ScienceWeek

1. INTRODUCTION

ON ALZHEIMER'S DISEASE

The following points are made by R.L. Nussbaum and C.E. Ellis (New Engl. J. Med. 2003 348:1356):

1) The most common neurodegenerative disease, Alzheimer's disease constitutes about two thirds of cases of dementia overall (ranging in various studies from 42 to 81 percent of all dementias), with vascular causes and other neurodegenerative diseases such as Pick's disease and diffuse Lewy-body dementia making up the majority of the remaining cases.(1,2)

2) Alzheimer's disease is a progressive neurologic disease that results in the irreversible loss of neurons, particularly in the cortex and hippocampus.(3) The clinical hallmarks are progressive impairment in memory, judgment, decision making, orientation to physical surroundings, and language. Diagnosis is based on neurologic examination and the exclusion of other causes of dementia; a definitive diagnosis can be made only at autopsy. The pathological hallmarks are neuronal loss, extracellular senile plaques containing the peptide beta-amyloid, and neurofibrillary tangles; the latter are composed of a hyperphosphorylated form of the microtubular protein tau.(4) Amyloid in senile plaques is the product of cleavage of a much larger protein, the beta-amyloid precursor protein, by a series of proteases, the alpha-, beta-, and gamma-secretases.(5) The gamma-secretase, in particular, appears to be responsible for generating one particular beta-amyloid peptide -- A42 -- that is 42 amino acids in length and has pathogenetic importance because it can form insoluble toxic fibrils and accumulates in the senile plaques isolated from the brains of patients with Alzheimer's disease.

3) Measures of the prevalence of Alzheimer's disease differ depending on the diagnostic criteria used, the age of the population surveyed, and other factors, including geography and ethnicity. Excluding persons with clinically questionable dementia, Alzheimer's disease has a prevalence of approximately 1 percent among those 65 to 69 years of age and increases with age to 40 to 50 percent among persons 95 years of age and over. Although the mean age at the onset of dementia is approximately 80 years, early-onset disease, defined arbitrarily and variously as the illness occurring before the age of 60 to 65 years, can occur but is rare. In one community-based study in France, the prevalence of early-onset disease (defined by an onset before the age of 61 years) was 41 per 100,000; thus, early-onset cases make up about 6 to 7 percent of all cases of Alzheimer's disease. About 7 percent of early-onset cases are familial, with an autosomal dominant pattern of inheritance and high penetrance. Thus, familial forms of early-onset Alzheimer's disease, inherited in an autosomal dominant manner, are rare; however, their importance extends far beyond their frequency, because they have allowed researchers to identify some of the critical pathogenetic pathways of the disease.

4) Missense mutations that alter a single amino acid and therefore gene function have been identified in three genes in families with early-onset autosomal dominant Alzheimer's disease. Family linkage studies and DNA sequencing identified mutations responsible for early-onset autosomal dominant forms of the disease in the gene encoding beta-amyloid precursor protein itself on chromosome 21, as well as in two genes with similarity to each other, presenilin 1 (PSEN1) on chromosome 14 and presenilin 2 (PSEN2) on chromosome 1. PSEN1 mutations are more common than PSEN2 mutations. In a study of French families, for example, half of patients with familial, early-onset Alzheimer's disease that was inherited as an autosomal dominant trait had mutations in PSEN1, whereas approximately 16 percent of families had mutations in the beta-amyloid precursor protein (APP) gene itself. PSEN2 mutations were not found, and the genes responsible for the remaining 30 percent or so of cases were unknown.

