Most people with Alzheimer’s disease (AD) have a sporadic form of the illness that is likely caused by a combination of small changes in a large number of genes together with environmental factors. Persons with the common, sporadic form may or may not have a family history of AD. A few families, however, have a strongly genetic form of Alzheimer’s disease resulting from rare mutations in specific genes. In this rare form of AD, about 50% of the children of a parent with the disorder will develop AD (much like the genetic transmission of Huntington’s disease), reflecting so-called “autosomal dominant” inheritance. This strong pattern of inheritance is consistent throughout generations of an affected family. Families with this rare form of AD are scattered throughout the world, and an international group of scientists are working with these families in order to learn more about the biology and course of AD. A number of these scientists have formed DIAN, the Dominantly Inherited Alzheimer Network.
DIAN scientists, led by Randy Bateman from Washington University in St. Louis, recently published a very important and provocative paper in the New England Journal of Medicine characterizing the sequence of changes in the brains of people at risk for dominantly inherited Alzheimer’s disease (DIAD). Based on their analyses, it appears that changes associated with this rare form of AD are observable at least 25 years before the onset of clinical symptoms! This strongly suggests that clinical symptoms become apparent at a late stage of a prolonged pathological process.
As we already mentioned, if a person has DIAD (as documented by family history and genetic testing), then about 50% of the person’s children will inherit the disorder. Whether individual children have inherited the AD gene can be determined by genetic analysis of blood samples. Scientists in DIAN measured various parameters in siblings who carry the AD gene (and who will develop the illness) and siblings who do not have the gene. The latter group still could develop sporadic AD, but they won’t develop DIAD. It is often the case that DIAD develops at a younger age than sporadic AD. In the group that was studied, the parents’ average age of symptom onset was about 46 years, whereas sporadic AD is most commonly seen in persons above the age of 70. The age when the DIAD parents first show symptoms is a good predictor of the age of symptom onset in their affected children.
The first change to occur in adult children who inherited the DIAD gene was a decrease in the amount of a chemical called beta-amyloid in cerebrospinal fluid (CSF) – the fluid that bathes the brain and spinal cord. (A relatively simple procedure called a lumbar puncture is used to obtain a sample of this fluid.) Amazingly, this change in CSF beta-amyloid began about 25 years prior to the age at which their parents first showed symptoms. In other words, the decrease in CSF beta-amyloid began, on average, when the affected children were in their early 20s and were showing no clinical signs of AD. About 10 years later, beta-amyloid accumulation was observed in the affected children’s brains using a specific type of neuroimaging procedure. This means that 15 years prior to the predicted onset of symptoms, amyloid deposits were “visible” in the brain. Levels of tau, another important substance known to be involved in AD, increased in the CSF shortly after amyloid could be visualized in the brain. At about the same time, the hippocampus, a part of the brain involved in memory function, started to shrink. About 5 years after that, very subtle changes in certain types of memory could be detected. This was still about 10 years prior to the expected onset of illness. About 5 years later, adult children carrying the AD gene began demonstrating very mild clinical symptoms that a well-trained research physician could detect with an extended interview of the participant and a very knowledgeable collateral source. These symptoms became increasingly noticeable over time, and about 3 years after the average age of onset in their parents, these adult children demonstrated clear cut clinical AD.
These important findings indicate that several decades prior to any observable clinical symptoms, AD-related changes are occurring in the brains of persons who inherited the gene for this rare form of AD. It is likely that a cascade of events starts very slowly and, over time, causes other changes that eventually lead to an inevitable downhill clinical course. Beta-amyloid seems to be involved very early in this cascade. This substance has also been implicated in animal models of AD.
It is likely, but not yet proven, that similar mechanisms occur in more common (sporadic) forms of AD. Such changes probably start at a later age since the onset of sporadic AD typically occurs when people are over 70 years of age. Nevertheless, it is possible, and perhaps likely, that changes in the brain begin decades prior to clinically observable symptoms.
Treatments that have been developed to stop AD have so far been unsuccessful. It is reasonable to ask whether this lack of success reflects the fact that these treatments are initiated after the illness is clinically evident, many years after changes have already started occurring in the brain. Another critical group of studies will begin soon in which family members of persons with DIAD will participate in medication trials to determine if promising treatments can alter the rate of changes in CSF beta-amyloid and other pre-symptomatic biomarkers. Drugs that prevent changes in these biomarkers can then be tested to see if they prevent or delay the onset of illness. If drugs can stop or delay the progression of illness in the DIAD families, they may work for more common, sporadic forms of the illness. These studies will involve a unique partnership between academia and the pharmaceutical industry taking advantage of state-of-the-art science and treatments.
All of us should be grateful that families with such a devastating inherited disease are willing to volunteer in these important studies. We hope that their altruism will help scientists discover strategies to halt or prevent the long chain of events that precedes the development of clinical AD.
This column was co-written by Eugene Rubin MD, PhD and Charles Zorumski MD.