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