[Frontiers in Bioscience 2, d253-259, June 1, 1997]

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Hriday K. Das, Ph.D., and Harbans Lal, Ph.D.

Department of PharmacologyUniversity of North Texas Health Science Center at Fort Worth, Fort Worth, Texas 76107

Received 4/4/97; Accepted 5/28/97


Alzheimer's disease (AD) is a neurodegenerative disorder characterized by a progressive decline in memory, judgment, ability to reason, and intellectual function and is accompanied by a wide range of neuropathologic features including extracellular amyloid plaques and intra-neuronal neurofibrillary tangles (1, 2). The cause of AD is unknown and as yet no cure for this disease is available. AD afflicts approximately 4 million American adults. More than 100,000 victims die annually of complications of AD making it the fourth leading cause of death in adults after heart disease, cancer, and stroke. The disease is caused by the degeneration of neurons in the brain. Complications associated with AD usually result in death within 10 years from the onset of the disease.

Although the etiology of this disease is complex, at least three genetic loci that confer inherited susceptibility to this disease have been identified. A locus (AD3) mapped by linkage studies to human chromosome 14q24.3 may account for 70% of early-onset (onset at age 30-50 years) autosomal dominant AD (3). Early-onset AD comprises up to 10% of all cases of AD (3-6). Mutations in the gene for the b-amyloid precursor protein (APP) have been found in a small number of families (<3% of cases) with a disease onset before 65 years of age (7, 8). The apoE4 allele of the apolipoprotein E (apoE) is associated with a significant proportion of cases with late onset (>60 years) AD which comprises more than 90% of AD cases (9).

Recently two early onset AD genes (S182 and STM2) have been identified (4, 10, 11). These genes are called presenilin 1 and 2 (PS1 and PS2), respectively. PS1 and PS2 genes are mutated in about half of all inherited cases (5, 6, 10, 11). On the other hand, mutation of the gene encoding the b-amyloid peptide BA4 is seen in a few percent of patients with AD. Mutated forms of PS1 and PS2 genes cause increased production of b-amyloid peptide BA4 from its precursor and lead to formation of abundant amyloid plaques and memory loss (12, 13). Mutated PS2 gene can cause increased apoptotic activity and thus accelerate the process of neurodegenaration (14).

In the late onset AD, an increased frequency of type 4 apolipoprotein E (apoE4) allele has been described (9). In 42 families with late onset AD, with increasing apoE4 allele, the risk of AD increased from 20% to 90% and the mean age of onset of the disease decreased from 84 to 68 years (15). ApoE4 is found in senile plaques, in neurofibrillary tangles and at the sites of congophilic angiopathy in Alzheimer's disease and in the prion protein amyloid plaque of Creutzfeldt-Jacob's disease and scrapie (16-18). ApoE4 binds to beta amyloid peptide (BA4) in vitro (19). The localization of apoE4 in the pathological lesions of Alzheimer's disease suggests a functional pathogenic role for apoE4. Binding of apoE4 to BA4 peptide may be a requisite step in tagging these peptides for their intra and extracellular metabolism. Genetically, apoE4 allele is found to be associated with an increased susceptibility to Alzheimer's disease and appears to be a possible risk factor or susceptibility gene in the late-onset familial and sporadic Alzheimer's disease. The association of apoE4 with AD suggests that 1) the apoE transport system is involved in the pathophysiology of the disease or 2) the apoE4 allele is in genetic dysequilibrium with another gene that is involved in the development of the disease.