Biomedical Frontiers: Winter 1995, Vol.2, No.2
Untangling Alzheimer's Disease

Several clinical and basic research programs are dedicated to understanding and treating Alzheimer's disease (AD) at Columbia-Presbyterian Medical Center.

During the last five years, clinical programs led by Dr. Richard Mayeux, director of the Gertrude H. Sergievsky Center for the study of nervous system disorders, have investigated the heterogeneity of AD, incorporating brain imaging and genetic epidemiology in their efforts. Clinical trials for investigational drugs also were initiated recently.

In collaboration with Dr. Barry Gurland, director of the Center for Geriatrics and Gerontology, a framework to study dementia in a multiethnic population was developed. This enables AD diagnosis to be as free of bias to culture, language, and education as possible. In a second collaboration with Dr. Tom Tatemichi, assistant professor of neurology, and Dr. J.P. Mohr, Daniel Sciarra Professor of Neurology, Dr. Mayeux and his team developed a study of stroke victims who are most likely to develop dementia. This group has continued to contribute to the role of cerebral vascular disease and dementia.

In the summer of 1993, Dr. Mayeux and others at the Sergievsky Center were one of several groups to report a higher frequency of the e4 allele of apolipoprotein E among patients with AD. Patients with AD were 17 times more likely to have two copies of the apolipoprotein e4 allele compared to controls and four times more likely to have one copy of the e4 allele. The data support the hypothesis that apolipoprotein e4 is associated with susceptibility to AD or may be physically linked to another susceptibility gene. The researchers also found an association of apolipoprotein e2 and AD in African-Americans.

Dr. Mayeux and Dr. Nicole Schupf, associate research scientist at the Sergievsky Center, also have been involved in a study of the relationship of Alzheimer's disease and Down's syndrome, a disease characterized by an extra chromosome 21. Because adults with Down's syndrome develop neuropathological changes of AD by age 40, and because the extra chromosome usually results from problems in the mother's eggs, Drs. Schupf and Mayeux hypothesized there might be an increased frequency of AD among the mothers of people with Down's syndrome. The researchers found women under 35 who gave birth to Down's syndrome babies are five times more likely to develop AD later in life than mothers of children with other developmental disorders. The researchers now are studying the relationship between this susceptibility of women to getting an extra copy of chromosome 21 in eggs to changes in other tissues that could lead to AD. They believe this association might be due to accelerated aging in these women.

Under investigation by CPMC basic scientists, led by Dr. Michael Shelanski, Delafield Professor of Pathology and department chair, are the causes of the two major pathological hallmarks in the brains of AD: neurofibrillary tangles and senile plaques. A senile plaque in AD is a complex lesion with a core made up of a central deposit of extracellular amyloid fibrils surrounded by dystrophic neurites; activated microglia, immune cells in the brain; astrocytes; and other biomolecules. The plaque core fibrils are amyloid filaments composed of the b-amyloid peptide, a proteolytic fragment of the b-amyloid precursor protein.

Neurofibrillary tangles in the neuronal cell body are composed of abnormally phosphorylated paired helical filaments (PHF). This abnormal phosphorylation presumably changes the microtubule associated protein, tau, causing it not to bind to microtubules. Phosphorylated tau protein not bound to microtubules is thought to self-associate, resulting in PHFs.

The relationship between the amyloid plaques and the formation of paired helical filaments is not known. But there is evidence that interleukin-1 is overexpressed in AD and that it might be responsible for some of AD's progressive neuronal degeneration. The interaction of amyloid proteins with microglia leads to the release of cytokines like IL-1. Recent results at Columbia have shown abnormally phosphorylated tau in neurons can be induced by IL-1. Thus, IL-1 could lead to activation of tau specific kinases or inactivation of tau specific phosphatases.

Columbia researchers are studying the effect of amyloid peptides and plaques on microglial cells; the effect of IL-1, which is released by microglial cells in AD, on the phosphorylation of tau; and the kinases and phosphatases acting on tau in normal and AD brains.