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Approximately 10% of all persons over the age of 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 young as the third decade, 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 that evolves over years. In typical amnestic AD, brain imaging reveals atrophy that begins in the medial temporal lobes before spreading to lateral and medial parietal and temporal lobes and lateral frontal cortex. Microscopically, there are neuritic plaques containing amyloid beta (Aβ), neurofibrillary tangles (NFTs) composed of hyperphosphorylated tau filaments, and Aβ accumulation of 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 apolipoprotein ε4 (Apo ε4). Carrying one Ε4 allele increases the risk for AD by 2- to 3-fold, whereas two alleles increase the risk 16-fold.


The cognitive changes of AD tend to follow a characteristic pattern, beginning with memory impairment and progressing to language and visuospatial deficits. Yet, approximately 20% of patients with AD present with nonmemory complaints such as word-finding, organizational, or navigational difficulty. In other patients, upstream visual processing dysfunction (referred to as posterior cortical atrophy syndrome) or a progressive “logopenic” aphasia 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 “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 applied. This construct provides useful prognostic information, because approximately 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 person with biomarker evidence of AD (amyloid imaging positive with positron emission tomography or low cerebrospinal Aβ42 and mildly elevated tau) in the absence of symptoms. These refinements have been developed in anticipation of early-stage treatment and prevention trials that have already ...

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