Intranasal insulin administration dose-dependently modulates verbal memory and plasma amyloid-beta in memory-impaired older adults

Abstract

Intranasal insulin administration raises central nervous system (CNS) insulin levels in humans and acutely facilitates verbal memory in patients with Alzheimer's disease (AD), an effect that may differ by APOE genotype. The purpose of this study was to examine the cognitive dose response curves for intranasal insulin administration, and determine whether the effects of insulin differ between participants with (epsilon4+) and without (epsilon4-) the APOE- epsilon4 allele. On separate mornings, 33 memory-impaired adults with AD or amnestic mild cognitive impairment and 59 normal adults each underwent five intranasal treatment conditions consisting of insulin (10, 20, 40, or 60 IU) or placebo. Cognition was tested 15-minutes post-treatment, and blood was acquired at baseline and 45-minutes post-treatment. Plasma insulin and glucose levels were unaffected by treatment. Insulin administration facilitated recall on two measures of verbal memory in memory-impaired epsilon4- adults, with performance generally peaking at 20 IU. In contrast, memory-impaired epsilon4+ subjects demonstrated a relative decline in verbal memory. Insulin also differentially modulated plasma amyloid-beta for memory-impaired subjects and normal controls, effects that again differed by APOE genotype. These findings suggest that groups with different genetic risks for AD may show differential dose-response curves following intranasal insulin administration.

Figures

Figure 1

(A) Immediate and (B) delayed story recall scores for memory-impaired adults with (E4+) and without (E4−) the APOE-ε4 allele. The memory-impaired/ε4− group’s immediate recall improved at the 10, 20, and 40 IU doses, whereas the ε4 carriers performance declined (ps=0.0484, 0.0317, 0.0273). A similar trend of reduced performance was observed for delayed recall for ε4 carriers, who had lower delayed recall compared to non-ε4 carriers at the 10, 20, and 40 IU doses (ps=0.1061, 0.0739, and 0.0595).

Figure 2

(A) Immediate and (B) delayed list learning scores for memory-impaired adults with (E4+) and without (E4−) the APOE-ε4 allele. The memory-impaired/ε4− group showed maximal benefit at the 20 IU dose relative to the memory-impaired/ε4+ group (ps=0.0637and 0.0416 for between group comparisons for immediate and delayed recall).

Figure 3

Plasma Aβ42 levels (pg/ml) for (A) memory-impaired and (B) normal adults. Aβ42 levels increased for memory-impaired adults from saline to 10 IU regardless of ε4 status (p=.0213). For memory-impaired adults without the APOE-ε4 allele, Aβ42 levels at the highest insulin dose were greater than levels observed following saline administration (p=0.0071). Normal adults without the APOE-ε4 allele showed a U-shaped dose response curve, in which Aβ42 levels decreased in the 10 and 20 IU dose conditions compared with saline (ps=0.0585 and 0.0285).