Genetic Counseling and Testing


Since AD is genetically heterogeneous, genetic counseling of persons with AD and their family members must be carefully tailored to the family history.  Autopsy confirmation of the diagnosis of AD generally adds greatly to the accuracy of genetic counseling and should be sought whenever possible.  Accurate family history information and age of onset of affected family members is critical in determining if a particular family may have a single gene mutation as the underlying etiology.
 

Sporadic AD

Genetic counseling for people with the sporadic type of AD and their family members must be empiric and relatively nonspecific.  It should be pointed out that AD is common and we all have an approximately 10-12% risk of developing dementia.

First degree relatives of a person with AD have a cumulative lifetime risk of developing AD of about 15-30% (typically reported as a 20-25% risk) . There is disagreement as to whether the age of onset of the affected person changes the risk to first degree relatives.  One study found that early onset increased the risk , while another study did not.  The number of additional affected family members probably increases the risk to close relatives, but the magnitude of  that increase is unclear unless the pattern in the family is characteristic of autosomal dominant inheritance.

While there is an association of AD with the e4 allele of apolipoprotein E (Apo E), the Apo E genotype is not useful for prediction of AD in asymptomatic persons.
 

Down Syndrome

All persons with Down Syndrome develop the neuropathological hallmarks of AD after 40 years. Where carefully observed or tested, more than half of these individuals also show evidence of cognitive decline.  Family members of persons with Down Syndrome are not at increased risk for AD.
 

Early Onset Familial Alzheimer Disease (EOFAD)

Persons with early onset (before age 60) and a strongly positive family history in more than one generation probably represent one of the uncommon instances of autosomal dominant early onset FAD.  Consideration should be given to referring such families to Alzheimer disease research centers.  A minority of these families will have a point mutation in the APP gene, but this testing is only available on a research basis.  One such family with an APP mutation has undergone presymptomatic direct DNA testing through a research protocol, similar to the testing now available for Huntington's disease .

Since the genes for early onset FAD on chromosomes 14 and 1 have been identified (Presenilin 1 and Presenilin 2, respectively), there is now potential for direct DNA diagnosis of mutations in such families.  Direct DNA testing for Presenilin 1 (chromosome 14) is now commercially available.

The highest yield for a positive direct DNA test for a mutation in the Presenilin 1 gene will be for persons with early onset (less than 60 years) AD who have another affected family member (especially a parent) with early onset AD.  The test will have a low yield in persons with late onset AD, both sporadic and familial.  People with early onset sporadic AD will also have a low yield but new mutations, false paternity and early death of an affected parent will sometimes result in a positive test result in persons with no family history of AD. If a mutation in the Presenilin 1 gene is not detected, the patient may still have a genetic form of AD (e.g. APP or Presenilin 2 mutations).

Testing an affected family member to ascertain the specific mutation in that person is necessary prior to using direct DNA testing in asymptomatic family members.  When direct DNA testing is performed in asymptomatic persons, it should be done in the context of formal genetic counseling.
 

Late Onset Familial Alzheimer Disease

Many families have multiple affected members all of whom have onset of dementia after the age of 65 or 70.  Having two, three, or more affected family members probably raises the risk to other first degree relatives in excess of that noted above for the sporadic cases, although the exact magnitude of the risk is not clear. found a 35-45% risk of dementia if a person's sib had early onset (less than 70 years) AD and one parent was also affected.also reported preliminary data suggesting that offspring of parents with conjugal AD (both spouses affected) had an increased risk of dementia.

The specific gene (or genes) responsible for late onset AD are as yet unknown.  Specific direct DNA testing is therefore not available.