Oral O3-03: prevention, Associations, Biomarkers and Mouse ModelsS502
TUESDAY, JULY 19, 2011
ORAL O3-03
PREVENTION, ASSOCIATIONS, BIOMARKERS
AND MOUSE MODELS
O3-03-01 COGNITIVE ABILITIES, WELL-BEING AND
INTERNET SEARCH PERFORMANCE IN OLDER
PEOPLE
Veronika van der Wardt1, Stephan Bandelow1, Eef Hogervorst1,1Loughborough University, Loughborough, United Kingdom.
Background: Internet and computer use could offer significant benefits to
older people with and without cognitive impairments, as it has been found
to improve cognitive abilities and delay dementia onset (Hall & al., 2009;
Newson & Kemps, 2006; Verghese, 2003). In addition, the Internet offers
access to services, information and support. However, Internet and com-
puter use also requires cognitive abilities that decrease with age (Czaja &
al.,2006; Laberge & Scialfa, 2005), and, although the impact of mood and
well-being on cognitive abilities has been established (Burton & al.,
2009; O’Rourke & al., 2009), their role in the relationship between cog-
nition and Internet use has not yet been investigated. Methods: Partici-
pants included 27 vulnerable service users of community support
groups (19% male, mean age ¼ 62.77, SD ¼ 8.93) with and without cog-
nitive impairment. Internet use was assessed using a questionnaire which
measured frequency and diversity of Internet use. In addition, well-being,
mood, verbal learning and memory as well as psychomotor speed were
examined. Results: Spearman’s rank correlations showed significant cor-
relations between Internet search scores and all cognitive scores (table)
but cognitive scores and Internet search were not significantly related
to well-being or mood. Logistic regression analysis confirmed this result
for Frequency of Internet searching: psychomotor speed (Exp (B) ¼ 1.29;
95%; CI ¼ 1.01 to 1.66) significantly predicted Internet Searching after
controlling for education. For Diversity of Internet searching, the regres-
sion analysis was not significant. Conclusions:This confirmed earlier find-
ings that cognitive abilities contribute to Internet use, and indicated that
well-being or mood do not affect this relationship. Although our study
only used few measures for cognitive abilities, all were significantly related
to the diversity and frequency of Internet searching. To improve Internet ac-
cess for older people, website developers should thus consider the follow-
ing: a) not requiring information to be stored in memory; b) limiting the
amount of information on the screen at any one time; c) allowing sufficient
time to enter and read information; d) limiting the number of choices people
can make at any one step.
Table 1
Spearman’s rank correlations for Internet search scores (frequency and
diversity and cognitive abilities
Variable Diversity HVLT Digit MMSE
Internet
Search
Symbol
Frequency
Internet
Search
.97**
N ¼23
.69**
N ¼ 24
.75**
N ¼ 20
.48*
N ¼ 24
HVLT
.61**N ¼ 20
.80**
N ¼ 19
.68**
N ¼ 24
Digit Symbol
.73**N ¼ 16
.65**
N ¼ 19
MMSE
.49*N ¼ 20
* Correlation is significant at the 0.05 level (2-tailed).
** Correlation is significant at the 0.01 level (2-tailed).
O3-03-02 COMPOSITE COGNITIVE ENDPOINTS WITH
IMPROVED POWER TO DETECT
PRESYMPTOMATIC ALZHEIMER’S DISEASE
TREATMENT EFFECTS IN APOE4 CARRIERS:
FINDINGS FROM THE ALZHEIMER’S
PREVENTION INITIATIVE
Jessica Langbaum1, Suzanne Hendrix2, Napatkamon Ayutyanont1,
Pierre Tariot1, Adam Fleisher1, Richard Caselli3, Kewei Chen1,
Carolyn Langlois1, David Bennett4, Eric Reiman1, 1Banner Alzheimer’s
Institute, Phoenix, Arizona, United States; 2Pentara Corporation, Salt Lake
City, Utah, United States; 3Mayo Clinic, Scottsdale, Arizona, United States;4Rush University Medical Center, Chicago, Illinois, United States.
