Dementia is a growing public health concern, with an estimated prevalence of 57 million adults worldwide. Alzheimer’s disease (AD) accounts for 60-80% of the cases. Clinical trials testing potential drugs and neuroprotective agents have proven futile, and currently approved drugs only provide symptomatic benefits. Emerging epidemiological and clinical studies suggest that lifestyle changes, including diet and physical activity, offer an alternative therapeutic route for slowing and preventing cognitive decline and dementia.
The Global Burden of Dementia and the Role of Lifestyle Medicine
With age being a prime risk factor for dementia and the rising life expectancy, the global burden of this devastating condition is expected to increase exponentially. According to the Global Burden of Disease (GBD) 2019 study, the disability-adjusted life-years (DALYs) of Alzheimer’s disease (AD) and other dementias is 4.3% of total DALYs (2.02-9.7%) globally and 5.3% of total DALYs (2.66-10.86%) in the United States for individuals 70 years old (Institute for Health Metrics and Evaluation GBD2019). The number of individuals with dementia is expected to increase from 57.4 (95% CI 50.4-65.1) million cases globally to 152.8 (130.8-175.9) million cases from 2019 to 2050 (1). AD is the most common type of dementia, accounting for at least two-thirds of cases of dementia in patients ages 65 and older (2).
According to the World Health Organization (WHO), AD is a progressive disease divided into three clinical stages. The first stage is mild cognitive impairment (MCI), an intermediate stage between normal cognitive functioning and frank AD dementia. MCI affects individuals’ memory with or without affecting their daily lives (3). Examples of MCI include losing personal belongings and forgetting to attend appointments. MCI may persist throughout life or progress to mild, moderate, and advanced AD forms. In other words, MCI can be considered a precursor of AD.
Currently, there are no cures for AD. Several drugs have been investigated as neuroprotective agents for AD. For example, cholinesterase inhibitors, which increase acetylcholine availability, may reduce the progression of cognitive decline; however, there is no substantial evidence that these treatments are neuroprotective or slow the course of the disease (4, 5). Another studied drug, memantine, is an uncompetitive antagonist of glutamate N-methyl-D-aspartate (NMDA) receptors, which plays a role in learning and memory (6, 7). Excessive NMDA stimulation may lead to neurotoxicity (8). Memantine may block the pathological stimulation of NMDA receptors. A literature review, however, suggests that the effects of memantine may be minor and are often not clinically significant (9). Another line of drugs, monoamine oxidase (MAO) inhibitors, can potentially deplete the production of neurotoxic compounds (10). Recently, aducanumab and lecanemab, antibodies directed against amyloid beta (Aβ), the main component of amyloid plaques, have received much attention based on promising results in a meta-analysis of findings from several clinical trials (11). Nevertheless, in a recent lecanemab trial, the clinical benefit was moderate and associated with significant adverse events (12, 13). Certain cholesterol transporters have also been linked to amyloid transport into the brain; therefore, these pathways are also considered potential therapeutic targets (10). Strikingly, as of January 2022, there were 143 potential therapeutic agents in the AD drug development pipeline (14). Unfortunately, most clinical trials have proven futile, and some drugs only alleviate symptoms.
AD is a highly complex disease comprising multiple genetic and environmental factors, some of which are modifiable. Genetically, there are monogenic and polygenic forms of the disease, with the latter accounting for more than 95% of the cases (15). In other words, most AD cases are not explained by a single genetic cause but are rather influenced by multiple genes in combination with lifestyle and environmental factors. Approximately one-third of AD cases could be related to low educational levels, smoking, alcohol use, depression, diabetes, hypertension, obesity, and physical inactivity (16). Recent advances in network medicine have revealed common molecular and pathophysiological mechanisms shared between AD and other comorbid diseases (17).
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A hypothesis for the development of AD has been proposed based on genomics (GWAS, whole-genome/exome sequencing, targeted gene sequencing, and functional genomics), transcriptomics (microarrays and RNA-seq), radiomics (brain imaging), pharmacogenomics (drug-target network and drug-gene signatures), and interactomics (protein-protein interactome) that identifies six endophenotypes, including amyloidosis, tauopathy, neuroinflammation, mitochondrial dysfunction, vascular dysfunction, and lysosomal dysfunction (18). The risk for and progression rate of most, and perhaps all, of these AD endophenotypes should respond positively to healthy habits associated with lifestyle medicine, including eating well, being physically active, getting enough good quality sleep, being socially engaged, avoiding exposure to air pollution and second-hand tobacco smoke, quitting smoking, and reducing alcohol drinking (19, 20).
Lifestyle medicine focuses on six pillars of a healthy lifestyle: nutrition, exercise, stress management, social support, sleep, and avoiding risky behaviors, such as smoking tobacco. Adherence to the six pillars is expected to reduce the risk of Alzheimer’s disease.
