Alzheimer's Disease: Integrative Geriatric Medicine

Alzheimer Disease Mikhail Kogan, MD and Bianca Palushaj, MD Alzheimer disease (AD) manifests as a progressive cognitive decline a ecting an individual’s memory, language, and social functioning. Later stages lead to complete dependency for basic activities of daily life and prem...

Alzheimer Disease Mikhail Kogan, MD and Bianca Palushaj, MD Alzheimer disease (AD) manifests as a progressive cognitive decline a ecting an individual’s memory, language, and social functioning. Later stages lead to complete dependency for basic activities of daily life and premature death. An estimated 47 million people have AD worldwide, including more than 5.3 million people in the United States alone. Approximately 500,000 people die of AD every year in the United States, making it sixth leading cause of death.1 AD is the most common form of dementia, comprising 70%to 90% of all cases. The annual cost of dementia care in the United States is thought to be between $150 and $215 billion. In 2015, Alzheimers Association estimated the global cost of dementia care, including informal care from family and caregivers, at over $800 billion. Care costs in Europe and North America accounted for 70% of this burden.2,3 For decades, dementia has been one of the most expensive diseases in the United States in terms of total costs to the economy; the annual cost of formal dementia care exceeds the direct health care expenditures for heart disease or cancer.4 It is projected that by 2050, nearly 14 million Americans will have dementia, including 50% of those older than 80 years.1 Pathophysiology Scientists have long understood that AD is caused by brain lesions known as plaques—beta- amyloid clusters that build up between nerve cells. As plaques accumulate, they block cell-to- cell signaling and trigger an in ammatory response from the brain’s immune system that kills nerve cells. Twisted strands of dead nerve cells, known as tangles, also provide stimuli for in ammation. In ammation is clearly an important contributor to the pathological process of AD. A seminal paper entitled, “In ammation and Alzheimer’s Disease,” describes a complex web of interacting in ammatory mediators in the periphery and in the AD brain.5 High plasma levels of C-reactive protein (CRP) in midlife and elevated interleukin-6 in old age are strong predictors of AD risk.5–7 Neurons contain large amounts of metabolically active mitochondria, and synaptic activity depends on good mitochondrial function. A recent theory proposes that accumulation of beta-amyloid damage may cause mitochondrial dysfunction and memory loss in AD 8,9 (see Tables 12.1 and 12.2 for a summary of risk factors). Table 12.1 Risk Factors of Alzheimer Disease (AD) Risk Factor Comments Advanced age Advanced age is the most important risk factor in AD; 10% of persons who are 65 years old develop AD. The incidence at 85 years is as high as 50%.161 APOE-ε4 Individuals with two APOE-ε4 genes are at least eight times more likely to develop A. The APOE4 gene exerts its maximal e ect on people in their 60 s.162 Body weight U-shaped risk distributionobesity likely the result of in ammatory and insulin resistance factors and underweight because of poor nutritional factors.163–165 Cardiovascular disease (CVD) Hypoperfusion leads to mitochondrial dysfunction and neuronal death.166 Diabetes and insulin resistance In AD, brain glucose usage and energy production are impaired.167 Diabetes is a risk factor not only for strokes and vascular dementia but also for AD.168 Family history of AD Three- to four-fold increased AD risk among those with rst-degree relatives with the disease.169 Education Higher education is associated with lower risk of AD later in life.170 Glutathione (GSH) low Numerous studies have shown low neuronal GSH level in patients with AD.99–101 fl fl fl fl fl ff fl ff fi  Hypertension Numerous studies have linked midlife hypertension to AD risk.67,171,172 Hormonal imbalances Low estrogen173 Cortisol deregulation52,53 Low DHEA and pregnenolone are common in AD patients Hypothyroid and can cause dementia-like symptoms Methylation defects MTHFR mutations and high homocysteine levels—see text Minimal cognitive impairment (MCI) 10%15% will progress to dementia. Patients with MCI function normally in daily activities requiring nonmemory cognitive abilities such as thinking, understanding, and decision making.174 Sleep apnea One of the more recently found factors, likely the result of nocturnal hypoxia.175 Smoking Surprisingly mixed ndings; nicotine may have protective e ects making association less clear.176 Chronic stress See text Toxicities Mercury, mold, lead, organophosphates, and others—see text Traumatic brain injury (TBI) AD risk is doubled in patients who have experienced TBI early in life. Table 12.2 Nutritional and Minerals/Vitamins Risk Factors for Alzheimer Disease (AD) Consuming high-glycemic index diets High-glycemic foods are well known to have proin ammatory e ects; this is addressed in detail in a separate chapter. Low omega-3 dietary content See text for details. Low vitamins B12 and B6 Well-known risk factors clearly associated with AD risk.177 Niacin (B1) de ciency Causes WernickeKorsako : dementia, sight and muscular coordination problems, confabulations, and hallucinations Thiamine (B3) de ciency Causes pellagra: dementia, diarrhea, and dermatitis Selenium de ciency Studies have suggested that low selenium levels increase AD risk.178,179 One study demonstrated a direct correlation between plasma selenium concentration and cognitive function.180 Vitamin E insu ciency Numerous studies have associated low vitamin E levels with AD, but the data are mixed.181,182 Copper excess Studies have shown free copper, not bound to ceruloplasmin, is increased in patients with AD and correlates negatively with cognition.183,184 Dietary copper is in organic form and is processed by the liver to bind to ceruloplasmin. In contrast, inorganic copper from supplements and from un ltered drinking water in areas where copper pipes are used can bypass the liver and enter metabolism as free copper readily delivered to and deposited in the brain.185 Zinc insu ciency Zinc intake has been thought to decrease available copper and may therefore have a protective role. In a recent systematic review, low zinc intake was attributed to AD risk.186 Vitamin D de ciency A meta-analysis of 37 studies found that adults with low serum vitamin D concentrations (