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Approximately 50 million people across the world are living with dementia. Alzheimer’s disease (AD) is the most common cause of dementia, contributing to an estimated 60–70% of all cases. 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 the inferior temporal, lateral, medial parietal, and dorsolateral frontal cortices. 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 (amyloid angiopathy, see “Pathology,” below). The identification of causative mutations and susceptibility genes for AD has provided a foundation for progress in understanding the biologic basis of the disorder. The major genetic risk factor 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 in women whereas carrying two alleles increases the risk ten- to fifteenfold in both sexes. Rapid progress in the development of imaging, cerebrospinal fluid (CSF), and plasma biomarkers of Aβ and phosphorylated tau has enabled detection of AD pathologic hallmarks in living people, opening the door to early detection and intervention with biologically specific therapies.


The cognitive changes of AD tend to follow a characteristic pattern, beginning with memory impairment and progressing to deficits in executive, language, and visuospatial functions. Yet ~20% of patients with AD present with nonmemory 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. Depression, social withdrawal, and anxiety occur in early disease stages and may represent a prodrome before cognitive symptoms are apparent.

In early stages of typical amnestic AD, the memory loss may go unrecognized or be ascribed to benign forgetfulness of aging. The term subjective cognitive decline refers to self-perceived worsening in memory or other cognitive abilities that may not be noticeable to others or apparent on formal neuropsychologic testing. Once the memory loss becomes noticeable to the patient and family and friends and is confirmed on standardized memory tests, the term mild cognitive impairment (MCI) is often used. This construct provides useful prognostic information, ...

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