The Link Between Comorbidities and Alzheimer's Disease
AD is associated with a wide range of comorbidities (17). T2D and cardiovascular disease are among the most common comorbidities with the most negative impact in AD patients. T2D is the most prevalent metabolic disorder, affecting an estimated 462 million individuals globally (21). In both men and women, having T2D results in approximately a 60% higher risk of developing dementia than those without T2D (22). For this reason, AD is often referred to as type 3 diabetes. Insulin resistance negatively impacts cognition (23). Excess insulin leads to the availability of glucose and fats, which may increase reactive oxygen species that can negatively affect brain health (24).
Healthcare providers should therefore assess the risk for MCI and AD in patients with T2D, cardiovascular disease, renal disease, and other complications. For instance, the Mini-Mental Status Exam (MMSE) and the Montreal Cognitive Assessment (MoCA) provide valuable information about the patient’s cognitive status that the physician may use to guide them in delivering specific lifestyle changes that the patient might implement. One crucial modifiable risk factor for AD is a healthy eating pattern. Evidence from epidemiological studies suggests that certain nutrients that reduce the risk of T2D may have protective effects against AD (25).
Although the molecular mechanisms that link T2D and MCI with AD are not fully understood, several studies have revealed shared pathways and characteristics between the two diseases. For example, amyloid and tau proteins are common molecular pathological features in AD and T2D (27). In addition, transcription factors, which switch genes on or off, regulate the expression of genes similarly in AD and T2D (28). Notably, inflammation, insulin and glucose metabolism, and the phosphatidylinositol 3-kinase and protein kinase B/Akt (PI3K-AKT) play a pivotal role in developing T2D and AD (28). Brain degeneration is a pathophysiological change shared between MCI, AD, and T2D (29). Specifically, medial temporal lobe atrophy is a common finding in MCI and AD (30). Neuroimaging studies have reported that diabetes is also associated with smaller total cerebral brain volumes and a decline in executive function in individuals without cerebrovascular disease or dementia (31, 32). In addition, chronic hypovolemia, most likely due to dehydration, is present in diabetes, hypertension, and AD (33). Furthermore, total body water decreases as we age (34). Thus, drinking more water would rehydrate the brain (35). Increasing evidence also suggests a link between AD and atherosclerosis, the buildup of fats in the arteries, which can result from chronic poor dietary choices.
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In summary, T2D, cardiovascular disease, and AD share several mechanistic molecular pathways that lead to disease. The pathways present potential therapeutic targets that may reduce the risk of these chronic diseases. Nutrient-rich eating patterns are expected to reduce the risk or slow the progression of dementia by reducing the risk of T2D and cardiovascular disease.
The Influence of Diet and Dietary Components in Dementia
Studies suggest that metabolism generally slows down during aging and may exacerbate AD (37). Eating a nutrient-rich diet throughout life, beginning at a young age, contributes positively to healthy aging. Multiple challenges to eating a nutritious diet arise with age due to a combination of physiologic, social, environmental, economic, and physical barriers (38). Lifelong adherence to healthy dietary patterns that include whole, unprocessed plant foods, such as those described below, may reduce the risk of dementia later in life (39-41).
Eating more nutrient-rich whole foods in a healthy diet reduces the risk of dementia. Eating more ultra-processed foods in a Western diet increases the risk of dementia (42).
The Mediterranean Diet: A Lifestyle Approach to Brain Health
The Mediterranean diet is an eating pattern influenced by the cuisines surrounding the Mediterranean Sea. Key features of the diet include ample plant-based, unprocessed foods, including whole grains, fresh vegetables, beans, legumes, seeds, extra virgin olive oil, nuts, and fruits (41, 43). Foods such as fatty fish, moderate amounts of lean poultry, low-fat dairy products, and red wine are often part of a Mediterranean diet. The Mediterranean diet limits butter/cream, red meats, processed foods, sweets, refined oils, and fried foods (44). More than an eating pattern, the Mediterranean diet can be considered a lifestyle.
Adherence to the Mediterranean diet has been shown to improve health outcomes across many diseases, including cognitive decline and neurodegeneration (47, 48). Evidence from molecular and epidemiological studies supports a neuroprotective effect of the Mediterranean diet in cognitive decline and dementia. For instance, a comparison of gene expression data from the blood of individuals with dementia and those who followed the Mediterranean diet were inversely correlated and showed that consuming omega-3 fatty acids from foods such as nuts, olive oil, and fish may help reduce the risk of dementia (42). Indeed, foods common to a Mediterranean-style diet have anti-inflammatory, antioxidant, and neuroprotective properties (49). For example, consuming long-chain omega-3 fatty acids from fish and polyphenols from fruit, red wine, and tea have positively affected brain health and cognition in older adults (50). Recently, longitudinal analysis derived from individuals without dementia in the Alzheimer’s Disease Neuroimaging Initiative (ADNI) revealed that long-term use of omega-3 fatty acid supplements exhibited a 64% reduced risk of AD (51).
