsic to the human condition seems sometimes cast aside in this evolution from homo sapiens to homo technologicus. Discerning transition points in the heart failure disease trajectory when established therapies confer more maleficence than beneficence is central to the art of medicine and requires participation of both the internist and the subspecialist. Dilemmas frequently arise with respect to policies on ICD therapy in those subject to inexorable disease progression or surviving to very advanced age. Although treatment decisions should not be based primarily on chronological age, the net gain accruing from initiating such device therapy in older patients is unclear, the assumed benefit potentially attenuated by a relative increase in the incidence of noncardiovascular modes of death, including cancer and dementia. Evidence shows that about 50% of patients receiving an ICD after the age of 65 years may be dead or in hospice 5 years out from implantation.1Kramer DB Reynolds MR Normand SL et al.Hospice use following implantable cardioverter-defibrillator implantation in older patients: results from the National Cardiovascular Data Registry.Circulation. 2016; 133: 2030-2037Crossref PubMed Scopus (23) Google Scholar Similarly, the quantum of benefit following adoption of the oftentimes de facto default position in undertaking replacement of battery-depleted ICD generators in older patients experiencing decline from multiple morbidities is difficult to ascertain.2Kaufman SR Meuller PS Ottenberg AL Koenig BA Ironic technology: old age and the implantable defibrillator in US health care.Soc Sci Med. 2011; 72: 6-14Crossref PubMed Scopus (40) Google Scholar Some of these individuals, with clinician guidance, might choose to navigate their mortality to some extent in accepting the possibility of sudden death as an alternative to a protracted and burdensome demise by progressive heart failure or another fatal disease. The avoidable harms associated with device activity close to the end of life have been well described.3Kinch Westerdahl A Sjöblom J Mattiasson AC Rosenqvist M Frykman V Implantable defibrillator therapy before death. High risk of painful shocks near the end of life. Circulation . 2014; 129: 422-429Crossref PubMed Scopus (85) Google Scholar Elucidating such preferences can be difficult, and an unspoken understanding may come into play among patients and clinicians to shy away from this uncomfortable discourse. Some patients have little comprehension of the reality of their disease state or may be unwilling to accept this as conceding mortality conflicts with their innate survival instinct. At times, clinicians are fearful that openly discussing end-of-life care, including reference to ICD deactivation or nonreplacement, may undermine a long-established bond of trust with their patients. In reality, having that conversation with a health professional familiar to them helps patients and families avoid feeling abandoned, bolsters shared decision making in the formulation of agreed treatment plans, and fosters the development of coping strategies to address their physical and psychological symptom burdens. This approach requires sensitivity to patients’ psychosocial needs, as well as to their cultural norms and values. Discussion on device management should not be deferred until the patient is in the throes of a clinical crisis or the final phase of his or her illness. Rather, this interchange with the patient's internist and cardiologist should take place at regular intervals along the disease course, conversations on the continuing utility of ICD therapy or matters relating to end-of-life care being normalized as part of a clinical dialogue. This will better ensure that treatment strategies remain consistent with patients' changing preferences.4Rich MW Chyun DA Skolnick AH et al.American Heart Association Older Populations Committee of the Council on Clinical Cardiology, Council on Cardiovascular and Stroke Nursing, Council on Cardiovascular Surgery and Anesthesia, and Stroke Council; American College of Cardiology; and American Geriatrics Society. Knowledge gaps in cardiovascular care of the older adult population: a scientific statement from the American Heart Association, American College of Cardiology, and American Geriatrics Society.Circulation. 2016; 133: 2103-2122Crossref PubMed Scopus (111) Google Scholar The informed consent process provides a forum to facilitate this interaction. Valid informed consent is founded on the impartial transfer of comprehensive information describing the benefits and risks of any proposed clinical intervention, presented in a manner that patients and families can readily understand. Unfortunately, the standard ICD consent process tends to concentrate on short-term periprocedural risks rather than broader device-related issues or those that may emerge later in life. Although it might be inappropriate to concentrate on end-of-life concerns at the time of consent for the de novo ICD implant, embedding this topic within a proposition that the currently perceived benefits of this device therapy are conditional, and may be altered by changing circumstances, establishes this connection. Cognitive impairment is a frequent accompaniment of aging, and bundling advance care planning with the consent process affords patients and their next of kin the opportunity to consider and document their choices regarding cardiovascular care and other treatment options against any subsequent loss of intellectual capacity.5Kirkpatrick JN Hauptman PJ Goodlin SJ Bundling informed consent and advance care planning in chronic cardiovascular disease: we need to talk.JAMA Intern Med. 2015; 175: 5-6Crossref PubMed Scopus (17) Google Scholar Such matters have been the theme of a recent review, primarily focused on improving the consent process pertinent to ICD-eligible elderly patients through an enhanced communicative and reflective process.6Eiser AR Kirkpatrick JN Patton KK McLain E Dougherty CM Beattie JM Putting the “informed” in the informed consent process for implantable cardioverter-defibrillators: addressing the needs of the elderly patient.Pacing Clin Electrophysiol. 2018; 41: 312-320https://doi.org/10.1111/pace.13288Crossref PubMed Scopus (4) Google Scholar Decision making in older individuals tends to be more intuitive than deliberative, and they are prone to accept the counsel of authority figures such as clinicians. Thus, advice from those responsible for their care may significantly influence the receivers’ views. Importantly, decision making for ICD therapy recently has been shown to be subject to cognitive bias favoring implantation.7Matlock DD Jones J Nowels CT Jenkins A Allen LA Kutner JS Evidence of cognitive bias in decision making around implantable-cardioverter defibrillators: a qualitative framework analysis.J Card Fail. 2017; 11: 794-799Abstract Full Text Full Text PDF Scopus (18) Google Scholar The background to this is likely to be multifactorial. Cardiovascular societal guidelines represent structural models of acceptable care, and clinicians might be inclined to nudge patients toward compliance with such nationally endorsed treatment paradigms to optimize therapy, as well as a safeguard against possible criticism of their practice performance. However, older patients were under-represented in the trials underpinning guideline development, and in real-life clinical practice the situation is more nuanced. For that reason, it is important to frame ICD decision making against the multifaceted totality of health conditions likely to impact well-being and prognosis, many of which fall within the scope of general internal medicine. Thus, these issues are not confined to the realm of cardiac electrophysiology teams; instead, they are relevant to all health professionals responsible for the care of those with acute or chronic heart failure. A multidisciplinary approach is required with the need to ensure consensus building across a range of clinical stakeholders. Good coordination and information exchange are essential to prevent care fragmentation, and the appointment of a designated interlocutor may be beneficial in facilitating consistency of communication with the patient and family. The primary care provider, whether internist, geriatrician, or family physician, may be best placed to undertake this role, and also support patients and families in decision making (Figure). It is important that systems of care are in place to document the presence and status of devices, to provide staff training in their management, and to ensure the ready availability of expertise and the means to manage ICD problems, device reprogramming, and deactivation across a variety of care sectors. Given the changing demography toward an aging population, quandaries on initiating ICD therapy or the need to consider nonreplacement or deactivation will more frequently arise in clinical practice. As responsible stewards of good medical care, clinicians need to be aware of the difficult judgment calls that may arise in relation to these implants, and to ensure that individualized treatment plans are in place to support the complex needs of this growing and increasingly susceptible elderly population.