APOE-ε4 is associated with increased hippocampal atrophy rates in Alzheimer's disease
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MCI patients, and may lead to alterations in white matter integrity and blood flow that improve episodic memory performance. The improved memory performance and alterations in brain function in MCI patients were remark- able given their previous history and future probability of cognitive decline. Furthermore, these findings suggest the large-scale cerebrovascular and neurotrophic effects of exercise may reflect massive neuronal plasticity in MCI patients. Longitudinal clinical trials are required to determine whether moderate intensity walking exercise is effective in MCI to reduce or delay conversion to AD. P1-268 APOE-ε4 IS ASSOCIATED WITH INCREASED HIPPOCAMPAL ATROPHY RATES IN ALZHEIMER’S DISEASE Emily Manning 1 , Josephine Barnes 1 , David Cash 2 , Jonathan Bartlett 3 , Kelvin Leung 4 , Sebastien Ourselin 1 , Nick Fox 4 , 1 University College London, London, United Kingdom; 2 University College London, London, United Kingdom; 3 London School of Hygiene and Tropical Medicine, London, United Kingdom; 4 UCL Institute of Neurology, London, United Kingdom. Contact e-mail: [email protected] Background: Previous studies have reported higher hippocampal atrophy rates in APOE ε4 carriers (ε4+) compared with non-carriers (ε4-) in AD. However the modulating effect of the APOE gene on brain and hippocampal atrophy at different stages of AD is unclear. We aimed to investigate whether ε4+ carriers have higher brain and hippocampal atrophy rates compared with non-carriers in Alzheimer’s disease (AD), mild cognitive impairment (MCI) and controls and if so, whether higher hippocampal rates are ob- served after adjusting for brain atrophy rate. Methods: MRI scans from all visits in ADNI (148 AD, 307 MCI, 167 controls) were used. Hippocam- pal and brain atrophy rates were calculated using the boundary shift integral. MCI subjects were divided into "progressors" (MCI-P) if diagnosed with AD within 36 months or "stable" (MCI-S) if a diagnosis of MCI was main- tained. A joint multi-level mixed-effect linear regression model was used to analyse the effect of ε4 carrier-status on hippocampal and brain atrophy rates, adjusting for age, gender, MMSE and brain-to-intracranial volume ra- tio. The difference in hippocampal rates between ε4+ and ε4- after adjust- ment for concurrent brain atrophy rate was then calculated. Results: Mean adjusted whole brain atrophy rates were higher in ε4+ compared with ε4- in AD, MCI-P and MCI-S although this was only significant in MCI-S. Mean adjusted hippocampal atrophy rates in ε4+ were significantly higher in AD, MCI-P and MCI-S (p0.055, all tests) compared with ε4- (see table). After adjustment for brain atrophy rate, the difference in mean ad- justed hippocampal atrophy rate between ε4+ and ε4- was reduced (by w70% in MCI_S, w40% in MCI-P and w30% in AD). There was border- line evidence that brain-rate-adjusted hippocampal atrophy rate was higher in AD ε4+, (p¼0.060) but not in MCI-P or MCI-S. Conclusions: These find- ings show that hippocampal atrophy rates in ε 4+ are higher than in ε 4- in AD and MCI. Some of this difference is explained by higher brain atrophy rates, however there is borderline evidence that hippocampal atrophy rates in ε 4+ are higher than ε 4- after adjusting for concurrent brain atrophy rates. These results suggest that the APOE ε 4 allele drives atrophy to the medial- temporal lobe region in AD. P1-269 ARE EARLY ATROPHY PATTERNS IN AUTOSOMAL DOMINANT FAMILIAL ALZHEIMER’S DISEASE GENE-DEPENDENT? Kirsi Kinnunen 1 , Natalie Ryan 1 , David Cash 1 , Ant onio Bastos Leite 2 , Sarah Finnegan 1 , Manuel Cardoso 3 , Kelvin Leung 1 , Marc Modat 3 , Tammie Benzinger 4 , Clifford Jack 5 , Daniel Marcus 6 , Marcus Raichle 7 , Paul Thompson 8 , John Ringman 8 , Bernardino Ghetti 9 , Stephen Salloway 10 , Reisa Sperling 11 , Peter Schofield 12 , Colin Masters 13 , Richard Mayeux 14 , Ralph Martins 15 , Michael Weiner 16 , Randall Bateman 17 , Alison Goate 6 , Anne Fagan 17 , Nigel Cairns 17 , Virginia Buckles 18 , John Morris 17 , Martin Rossor 19 , Sebastien Ourselin 3 , Nick Fox 1 , 1 Dementia Research Centre, UCL Institute of Neurology, London, United Kingdom; 2 University of Porto, Faculty of Medicine, Porto, Portugal; 3 University College London, London, United Kingdom; 4 Washington University School of Medicine, St. Louis, Missouri, United States; 5 Mayo Clinic, Rochester, Minnesota, United States; 6 Washington University, St. Louis, St. Louis, Missouri, United States; 7 Washington University School of Medicine, St. Louis, Missouri, United States; 8 UCLA, Los Angeles, California, United States; 9 Indiana University, Indianapolis, Indiana, United States; 10 Brown University, Providence, Rhode Island, United States; 11 Brigham and Women’s Hospital, Boston, Massachusetts, United States; 12 Neuroscience Research Australia, Randwick-Sydney, Australia; 13 University of Melbourne, Melbourne, Australia; 14 Columbia University, New York, New York, United States; 15 Edith Cowan University, Perth, Australia; 16 University of California San Francisco, San Francisco, California, United States; 17 Washington University, St. Louis, Missouri, United States; 18 Alzheimer’s Disease Research Center, St. Louis, Missouri, United States; 19 Dementia Research Centre, UCL Institute of Neurology, London, United Kingdom. Contact e-mail: [email protected] Background: Familial AD (FAD) is a rare autosomal dominantly inherited form of AD caused by mutations in genes encoding presenilin 1 (PS1), pre- senilin 2 (PS2) and amyloid precursor protein (APP). It has not been estab- lished whether mutations in these different genes cause similar patterns of early brain atrophy. The Dominantly Inherited Alzheimer Network (DIAN; http://dian-info.org) is a multi-centre project studying a large cohort of individuals at risk of carrying FAD mutations. In this study, we investigate volumetric differences in key brain structures between carriers of the two most commonly mutated genes: PS1 and APP. Methods: From the DIAN cohort, 159 participants were included in the analysis: 88 mutation carriers (77 PS1, 11 APP) who were asymptomatic (aMut+) or early symptomatic (esMut+), with Clinical Dementia Rating (CDR) scores of 0 (aMut+) or 0.5 (esMut+), and 71 non-carriers (NC). Table 1 shows their key demo- graphics. Regions of interest were automatically delineated from volumetric T1-weighted MRI scans, reviewed by a consultant neuroradiologist, and edited when necessary. Whole-brain, cortical grey matter (GM), and bilateral average thalamus, caudate, putamen, nucleus accumbens, and hip- pocampus volumes were then calculated. Between-groups analyses of Adjusted mean difference in atrophy rate (%/year) [95% CI] for ε4 carriers compared with non-carriers in controls, stable MCI, MCI progressors and AD. controls (n¼167) MCI stable (n¼169) MCI progressors (n¼138) AD (n¼148) Difference in mean adjusted* whole brain atrophy rate (%/year) -0.003 [-0.12, 0.11] p¼0.958 -0.24 [-0.38, -0.10] p¼0.001 -0.15 [-0.37, 0.06] p¼0.157 -0.17 [-0.40, 0.04] p¼0.113 Difference in mean adjusted* hippocampal** atrophy rate (%/year) -0.02 [-0.45, 0.40] p¼0.914 -0.80 [-1.42, -0.18] p¼0.012 -0.92 [-1.85, 0.02] p¼0.055 -1.32 [-2.4, -0.27] p¼0.014 Difference in mean adjusted* hippocampal** atrophy rate (%/year) after adjustment for concurrent whole brain atrophy -0.02 [-0.38, 0.34] p¼0.925 -0.27 [-0.84, 0.31] p¼0.364 -0.53 [-1.31, 0.25] p¼0.182 -0.88 [-1.81, 0.04] p¼0.060 *all values were adjusted for disease-group specific mean age, baseline brain to total intracranial volume ratio, MMSE score and gender **average of left and right Poster Presentations: P1 P251
Transcript of APOE-ε4 is associated with increased hippocampal atrophy rates in Alzheimer's disease
Poster Presentations: P1 P251
MCI patients, andmay lead to alterations in white matter integrity and blood
flow that improve episodic memory performance. The improved memory
performance and alterations in brain function in MCI patients were remark-
able given their previous history and future probability of cognitive decline.
