Quantitative analysis of senile plaques in Alzheimer disease: observation of log-normal size distribution and molecular epidemiology of differences associated with apolipoprotein E genotype and trisomy 21 (Down syndrome).
The discovery that the epsilon 4 allele of the apolipoprotein E (apoE) gene is a putative risk factor for Alzheimer disease (AD) in the general population has highlighted the role of genetic influences in this extremely common and disabling illness. It has long been recognized that another genetic abnormality, trisomy 21 (Down syndrome), is associated with early and severe development of AD neuropathological lesions. It remains a challenge, however, to understand how these facts relate to the pathological changes in the brains of AD patients. We used computerized image analysis to examine the size distribution of one of the characteristic neuropathological lesions in AD, deposits of A beta peptide in senile plaques (SPs). Surprisingly, we find that a log-normal distribution fits the SP size distribution quite well, motivating a porous model of SP morphogenesis. We then analyzed SP size distribution curves in genotypically defined subgroups of AD patients. The data demonstrate that both apoE epsilon 4/AD and trisomy 21/AD lead to increased amyloid deposition, but by apparently different mechanisms. The size distribution curve is shifted toward larger plaques in trisomy 21/AD, probably reflecting increased A beta production. In apoE epsilon 4/AD, the size distribution is unchanged but the number of SP is increased compared to apoE epsilon 3, suggesting increased probability of SP initiation. These results demonstrate that subgroups of AD patients defined on the basis of molecular characteristics have quantitatively different neuropathological phenotypes.
Hyman
B T
BT
Neurology Service, Massachusetts General Hospital, Boston 02114, USA.
West
H L
HL
Rebeck
G W
GW
Buldyrev
S V
SV
Mantegna
R N
RN
Ukleja
M
M
Havlin
S
S
Stanley
H E
HE
D000368:Aged; D000369:Aged, 80 and over; D000544:Alzheimer Disease / Q000453:epidemiology / Q000235:genetics / Q000473:pathology*; D016229:Amyloid beta-Peptides / Q000302:isolation & purification / Q000648:ultrastructure*; D001057:Apolipoproteins E / Q000235:genetics*; D001921:Brain / Q000473:pathology* / Q000648:ultrastructure; D003704:Dementia; D004314:Down Syndrome / Q000235:genetics / Q000473:pathology*; D005838:Genotype; D006801:Humans; D007091:Image Processing, Computer-Assisted; D007150:Immunohistochemistry
D016229:Amyloid beta-Peptides; D001057:Apolipoproteins E