This chapter looks at Alzheimer’s disease, the most common cause of dementia. Incidence and prevalence figures are reviewed, along with an explanation of the two abnormal proteins involved in the development of the disorder, and the ‘amyloid cascade’ hypothesis. Cognitive assessment of Alzheimer’s disease is considered in terms of where this fits within the diagnostic process and diagnostic criteria. The bulk of the chapter focuses on the typical form of Alzheimer’s disease, and the chapter concludes with discussion of some atypical variants, such as posterior cortical atrophy (PCA), logopenic primary progressive aphasia (lvPPA), and frontal variant.

This chapter describes pseudoscience and questionable ideas related to neurocognitive disorders. The chapter opens by discussing facts that rebut pervasive myths and pseudoscience. Provider barriers to diagnosis and patient education are also considered. The chapter elaborates on the problems associated with persistent searchers for a cure and the hype of pharmacological interventions. The chapter closes by reviewing research-supported approaches.

There are many things we can do to reduce the risk of Alzheimer’s, including high levels of physical and mental activity, avoidance of hypertension, head injury, high-fat, low-fiber diet, smoking, etc. These risk factors have been documented by decades of human and animal research and have allowed for the development of protective lifestyle measures that lead to a lowered risk of disease. These lifestyle factors apply to all phases of the life cycle, including childhood, as well as late life, and contribute to diminishing the risk of getting dementia, as well as delaying its onset and speed of progression. In the applications section there is a comprehensive discussion of these factors that will lower the risk of neurodegenerative diseases, improve our resilience so that function can be maintained despite development of disease, and enhance the capacity of all of the four reserve factors: cognitive, physical, psychological, and social. The actions recommended are all also valuable for lowering the risk of heart disease and stroke as well as some forms of cancer. Enhancing these reserve factors will enable you to augment your enjoyment of the opportunity aging presents.

Memory and cognition are critical parts of who we are. Our capacity for recall allows us to use past experience to guide our actions. Our cognitive abilities allow us to monitor events and evaluate plans for action. In aging there are varying degrees of decline in cognitive function which begin in the 30s and are quite common. They are not a disease and are accompanied by the growth of wisdom which can negate the influence of age-related memory changes. Memory losses with aging can be avoided with consideration of the importance of attention for memory. The role of forgetting as a normal activity of the brain is critical. It is necessary to realize that the influences of aging and age-related disease (such as Alzheimer’s) on brain function are not determined only on the processes of aging and disease -- the effect of these processes on our performance abilities depends upon our cognitive, physical, psychological, and social reserves. We all need to enhance these reserve capacities to decrease the influence of the aging process and developing brain disease on our function. This chapter reviews the functions of memory and how losses that accompany aging can best be managed.

For most of human history few people got to be old. Older persons are not as well pepared to face stresses as younger persons because of evolutionary factors. So, it is necessary for older persons to consider the effects of their lifestyle choices on their ability to age successfully. Awareness of these factors is important for our appreciation of the impact which our activities have on our aging. For most of the past 100,000 years of human history we were living in a different environment than the one we have today. The genes we have now were chosen through natural selection because they enhanced the survival of our ancestors who were living in these different environments. This view provides valuable insights into the role environmental factors have in determining maintenance of function with aging. This chapter presents the vital perspective that what we do affects the accomplishment of our goals for aging. These goals must go beyond survival and avoidance of disease and also strive for maintenance of the highest level of fitness and resistance to loss of function (reserve capacities) so that we can resist the declines with aging, as well as the challenges which inevitably occur.

The neurodegenerative diseases Alzheimer’s, Parkinson’s, frontotemporal lobar degeneration, Lewy body disease, and amyotrophic lateral sclerosis are all age-related and caused by genes in only 1-10 percent of cases. Dementia describes a syndrome in which there are cognitive difficulties including impaired memory, judgment, planning, language, and other deficits. Alzheimer’s is the commonest cause of dementia. In the brain in neurodegenerative diseases there is abnormal folding of proteins creating thread-like filaments called amyloid. There is also abnormal activation of inflammation with free radicals and harmful cells. There are things we can do regarding diet and other actions that can lower the risk of developing neurodegenerative diseases with aging. High levels of physical and mental activity throughout life along with attention to a healthy plant-based diet can enhance our four reserves and diminish amyloid deposition and overactivity of the immune system. Lifestyle measures can also protect us from the effect of brain pathologies that may develop. There are many causes of memory loss other than Alzheimer’s disease which are completely reversible when properly recognized.

