Abstract
Background: Insulin resistance (IR) is linked with the occurrence of
pathological features observed in Alzheimer’s disease (AD), including neurofibrillary
tangles and amyloid plaques. However, the extent to which IR is associated with AD
pathology in the cognitively asymptomatic stages of preclinical AD remains unclear.
Objective: To determine the extent to which IR is linked with amyloid and
tau pathology in late-middle-age.
Method: Cerebrospinal fluid (CSF) samples collected from 113 participants
enrolled in the Wisconsin Registry for Alzheimer’s Prevention study (mean age = 60.6
years), were assayed for AD-related markers of interest: Aβ
42, P-Tau181, and T-Tau. IR was determined using the Homeostatic
Model Assessment for Insulin Resistance (HOMA-IR). Linear regression was used to test the
effect of IR, and APOE
ɛ4, on tau and amyloid pathology. We hypothesized that greater IR would
be associated with higher CSF P-Tau181 and T-Tau, and lower CSF
Aβ
42.
Results: No significant main effects of HOMA-IR on P-Tau181,
T-Tau, or Aβ
42 were observed; however, significant interactions were observed between
HOMA-IR and APOE
ɛ4 on CSF markers related to tau. Among APOE
ɛ4 carriers, higher HOMA-IR was associated with higher
P-Tau181 and T-Tau. Among APOE
ɛ4 non-carriers, HOMA-IR was negatively associated with
P-Tau181 and T-Tau. We found no effects of IR on Aβ
42 levels in CSF.
Conclusion: IR among asymptomatic APOE
ɛ4 carriers was associated with higher P-Tau181 and T-Tau in
late-middle age. The results suggest that IR may contribute to tau-related
neurodegeneration in preclinical AD. The findings may have implications for developing
prevention strategies aimed at modifying IR in mid-life.