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Several clinical trials have found positive health outcomes of the Mediterranean diet on brain health in several populations. For instance, a randomized controlled trial (RCT), the PREDIMED-NAVARRA study in Spain of 522 individuals at high vascular risk, showed that participants allocated to the Mediterranean diet displayed higher MMSE and Clock Drawing Test (CDT) scores compared to those on a low-fat diet after 6.5 years of nutritional intervention (52). Similarly, a trial using a randomized subgroup of 285 participants from the same population cohort showed that a Mediterranean diet supplemented with extra virgin olive oil improved cognitive function compared to a low-fat diet after 6.5 years of nutritional intervention (53). These results were obtained after adjustment for risk factors such as sex, age, education, physical activity, body mass index, diabetes, hyperlipidemia, smoking, and hypertension. A prospective French cohort study of 1,410 adults (≥65 years) found that higher adherence to a Mediterranean diet was associated with slower MMSE cognitive decline but not with risk for incident dementia over a 5-year period (54).
In contrast, some RCTs have not found beneficial effects of the Mediterranean diet on cognitive functions. For instance, the MedLey study conducted in Australia, which allocated participants to a Mediterranean diet, did not show improvement in cognition among healthy older adults (56). This cohort included 137 men and women randomly assigned to either a Mediterranean diet or control diet for 6 months. In this regard, the duration of this trial was shorter compared to previous trials reporting positive outcomes. A systematic review and meta-analysis of 5 RCTs determined that the effects of the Mediterranean diet on cognition and brain morphology and function were mainly non-significant with small effect sizes (57), except the significant associations of 3 composite cognitive scores in memory, frontal, and global function obtained from PREDIMED trial (52, 53).
In addition to cognitive functions, several groups have investigated the effects of the Mediterranean diet on brain structure and neuropathological features of AD. For example, a higher Mediterranean diet adherence score was associated with lower amyloid beta accumulation in 77 cognitively normal subjects from the Australian Imaging Biomarkers and Lifestyle Study of Aging after a 3 years period (58). The group of cognitively normal subjects was described as Aβ accumulators suggesting these patients were likely to develop AD. Other investigations have explored the relationship between the Mediterranean diet and structural neuroimaging markers. For example, a cross-sectional study of 52 cognitively normal individuals reported that those with a higher adherence to a Mediterranean diet.
Dexter Holland: A Multifaceted Approach to Health and Wellness
Dexter Holland, the frontman of the Offspring, embodies a multifaceted approach to health and wellness that extends beyond diet and exercise. His dedication to both his music career and his academic pursuits highlights the importance of mental stimulation and lifelong learning in maintaining cognitive function.
Holland's pursuit of a Ph.D. in molecular biology, with a focus on HIV, demonstrates his intellectual curiosity and commitment to understanding complex scientific concepts. His ability to balance his music career with his academic studies suggests a high level of discipline and time management skills, which are essential for maintaining a healthy lifestyle.
In addition to his intellectual pursuits, Holland is also physically active. He participates in 70.3 half-Ironman triathlons and typically trains five days a week during the season. This level of physical activity is known to have numerous benefits for brain health, including improved cognitive function and reduced risk of dementia.
Holland's approach to health and wellness aligns with the principles of lifestyle medicine, which emphasizes the importance of nutrition, exercise, stress management, social support, sleep, and avoiding risky behaviors. By incorporating these principles into his daily life, Holland is setting an example for others to follow in their pursuit of optimal health and well-being.
Overcoming Challenges and Maintaining a Healthy Lifestyle on Tour
Holland acknowledges the challenges of maintaining a healthy lifestyle while touring with the Offspring. He recognizes the importance of getting enough sleep, eating nutritious meals, and avoiding excessive alcohol consumption. He also emphasizes the need to prioritize physical fitness, even when on the road.
Holland's experience highlights the importance of making conscious choices to prioritize health and wellness, even in challenging circumstances. By developing strategies for overcoming obstacles and maintaining a healthy lifestyle, individuals can improve their overall well-being and reduce their risk of chronic diseases, including dementia.
The Importance of Passion and Precision in All Aspects of Life
Holland's success in both music and science can be attributed to his passion and precision in all aspects of his life. He approaches both his music and his scientific research with a high level of dedication and attention to detail. This commitment to excellence has enabled him to achieve success in multiple fields.
Holland's story serves as an inspiration to others who may be pursuing multiple interests or facing challenges in their personal or professional lives. By embracing passion and precision, individuals can overcome obstacles and achieve their goals, while also maintaining a healthy and fulfilling lifestyle.