Apart from longevity, family history is the principal risk factor for Alzheimer disease. It is not surprising, therefore, that those with a family history of this devastating disease are anxious to know more about its genetics. Having a first-degree relative with Alzheimer disease approximately doubles the risk of contracting it. The review summarized here considers our present state of knowledge on this subject.

Early-onset Alzheimer disease

Alzheimer disease is typically divided into early-onset and late-onset forms, with 60 or 65 years of age as the dividing point. A familial pattern is more obvious in the early-onset form, as the family members usually live through the risk period. Three genes have been associated with early-onset Alzheimer disease - the APP gene, and two presenilin genes (PS1 and PS2). Together, they account for about half the cases of early-onset disease, but it must be remembered that the early-onset form represents a small fraction of all Alzheimer disease.

The APP or amyloid-protein precursor gene is located on chromosome 21. It has been found in only about 20 families worldwide. Six different pathogenic mutations in the APP gene have been identified; they were all associated with the onset of Alzheimer disease, at ages ranging from 39 to 67 years.

The presenilin gene PS1 is located on chromosome 14, and PS2 is found on chromosome 1. There have been 45 different mutations of PS1 reported, but only two with PS2. The mean ages for onset of Alzheimer disease in these groups of patients were 45 years and 52 years, respectively. About 70% of these were found in patient-groups (single kindred or single patients) that suggested new patients or families screened would be likely to be negative for known presenelin gene defects, even when they were harboring a mutation. In other words, it is not practical to offer genetic testing for early-onset Alzheimer disease using the presenelin genes at the present time, except in suspected cases of early-onset familial disease.

Late-onset Alzheimer disease

Up to this year, only one late-onset Alzheimer disease gene had been identified with certainty: APOE on chromosome 19. The apolipoprotein E gene has three alleles - E2, E3, and E4. The E4 allele is over-represented in early- and late-onset cases. While the allele is present in 20-30% of the general population, it is found in 45-60% of Alzheimer patients. Homozygotes for this allele occur in 2-3% of the general population, but in 12-15% of Alzheimer patients. APOE4 acts primarily as a modifier of age at onset in otherwise susceptible individuals. It appears to interact with APP, so that its peak effect occurs in patients in their 60s, rather than in their 70s and 80s, when the disease is more common.

Quite recently the authors of this article (Blacker and Tarzi) reported that a deletion in the A2M gene (the alpha-2 macroglobulin gene) is present in 20% of the general population, and seems to confer a similar level of risk for Alzheimer disease as the APOE4 allele does.¹ It is speculated that the presence of this deletion confers a risk factor for developing the disease at any time, as opposed to the APOE4 allele, which confers the "when" information.

As APOE4 and A2M are neither necessary nor sufficient on their own to cause Alzheimer disease at any age, they cannot be recommended for use in predictive tests for the disease, nor, at this time, as diagnostic aids.

Implications

At a recent international conference on this subject, more than 70 reports involving at least a dozen other genes were presented.² Those working in the field believe that additional genes or loci will be confirmed as having a causal role in Alzheimer disease. A fairly complete battery of genetic targets for screening might provide improved predictive results, but this has ethical consequences beyond the scope of this summary.

Much more important is the fact that the identities of the genes discovered provide clues to the early molecular pathological changes leading to the disease. The occurrence of neurofibrillary tangles and senile plaques in the brain characterize Alzheimer disease; the plaques contain a core of amyloid. As the name implies, APP is used to form amyloid; mutations in the gene enhance the production of a longer form of the peptide (42 instead of 40 amino-acids) which is associated with increased amyloid deposition. Moreover, plasma from Alzheimer patients carrying the presenilin genes contains increased amounts of this longer amyloid. Finally, A2M may be involved in the clearance of amyloid from synaptic clefts in the brain. These findings provide enormous impetus to the search for rational pharmacological approaches to prevent and treat this disease. The discovery of additional genes associated with Alzheimer disease will contribute more points for pharmacological attack.