Dementia usually is considered a disease of the elderly, but Alzheimer’s disease and other types of dementia are detected in many who are younger than 65, and early diagnosis of the disorders can be elusive, a leading specialist on dementias told a recent Capitol Hill briefing hosted by AAAS.
Murray Grossman, a professor of neurology at the University of Pennsylvania, said it is important for health professionals and affected families to recognize that early-onset dementias are not uncommon, that each type is triggered by different microscopic pathologies in the brain, and that treatments are on the horizon.
“Disease-modifying treatments are emerging for each specific cause of dementia,” Grossman said. But education on the extent and character of the various early-onset (also called young-onset) dementias is crucial in order to assure that cases are identified early enough for interventions that might help.
Grossman spoke 12 September at the third series of neuroscience briefings hosted at the Rayburn House Office Building by AAAS through the support of the Dana Foundation. The briefings were organized in conjunction with Rep. Brian Bilbray (R-California) and Rep. Chaka Fattah (D-Pennsylvania). Alan I. Leshner, CEO of AAAS and a former deputy director and acting director of the National Institute of Mental Health, served as moderator.
Patrick A. Griffith, professor of internal medicine and chief of neurology at the Morehouse School of Medicine in Atlanta, also spoke at the briefing about dementia in African Americans, who are 2.5 times more likely than whites to be affected by Alzheimer’s disease. “Proportionately, there are more African-Americans with Alzheimer’s disease than any other group,” Griffith said.
In the African American community, women and those who have a first-degree relative (a parent, a brother or sister, a son or daughter) with the disease are the most susceptible to Alzheimer’s, Griffith said. African Americans also are particularly susceptible to a form of dementia associated with vascular disease and restricted blood flow to the brain, he said. Many live in Southeastern states that make up the so-called “stroke belt” where the incidence of vascular disease is higher than elsewhere in the United States.
African Americans also tend to be diagnosed with Alzheimer’s at later stages of the disease, Griffith said, and cases of early-onset dementia, both for Alzheimer’s and other disorders, may be missed. He said that some care providers who treat African Americans still consider Alzheimer’s to be an “old timer’s disease” and can miss signs of early-onset dementia. Families also may only bring a relative’s condition to the attention of health care providers when behaviors such as memory loss and confusion can no longer be overlooked.
Young-onset dementia—a progressive decline in mental processes that is severe enough to interfere with job performance and social functioning in those less than 65 years of age—is not rare, Grossman said. Two community surveys found incidence rates of 1 in 2000 for those between the ages of 30 and 65 and 1 in 1000 for ages 45 to 65.
Patients with late-onset Alzheimer’s disease typically show memory problems as the first symptoms, Grossman said. The problems have been traced to deterioration in the hippocampus, a brain structure associated with memory, and other neural tissues. The microscopic brain abnormalities associated with the disease include clumps of proteins called amyloid plaques and tangles of another protein called tau.
In the young-onset forms of Alzheimer’s, the first symptoms often involve problems other than memory loss, Grossman said, and the physical manifestations of the disease appear in brain structures other than the hippocampus.
A variant that causes language difficulties is marked by deterioration in the left frontal and temporal lobes of the brain. A second variant, focused in the prefrontal cortex, involves problems with executive function: having trouble concentrating, making decisions, staying on task, or paying attention to several things at once. And a third variant, focused in the parietal lobe of the brain, is marked by visual-spatial problems such as misjudging distances and motion. Shadows on the floor may look like holes, for example, and a patient may have trouble finding food on a plate.
In patients with young-onset variants of Alzheimer’s, the underlying brain pathology is essentially the same as late-onset cases of the disease—appearance of amyloid plaques and tau tangles. Researchers have been pursuing treatments that would normalize amyloid metabolism in the brain and rid neurons of the tau tangles that cripple their function.
But clinical trials aimed at reducing brain degeneration in Alzheimer’s patients with mild to moderate dementia have been disappointing so far. Many specialists argue that the emerging ability to detect the start of the disease years before initial symptoms appear could allow treatment at a preclinical stage where intervention may be more effective. This may be possible in patients with an inherited disorder, Grossman said, “but we are only beginning to develop early markers of Alzheimer’s disease for individuals in the general population.”
There are many other young-onset dementias in addition to those involving Alzheimer’s disease, and each has its own diagnosis and treatment challenges. The disorders can mimic young-onset Alzheimer’s in their initial symptoms, Grossman said, including progressive language problems, executive and social problems, and visual-spatial difficulties.
“These conditions can be very similar to young-onset Alzheimer’s disease,” Grossman said. “It is essential to distinguish these cases from Alzheimer’s disease because they are caused by a very different microscopic abnormality. If we want to treat patients effectively, we have to make sure we understand what they have.”
These conditions include a spectrum of disorders called frontotemporal degeneration or FTD. Cases of early-onset FTD are seen just as often as early-onset Alzheimer’s in patients younger than 65, Grossman said.
One FTD variant is called semantic dementia and is marked by an inability to name or recognize familiar objects. Grossman showed a video of a woman who had worked as a chef and could not name or recognize a vegetable peeler. In 85% of cases, semantic dementia is marked by deposits of a protein called TDP-43 in the left temporal lobe of the brain, Grossman said. The protein normally protects neurons from inflammatory damage, he said, and use of specific kinds of anti-inflammatory agents might be useful in treating the disorder.
Another early-onset FTD variant is called progressive nonfluent aphasia. Grossman showed a video of a woman with the disease who had very slow and effortful speech, and struggled to describe what she did from day to day during the week. This is related in part to grammatical difficulty in understanding and expressing sentences, Grossman said. The disorder affects the lower frontal lobe of the brain, he said, and is marked in 75% of cases by misfolded tau proteins that differ in their appearance from the tangles seen in Alzheimer’s disease. A clinical trial is underway with a medication aimed at stabilizing the nerve cell structures where the tau protein is found.
Given the variety of early-onset dementias, how can specialists determine who has which disease? FTD can be distinguished from Alzheimer’s through multi-modal imaging studies that picture several aspects of brain structure, Grossman said, and there are promising efforts to find biomarkers in cerebrospinal fluid that can accurately help doctors diagnose the disorder in living patients.
FTD appears to be inherited in about 30% of cases, Grossman said, and specific genetic mutations have been identified in about half of these FTD cases, Grossman said. The pattern of inheritance is autosomal dominant, meaning that a patient only needs to get an abnormal gene from one parent in order to inherit the disease.
Genetics also plays a role in early-onset Alzheimer’s. About half of the cases are called familial Alzheimer’s disease or FAD, which is caused by one of several single-gene mutations that promote formation of the abnormal amyloid proteins. FAD is also autosomal dominant, so a child whose mother or father carries a genetic mutation for the disorder has a 50/50 chance of inheriting the mutation. If the mutation is in fact inherited, the child almost surely will develop the disease.
In one effort to treat young-onset Alzheimer’s, a collaborative effort called the Alzheimer’s Prevention Initiative has begun testing an anti-amyloid agent in about 300 people from a large extended family in Colombia who carry a gene mutation that causes Alzheimer’s by age 45.