About 3 million people have been diagnosed in the United States. However, the real figure has been estimated at more than 5 million in the United States and over 30 million worldwide.¹ One estimate projects 13 million AD patients in the United States and over 100 million worldwide by 2050. At present, 50% of adults older than 85 years are likely to have a memory disorder, and most of these cases are due to AD, which is now the sixth leading cause of death in the United States.² In economic terms, we will be faced with costs far in excess of the more than $100 billion currently incurred by this condition.^3,4

The AD brain is characterized by extracellular neuritic plaques of beta amyloid peptide and intracellular neurofibrillary tangles of hyperphosphorylated tau protein. So far, only one gene, APOE, has been unequivocally identified as a genetic risk factor for the most common sporadic type, late-onset AD. However, early onset AD, which is a familial type, is known to be associated with the APP, PS-1, and PS2 genes.⁵

APOE (mapped to chromosome 19) has 3 major alleles, of which is considered normal, is associated with hyperlipoproteinemia and atherosclerosis, and is implicated in AD and atherosclerosis. When is homozygous, the risk of developing AD by age 75 years is increased 10 to 30 times more than in people without alleles.⁶ One function of the gene product of APOE, apolipoprotein E, is to promote proteolytic breakdown of beta amyloid. However, the allele does not appear to be very effective in this role, resulting in accumulation of beta amyloid in plaques characteristic of the AD brain.⁷ In spite of this, it is noteworthy that the allele is not a determinant of AD, ie, it is neither necessary nor sufficient to cause the disease: One third or more of patients with late-onset AD are negative, whereas some patients homozygous for never develop AD.^8,9

Discovery of susceptibility genes other than APOE for late-onset AD has been elusive.¹⁰ However, genome scanning to identify genetic markers of late-onset AD is meeting with success. A just-published study reporting on the use of genome-wide analysis of more than 1,300 families prone to late-onset AD established a strong association with several novel genes on different chromosomes in addition to APOE.¹¹ Interestingly, the strongest of these new markers is located on chromosome 14 in the vicinity of PS-1, a gene associated with early onset AD. One of the other markers is in a gene that causes spinocerebellar ataxia. Another is in a gene involved with the innate immune system. And still another is in a gene that codes for a synapse protein (dementia is correlated with loss of synapses). In addition, the study found several gene markers that are less strongly associated with AD.

The clinical implications of finding new genes associated with AD are listed in Table 1.