During stressful experiences the endocrine and brain systems involved have distinct neurochemical processes which enhance the power of the memory. Post-traumatic stress disorder is due not only to psychological factors, but neurochemical and evolutionary ones as well. It is valuable for people who have experienced stressful life events to realize that the power these memories have is not entirely psychological. It is in a deeply developed neural pathway created and preserved in the brain in a resilient fashion. Understanding that this is not a question primarily of “getting over It,” but rather “learning to live with it” may help. Stress has many effects on the brain and the body. Bolstering your physical reserves with physical activity, effective sleep, and a healthy diet enhances the ability to deal with stress. The experience of stress involves not only the brain, but also the body’s cardiovascular system and other parts. It is best if the work of dealing with stressful factors is accomplished early, before the achlyievement of great age. Several strategies can help to deal with stress: restful sleep, meditation, diet, cognitive and physical exercise, and avoidance of toxins.

Humans are born with 23 pairs of chromosomes and 20,000-25,000 genes. Genes are sequences of nucleotides (the basic structural unit of nucleic acids) that code for the amino acid sequence of proteins. It is important to know that the genetic information contained in the chromosomes does not directly determine what happens to us. Rather, the genes provide information about what can be done. What actually happens is an interaction between the genes and the environment. That is, how we live influences the action of our genes - the context is supreme. Genes are the cause of Alzheimer’s in only 1 percent of cases. A form of the apolipoprotein E gene called e4 increases the risk of getting Alzheimer’s by 2-10 times, depending on the dose of the gene (one or two copies). However, many persons with the risk form of the gene are not affected. In the majority of cases of Alzheimer’s there is a key interaction of genes and environmental factors which determines who becomes affected and at what age. Although genetic testing can be done to predict risk it is not currently recommended, as genetic tests are not needed to have commitment to preventive measures.

Understanding of the magnificence and uniqueness of the brain is important for realizing the goals of aging. We must respect its central role in our lives and work to see what we must do to enhance its health throughout life. The brain is precisely responsive to activities and its structure is changed by learning. It is also uniquely sensitive to damage and has a limited capacity for repair, compared to other body parts. What we do changes the brain, and the nature of our mental activities modifies the ability of the brain to resist declines with aging and disease. Cognitive involvement in educational, occupational, and recreational tasks throughout life, as well as physical activities, helps to enhance resistance to decline with age and diseases such as Alzheimer’s. This chapter examines how the four reserves (cognitive, physical, psychological, and social) help to maintain brain function with age. Recent research has uncovered the influence of our partner microbes in the gut on learning, memory, and age-related diseases of the brain. These developments beautifully illustrate how there are things we can all do to maintain brain function with age.

Drug development teams once focused on study design and company priorities, must now expand their efforts to include the professional, patient, and policy advocacy landscape. These groups are essential to setting research and policy priorities and are influential voices in securing funding at the federal, state, and private investment levels, as well as input to optimize the probability of success of clinical development programs. Professional associations and patient advocacy groups also enable collaboration across industry to address challenges that require resources beyond any one entity. This is particularly relevant to complex conditions such as Alzheimer’s disease.

The assessment of cognition is a key feature of study participant selection, evaluation, and characterisation in Alzheimer’s disease (AD) clinical drug trials. Measurement science requires using reliable, valid, and sensitive instruments for these purposes and typical trial measures, such as the ADAS-cog and MMSE, show adequate levels of reliability. Due to the absence of adequate indices of working memory, attention, and executive function, they cannot be considered valid tests. Further, scoring conventions and range restrictions limit their sensitivity. Hence a number of innovative solutions have been proposed and tested, with varying degrees of success. In this chapter we review critically cognitive measures such as the Neuropsychological Test Battery, the Repeatable Battery for the Assessment of Neuropsychological Status, and digital cognitive tests, such as those drawn from the CogState, CANTAB, and CDR systems. These measures are all considered with specific regard to issue of validity, assay sensitivity, and clinical relevance. We propose a methodology for establishing proof of concept for new chemical entities to rescue or preserve cognition in individuals living with AD.