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Alzheimer Disease: Current Concepts & Future Directions

Alzheimer Disease is a devastating neurodegenerative disease which affects millions of people, and threatens to become a public health crisis in coming years

by Erik S. Musiek, MD, PhD & Suzanne E. Schindler, MD, PhD

Published in Missouri Medicine, the Journal of the Missouri State Medical Association, September/October 2013

Abstract

Alzheimer disease (AD) is the most common cause of dementia in individuals over age 65, and is expected to cause a major public health crisis as the number of older Americans rapidly expands in the next three decades. Herein, we review current strategies for diagnosis and management of AD, and discuss ongoing clinical research and future therapeutic directions in the battle against this devastating disease.

Introduction and Epidemiology

Alzheimer's disease (AD) is a major public health problem in the United States and throughout the world. AD is the most common cause of dementia in people over the age of 65 and affects well over five million people in the United States (U.S.), including 110,000 people in Missouri¹. As the population ages, the number of American AD cases is projected to explode to 16 million by 2050, with an estimated annual cost of 1 trillion dollars.¹ Aside from its devastating effect on affected individuals, AD also takes an enormous toll on caregivers, as caring for an Alzheimer's patient has been associated with financial stress, depression, and increased risk for other medical problems. Moreover, while the numbers of deaths caused by the other major killer diseases in the U.S., such as heart disease, cancer, and HIV, have declined in the past decade, deaths caused by AD continue to increase (see Figure 1). While no curative therapies have yet been developed, diagnosis of AD early in the disease course is important in that it allows for optimal initiation of symptomatic therapy and lifestyle modification, provides the opportunity for the patient to make plans for her own future, and may someday facilitate the preservation of cognition through disease-modifying therapy.

Alzheimer's disease is characterized clinically by an insidious onset and progressive decline of cognitive function, usually beginning with impairment of short term memory. The classic neuropathologic hallmarks of AD are amyloid plaques, which are formed by aggregation of the amyloid-beta (Aβ) peptide, and neurofibrillary tangles, which consist of misfolded tau protein (see Figure 2). Autopsy data demonstrate that amyloid plaques begin forming in the brain many years before the onset of any symptoms. Amyloid plaques likely initiate a pathological cascade of events, including tau misfolding, oxidative stress and synaptic injury that eventually lead to neuronal death and brain dysfunction.² The medial temporal lobe, which plays a critical role in short term memory, is particularly affected in AD, explaining the early characteristic deficits in short term memory.

Age is the strongest risk factor for the development of AD. At age 65, 13% of Americans have AD and by age 85 over 45% are affected.¹ Family history impacts AD risk, as individuals with an affected first degree relative (parent or sibling) have a two- to three-fold increased risk of developing AD. The vast majority of AD cases (99%) are sporadic, following no clear Mendelian genetic inheritance pattern. For sporadic AD, Apolipoprotein E (ApoE) genotype is the major genetic susceptibility factor. ApoE ε3 is the most common genotype in the overall population. In comparison to ε3, the ε2 allele imparts a decreased risk of AD, while the ε4 allele is associated with an increased risk. Two copies of the ε4 allele increase the risk of AD by 12-fold, and about half of all AD patients harbor at least one ApoE ε4 allele.³ Recent evidence suggests that ApoE is important in Aβ metabolism and amyloid plaque formation.³ Several other genes have recently been identified which modulate the risk of sporadic AD, and ongoing research is investigating their functions. In less than 1% of cases, a dominantly inherited familial form of AD is caused by mutations in amyloid precursor protein (APP), presenilin 1 (PSEN1), or presenilin 2 (PSEN2). Disease-causing mutations have been shown to influence production of Aβ peptide.⁴ Most patients with dominantly inherited AD present with symptoms between age 30-50.

Proposed environmental risk factors for AD include traumatic brain injury, low educational attainment, diabetes, obesity, and cardiovascular risk factors such as high cholesterol and coronary artery disease.¹ Women have a significantly higher lifetime risk of AD than men, due in part to their longer average lifespan. Caucasians have lower rates of AD than do African Americans or Hispanic Americans, though the reason for this is unknown. Exercise, healthy diet (including high intake of fish, fruits, and vegetables), and remaining cognitively involved and stimulated are all associated with lower risk of AD, although it has not been proven that any specific food or activity can prevent AD or slow its course. While a variety of over the counter agents have been purported to bolster cognition or prevent AD, most of these have not been rigorously tested, and none have been proven efficacious in randomized controlled clinical trials in humans.

Figure 1. Percent change in number of deaths caused by major diseases in the US, 2000-2008. Source: The Alzheimer's Association.

Figure 2. Amyloid plaques and neurofibrillary tangles within neurons in a silver-stained brain section from an Alzheimer's disease patient.

Phenotype

The typical clinical course of AD dementia is characterized by an insidious onset and slow progression of symptoms over years.⁵ The initial symptoms are often related to short term memory deficits, such as repeating questions or statements, forgetting appointments, misplacing items, or forgetting important details about events. In the early stages, these symptoms can be very subtle, and can manifest simply as slight decline in the patient’s ability to perform complex tasks. Problems with orientation, including confusion about the date or getting lost, are often seen early in AD dementia. As the disease progresses, patients often require assistance managing finances, shopping, driving, and keeping track of their schedule. In moderate AD dementia, patients depend heavily upon a caregiver and often require assistance maintaining their hygiene. At the end stages of AD dementia, patients are completely dependent on others, may forget the identities of their closest friends and family members, and may become bed-bound. The proximate cause of death is usually aspiration or infection.

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