Insulin metabolism and the risk of Alzheimer disease: the Rotterdam Study.
OBJECTIVE
Diabetes mellitus has been associated with an increased risk of Alzheimer disease (AD), but how it exerts its effect remains controversial. Possible pathophysiologic mechanisms are glucose toxicity and a direct effect of insulin on amyloid metabolism. Most studies had short follow-up, and longer-term effects of diabetes on AD risk are unknown. We investigated whether fasting glucose and insulin levels and insulin resistance are associated with the risk of AD and whether this risk is constant over time.


METHODS
The study was based on 3,139 participants of the Rotterdam Study, a population-based cohort study. All subjects were free from dementia, did not have a history of diabetes, and had fasting levels of glucose and insulin measured at baseline. Insulin resistance was estimated with the homeostasis model assessment. We investigated how fasting glucose, insulin, and insulin resistance are related to the risk of AD in 3 different strata according to time-to-event, using Cox proportional hazards models.


RESULTS
During follow-up, 211 participants developed AD, 71 of them within 3 years of baseline. Levels of insulin and insulin resistance were associated with a higher risk of AD within 3 years of baseline. After 3 years, the risk was no longer increased. Glucose was not associated with a higher risk of AD. There was no interaction of APOE ε4 carriership and insulin metabolism on the risk of AD.


CONCLUSIONS
Our findings suggest that insulin metabolism influences the clinical manifestation of AD only within 3 years.
Department of Epidemiology, Erasmus MC University Medical Center, PO Box 2040, 3000 CA Rotterdam, The Netherlands.
E M C
EM
Schrijvers
J C M
JC
Witteman
E J G
EJ
Sijbrands
A
A
Hofman
P J
PJ
Koudstaal
M M B
MM
Breteler
D000368:Aged; D000369:Aged, 80 and over; D000483:Alleles; D000544:Alzheimer Disease / Q000209:etiology* / Q000235:genetics / Q000378:metabolism; D053327:Apolipoprotein E4 / Q000235:genetics; D001786:Blood Glucose / Q000378:metabolism*; D015331:Cohort Studies; D005260:Female; D005838:Genotype; D006801:Humans; D007328:Insulin / Q000378:metabolism*; D007333:Insulin Resistance; D008297:Male; D008875:Middle Aged; D016016:Proportional Hazards Models; D012306:Risk
D053327:Apolipoprotein E4; D001786:Blood Glucose; D007328:Insulin