Alzheimer's Disease

ALZHEIMER'S DISEASE SID GILMAN* Introduction In 1907, Alois Alzheimer described the clinical and neuropathological characteristics of a disease in a 51-year-old woman who had a progressive dementing disorder [I]. Although dementia occurring in older people ("senile" dementia) and senile plaques were well known at the time of Alzheimer's report, this patient was considered to be novel because of the young age of onset of her disorder and the neuropathological findings of both senile plaques and structures termed neurofibrillary tangles. In recognition of this unique combination of clinical and pathological features, the term Alzheimer's disease (AD) was developed and used initially only for presenile dementia, which was defined arbitrarily as a dementia occurring under age 65 [2]. Since the time of the original description, however, large numbers of patients have been examined both clinically and neuropathologically , and the term AD has come to be applied to patients with progressive dementia, usually occurring between 65 and 90, but seen at times in younger age groups as well. The feature in common for the diagnosis ofAD is a progressive dementing disorder, often with certain additional clinical features that are described below, and with the neuropathological findings of loss of neurons accompanied by senile plaques and neurofibrillary tangles . Hence, the diagnosis of AD currently is applied not only to presenile dementia, but to dementias occurring at almost any age in which the characteristic neuropathological features can be verified. Currently, many investigators believe that the AD should be termed Alzheimer's diseases or Alzheimer 's syndrome, because the neuropathological changes may represent only the stereotyped response of the nervous system to different etiologies and not necessarily a unitary disease process. There is considerable merit in this view. * Department of Neurology and Michigan's Alzheimer's Research Center, University of Michigan, Ann Arbor, MI 48109.© 1996 by The University of Chicago. All rights reserved. 0031-5982/97/4002-0986$01.00 230 Sid Gilman ¦ Alzheimer's Disease ABBREVIATIONS AD: Alzheimer's disease, a progressive neurodegenerative disease leading to severe cognitive impairment accompanied by the development ofneurofibrillary tangles and neuritic plaques, and neuronal loss. APP: amyloid precursor protein, from which Aß peptides are derived; APP mutations are linked to early-onset familial AD. apo-E: apolipoprotein E, a protein encoded by a gene on chromosome 19 expressed in three forms (E2, E3, E4) that are related to the risk of developing Alzheimer's disease. NGF: nerve growth factor, a neurotrophic factor that promotes and supports cell division of cholinergic neurons in the developing nervous system and regeneration after injury. PET: positron emission tomography, a technique used for imaging metabolic and biochemical processes in the brains of living humans. PS-I or S182: presenilin 1, a gene on chromosome 14 with mutations linked to early-onset familial Alzheimer's disease. PS-2 or STM-2: presenilin 2, a gene on chromosome 1 with mutations linked to early-onset familial Alzheimer's disease. AD is one of a large number of neurodegenerative diseases, which are characterized by the gradually progressive deterioration and loss of neurons in various parts of the central nervous system without known cause. Many of the degenerative diseases result in dementia, which is defined as a global impairment of cognitive function sufficient to interfere with normal social and occupational functioning [3] . People with early disease and mild impairment may not have difficulties in their occupations and they may not appear to be socially disabled, however, boundary problems are common , and usually people who begin with a dementing illness that allows preservation of social and occupational function eventually cross the threshold and fall into the formal definition of dementia. Clinical Presentation The initial disturbances in AD usually consist ofan insidiously progressive disorder of memory, at times with abnormalities of speech, language, and spatial orientation. Disturbances ofjudgment occur commonly in the early stages of the disease, at times leading to disastrous personal and financial decisions. Patients with AD also often develop symptoms that lead to gross behavioral disturbances, including suspiciousness to the point of paranoia; hallucinations, both visual and auditory; disturbances ofmotor activity, with wandering, purposeless movements, and inappropriate acts; aggressiveness, both verbal and physical, usually with agitation; reversal of day and night...