Family History of Alzheimer's disease - what does it mean?

Frequently in the Roskamp institute Memory Clinic we are asked what a family his tory of Alzheimers disease means for the children and other blood relatives of su fferers. Although this question is always handled on an individual basis there are some general guidelines that can be offered to access risk for the disease t o children and other family members related to a sufferer. Naturally, family me mbers who perceive they are at risk for developing the disease themselves may su ffer from a great degree of anxiety it is therefore important to ask the staff a t the Roskamp Institute what the individual risk is for developing the disease. In general the genetic risk for Alzheimers disease can be divided into two categ ories; early onset familial disease which is highly genetic and occurs in famili es which may have onsets of the disease in the 40s,50s or 60s; late onset disea se which is frequently familial but where the disease onsets in the seventh deca de onwards. We shall consider these two scenarios separately. Early onset Alzheimers disease. The term early onset Alzheimers is frequently misunderstood or used in a confusing way. What we generally mean by early onset Alzheimers is Alzheimers that onsets before the age to 60 years. This is in contrast to the term early onset as refe rencing the early stage of the disease. This is a confusing way to use the term and is discouraged. Early stage disease is a better term to describe the early phases of the disease. Early onset familial disease occurs in families that are affected in multiple generations by mutations in genes that can trigger the dis ease. Families of early onset disease thankfully are very rare but they have pr ovided great insight into the disease process probably in all cases of the disea se (early and late onset). Sadly, frequently in these families the disease is i nherited in what is known as an autosomal dominant fashion. Autosomal dominant inheritance means that 50% of the offspring of each generation on average are im pacted by the disease. Some generations may be very fortunate and although they may be at risk for inheriting the diseased gene from one or the other parent no ne of the siblings in a sibship may be affected. On the contrary sibships can b e very unlucky in which case more than 50% are impacted with the disease. For e ach child of an affected parent there is a 50% chance of inheriting the disease and this chance is not influenced by whether other siblings have already inherit ed the disease or not. Unfortunately the inheritance of these rare genetic variance means that individu als at risk are highly likely to develop the disease if they live long enough. One of the important characteristics of these familial mutations is that the dis ease tends to onset around approximately the same time of life. Thus if a famil y has a mean (average) age of onset of 52 and one inherits one of these rare gen eric errors then one is unlikely to live to 60 without developing signs or sym ptoms of the disease. By contrast if one does not carry the mutation then there is no more risk for the disease than the general population. Again it is most important to emphasize that such families are extremely rare an d early onset Alzheimers is not the most likely reason for patients or their fami lies to visit the Roskamp Institute Clinic. In fact, approximately 1% or less o f cases of Alzheimers Disease have what can be described as early onset disease. In the past, individuals who come from such families have sought genetic counse ling including genetic testing for these genetic errors. It is relatively strai ghtforward to detect such errors but clearly the genetic information is highly s ensitive. Family members should therefore think very carefully before seeking s uch information however initially finding out more about early onset disease is a recommended step. Clinicians at the Roskamp Institute are happy to discuss early onset disease wit h patients and their families as they wish. Finally it should be noted that man

y cases of early onset disease occur without a family history. Thus individuals can manifest the disease before the age of 60 but have no other known family me mbers either in the prior generations or in subsequent generations that develop the disease the cause of early onset Alzheimers that is not familial is not well understood but importantly there is no risk to subsequent family members for dev elopment of the disease. Late onset (common) Alzheimers disease. Much more commonly patients and their fa milies come to the clinic at the Roskamp Institute and seek advice on the inheri tance of Alzheimers when one or more members of the family has late onset disease . This is defined as disease which onsets over the age of 60 and this is by far in a way the most common cause of the disease. It is estimated that approximate ly 4 million Americans presently either have the disease or are in the early or pre clinical stages - most of these cases are late onset Alzheimers Disease. The predicted numbers for future disease prevalence are very high. For instance it is estimated that by mid century there could be as many as two hundred million i ndividuals afflicted with the disease. Most late onset Alzheimers disease does not exhibit a clear autosomal dominant pa ttern meaning that the risk to offspring of individuals suffering with the disea se is usually considerably less than 50%. Certain genetic risk factors for late onset disease have been identified - the most important of which is apolipoprot ein E (APOE). There are 3 common forms of APOE: E2, E3 and E4. The discovery b y Allen Roses and his colleagues at Duke University showed that Alzheimers diseas e sufferers were much more likely to carry one or two copies of the E4 allele (g enetic form) of APOE than the normal population. Carrying one copy of APOE 4 in creases ones risk for the disease by approximately three times and carrying two copies can increase the risk for the disease by up to fifteen times compared to individuals who do not carry an APOE 4 allele. Many family members express interest in being genetically tested for their risk for the disease. Such tests are commercially available but most centers discour age the use of testing prior to symptoms because many individuals who carry an A POE 4 allele do not necessarily develop the disease at least until late old age. Conversely its very possible to develop Alzheimers disease without carrying an A POE 4 allele. Therefore on an individual basis the test is not overly helpful in specifying who may or may not develop the disease. However on a group basis AP OE genetic testing is very helpful to give an average estimate of the numbers of individuals who will subsequently develop Alzheimers. It is anticipated that as better treatments are available for Alzheimers disease there will be greater interest in genetic testing. For instance it is expected that as treatments are used earlier and earlier in the stages of the disease tha t individuals in the very early stage or maybe with no symptoms at all might see k medical treatment once such treatment has been established as effective in sto pping the rate of progression or disease onset. Despite the fact that genetic testing is not used frequently in clinical practic e it is a tremendous tool in assisting researchers in understanding when and why the diseases develops and in planning clinical trials to take into account who is most likely to develop the disease. Already there is evidence from several c linical trials that individuals that carry the APOE 4 allele may be more refract ory to certain treatments. As drug development progresses it will be important to develop medications that are able to tackle the severest form of the disease i.e. those patients who are carrying and APOE 4 allele. Summary: The two types of familial Alzheimers disease differ in the risk for of fspring of developing the disease. The early onset cases as noted have children that are highly at risk for developing the disease if there is a family history . By contrast late onset disease or low clustering in families is much less gen

etically predisposed. In both cases genetic tests are available but are general ly discouraged particularly for late onset disease. Roskamp Institute researche rs and clinicians are well versed in the genetic aspects of the disease and can advise on an individual or family basis as required. The Roskamp Institute is a not-for-profit research Institute located in Sarasota and Tampa, Florida, that is dedicated to understanding the causes of, and findi ng cures for, neuropsychiatric and neurodegenerative disorders and addictions wi th an emphasis on Alzheimer s disease. The Institutes Memory Clinics also offer c omprehensive cognitive and medical assessment toward differential diagnosis of A lzheimers disease and offers treatments and disease management options once the d iagnostic evaluation is complete. By Dr. Michael Mullan, Director of Alzheimer Research Institute, The Roskamp Ins titute for more information on Alzheimers please visit: http://www.mullanalzheimer.com http://www.mullanalzheimer.info