Efficacy of rosiglitazone in a genetically defined population with mild-to-moderate Alzheimer's disease

Abstract

Mild-to-moderate AD patients were randomized to placebo or rosiglitazone (RSG) 2, 4 or 8 mg. Primary end points at Week 24 were mean change from baseline in AD Assessment Scale-Cognitive (ADAS-Cog) and Clinician's Interview-Based Impression of Change Plus Caregiver Input global scores in the intention-to-treat population (N ¼ 511), and results were also stratified by apolipoprotein E (APOE) genotype (n ¼ 323). No statistically significant differences on primary end points were detected between placebo and any RSG dose. There was a significant interaction between APOE e4 allele status and ADAS-Cog (P ¼ 0.014). Exploratory analyses demonstrated significant improvement in ADAS-Cog in APOE e4-negative patients on 8 mg RSG (P ¼ 0.024; not corrected for multiplicity). APOE e4-positive patients did not show improvement and showed a decline at the lowest RSG dose (P ¼ 0.012; not corrected for multiplicity). Exploratory analyses suggested that APOE e4 non-carriers exhibited cognitive and functional improvement in response to RSG, whereas APOE e4 allele carriers showed no improvement and some decline was noted. These preliminary findings require confirmation in appropriate clinical studies.

Ketone Bodies as a Therapeutic for Alzheimer's Disease

“…58 This was also observed in the rosglitazone study. 57 In a follow-up study of 31 subjects with mild to moderate probable AD, E4(Ϫ) subjects were found to have significantly lower glucose disposal rates. 55 High-fasting insulin and low-glucose disposal rates both suggest that E4(Ϫ) subjects are insulin resistant, and correcting this insulin resistant state by administration of insulin either systemically, 55 nasally, 54 or by use of the insulin sensitizing agent rosglitazone 57 may explain the beneficial effects seen in these studies.…”

“…E4(ϩ) subjects show no difference or got slightly worse. 57 Why would these treatments work preferentially in participants lacking the AD risk factor APOE4? In the rosglitazone study it was proposed that fragments of ApoE4 protein interfered with mitochondrial function and prevented E4 carriers from responding to PPAR␥ activation.…”

“…In the rosglitazone study it was proposed that fragments of ApoE4 protein interfered with mitochondrial function and prevented E4 carriers from responding to PPAR␥ activation. 57 It is possible that such damaged mitochondria also fail to metabolize KB.…”

Targeting the Prodromal Stage of Alzheimer's Disease: Bioenergetic and Mitochondrial Opportunities

“…A Phase III clinical trial of pioglitazone for MCI due to AD is currently underway (ClinicalTrials.gov identifier: NCT01931566). Rosiglitazone tested in MCI and early AD showed improved delayed recall [94], but failed to show significant cognitive benefits in a subsequent larger trial with over 1400 patients with mild-tomoderate AD (ClinicalTrials.gov identifier: NCT00490568) [95]. One major challenge for these candidates is they have poor BBB penetration [78].…”

ApoE genotyping as a progression-rate biomarker in phase II disease-modification trials for Alzheimer's disease

“…11 Nonetheless, smaller studies have generated some striking findings. For instance, the PPARg agonist rosiglitazone (RSG) was efficacious only in e4-negative patients, 12 making e4 genotype a candidate RSG responder/ non-responder biomarker for AD. Surprisingly, e4 allele carriers treated with placebo in this study showed a slower rate of cognitive decline than e4 non-carriers.…”