Page 4 - Drug Class Review

Final Report Update 1 Drug Effectiveness Review Project

INTRODUCTION

A. Overview
Alzheimer’s disease (AD), the most common adult form of dementia, is an age-associated

neurodegenerative disorder pathologically characterized by the abnormal accumulation of intracellular
neurofibrillary tangles and extracellular amyloid plaques in selected brain regions. Primary clinical
manifestations of AD include the insidious onset and gradual progression of cognitive impairment

affecting multiple domains. Impaired recent memory (difficulty learning new information) is the clinical
hallmark of AD; other associated cognitive signs include disturbances in language, visuospatial processes,
and executive control functions such as insight and judgment. Alterations in behavior (e.g., irritability,

paranoia), mood (e.g., depression), and personality (e.g., apathy) frequently occur in AD, are more
variable than cognitive symptoms, and often contribute disproportionately to caregiver distress.

Following the original case description in 1907 AD was initially viewed as a “pre-senile” dementia, with
onset below age 65 years. Over time the term “senile dementia of the Alzheimer type” arose to
acknowledge that dementia with AD-like clinical and pathological features occurred more commonly

after age 65 years.

The historical distinction between pre-senile and senile forms of AD was abandoned in standard
diagnostic criteria for AD developed over the last 25 years; the Diagnostic and Statistical Manual of
Psychiatric Disorders (DSM-IV) and the National Institute of Neurological and Communicative Disorders

and Stroke, and Alzheimer’s Disease and Related Disorders Association (NINCDS-ADRDA) have
eliminated the historical distinction. The two main types of AD currently recognized are a generally
later-onset sporadic form, representing about 95% of all cases, and autosomal-dominant familial forms

involving specific mutations in one of three genetic loci (APP, presenilin 1, and presenilin 2) and
typically associated with the early-onset of AD symptoms. Genetic polymorphism of the apolipoprotein
epsilon locus (apo E4 allele) increases the risk of developing AD two to three-fold and is associated with

an earlier age of onset in sporadic AD. Within the last decade, a syndrome referred to as “Mild Cognitive
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Impairment” (MCI) has gained recognition as a prodrome of AD in many but not all cases. MCI is
distinguished from AD by the presence of only short-term memory deficits and the absence of clear-cut
functional limitations independent of memory difficulties.

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