Furthermore, these findings suggest the large-scale cerebrovascular and
neurotrophic effects of exercise may reflect massive neuronal plasticity in
MCI patients. Longitudinal clinical trials are required to determine whether
moderate intensity walking exercise is effective in MCI to reduce or delay
conversion to AD.
P1-268 APOE-ε4 IS ASSOCIATEDWITH INCREASED
Adjusted mean
Difference in m
rate (%/yea
Difference in m
atrophy rate
Difference in m
atrophy rate
concurrent
*all values w
**average o
HIPPOCAMPAL ATROPHY RATES IN
ALZHEIMER’S DISEASE
Emily Manning1, Josephine Barnes1, David Cash2, Jonathan Bartlett3,
Kelvin Leung4, Sebastien Ourselin1, Nick Fox4, 1University College
London, London, United Kingdom; 2University College London, London,
United Kingdom; 3London School of Hygiene and Tropical Medicine,
London, United Kingdom; 4UCL Institute of Neurology, London, United
Kingdom. Contact e-mail: [email protected]
Background: Previous studies have reported higher hippocampal atrophy
rates in APOE ε4 carriers (ε4+) compared with non-carriers (ε4-) in AD.
However the modulating effect of the APOE gene on brain and hippocampal
atrophy at different stages of AD is unclear.We aimed to investigatewhether
ε4+ carriers have higher brain and hippocampal atrophy rates compared
with non-carriers in Alzheimer’s disease (AD), mild cognitive impairment
(MCI) and controls and if so, whether higher hippocampal rates are ob-
served after adjusting for brain atrophy rate. Methods: MRI scans from
all visits in ADNI (148 AD, 307 MCI, 167 controls) were used. Hippocam-
pal and brain atrophy rates were calculated using the boundary shift integral.
MCI subjects were divided into "progressors" (MCI-P) if diagnosed with
AD within 36 months or "stable" (MCI-S) if a diagnosis of MCI was main-
tained. A joint multi-level mixed-effect linear regression model was used to
analyse the effect of ε4 carrier-status on hippocampal and brain atrophy
rates, adjusting for age, gender, MMSE and brain-to-intracranial volume ra-
tio. The difference in hippocampal rates between ε4+ and ε4- after adjust-
ment for concurrent brain atrophy rate was then calculated. Results:
Mean adjusted whole brain atrophy rates were higher in ε4+ compared
with ε4- in AD, MCI-P and MCI-S although this was only significant in
MCI-S. Mean adjusted hippocampal atrophy rates in ε4+ were significantly
higher in AD,MCI-P andMCI-S (p�0.055, all tests) compared with ε4- (see
table). After adjustment for brain atrophy rate, the difference in mean ad-
justed hippocampal atrophy rate between ε4+ and ε4- was reduced (by
w70% in MCI_S,w40% in MCI-P andw30% in AD). There was border-
line evidence that brain-rate-adjusted hippocampal atrophy rate was higher
in AD ε4+, (p¼0.060) but not inMCI-P orMCI-S.Conclusions:These find-
ings show that hippocampal atrophy rates in ε 4+ are higher than in ε 4- in
AD and MCI. Some of this difference is explained by higher brain atrophy
rates, however there is borderline evidence that hippocampal atrophy rates
in ε 4+ are higher than ε 4- after adjusting for concurrent brain atrophy rates.
difference in atrophy rate (%/year) [95% CI] for ε4 carriers comp
controls (n¼167)
ean adjusted* whole brain atrophy
r)
-0.003
[-0.12, 0.11]
p¼0.958
ean adjusted* hippocampal**
(%/year)
-0.02
[-0.45, 0.40]
p¼0.914
ean adjusted* hippocampal**
(%/year) after adjustment for
whole brain atrophy
-0.02
[-0.38, 0.34]
p¼0.925
ere adjusted for disease-group specific mean age, baseline brain to
f left and right
These results suggest that the APOE ε 4 allele drives atrophy to the medial-
temporal lobe region in AD.