Background:We have proposed an Alzheimer’s Prevention Initiative (API)
to relate a pre-symptomatic Alzheimer’s disease (AD) treatment’s bio-
marker effects to clinical outcome in cognitively normal people who, based
on age and genetic background, are at highest imminent risk of symptomatic
AD. Here, we used longitudinal data from two cohort studies at the Rush
Alzheimer’s Disease Center to identify a new cognitive composite score
that is sensitive to cognitive decline associated with pre-symptomatic AD
to inform on the design of a randomized clinical trial (RCT) in apolipopro-
tein E (APOE) e4 carriers. Methods: Using a battery of 19-21 cognitive
tests, the annualized mean-to-standard-deviation ratios (MSDR) of the
change over time were calculated for the un-weighted sum of every combi-
nation of two to six tests for those who developed cognitive impairment
(MCI or AD) in the five years prior to diagnosis. Measurements were ad-
justed for aging/practice effects using data from participants who remained
cognitively normal. The best combinations were evaluated for construct
validity. This optimal test combination was then examined in APOE4 car-
riers. Results: The optimal combination of measurements that was selected
to sensitively measure cognitive decline over time included Logical
Memory-delayed recall, CERADword list-delayed recall, category fluency,
Ravens progressive matrices, and MMSE (annual MSDR ¼0.182847). A
similar composite test was independently developed using data from
a longitudinal cohort of cognitively normal PS1 E280A mutation carriers
(Ayutyanont et al, ICAD abstract 2011). This composite score was also
shown to be sensitive to decline in APOE4 carriers relative to non-carriers
between the ages of 70 and 85. Using this composite cognitive endpoint,
we estimate that 4,360/1,100 APOE4 carriers per group would permit us
to detect a 30% treatment effect in a 24/60-month RCT, respectively. Con-
clusions: In this first phase of the process, we have identified a combination
of cognitive tests to evaluate pre-symptomatic AD treatments in cognitive
normal people at high imminent risk for late-onset AD, and have shown
that a similar combination performs well in individuals at highest risk for
early-onset AD. We will continue to develop and refine this approach in
preparation for the pre-symptomatic AD/surrogate marker development tri-
als proposed in the API.
O3-03-03 DIETARY NUTRIENTS AND PLASMA
b-AMYLOID
Yian Gu1, Nicole Schupf1, Stephanie Cosentino2, Jose Luchsinger1,
Yaakov Stern1, Richard Mayeux1, Nikolaos Scarmeas1, 1Columbia
University, New York, N.Y., United States; 2Columbia University, New York,
N.Y., United States.
Background:Our previous work from theWashingtonHeights-Inwood Co-
lumbia Aging Project (WHICAP) suggests that high plasma ß-amyloid
(Aß40 and Aß42) levels are associated with faster cognitive decline and in-
creased risk for Alzheimer’s disease in the elderly. However, little is known
about environmental, including dietary, factors that may be associated with
Aß40 or Aß42. Methods: In this cross-sectional study, plasma Aß40 and
Aß42 (measured with double-antibody sandwich ELISA) and dietary data
(61-item food frequency questionnaire) were available for 1091 cognitively
Oral O3-03: prevention, Associations, Biomarkers and Mouse Models S503
healthy elderly (age > 65) in WHICAP, a community-based and ethnically
diverse cohort in New York. The associations between plasma Aß40 and
Aß42 levels and calorie-adjusted dietary intake of 10 nutrients [saturated
fatty acid (SFA), mono-unsaturated fatty acid (MUFA), u-3 poly-unsatu-
rated fatty acid (PUFA), u-6 PUFA, vitamin E, vitamin C, ß-carotene, vita-
min B12, folate, and vitamin D], selected due to their potential association
with dementia risk, were examined using linear regression models, first
