Defining Molecular Targets to Prevent Alzheimer Disease

Abstract

An explosion of new techniques to explore DNA and protein biology during the last 2 decades has illuminated one of the most enigmatic and intractable subjects in biomedicine—neurodegeneration. Eponymic diseases of the nervous system that were untilrecentlycharacterizedbymechanisticignoranceandtherapeuticnihilismarefalling steadily to the power of molecular genetics, cell biology, biochemistry, and animal modeling. Alzheimer, Huntington, Creutzfeld-Jacob, and Parkinson diseases, as well as amyotrophic lateral sclerosis, spinocerebellar atrophies, frontotemporal dementia, and other previously obscure diseases, have all yielded rapid progress in the deciphering of their biochemical pathology and genetic underpinnings. This sea change in our understanding of a group of incurable diseases that confer enormous personal and societal burdens has brought us to the verge of rationally designed therapies and, in some cases, into actual human trials. Perhaps the foremost example, both in terms of its impact on society and how far we have moved toward clinical application, is that of Alzheimer disease (AD). Thismostcommonofthelate-lifedementias is rising in prevalence with the aging ofpopulationsindevelopedcountriesand may now affect 20 to 30 million people worldwide. I will review the classic neuropathological lesions of AD that, despite some doubts along the way, turned out to provide a road map to the etiology and pathogenesis of the disease. Then, I willdiscusshowelucidatingthegenotypeto-phenotype relationships of certain genetic alterations linked to familial forms ofADhaspinpointedmoleculartargetsfor treatment and prevention, some of which are now being addressed in clinical trials.

Keywords

Affiliated Institutions

• Brigham and Women's Hospital US
• Harvard University US

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