Frank, Richard

The current criteria for classification of Alzheimer's disease (AD) have deficiencies that limit drug development, research, and practice. The current standard for the clinical diagnosis of AD, the National Institute of Neurological and Communicative Disorders and Stroke (now known as the National Institute of Neurological Disorders and Stroke), and the Alzheimer's Disease and Related Disorders Association (now known as the Alzheimer's Association) criteria, are nearly 25 years old and have not been revised to incorporate advances in the epidemiology and genetics of AD, studies of clinicopathologic correlations and recent studies of potential diagnostic biomarkers. In a very real sense our ability to diagnose AD with a very high level of certainty has outpaced our current diagnostic criteria. The Alzheimer's Association Research Roundtable convened a meeting in April 2009 to discuss new data and technologies that could, with further development, enable improvements in the clinical diagnosis of AD, especially in its earliest and mildest stages. This meeting reviewed the current standards for detecting and defining the clinical presentation of AD and discussed areas that could contribute to earlier and more accurate definitive clinical diagnosis. These included clinical, neuropsychological, and other performance‐based assessments, genetic contributions, and biochemical and neuroimaging biomarkers that could reflect AD pathology and lead to better ascertainment of AD, mild cognitive impairment, and presymptomatic AD.

A commonly carried allele of the obesity-related FTO gene is associated with reduced brain volume in the healthy elderly

Ho, April J., Stein, Jason L. , Hua, Xue , Lee, Suh , Hibar, Derrek P., Leow, Alex , Dinov, Ivo D. , Toga, Arthur W. , Saykin, Andrew J. , Shen, Li , Pankratz, Nathan , Huentelman, Matthew J. , Craig, David W. , Gerber, Jill D., Allen, April N., Corneveaux, Jason J., Stephan, Dietrich A. , DeCarli, Charles , Dechairo, Bryan, Jack, Clifford R. , Weiner, Michael W. , Raji, Cyrus A. , Becker, James T. , Carmichael, Owen , Thompson, Paul M. , Initiative, the Alzheimer's Disease Neuroimaging, Thal, Leon J., Petersen, Ronald C., Jagust, William J. , Trojanowki, John Q., Toga, Arthur W., Gamst, Anthony, Potter, William Z., Montine, Tom, Anders, Dale, Felmlee, Joel P. , Schuff, Norbert, Alexander, Gene E. , Bandy, Dan, Foster, Norm, Reiman, Eric M. , Shaw, Les, Korecka, Magdalena , Toga, Arthur W., Crawford, Karen , Neu, Scott, Kornak, John , Kachaturian, Zaven, Frank, Richard , Molchan, Susan, Vorobik, Remi, Schneider, Lon S. , Pawluczyk, Sonia, Spann, Bryan , Fleisher, Adam , Vanderswag, Helen, Heidebrink, Judith L. , Johnson, Kris , Doody, Rachelle S., Villanueva‐Meyer, Javier , Chowdhury, Munir , Bell, Karen L. , Mintun, Mark A., Schneider, Stacy, Marson, Daniel , Griffith, Randall, Badger, Beverly, Grossman, Hillel, deToledo‐Morrell, Leyla, Bach, Julie , Duara, Ranjan , Isaacson, Richard , Strauman, Silvia, Albert, Marilyn S. , Pedroso, Julia, Toroney, Jaimie, Santi, Susan M De, Doraiswamy, P. Murali , Petrella, Jeffrey R. , Aiello, Marilyn, Clark, Christopher M. , Pham, Cassie, Nuñez, Jessica, Smith, Charles D., Given, Curtis A., Hardy, Peter , DeKosky, Steven T. , Oakley, MaryAnn, Simpson, Donna M., Ismail, M. Saleem , McCallum, Colleen, Cramer, Steven C. , Mulnard, Ruth A., Mc-Adams-Ortiz, Catherine, Martin-Cook, Kristen, Devous, Michael D. , Cellar, Janet S., Anderson, Heather S., Laubinger, Mary M., Bartzokis, George, Lu, Po H. , Fletcher, Rita, Parfitt, Francine, Farlow, Martin R. , Herring, Scott, Hake, Ann Marie , Dyck, Christopher H. van , MacAvoy, Martha G., Bifano, Laurel A., Chertkow, Howard, Bergman, Howard , Hosein, Chris, Graham, Simon J. , Caldwell, Curtis, Assaly, Michele, Hsiung, Ging‐Yuek Robin , Kertesz, Andrew , Trost, Dick, Bernick, Charles , Johnson, Nancy , Sadowsky, Carl, Villena, Teresa, Mesner, Scott, Aisen, Paul, Johnson, Kathleen, Behan, Kelly E., Johnson, Keith A. , Rosen, Allyson , Tinklenberg, Jared, Ashford, Wes, Connor, Donald J., Obradov, Sanja, Jayam‐Trouth, Annapurni , Wang, Paul J. , Auchus, Alexander P. , Huang, Juebin , DeCarli, Charles , Kittur, Smita, Mirje, Seema, Borrie, Michael, Lee, T‐Y, Asthana, Sanjay , Carlsson, Cynthia M., Highum, Diane, Preda, Adrian , Tariot, Pierre N. , Hendin, Barry , Kataki, Maria , Zimmerman, Earl A. , Celmins, Dzintra, Brown, Alice D., Gandy, Sam, Marenberg, Marjorie E., Rovner, Barry W. , Blank, Karen, Anderson, Karen, Santulli, Robert B. , Paré, Nadia, Williamson, Jeff D. , Raj, Balebail Ashok, Giordano, Amy T., Ott, Brian R. , Wu, Chuang‐Kuo, Cohen, Ronald A. , Wilks, Kerri, Lee, Ting‐Yim , Foroud, Tatiana , Potkin, Steven G. , López, Oscar L. , Initiative, the Alzheimer's Disease Neuroimaging, Toga, Arthur W., Beckett, Laurel , Green, Robert C. , Bernstein, Matt A. , Fox, Nick C. , Koeppe, Robert A. , Foster, Norm, Chen, Kewei , Lee, Virginia M.‐Y. , Toga, Arthur W., Harvey, Danielle , Snyder, Peter J. , Kaye, Jeffrey , Quinn, Joseph F. , Lord, Joanne L. , Stern, Yaakov , Honig, Lawrence S. , Morris, John C. , Tang, Cheuk Ying , Stern, Jessica A. , Shah, Raj C. , Duara, Ranjan , Rusinek, Henry , Leon, Mony J. de , Porsteinsson, Anton P. , Diaz‐Arrastia, Ramon , Levey, Allan I. , Lah, James J. , Burns, Jeffrey M. , Silverman, Daniel H.S. , Johnson, Heather K. , Black, Sandra E. , Feldman, Howard , ROGERS, John H. , Gitelman, Darren R. , Mesulam, Marsel M. , Sperling, Reisa Anne , Rentz, Dorene M. , Sabbagh, Marwan Noel , Killiany, Ronald , Norbash, Alexander , Obisesan, Thomas O. , Friedland, Robert P. , Fletcher, Evan M. , Johnson, Sterling C. , Nguyen, Dana R. , Scharre, Douglas W. , Beversdorf, David Q. , Gandy, Sam , Pearlson, Godfrey D. , Sink, Kaycee M. , Potter, Huntington , Jack, Clifford R , Saykin, Andrew J , Shen, Li , Preda, Adrian , Toga, Arthur W , Stein, Jason L , Thompson, Paul M , Hsiung, Gink-Yuek , Pankratz, Nathan

