Genetics Program Research - AD Basic Research

While great strides have been made in the genetics and histochemistry of Alzheimer disease (AD), mechanisms leading to disease are not fully understood. Advanced age, a positive family history of dementia, and the e4 allele of apolipoprotein E (APOE) are three prominent risk factors. Our intensive studies of these factors and numerous postulated AD susceptibility genes have resulted in a better understanding of the genetic basis and age dependent penetrance of the disorder, as well as provided several clues about the interaction of genetic and non-genetic factors on disease risk. Our work has provided several lines of evidence supporting the idea that risk factors for vascular disease increase AD susceptibility and/or influence the expression of the disorder. The Genetics Program directs and collaborates in several projects aimed at identifying novel genetic factors, and examining interactions between genes, non-genetic risk factors, and novel biomarkers for developing AD. Several of these projects are described below. Results of these studies will speed the development of new diagnostic techniques and treatments for AD.

Genetic Mapping Studies

More than a decade ago, in collaboration with Dr. Peter St. George-Hyslop at the University of Toronto, we mapped a gene for early-onset familial AD to chromosome 14 which was identified in 1995 as presenilin 1. The discovery of this gene (PS1) and the protein it encodes engendered an entire “cottage industry” of scientists focused on the role of presenilins in AD pathogenesis including APP processing. More recently, we partnered again with Dr. St. George-Hyslop in a search for proteins which modulate the effect of presenilin on APP processing. This effort led to the identification of a novel protein called nicastrin (aptly named after the Italian village which is home to one of the original large extended families instrumental in the identification of PS1). Our subsequent studies determined that nicastrin is a functional component of PS1 complexes involved in the unusual intramembranous proteolytic processing of transmembrane proteins including ßAPP.

For nearly ten years, our laboratory (and most AD geneticists worldwide) has concentrated efforts in mapping genes for the common late onset form of AD. In a collaborative project with Dr. St. George-Hyslop, we confirmed the location of an AD gene on chromosome 12 in a large sample of families of European origin. Despite replication of this finding in other outbred populations by other investigators, the chromosome 12 AD gene (and, incidentally, putative AD genes on several other chromosomes) has been elusive. To mediate against the likely confounding influences of genetic heterogeneity and population admixture on gene searches, we organized a large genetic study of AD in an inbred Arab community in northern Israel. Previous epidemiological studies in this community called Wadi Ara revealed an extraordinarily high prevalence of AD (about twice that in western European countries). We discovered that the high disease prevalence is not associated with APOE e4 which is virtually absent in this community. A subsequent genome scan and follow up study revealed evidence for AD loci on chromosomes 9, 10 and 12, regions implicated in studies of other outbred populations.

The MIRAGE (Multi Institutional Research of Alzheimer Genetic Epidemiology) Project, funded by the National Institute on Aging since 1991, is the largest genetic epidemiology study of AD in the world. Thus far, we have collected detailed clinical, risk factor and family history information on more than 2,500 rigorously examined AD patients. Analyses of these data and DNA from a large portion of these families has resulted in more than 50 original research papers focusing on a variety of genetic and non-genetic factors including head trauma, alcohol consumption, smoking, depression, use of various medications (e.g., non-steroidal inflammatory drugs, statins, estrogen), and parental age. Genetic modeling and survival analysis studies revealed that the common form of AD which appears typically after age 65 is neither inevitable nor a Mendelian disease, but still highly heritable with one or two genes having a major influence on susceptibility. We know now that one of these genes is APOE. The discovery in 1993 that the e4 variant of APOE is associated with AD in a dose-dependent fashion has been confirmed in dozens of studies of populations from many parts of the world. However, the MIRAGE Study revealed that the e4 variant is more weakly associated with disease in men and persons older than 75 years. The MIRAGE Study has also assembled the largest collection of African American families for AD research. Initial studies of these families have shown that first-degree biological relatives of African Americans with AD have a higher life time risk of dementia than do relatives of Whites with AD. However, the additional risk of dementia conferred by being a biological relative or by being female is similar in African American and White families. Our studies of the AD/e4 association in African Americans provided for the first time clear evidence that APOE genotype influences AD risk in an age-dependent fashion similar to Whites.

We have now turned the attention of the MIRAGE and Wadi Ara studies to the growing body of evidence from pathological, epidemiological and genetic studies that risk factors for vascular disease also enhance risk of AD. However, since most epidemiological studies lack neuroimaging data, it is unclear whether the apparent association between vascular risk factors and AD is mediated via ischemic injury to the brain, acceleration of the primary Alzheimer neurodegenerative process, or some other process. Some vascular risk factors are more prevalent in African American and Japanese American populations than in Caucasians. In the current phase of the MIRAGE Study, we are evaluating the association among genes involved in vascular function, indicators of cerebrovascular health including blood pressure and structural brain imaging (MRI), and susceptibility to AD in an anticipated sample of 1000 families (Caucasian, African American, and Japanese American) comprising at least one AD patient and one cognitively healthy sibling. The ultimate goal of this study is to find new risk factors and potential targets (genetic and non-genetic) for therapy. While non-genetic risk factors may be more easily modifiable, genetic risk factors or some combination of genetic and non-genetic risk factors, may allow us to identify vulnerable individuals and focus preventive therapies upon those who have the highest risk. Therefore, results from this study may have immediate impact on the development of new treatment or prevention strategies.

Lindsay Farrer, Ph.D., Project Director

ADAPT (Alzheimer's Disease Anti-inflammatory Prevention Trial) - a new prevention study funded by the National Institute on Aging (NIA), part of the National Institutes of Health (NIH), to determine if non-steroidal anti-inflammatory medication will prevent or delay the onset of Alzheimer's disease.

MIRAGE (Multi-Institutional Research in Alzheimer's Genetic Epidemiology) - the goal of MIRAGE is to evaluate the association between genetic and non-genetic risk factors for Alzheimer's disease.

REVEAL (Risk Evaluation and Education for Alzheimer's Disease) - provides healthy adult children and siblings of Alzheimer's Disease (AD) patients with genetic susceptibility testing and risk assessment fo AD (information about their own chances to develop the disease).

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