References (abridged):

1. Helmer C, Joly P, Letenneur L, Commenges D, Dartigues JF. Mortality with dementia: results from a French prospective community-based cohort. Am J Epidemiol 2001;154:642-648

2. Aronson MK, Ooi WL, Geva DL, Masur D, Blau A, Frishman W. Dementia: age-dependent incidence, prevalence, and mortality in the old old. Arch Intern Med 1991;151:989-992

3. McKhann G, Drachman D, Folstein M, Katzman R, Price D, Stadlan EM. Clinical diagnosis of Alzheimer's disease: report of the NINCDS-ADRDA Work Group under the auspices of Department of Health and Human Services Task Force on Alzheimer's Disease. Neurology 1984;34:939-944

4. Clark CM, Ewbank D, Lee VM-Y, Trojanowski JQ. Molecular pathology of Alzheimer's disease: neuronal cytoskeletal abnormalities. In: Growdon JH, Rossor MN, eds. The dementias. Vol. 19 of Blue books of practical neurology. Boston: Butterworth–Heinemann, 1998:285-304

5. Hutton M, Perez-Tur J, Hardy J. Genetics of Alzheimer's disease. Essays Biochem 1998;33:117-131

Related Material:

ON ALZHEIMER'S DISEASE

The following points are made by R. Mayeux and M. Sano (New Engl. J. Med. 1999 341:1670):

1) Alzheimer's disease, which is characterized by progressive loss of memory and cognitive function, affects 15 million people worldwide. The incidence increases steadily from 0.5 percent per year at the age of 65 years to nearly 8 percent per year after the age of 85 years.(1) Because survival for a decade is common, the prevalence increases from 3 percent at the age of 65 years to 47 percent after the age of 85 years.(2) Mutations in the gene for the amyloid precursor protein and the genes for presenilin 1 and 2 cause rare, dominantly inherited forms of the disease occurring before the age of 60 years, and the 4 variant of apolipoprotein E is associated with the sporadic form and some familial forms with onset after the age of 60 years.(3,4)

2) Criteria for the diagnosis of Alzheimer's disease were established in 1984.(5) Patients who meet the criteria and who have no other illness that can cause dementia, such as hypothyroidism or cerebrovascular disease, receive a diagnosis of "probable Alzheimer's disease". If they meet the criteria and also have another disease that can cause dementia, they are given a diagnosis of "possible Alzheimer's disease". Definite cases are those confirmed by the postmortem findings of dense plaques containing the beta-amyloid peptide and elements of degenerating neurons, neurofibrillary tangles composed of abnormally phosphorylated tau protein, and loss of neurons and synapses in the brain. Degeneration in the basal forebrain profoundly reduces the content of acetylcholine and the activities of choline acetyltransferase. Although other neurotransmitters can be involved, the loss of acetylcholine occurs early and correlates with the impairment of memory. Symptomatic treatment for Alzheimer's disease has focused on augmenting cholinergic neurotransmission.

References (abridged):

1. Evans DA, Funkenstein HH, Albert MS, et al. Prevalence of Alzheimer's disease in a community population of older persons: higher than previously reported. JAMA 1989;262:2551-2556

2. Hebert LE, Scherr PA, Beckett LA, et al. Age-specific incidence of Alzheimer's disease in a community population. JAMA 1995;273:1354-1359

3. Price DL, Sisodia SS. Mutant genes in familial Alzheimer's disease and transgenic models. Annu Rev Neurosci 1998;21:479-505

4. Lendon CL, Ashall F, Goate AM. Exploring the etiology of Alzheimer disease using molecular genetics. JAMA 1997;277:825-831

5. McKhann G, Drachman D, Folstein M, Katzman R, Price D, Stadlan EM. Clinical diagnosis of Alzheimer's disease: report of the NINCDS-ADRDA Work Group under the auspices of Department of Health and Human Services Task Force on Alzheimer's Disease. Neurology 1984;34:939-944

Related Material:

ALZHEIMER'S DISEASE: INCIDENCE, PREVALENCE, AND ECONOMIC IMPACT

Alzheimer's disease is now tabulated as the 12th leading cause of death in the US, with a 1997 death-rate per 100,000 population of 8.4, which is higher than homicide and legal intervention (7.0), AIDS (6.2), and atherosclerosis (6.2). It is estimated that by 2025 more than 20 million people worldwide will be afflicted with the disease. In general, Alzheimer's disease is a degenerative brain disorder that develops in mid-to late-adult life, the disease resulting in a progressive and irreversible decline in memory coupled with a decline in various other cognitive functions. In terms of general pathology, the disease is characterized by the destruction of nerve cells and neural connections in the cerebral cortex of the brain and by a visible and significant loss of brain mass.