P1-269 ARE EARLYATROPHY PATTERNS IN
ared with non-
MCI stable (n¼-0.24
[-0.38, -0.10
p¼0.001
-0.80
[-1.42, -0.18
p¼0.012
-0.27
[-0.84, 0.31
p¼0.364
total intracran
AUTOSOMAL DOMINANT FAMILIAL
ALZHEIMER’S DISEASE GENE-DEPENDENT?
Kirsi Kinnunen1, Natalie Ryan1, David Cash1, Ant�onio Bastos Leite2,
Sarah Finnegan1, Manuel Cardoso3, Kelvin Leung1, Marc Modat3,
Tammie Benzinger4, Clifford Jack5, Daniel Marcus6, Marcus Raichle7,
Paul Thompson8, John Ringman8, Bernardino Ghetti9, Stephen Salloway10,
Reisa Sperling11, Peter Schofield12, Colin Masters13, Richard Mayeux14,
Ralph Martins15, Michael Weiner16, Randall Bateman17, Alison Goate6,
Anne Fagan17, Nigel Cairns17, Virginia Buckles18, John Morris17,
Martin Rossor19, Sebastien Ourselin3, Nick Fox1, 1Dementia Research
Centre, UCL Institute of Neurology, London, United Kingdom; 2University
of Porto, Faculty of Medicine, Porto, Portugal; 3University College London,
London, United Kingdom; 4Washington University School of Medicine, St.
Louis, Missouri, United States; 5Mayo Clinic, Rochester, Minnesota, United
States; 6WashingtonUniversity, St. Louis, St. Louis, Missouri, United States;7Washington University School of Medicine, St. Louis, Missouri, United
States; 8UCLA, Los Angeles, California, United States; 9Indiana University,
Indianapolis, Indiana, United States; 10Brown University, Providence,
Rhode Island, United States; 11Brigham and Women’s Hospital, Boston,
Massachusetts, United States; 12Neuroscience Research Australia,
Randwick-Sydney, Australia; 13University of Melbourne, Melbourne,
Australia; 14Columbia University, New York, New York, United States;15Edith Cowan University, Perth, Australia; 16University of California
San Francisco, San Francisco, California, United States; 17Washington
University, St. Louis, Missouri, United States; 18Alzheimer’s Disease
Research Center, St. Louis, Missouri, United States; 19Dementia Research
Centre, UCL Institute of Neurology, London, United Kingdom.
Contact e-mail: [email protected]
Background: Familial AD (FAD) is a rare autosomal dominantly inherited
form of AD caused by mutations in genes encoding presenilin 1 (PS1), pre-
senilin 2 (PS2) and amyloid precursor protein (APP). It has not been estab-
lished whether mutations in these different genes cause similar patterns of
early brain atrophy. The Dominantly Inherited Alzheimer Network
(DIAN; http://dian-info.org) is a multi-centre project studying a large cohort
of individuals at risk of carrying FADmutations. In this study, we investigate
volumetric differences in key brain structures between carriers of the two
most commonly mutated genes: PS1 and APP. Methods: From the DIAN
cohort, 159 participants were included in the analysis: 88 mutation carriers
(77 PS1, 11 APP) who were asymptomatic (aMut+) or early symptomatic
(esMut+), with Clinical Dementia Rating (CDR) scores of 0 (aMut+) or
0.5 (esMut+), and 71 non-carriers (NC). Table 1 shows their key demo-
graphics. Regions of interest were automatically delineated from volumetric
T1-weighted MRI scans, reviewed by a consultant neuroradiologist, and
edited when necessary. Whole-brain, cortical grey matter (GM), and
bilateral average thalamus, caudate, putamen, nucleus accumbens, and hip-
pocampus volumes were then calculated. Between-groups analyses of
carriers in controls, stable MCI, MCI progressors and AD.
169) MCI progressors (n¼138) AD (n¼148)
]
-0.15
[-0.37, 0.06]
p¼0.157
-0.17
[-0.40, 0.04]
p¼0.113
]
-0.92
[-1.85, 0.02]
p¼0.055
-1.32
[-2.4, -0.27]
p¼0.014
]
-0.53
[-1.31, 0.25]
p¼0.182
-0.88
[-1.81, 0.04]
p¼0.060
ial volume ratio, MMSE score and gender
