APOE-ε2: Molecular features, biomarker signature, and neurobehavioral implications
Transcript of APOE-ε2: Molecular features, biomarker signature, and neurobehavioral implications
Featured Research Sessions: F5-04: Neuroprotection in Alzheimer’s Disease: Genetic, Molecular and Environmental FactorsP826
expression is reduced in AD mice. Consequently, SIRT3 substrates includ-
ing mitochondrial fission/fusion GTPases are hyperacetylated. Fasting in
SIRT3-null mice causes excessive oxidative stress, mitochondrial fragmen-
tation, and hyperacetylation of mitochondrial fission/fusion GTPases. Re-
ducing Ab-induced oxidative stress with N-acetyl-cysteine has
restoresmitochondrial dynamics and the acetylation of fission/fusion
GTPases. Conclusions: SIRT3 and mitochondrial dynamics might regulate
hormesis. Enhancing SIRT3 activity might slow neuronal injury in AD.
F5-02-04 THERAPEUTIC APPROACHES TO REMEDY
DEFICITS IN GLUCOSE METABOLISM AND
MITOCHONDRIA
Flint Beal, Weill Cornell Medical College, New York, New York, United
States. Contact e-mail: [email protected]
Background:Many abnormalities in mitochondria and glucose metabolism
have been reported in Alzheimer’s Disease (AD).A critical role of mito-
chondria in AD is supported by direct genetic linkage in some forms of
AD (e.g., TFAM). Together these data suggest that glucose metabolism
and abnormal mitochondria are valid therapeutic targets in AD. Multiple
therapeutic strategies have been developed to treat mitochondrial disorders
in other diseases including neurodegenerative diseases and stroke. Similar
strategies for developing therapies may be beneficial in AD.Methods:Mul-
tiple in vitro approaches have been used to determinemechanism, especially
transcriptional mechanism, and develop therapeutic strategies. Numerous
tactics have been validated in transgenic mice. Some of the approaches
have been tested in other neurodegenerative diseases including Parkinson’s
and Huntington’s disease. Results: Multiple in vitro approaches have been
used to determine mechanism, especially transcriptional mechanism, and
develop therapeutic strategies. Numerous tactics have been validated in
transgenic mice. Some of the approaches have been tested in other neurode-
generative diseases including Parkinson’s and Huntington’s disease.
Conclusions: Multiple strategies are available for treating abnormalities
in glucose utilization and mitochondria. These strategies need to be tested
in models of Alzheimer’s disease neurodegenerative disorders.
FEATURED RESEARCH SESSIONS: F5-03
GENERATING AND EVALUATING EVIDENCE TO INFORM
INSURANCE COVERAGE POLICY FOR ALZHEIMER’S
DIAGNOSTIC TESTS: A MULTISTAKEHOLDER INITIATIVE
F5-03-01 PERSPECTIVE FROM WELLPOINT, A LARGE,
NATIONAL INSURER
John Whitney, Wellpoint, Inc., Chicago, Illinois, United States. Contact
e-mail: [email protected]
Background:As the search for more effective treatments for AD continues,
many questions remain about how to design clinical trials so that it is pos-
sible to evaluate different tests for AD in a way that will generate “adequate”
evidence not only for patients and clinicians, but for insurers as well.
Methods: A policy development group was convened consisting of patient
advocates, clinicians, clinical researchers, manufacturers, and insurers
(Medicare, UnitedHealthcare, Wellpoint, Kaiser). Through review of back-
ground information on the role of biomarkers in diagnosis, insurer evidence
hierarchies, and the current literature on AD diagnostics, the policy group
produced a white paper with specific recommendations to guide the design
of future research. Results: Current evidence on AD diagnostic testing was
categorized using a well-known evidence hierarchy. Of 575 articles identi-
fied, 570 (>99%) reported technical efficacy and diagnostic accuracy infor-
mation, while only 5 (<1%) evaluated data on the impact of testing on
clinicians’ diagnostic impression, and none produced evidence of the impact
of testing on physician decision-making or patient outcomes. Among 15 rec-
ommendations in thewhite paper, key recommendations for research design
include: 1) evaluation of the impact of diagnostic test results on subsequent
patient management; 2) use of simpler, more accessible, and less expensive
test options in enrichment studies using “gold standard” tests for study in-
clusion; and 3) use of decision analysis modeling to simulate long-term clin-
ical and economic outcomes. Conclusions: This initiative presents a set of
research recommendations for AD diagnostic testing that will help clinical
researchers and manufacturers generate the level of evidence required to
meet insurer coverage standards.
F5-03-02 PERSPECTIVE FROM THE CLINICAL RESEARCH
AND MANUFACTURING COMMUNITIES
Howard Feldman, University of British Columbia Faculty of Medicine,
Vancouver, British Columbia, Canada.
Abstract not available.
F5-03-03 DISCUSSANT
Reisa A. Sperling, Center for Alzheimer Research and Treatment, Brigham
and Women’s Hospital, Harvard Medical School. Contact e-mail:
Abstract not available.
F5-03-04 PERSPECTIVE FROM AETNA, A LARGE,
NATIONAL INSURER
Robert McDonough, Aetna, Inc., Hartford, Connecticut, United States.
Contact e-mail: [email protected]
Abstract not available.
FEATURED RESEARCH SESSIONS: F5-04:
NEUROPROTECTION IN ALZHEIMER’S DISEASE: GENETIC,
MOLECULAR AND ENVIRONMENTAL FACTORS
F5-04-01 APOE-ε2: MOLECULAR FEATURES, BIOMARKER
SIGNATURE, AND NEUROBEHAVIORAL
IMPLICATIONS
Terry Goldberg, Litwin Zucker Alzheimer’s Disease Center, Manhasset,
New York, United States. Contact e-mail: [email protected]
Background: While the common APOE2 gene variant is neuroprotective
against Alzheimer’s disease (AD), the mechanisms by which E2 confers neu-
roprotection are largely unknown. Here, wewill provide a translational expla-
nation f APOE3 neuroprotection.Methods:We utilized post mortem cortical
tissue for protein and microarray studies, CSFAbeta and tau and sMRI mea-
sures in healthy controls, and MCI-AD conversion rates for neurobehavior.
Results:We demonstrated increased E2 protein compared to E3 and E4 var-
iants in human post mortem cortex and a unique downstream transcriptional
profile determined by microarray and characterized by down-regulation of
LTP related transcripts and up-regulation of extracellular matrix/integrin re-
lated transcripts in E2 cases. In vivo studies of older individuals demonstrated
that a unique and advantageous biomarker signaturewas present in E2 carriers
involving enhanced CSF Ab clearance, diminished CSF phospho-tau levels,
and increased cortical thickness in the lateral temporal lobe. With respect
to neurobehavior, E2 reduced the probability of Mild Cognitive Impairment
(MCI) to AD conversion by approximately half. Conclusions: We suggest
that ApoE2 protein abundance in brain, coupled to the isoform’s known in-
ability to bind to a lipoprotein receptor found most commonly on neurons
in brain (LDLR), reduces possible excitoxicity, produces an advantageous
biomarker profile, and implicates an obligatory ApoE isoform-specific mech-
anism for the clearance of toxic Abeta (Ab) species from brain through the
vasculature. Critically, these experiments have direct implications for rational
APOE2-based drug development programs.
F5-04-02 A CODING MUTATION IN APP PROTECTS
AGAINSTALZHEIMER’S DISEASE AND AGE-
RELATED COGNITIVE DECLINE
Thorlakur Jonsson,DeCode Genetics, Reykjavik, Iceland. Contact e-mail: