Current insights into the pathophysiology of Alzheimer's disease: selecting targets for early therapeutic intervention

被引:23
作者
Hampel, Harald [1 ]
机构
[1] Goethe Univ Frankfurt, Dept Psychiat Psychosomat Med & Psychotherapy, D-60528 Frankfurt, Germany
关键词
MCI; neurodegeneration; asymptomatic; clinical trials; dementia; disease modification; Ginkgo biloba; EGb; 761; MILD COGNITIVE IMPAIRMENT; BIOMARKERS; PREVENTION; DIAGNOSIS; DEMENTIA; TRIALS;
D O I
10.1017/S1041610212000579
中图分类号
B849 [应用心理学];
学科分类号
040203 ;
摘要
The development of therapies for Alzheimer's disease (AD) presents numerous challenges for physicians, researchers, and the pharmaceutical industry, with many drug candidates showing promise at one stage of clinical research only to fall at the next hurdle. A great number of drugs with a variety of targets and clusters of mechanisms are currently in various stages of basic and clinical investigation. However, these hypothesis-derived agents may be tested much too late in the chronically progressive disease process to demonstrate meaningful effects or outcomes, mirroring the clinical syndromal scenario in which the underlying pathophysiological disease condition is frequently diagnosed extremely late. Moreover, the complexity of the disease calls for developments and improvements in study designs and methods modeled for different target populations and disease stages (e.g. asymptomatic to prodromal to syndromal). New integrated concepts and models of disease pathophysiology, use of validated and qualified biomarkers, outcomes and endpoints, particularly the development of a surrogate outcome, may allow targeting of characteristic mechanism-derived therapies of specifically affected biological systems at different time-points in the disease process, providing increasing opportunities for early and preventative intervention. A core set of feasible diagnostic and predictive biomarkers is already validated and in the process of standardization; however, continued and intensified research efforts will likely reveal a variety of novel biomarkers that grasp the complexity of the underlying disease process. In the future, trials of drugs to modify and prevent AD may embrace enrichment strategies and maybe be stratified by disease stage, genetic factors as well as by disease endophenotypes.
引用
收藏
页码:S10 / S17
页数:8
相关论文
共 16 条
[1]   Alzheimer's disease therapeutic research: the path forward [J].
Aisen, Paul S. .
ALZHEIMERS RESEARCH & THERAPY, 2009, 1 (01)
[2]   THE RISE AND FALL OF DIMEBON [J].
Bezprozvanny, Ilya .
DRUG NEWS & PERSPECTIVES, 2010, 23 (08) :518-523
[3]   What Can Be Inferred from the Interruption of the Semagacestat Trial for Treatment of Alzheimer's Disease? [J].
Cummings, Jeffrey .
BIOLOGICAL PSYCHIATRY, 2010, 68 (10) :876-878
[4]   Ginkgo biloba for Prevention of Dementia A Randomized Controlled Trial [J].
DeKosky, Steven T. ;
Williamson, Jeff D. ;
Fitzpatrick, Annette L. ;
Kronmal, Richard A. ;
Ives, Diane G. ;
Saxton, Judith A. ;
Lopez, Oscar L. ;
Burke, Gregory ;
Carlson, Michelle C. ;
Fried, Linda P. ;
Kuller, Lewis H. ;
Robbins, John A. ;
Tracy, Russell P. ;
Woolard, Nancy F. ;
Dunn, Leslie ;
Snitz, Beth E. ;
Nahin, Richard L. ;
Furberg, Curt D. .
JAMA-JOURNAL OF THE AMERICAN MEDICAL ASSOCIATION, 2008, 300 (19) :2253-2262
[5]   Research criteria for the diagnosis of Alzheimer"s disease: revising the NINCDS-ADRDA criteria [J].
Dubois, Bruno ;
Feldman, Howard H. ;
Jacova, Claudia ;
Dekosky, Steven T. ;
Barberger-Gateau, Pascale ;
Cummings, Jeffrey ;
Delocourte, Andre ;
Galasko, Douglas ;
Gauthier, Serge ;
Jicha, Gregory ;
Meguro, Kenichi ;
O'Brien, John ;
Pasquier, Florence ;
Robert, Philippe ;
Rossor, Martin ;
Solloway, Steven ;
Stern, Yaakov ;
Visser, Pieter J. ;
Scheltens, Philip .
LANCET NEUROLOGY, 2007, 6 (08) :734-746
[6]   Revising the definition of Alzheimer's disease: a new lexicon [J].
Dubois, Bruno ;
Feldman, Howard H. ;
Jacova, Claudia ;
Cummings, Jeffrey L. ;
DeKosky, Steven T. ;
Barberger-Gateau, Pascale ;
Delacourte, Andre ;
Frisoni, Giovanni ;
Fox, Nick C. ;
Galasko, Douglas ;
Gauthier, Serge ;
Hampel, Harald ;
Jicha, Gregory A. ;
Meguro, Kenichi ;
O'Brien, John ;
Pasquier, Florence ;
Robert, Philippe ;
Rossor, Martin ;
Salloway, Steven ;
Sarazin, Marie ;
de Souza, Leonardo C. ;
Stern, Yaakov ;
Visser, Pieter J. ;
Scheltens, Philip .
LANCET NEUROLOGY, 2010, 9 (11) :1118-1127
[7]   Progression of Mild Cognitive Impairment to Dementia in Clinic- vs Community-Based Cohorts [J].
Farias, Sarah Tomaszewski ;
Mungas, Dan ;
Reed, Bruce R. ;
Harvey, Danielle ;
DeCarli, Charles .
ARCHIVES OF NEUROLOGY, 2009, 66 (09) :1151-1157
[8]   Biomarkers for Alzheimer's disease: academic, industry and regulatory perspectives [J].
Hampel, Harald ;
Frank, Richard ;
Broich, Karl ;
Teipel, Stefan J. ;
Katz, Russell G. ;
Hardy, John ;
Herholz, Karl ;
Bokde, Arun L. W. ;
Jessen, Frank ;
Hoessler, Yvonne C. ;
Sanhai, Wendy R. ;
Zetterberg, Henrik ;
Woodcock, Janet ;
Blennow, Kaj .
NATURE REVIEWS DRUG DISCOVERY, 2010, 9 (07) :560-574
[9]   Reimagining Alzheimer's Disease-An Age-Based Hypothesis [J].
Herrup, Karl .
JOURNAL OF NEUROSCIENCE, 2010, 30 (50) :16755-16762
[10]   Alzheimer's disease: clinical trials and drug development [J].
Mangialasche, Francesca ;
Solomon, Alina ;
Winblad, Bengt ;
Mecocci, Patrizia ;
Kivipelto, Miia .
LANCET NEUROLOGY, 2010, 9 (07) :702-716