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Genomic Basis of Personalized Approach to Alzheimer Disease
Alzheimer’s disease (AD) is a polygenic disorder and several genes as well as poly-
morphisms are being identifi ed. These are mostly associated with membrane pro-
teins. Their role as a risk factor and relation to certain forms of AD is reported and
is under further investigation. Genomic research in AD has increased the under-
standing of pathomechanisms leading to neurodegeneration and dementia.
Identifi cation of rare, disease-causing mutations in amyloid precursor protein
(APP), PSEN1, and PSEN2 causing early-onset familial AD, was followed by the
discovery of APOE as the single most important risk factor for late-onset AD
(LOAD). Later genome-wide association studies delivered several additional AD
susceptibility loci that are common in the general population, but exert only very
small risk effects. As a result, a large proportion of the heritability of AD continues
to remain unexplained by the currently known disease genes.
The interaction of different transcription factors with the regulatory region of the
ApoE gene plays an important role in the neuroinfl ammatory process seen in AD
and is a target for developing new therapeutics for the disease. Genotype-specifi c
responses of AD patients to a particular drug or combination of drugs have been
demonstrated, although several studies examining the role of ApoE have produced
confl icting results. The pharmacogenomics of AD may, in the future, contribute to
optimizing drug development and therapeutics, increasing effi cacy and safety, and
reducing side effects.
Associations between the GAB2 gene and LOAD risk has been characterized in
APOE 34 carriers by genome-wide survey of >300,000 SNPs (Reiman et al. 2007 ).
Discovery of this LOAD susceptibility gene, if replicated, provides new opportuni-
ties to investigate LOAD pathogenesis, predisposition, treatment, and prevention.
Genome-wide studies using even higher density platforms and compound genetic
analyses in suffi ciently large samples of well-characterized cases and controls
promise to play increasingly important roles in the scientifi c understanding, evalu-
ation, personalized treatment, and prevention of AD.
Genotype-specifi c responses of AD patients to a particular drug or combination
of drugs has been demonstrated although several studies examining the role of
ApoE produced confl icting results. A study of the effect of galantamine on cognitive
performances in AD patients correlated it with apoE genotyping (Babic et al. 2004 ).
A signifi cant number of responders (71 %) were observed among apoE4 homozy-
gous patients. The subgroup of apoE4 homozygous patients with AD in its mild to
moderate stage may be considered as responders to galantamine. The pharmacoge-
nomics of AD may contribute in the future to optimize drug development and thera-
peutics, increasing effi cacy and safety, and reducing side effects in accordance with
the concept of personalized medicine.
Apart from ApoE, ~20 genes are associated with AD. One of these, SORL1, was
discovered during an international study that analyzed DNA from > 6,000 persons
from an isolated population in the Dominican Republic. The study found that
this gene can raise the risk of developing AD three times in this population
(Rogaeva et al. 2007 ). Another identifi ed gene, CALHM1, encodes the essential
component of a cerebral Ca2+ channel that controls Aβ levels and susceptibility to
12 Personalized Management of Neurological Disorders