The major neuropathological change in the brain of Alzheimer's disease patients is neuronal death, particularly in regions related to memory and cognition. One of the major pathological features of the disease is the abundant presence of amyloid plaques in the brain of the affected individuals. Intracellular bundles of paired helical filaments, composed largely of phosphorylated tau protein, accumulate in large amounts in dying neurons. On the neuron surfaces, insoluble aggregates of proteinaceous debris, termed "amyloid", appear in the form of neuritic plaques and vascular amyloid deposits. The frequency and distribution of the neurofibrillar tangles and of the neuritic plaques appear to correlate well with the extent of the cognitive impairment and other characteristic symptoms of the disease. (C. Nicolau et al Proc. Nat. Acad. Sci. 2002 99:332)

The following points are made by J. L. Cummings and G. Cole (J. Am. Med. Assoc. 2002 287:2335):

1) Alzheimer disease accounts for 60% to 70% of cases of progressive cognitive impairment in elderly patients. The total prevalence of Alzheimer disease in the United States is estimated at 2.3 million (range, 1.09-4.8 million).(1) The prevalence of Alzheimer disease doubles every 5 years after the age of 60 increasing from a prevalence of 1% among those 60- to 64-years-old to up to 40% of those aged 85 years and older.(2) The disease is more common among women than men by a ratio of 1.2 to 1.5.(3) The number of new cases per year is estimated at 360,000 equating to 980 new cases per day or 40 new cases every hour. The population of patients with Alzheimer disease will nearly quadruple in the next 50 years if the current trend continues.(1)

2) The direct costs for the care of patients in 1991 were calculated at US $20.6 billion and the total cost was calculated to be $76.3 billion.(4) Most direct costs of care for patients with Alzheimer disease are absorbed by the expense of nursing home care, approximately $47,000 per patient per year in the US.(5)

3) Several risk factors for AD have been identified in epidemiologic studies in addition to age and female sex. The most potent risk factor is the presence of the apolipoprotein epsilon-4 (APOE epsilon-4) allele. Of its 3 forms -- epsilon-2, -3, and -4 -- only the epsilon-4 allele increases the likelihood of developing Alzheimer disease. The lifetime risk of Alzheimer disease for an individual without the epsilon-4 allele is approximately 9%; the lifetime risk of Alzheimer disease for an individual carrying at least 1 epsilon-4 allele is 29%. While representing a substantial risk of Alzheimer disease, the epsilon-4 genotype is not sufficiently specific or sensitive for the diagnosis of Alzheimer disease to allow its use as a diagnostic test. Moreover, the epsilon-4 allele appears to increase the risk of Alzheimer disease more in white and Asian populations than in black and Hispanic populations. Other risk factors implicated in a variety of studies include head injury, low serum levels of folate and vitamin B-12, elevated plasma and total homocysteine levels, family history of Alzheimer disease or dementia, fewer years of formal education, lower income, and lower occupational status. Conversely, higher levels of education, moderate levels of daily wine consumption, and higher levels of fish in the diet have been associated with a lower risk for Alzheimer disease. Differences in the prevalence of Alzheimer disease among population groups worldwide suggest as yet undisclosed genetic or environmental effects on the prevalence of Alzheimer disease.

References (abridged):

1. Brookmeyer R, Gray S, Kawas C. Projections of Alzheimer's disease in the United States and the public health impact of delaying disease onset. Am J Public Health. 1998;88:1337-1342.

2. Von Strauss EM, Viitanen D, De Ronchi D, et al. Aging and the occurrence of dementia. Arch Neurol. 1999;56:587-592.

3. Gao S, Hendrie HC, Hall KS, Hui S. The relationships between age, sex, and the incidence of dementia and Alzheimer disease. Arch Gen Psychiatry. 1998;55:809-815.

4. Ernst RL, Hay JW. The US economic and social costs of Alzheimer's disease revisited. Am J Public Health. 1994;84:1261-1264.

5. Max W. The economic impact of Alzheimer's disease. Neurology. 1993;43:S6-S10.

ScienceWeek http://scienceweek.com