Longitudinal modeling of age-related memory decline and the APOE epsilon4 effect.
BACKGROUND
The APOE epsilon4 allele is associated with the risk of late-onset Alzheimer's disease. The age at which memory decline diverges among persons who are homozygous for the APOE epsilon4 allele, those who are heterozygous for the allele, and noncarriers is unknown.


METHODS
Using local advertisements, we recruited cognitively normal subjects between the ages of 21 and 97 years, who were grouped according to their APOE epsilon4 status. We then followed the subjects with longitudinal neuropsychological testing. Anyone in whom mild cognitive impairment or dementia developed during follow-up was excluded. We compared the rates of decline in predetermined cognitive measures between carriers and noncarriers of the APOE epsilon4 allele, using a mixed model for longitudinal change with age.


RESULTS
We analyzed 815 subjects: 317 APOE epsilon4 carriers (79 who were homozygous for the APOE epsilon4 allele and 238 who were heterozygous) and 498 noncarriers. Carriers, as compared with noncarriers, were generally younger (mean age, 58.0 vs. 61.4 years; P<0.001) and were followed for a longer period (5.3 vs. 4.7 years, P=0.01), with an equivalent duration of formal education (15.4 years) and proportion of women (69%). Longitudinal decline in memory in carriers began before the age of 60 years and showed greater acceleration than in noncarriers (P=0.03), with a possible allele-dose effect (P=0.008). We observed similar although weaker effects on measures of visuospatial awareness and general mental status.


CONCLUSIONS
Age-related memory decline in APOE epsilon4 carriers diverges from that of noncarriers before the age of 60 years, despite ongoing normal clinical status.
Caselli
Richard J
RJ
Department of Neurology, Mayo Clinic Arizona, Scottsdale, Arizona 85259, USA. caselli.richard@mayo.edu
Dueck
Amylou C
AC
Osborne
David
D
Sabbagh
Marwan N
MN
Connor
Donald J
DJ
Ahern
Geoffrey L
GL
Baxter
Leslie C
LC
Rapcsak
Steven Z
SZ
Shi
Jiong
J
Woodruff
Bryan K
BK
Locke
Dona E C
DE
Snyder
Charlene Hoffman
CH
Alexander
Gene E
GE
Rademakers
Rosa
R
Reiman
Eric M
EM
D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D053327:Apolipoprotein E4 / Q000235:genetics*; D003430:Cross-Sectional Studies; D005260:Female; D006579:Heterozygote; D006720:Homozygote; D006801:Humans; D008137:Longitudinal Studies; D008297:Male; D008568:Memory; D008569:Memory Disorders / Q000175:diagnosis / Q000235:genetics*; D008875:Middle Aged; D009483:Neuropsychological Tests; D055815:Young Adult
D053327:Apolipoprotein E4