Amyloid mediates the association of apolipoprotein E e4 allele to cognitive function in older people.
BACKGROUND
The neurobiological changes underlying the association of the apolipoprotein E (APOE) e4 allele with level of cognition are poorly understood.


OBJECTIVE
To test the hypothesis that amyloid load can account for (mediate) the association of the APOE e4 allele with level of cognition assessed proximate to death.


METHODS
There were 44 subjects with clinically diagnosed Alzheimer's disease and 50 without dementia, who had participated in the Religious Orders Study. They underwent determination of APOE allele status, had comprehensive cognitive testing in the last year of life, and brain autopsy at death. The percentage area of cortex occupied by amyloid beta and the density of tau positive neurofibrillary tangles were quantified from six brain regions and averaged to yield summary measures of amyloid load and neurofibrillary tangles. Multiple regression analyses were used to examine whether amyloid load could account for the effect of allele status on level of cognition, controlling for age, sex, and education.


RESULTS
Possession of at least one APOE e4 allele was associated with lower level of cognitive function proximate to death (p = 0.04). The effect of the e4 allele was reduced by nearly 60% and was no longer significant after controlling for the effect of amyloid load, whereas there was a robust inverse association between amyloid and cognition (p = 0.001). Because prior work had suggested that neurofibrillary tangles could account for the association of amyloid on cognition, we next examined whether amyloid could account for the effect of allele status on tangles. In a series of regression analyses, e4 was associated with density of tangles (p = 0.002), but the effect of the e4 allele was reduced by more than 50% and was no longer significant after controlling for the effect of amyloid load.


CONCLUSIONS
These findings are consistent with a sequence of events whereby the e4 allele works through amyloid deposition and subsequent tangle formation to cause cognitive impairment.
Bennett
D A
DA
Rush Alzheimer's Disease Center, Armour Academic Center, 600 South Paulina, Suite 1028; Chicago, IL 60612, USA. dbennett@rush.edu
Schneider
J A
JA
Wilson
R S
RS
Bienias
J L
JL
Berry-Kravis
E
E
Arnold
S E
SE
D000368:Aged; D000369:Aged, 80 and over; D000483:Alleles; D000544:Alzheimer Disease / Q000235:genetics* / Q000503:physiopathology*; D000682:Amyloid / Q000032:analysis / Q000378:metabolism*; D053327:Apolipoprotein E4; D001057:Apolipoproteins E / Q000235:genetics* / Q000502:physiology*; D001344:Autopsy; D016022:Case-Control Studies; D003072:Cognition Disorders / Q000235:genetics* / Q000503:physiopathology*; D005260:Female; D006801:Humans; D008297:Male; D012044:Regression Analysis
D000682:Amyloid; D053327:Apolipoprotein E4; D001057:Apolipoproteins E