Proceedings of the National Academy of Sciences | April 19, 2010 | Volume: 107 | Issue: 18 | Pages: 8404-8409

10.1073/pnas.0910878107

A recently identified variant within the fat mass and obesity-associated ( FTO ) gene is carried by 46% of Western Europeans and is associated with an ~1.2 kg higher weight, on average, in adults and an ~1 cm greater waist circumference. With >1 billion overweight and 300 million obese persons worldwide, it is crucial to understand the implications of carrying this very common allele for the health of our aging population. FTO is highly expressed in the brain and elevated body mass index (BMI) is associated with brain atrophy, but it is unknown how the obesity-associated risk allele affects human brain structure. We therefore generated 3D maps of regional brain volume differences in 206 healthy elderly subjects scanned with MRI and genotyped as part of the Alzheimer's Disease Neuroimaging Initiative. We found a pattern of systematic brain volume deficits in carriers of the obesity-associated risk allele versus noncarriers. Relative to structure volumes in the mean template, FTO risk allele carriers versus noncarriers had an average brain volume difference of ~8% in the frontal lobes and 12% in the occipital lobes—these regions also showed significant volume deficits in subjects with higher BMI. These brain differences were not attributable to differences in cholesterol levels, hypertension, or the volume of white matter hyperintensities; which were not detectably higher in FTO risk allele carriers versus noncarriers. These brain maps reveal that a commonly carried susceptibility allele for obesity is associated with structural brain atrophy, with implications for the health of the elderly.