unadjusted and then adjusted for age, gender, ethnicity, education, and
ß-amyloid assessment wave. Results: In an unadjusted model that simulta-
neously included all 10 nutrients, higher intake of u-3 PUFA was signifi-
cantly associated with lower Aß40 (ß ¼ -25.9, p¼0.001) and lower Aß42
(ß¼ -11.9, p¼0.001) levels; higher intake of MUFAwas significantly asso-
ciated with lower Aß40 (ß ¼ -1.6, p¼0.046) and Aß42 (ß ¼ -0.8, p¼0.023)
levels. In an adjusted model, u-3 retained a strong association with lower
plasma levels of Aß42 (ß ¼-13.6, p¼0.045) and Aß40 (ß ¼ -7.2,
p¼0.021), while MUFAwas no longer associated with Aß. Other nutrients
did not seem to be significantly associated with plasma levels of either Aß40
or Aß42. Conclusions: In cognitively healthy elders, higher dietary intake
of u-3 PUFA is associated with lower plasma levels of both Aß40 and
Aß42 (which are markers of slower cognitive decline and lower dementia
risk inour cohort). Thus, plasma ß-amyloid may be related to dietary habits.
O3-03-04 EARLY INTERVENTION WITH
DOCOSAHEXANOIC ACID (DHA) PROTECTS
APOE4 ACCELERATION OF COGNITIVE
DECLINE AND PLASMA BIOMARKERS IN APOE4/
5XFAD MICE
Greg Cole1, Dana Gant2, Fusheng Yang3, Mher Alaverdyan3,
Mary Jo Ladu4, Sally Frautschy1, 1UCLA and VA Greater Los Angeles
Healthcare System, Los Angeles, Calif., United States; 2UCLA & VA
Greater Los Angeles Healthcare System, North Hills, Calif., United States;3UCLA & VA Greater Los Angeles Healthcare System, Sepulveda, Calif.,
United States; 4University Illinois, Chicago, Chicago, Illinois, United
States.
Background: Apolipoprotein E4 (ApoE4), a genetic risk factor for Alz-
heimer disease (AD), accelerates amyloid and dementia and is central to
lipid and Abeta trafficking. Treatment with omega-3 (n-3) fatty acid
DHA is a safe intervention with favorable epidemiology and protective
properties in preclinical models. However, despite possible protection
with MCI and subjects lacking ApoE4, DHA showed no efficacy with
ApoE4 carriers in a large trial for mild to moderate AD. This raises
the possibility of human ApoE4 effects on DHA efficacy. Methods:
Human ApoE3 and ApoE4 targeted replacement (ApoE-TR) mice were
crossed to make “EFAD” mice expressing APP and PS1 with 5 familial
AD mutations (5xFAD). E3FAD and E4FAD mice began DHA-depleting
base diet with or without 0.6% DHA at 2-3 months of age (prior to amyloid
plaques). Mice underwent cognitive testing using Morris Water Maze
(MWM) at 7-8 months, an age when 5x FAD mice with mouse ApoE
have MWM deficits. Plasma was drawn prior to euthanasia and analysis
for Abeta and synaptic markers. Results: Compared with C57 controls,
DHA treated and untreated E4FAD mice showed no deficits in MWM
with visible platform trials to criterion. In contrast, untreated E4FAD
took twice as many trials to criterion with the hidden platform
(p¼0.006). E3FAD groups had significantly less amyloid accumulation
and cognitive decline. Several plasma biomarkers reported elevated
with amyloid burden in humans were significantly elevated in E4FAD
mice and reduced by DHA treatment. Ongoing analysis will determine
how well plasma biomarker responses tracked CNS pathology. Conclu-
sions: In our model, ApoE3 protects against onset of cognitive decline
relative to ApoE4. EFAD mice also show DHA can be protective with
very early intervention in an animal model where human ApoE4 accel-
erates amyloid and cognitive deficits. We find that several plasma bio-
markers that correlate with amyloid accumulation in humans are also
sensitive to ApoE4 and responsive to effective treatment with DHA. Tri-
als in older animals are necessary to test the hypothesis that DHA ef-
ficacy will belost at later stages of pathogenesis that more closely
resemble mild to moderate AD subjects. Overall, our data support con-
sideration of DHA for prevention trials.
