IDENTIFYING GENES PREDISPOSING TO SUCCESSFUL COGNITIVE AGING
The hypothesis driving this study is that centenarians are a select group of people who have a history of aging relatively slowly and who have either markedly delayed or entirely escaped diseases normally associated with aging, such as Alzheimer's disease (AD), cancer, stroke, and heart disease.
The ultimate challenge in this area of research is to identify the genes that are associated with such a survival advantage and the ability to age so well for such a long time without cognitive impairment. We have very exciting preliminary results revealing that centenarians can be the
key to discovering these genes.
Primarily because of funding by the Institute for the Study of Aging, continue careful annual neuropsychological testing and eventual neuropathological study of the centenarian subjects.
Approximately 20% of our participants wish to be postmortem brain donors, but we anticipate
increasing this rate to 50%, again, in part, due to the generosity of the Institute. These neuropsychological-neuropathological correlations will help us better understand what disease-free aging of the brain means and what it looks like; if causes of dementia are different in the extremely old compared with younger individuals; and the type and quantity of changes in the brain that correlate with different levels of cognitive impairment.
At the same time, we are studying the centenarians for genes that may play pivotal roles in determining how centenarians markedly delay or, in some cases, escape cognitive impairment. We have obtained the largest collection of centenarian sibships in the world (N ~ 200). Genome-wide scans from these individuals were performed and the data was given to our statistics colleagues at the Whitehead Institute and Rutgers University for linkage analyses. Based upon scans of 308 individuals making up 137 families, currently we have noted statistically significant linkage to a 20 cM region on chromosome 4. A manuscript reporting these results is currently in the review process. Discovery of genes that powerfully affect processes as broad as rates of aging and/or susceptibility to diseases, such as AD and stroke, would have dramatic impact upon understanding the underpinnings of aging and could, ultimately, lead to promising targets for drug discovery.
In our attempts to locate and recruit sibships, we have enrolled five families with many members achieving extreme old age. Such clustering lends itself to linkage studies similar to those performed in families with clustering for rare diseases (such as Tay-Sachs, cystic fibrosis, and sickle-cell anemia).
In this instance, we are not looking for the cause of a disease but rather a fantastic advantage. Four of these families are described in a recent article published in the Journal of the American Geriatrics Society. Unfortunately, because there is likely to be more than one gene (or the lack of a specific mutation) increasing the probability of achieving exceptional old age, we believe that even 10 members of one family being included in a linkage study is unlikely to produce statistically significant results. However, as we include cousins and perhaps children, such studies might prove to be feasible.
In another approach to gene discovery, we have established a collaboration with gene - expression expert Steven Gullens, PhD, from the Brigham and Women's Hospital. Because we are able to obtain brain tissue at postmortem autopsy within 4 hours of death, we will provide Dr. Gullens with ideal brain tissue samples from regions of specific interest regarding AD, as well as regions that play critical roles in cognition (e.g., frontal lobe and its influence upon executive function) for differential gene expression studies. Determining which genes are active in cognitively intact participants versus those with various causes of cognitive impairment versus
other younger controls should be an efficient approach to discovering genes critical to AD pathogenesis.
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