Investigators at Washington University School of Medicine in St. Louis have identified a genetic variation associated with an earlier age of onset in Alzheimer's disease.
Unlike genetic mutations previously linked to rare, inherited forms of early-onset Alzheimer's disease - which can strike people as young as their 30s or 40s - these variants influence an earlier presentation of symptoms in people affected by the more common, late-onset form of the disease.
Two principal features characterize Alzheimer's disease in the brain: amyloid plaques and neurofibrillary tangles. The plaques contain a protein called amyloid-beta. The tangles are made of a protein called tau.
The research team analyzed DNA from 313 subjects from Washington University's Alzheimer's Disease Research Center (ADRC), focusing on locations in the tau gene that previously have been found to vary between people.
"We focused on this gene for two reasons: First, it codes for the tau protein that we find in neurofibrillary tangles, and secondly, some studies in the scientific literature show an association between the gene and Alzheimer's disease, while others do not," says principal investigator Alison M. Goate, D. Phil., the Samuel and Mae S. Ludwig Professor of Genetics in Psychiatry and professor of neurology. "Even a study from our own group had found no association between tau gene variants and Alzheimer's disease."
But this study, reported in the June 10 issue of the Proceedings of the National Academy of Sciences, changes that. One reason past studies may have produced conflicting results is that most, if not all, people have amyloid plaques in the brain years before they develop clinical symptoms of Alzheimer's.
"It's not uncommon for us to determine that an older person is fully intact mentally only to find the presence of substantial Alzheimer's pathology on examining that person's brain after death," says John C. Morris, M.D., the Harvey A. and Dorismae Friedman Distinguished Professor of Neurology and director of the ADRC and of the Harvey A. Friedman Center for Aging. "We suspect that Alzheimer lesions may be present in the brain long before we can detect any clinical symptoms."
Previous research from Goate's colleagues David M. Holtzman, M.D., the Andrew B. and Gretchen P. Jones Professor and head of the Department of Neurology, and Anne M. Fagan, Ph.D., associate professor of neurology, measured soluble forms of amyloid-beta and tau proteins in the cerebrospinal fluid. They determined that amyloid-beta levels indicate whether or not amyloid plaques are present in the brain.
"A particular form of amyloid-beta called amyloid-beta 42, tends to be higher in the cerebrospinal fluid of normal individuals and lower in patients with Alzheimer's disease and in cognitively normal people who have amyloid plaques in the brain," says Holtzman. "Tau protein levels in the cerebrospinal fluid increase when a person starts developing dementia."
Finding those amyloid deposits once required examination of the brain after a person's death, but researchers now can detect their presence by assessing them with positron emission tomography (PET) imaging as well as measuring amyloid beta 42. When PET imaging detects amyloid in the brain, patients have lower levels of amyloid-beta 42 in their cerebrospinal fluid.
Goate's team found that four DNA sequence variants in the tau gene were associated with higher levels of tau protein in the cerebrospinal fluid. Then they divided patients into two groups. One group had evidence of plaques in the brain, while the other did not. The investigators found that the variations in the gene are only associated with an increase in tau protein levels in the cerebrospinal fluid when there is evidence of amyloid plaques in the brain.
Armed with those findings, Goate's team predicted that the variants in the tau gene that contributed to higher levels of tau protein in the cerebrospinal fluid would be associated with a younger age at the onset of Alzheimer's disease symptoms.