APOE-dependent phenotypes in subjects with mild cognitive impairment converting to Alzheimer's disease.
BACKGROUND
The E4 isoform of the APOE genotype is the most significant genetic risk factor for sporadic Alzheimer's disease (AD) and has recently been found to modulate disease expression in patients with AD.


OBJECTIVE
To investigate APOE-dependent cognitive and structural phenotypes in subjects with mild cognitive impairment who converted to AD within the following three years.


METHODS
Subjects converting to AD (n = 63) were compared to a control group with stable mild cognitive impairment (n = 131). Clinical, neuropsychological, and MRI data were obtained by the German Dementia Competence Network. Subgroups of converting and stable APOE E4 carriers and non-carriers were investigated longitudinally with MRI to examine structural correlates of conversion. Voxel-based morphometry was applied to investigate gray matter distribution.


RESULTS
At baseline, executive performance correlated with global and bilateral prefrontal gray matter volume and predicted conversion only among non-carriers. Converting carriers and non-carriers presented distinct patterns of brain atrophy on longitudinal analysis, in line with a dissociation between more pronounced occipital atrophy in carriers and more frontoparietal volume loss in non-carriers at follow-up.


CONCLUSIONS
The current findings suggest that in APOE E4 non-carriers with AD, executive dysfunction is closely linked to frontal gray matter atrophy and predictive of progression to dementia. The results are consistent with APOE genotype-dependent profiles of structural damage and cognitive decline in patients with imminent conversion to AD.
Central Institute of Mental Health, Medical Faculty Mannheim/Heidelberg University, Mannheim, Germany.
Katrin
K
Morgen
Lutz
L
Frölich
Heike
H
Tost
Michael M
MM
Plichta
Heike
H
Kölsch
Fabian
F
Rakebrandt
Otto
O
Rienhoff
Frank
F
Jessen
Oliver
O
Peters
Holger
H
Jahn
Christian
C
Luckhaus
Michael
M
Hüll
Hermann-Josef
HJ
Gertz
Johannes
J
Schröder
Harald
H
Hampel
Stefan J
SJ
Teipel
Johannes
J
Pantel
Isabella
I
Heuser
Jens
J
Wiltfang
Eckart
E
Rüther
Johannes
J
Kornhuber
Wolfgang
W
Maier
Andreas
A
Meyer-Lindenberg
D000544:Alzheimer Disease / Q000175:diagnosis / Q000235:genetics* / Q000503:physiopathology*; D001057:Apolipoproteins E / Q000235:genetics*; D001284:Atrophy / Q000209:etiology / Q000473:pathology; D060825:Cognitive Dysfunction / Q000175:diagnosis / Q000235:genetics* / Q000503:physiopathology*; D003430:Cross-Sectional Studies; D018450:Disease Progression; D056344:Executive Function; D005260:Female; D005838:Genotype; D006801:Humans; D008137:Longitudinal Studies; D008279:Magnetic Resonance Imaging; D008297:Male; D009483:Neuropsychological Tests; D010641:Phenotype; D020033:Protein Isoforms / Q000235:genetics; D013223:Statistics as Topic
D001057:Apolipoproteins E; D020033:Protein Isoforms