TY - JOUR
T1 - Genetic Heterogeneity in Alzheimer Disease and Implications for Treatment Strategies
AU - Ringman, John M.
AU - Goate, Alison
AU - Masters, Colin L.
AU - Cairns, Nigel J.
AU - Danek, Adrian
AU - Graff-Radford, Neill
AU - Ghetti, Bernardino
AU - Morris, John C.
N1 - Funding Information:
Acknowledgments This work was supported by the National Institute on Aging grant UF1 AG032438 (J.C. Morris, principal investigator), P50 AG016570, the Easton Consortium for Alzheimer’s Disease Drug Discovery and Biomarker Development, and the German Center for Neurodegenerative Diseases (DZNE).
Funding Information:
Neill Graff-Radford has received a National Institutes ofHealth grant (Dominantly Inherited Alzheimer Network study) and a grant from Eli Lilly.
Publisher Copyright:
© 2014, The Author(s).
PY - 2014/11
Y1 - 2014/11
N2 - Since the original publication describing the illness in 1907, the genetic understanding of Alzheimer’s disease (AD) has advanced such that it is now clear that it is a genetically heterogeneous condition, the subtypes of which may not uniformly respond to a given intervention. It is therefore critical to characterize the clinical and preclinical stages of AD subtypes, including the rare autosomal dominant forms caused by known mutations in the PSEN1, APP, and PSEN2 genes that are being studied in the Dominantly Inherited Alzheimer Network study and its associated secondary prevention trial. Similar efforts are occurring in an extended Colombian family with a PSEN1 mutation, in APOE ε4 homozygotes, and in Down syndrome. Despite commonalities in the mechanisms producing the AD phenotype, there are also differences that reflect specific genetic origins. Treatment modalities should be chosen and trials designed with these differences in mind. Ideally, the varying pathological cascades involved in the different subtypes of AD should be defined so that both areas of overlap and of distinct differences can be taken into account. At the very least, clinical trials should determine the influence of known genetic factors in post hoc analyses.
AB - Since the original publication describing the illness in 1907, the genetic understanding of Alzheimer’s disease (AD) has advanced such that it is now clear that it is a genetically heterogeneous condition, the subtypes of which may not uniformly respond to a given intervention. It is therefore critical to characterize the clinical and preclinical stages of AD subtypes, including the rare autosomal dominant forms caused by known mutations in the PSEN1, APP, and PSEN2 genes that are being studied in the Dominantly Inherited Alzheimer Network study and its associated secondary prevention trial. Similar efforts are occurring in an extended Colombian family with a PSEN1 mutation, in APOE ε4 homozygotes, and in Down syndrome. Despite commonalities in the mechanisms producing the AD phenotype, there are also differences that reflect specific genetic origins. Treatment modalities should be chosen and trials designed with these differences in mind. Ideally, the varying pathological cascades involved in the different subtypes of AD should be defined so that both areas of overlap and of distinct differences can be taken into account. At the very least, clinical trials should determine the influence of known genetic factors in post hoc analyses.
KW - Alzheimer’s disease
KW - Amyloid precursor protein
KW - Apolipoprotein E
KW - Genetic
KW - Heterogeneity
KW - Presenilin
UR - http://www.scopus.com/inward/record.url?scp=84919665907&partnerID=8YFLogxK
U2 - 10.1007/s11910-014-0499-8
DO - 10.1007/s11910-014-0499-8
M3 - Review article
C2 - 25217249
AN - SCOPUS:84919665907
SN - 1528-4042
VL - 14
JO - Current Neurology and Neuroscience Reports
JF - Current Neurology and Neuroscience Reports
IS - 11
M1 - 499
ER -