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ALZHEIMER’S DISEASE

Approximately 10% of all persons aged >70 years have significant memory loss, and in more than half the cause is Alzheimer’s disease (AD). It is estimated that the median annual total cost of caring for a single patient with advanced AD is >$50,000, while the emotional toll for family members and caregivers is immeasurable. AD can manifest as early as the third decade of life, but it is the most common cause of dementia in the elderly. Patients most often present with an insidious loss of episodic memory followed by a slowly progressive dementia. In typical amnestic AD, brain atrophy begins in the medial temporal lobes before spreading to lateral and medial parietal and temporal lobes and lateral frontal cortex. Microscopically, there are widespread neuritic plaques containing amyloid beta (Aβ), neurofibrillary tangles (NFTs) composed of hyperphosphorylated tau filaments, and Aβ accumulation in blood vessel walls in cortex and leptomeninges (see “Pathology,” below). The identification of causative mutations and susceptibility genes for AD has provided a foundation for rapid progress in understanding the biological basis of the disorder. The major genetic risk for AD is the ε4 allele of the apolipoprotein E (ApoE) gene. Carrying one ε4 allele increases the risk for AD by two- to threefold whereas two alleles increase the risk sixteenfold in both sexes.

CLINICAL MANIFESTATIONS

The cognitive changes of AD tend to follow a characteristic pattern, beginning with memory impairment and progressing to language and visuospatial deficits, followed by executive dysfunction. Yet, ~20% of patients with AD present with non-memory complaints such as word-finding, organizational, or navigational difficulty. In other patients, visual processing dysfunction (referred to as posterior cortical atrophy syndrome) or a progressive “logopenic” aphasia characterized by difficulties with naming and repetition are the primary manifestations of AD for years before progressing to involve memory and other cognitive domains. Still other patients may present with an asymmetric akinetic-rigid-dystonic (“corticobasal”) syndrome or a dysexecutive/behavioral, i.e., “frontal” variant of AD.

In the early stages of typical amnestic AD, the memory loss may go unrecognized or be ascribed to benign forgetfulness of aging. Once the memory loss becomes noticeable to the patient and spouse and falls 1.5 standard deviations below normal on standardized memory tests, the term mild cognitive impairment (MCI) is often used. This construct provides useful prognostic information, because ~50% of patients with MCI (roughly 12% per year) will progress to AD over 4 years. Increasingly, the MCI construct is being replaced by the notion of “early symptomatic AD” to signify that AD is considered the underlying disease (based on clinical or biomarker evidence) in a patient who remains functionally compensated. Even earlier in the course, “prodromal AD” refers to a ...

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