Alzheimer’s disease (AD) was first described more than 100 years ago. It was and still is characterized by the presence of amyloid plaques and neurofibrillary tangles (NFTs). These pathologic and histologic changes continue to define the disease and are the focus for current research. The brain changes can be correlated with biomarkers, imaging, and cognitive testing. Mild cognitive impairment (MCI) may represent an important step toward the development of dementia but may also represent a nonpathologic state. The long prodromal period before clinically detectable declines in cognition offer opportunities for intervention on multiple levels. The goal of future therapies is to decrease the accumulation of toxic proteins in the brain and prevent decline in cognitive function.
Given the pace at which the world’s population is aging, this complex and heterogeneous disease may well be the next worldwide epidemic. Alzheimer’s disease and MCI present serious challenges to the insurance industry. Knowledge of progression factors creates opportunities for risk stratification. A full understanding of potential future epidemiologic and treatment trends should form the basis for insurer actuarial modeling and product development planning.
IntroductionAlthough Alzheimer’s disease (AD) was first described more than a century ago, its complexity and heterogeneity have made early diagnosis and treatment elusive, and its pathogenesis remains uncertain. Research-based understanding of the disease, specifically the interplay between beta-amyloid, phosphorylated tau, and small vessel disease of the brain, biomarkers and imaging techniques that aid in diagnosis of dementia, and MCI definition and risk factors for disease will all be discussed. In addition, potential areas for disease modification through medications will be covered.
Aging Population Worldwide Translates Into Potential Dementia Epidemic
AD is the most common form of dementia, and epidemiologists predict it will be “the” epidemic of the 21st century. For asymptomatic individuals, the lifetime risk of developing AD at age 65 is 10.5%1. The world’s population is expanding in such a way that the highest risk cohort for developing the disease is also going to be the fastest-growing segment of the world's population over the next 30 years. By 2050, the U.S. Census Bureau is predicting there will be 88 million Americans over age 65. The world’s over-65 population is projected to swell to 1.6 billion by then, as well. Additionally, Asian and South American countries will all experience a quadrupling of individuals over 80 years of age2.
AD’s Long Preclinical Course
Alois Alzheimer, M.D., described the clinical symptoms and histologic changes in the brain of a woman with presenile dementia in 1906. The histologic features Dr. Alzheimer identified in the autopsy – amyloid plaques and neurofibrillary tangles – remain the defining features of the disease and the focus of AD research3.
The specific protein responsible for the formation of amyloid plaques was identified 30 years ago4 and is the product of the cleavage of the amyloid precursor protein (APP), which is tethered to the cell membrane for reasons still not clear. Once APP is cleaved into discrete fragments by secretases, the beta amyloid protein is cut at both ends of the molecule and is released to the space outside the neuron. It then begins to aggregate with other beta-amyloid fragments, forming oligomers, which are believed to be the core components of the amyloid plaques. Over time, other proteins are added to the misfolded oligomers and conglomerate to form insoluble plaques4. Accumulation of amyloid plaques may precede clinical symptoms by 20 years5.
The second histologic feature, the neurofibrillary tangle, is composed of tau protein and is a component of the microtubular system in neurons. The function of tau protein is to provide structural stability for axons and transport nutrients and neurotransmitter-containing vesicles, from the neuronal cell body to the axon4. The disruption of this microtubular system begins a destructive process that is characterized by accumulation of hyper-phosphorylated tau and the aggregation of tau fibrils, which eventually forms tangles within the cell that lead to synaptic dysfunction. Synaptic dysfunction and loss are the findings most closely associated with cognitive decline in brains of those with dementia6, 7. This stage of the disease is characterized by progressive cognitive decline that correlates with a clinical diagnosis of MCI transitioning to dementia7. Read More +