O3-03-05 FORMAL EDUCATION AFTER 60 YEARS
IMPROVES COGNITIVE PERFORMANCE
Eduardo Marques da Silva, Jose Farfel, Daniel Apolinario,
Regina Magaldi, Ricardo Nitrini, Wilson Jacob-Filho, University of S~ao
Paulo, S~ao Paulo, Brazil.
Background: Literacyplays a major role in mediating cognitive pro-
cesses. Amongst Brazilian elders, 32.2% declared themselves unable
to readand write. This study aims to determine the modifications in
the cognitive domains of illiterate older subjects submitted to 9 months
of a literacy program. Methods: The literacy programwas planned to pro-
vide basic reading and writing skills in a 2 hours daily, 5 days weekly, 9
months yearly class calendar. Literacy was graduated using a formal exam-
ination. Subjects were interviewedwith structuredmedical history question-
naires and examined by study clinicians at enrolment and follow-up visit at
the 9th month of protocol. Cognitive evaluation was gathered through the
NEUROPSI cognitive battery. Results: 56 subjects were included, mean
age 67.11 (6,6). After 9 months, NEUROPSI total score increased 1.18 stan-
dard deviations (SD) and reading and writing 1.14SD, language 1.1SD,
memory 0.64SD, attention 0.48SD, executive functions 0.28SD and visuo-
spatial abilities 0.24SD (p < 0.01 for all increases). On multivariate analy-
sis, for each level of literacy earned according to formal examination, there
was an increase of 0.66 points in attention, 0.94 in reading and writing,0.45
in language, 1.66 in memory and 4.45 in total NEUROPSI score (p< 0.05).
Conclusions: The results suggest that, despite the fact that there might be
theoretical differences in brain processing between those schooled earlier
or later in life, the cognitive performance of individuals educated in late
life improved when compared to baseline. Illiteracy should be considered
a public health problem and more studies evaluating late-life interventions
are necessary.
O3-03-06 FRAILTY CRITERIA AND MMSE PERFORMANCE
ARE RELATED: TOTAL SCORE AND SUBDOMAIN
ANALYSES USING DATA FROM THE FIBRA
MULTICENTER STUDY IN BRAZIL
Yassuda Monica1, Ludgleydson Ara�ujo2, Maria do Carmo Eul�alio3,
Jos�e Guilherme Moura4, Geraldine Alves dos Santos5,
Maria Eliane Siqueira6, Anita Liberalesso Neri7, 1University of S~ao Paulo,
S~ao Paulo, Brazil; 2Federal University of Piaui, Teresina, Brazil; 3State
University of Para�ıba, Campina Grande, Brazil; 4State Secretary of Health,
Bel�em do Par�a, Brazil; 5FEEVALE, Novo Hamburgo, Brazil; 6Pontif�ıcia
Universidade Cat�olica de Minas Gerais, Pocos de Cladas, Brazil; 7State
University of Campinas, Campinas, Brazil.
Background: Frailty can be considered an age-associated syndrome
linked to diminished physiological reserves, lower resistance to envi-
ronmental stressor, and higher risk for negative health outcomes,
such as immobility, hospitalization and death. However, there is debate
whether cognitive impairment should be included in frailty criteria,
and, more recently, frailty has been found to be predictive of MCI
and AD. Methods: The present study used data from the FIBRAmulticen-
ter study to investigate the association between the Cardiovascular Health
Study (CHS) frailty criteria and Mini-Mental State Examination (MMSE)
performance in a sample of 3,075 communities dwelling older adults, 65