Apolipoprotein E Gene Polymorphisms Affect the Efficacy of Thiazolidinediones for Alzheimer’s Disease: A Systematic Review and Meta-Analysis

Abstract

Although several studies have evaluated the efficacy of thiazolidinediones (TZD) for the treatment of Alzheimer's disease (AD), investigation of the impact of apolipoprotein E (ApoE) gene polymorphisms on the efficacy of TZD remains insufficient. We investigated the impact by conducting a systematic review and meta-analysis. MEDLINE, Cochrane Library, and Japana Centra Revuo Medicina were searched to identify relevant studies based on eligibility criteria. Mean differences (MD) of Alzheimer's Disease Assessment Scale-cognitive subscale (ADAS-Cog) total score with 95% confidence intervals (CI) were calculated for subgroups stratified by ApoE genotype. To evaluate the impact of ApoE gene polymorphisms, meta-regression analysis was also conducted to calculate the regression coefficient (Coef) of ApoE expression status with 95% CI. Three randomized controlled studies comparing rosiglitazone and placebo, with a total of 2381 subjects met the eligibility criteria. Key words Alzheimer's disease; meta-analysis; meta-regression analysis; rosiglitazone; systematic review; thiazolidinedione Dementia affects an estimated 47.5 million individuals worldwide, 60-70% of whom have Alzheimer's disease (AD). 1) Currently, although some drugs such as choline esterase inhibitors and memantine are used for treating AD, their efficacy is limited to delaying disease progression or relieving symptoms. 2) One reason for these limitations may be the fact that AD pathogenesis remains unclear. Therefore, despite the lack of established treatment, drug development has faced difficulties. 3) Several recent studies have reported an association between AD and diabetes mellitus (DM). [4][5][6] These studies demonstrated insulin resistance in the central nervous system (CNS) in some AD patients, which contributed to impaired cognitive functions. This association has been termed type 3 DM. 5,7) Based on this hypothesis, some studies were conducted to investigate the efficacy of anti-diabetic agents for the treatment of AD. 8-11) Among these agents, thiazolidinediones (TZD) exhibited various favorable effects in in vitro and in vivo studies. [10][11][12][13][14] These agents contributed to clearing of amyloid beta protein through apolipoprotein E (ApoE) function. 14) Some reports of clinical trials indicate that TZD improved cognitive function in AD patients. [15][16][17] Additionally, a systematic review and meta-analysis concluded that the efficacy of TZD was significant. 18) Although the efficacy of TZD has been demonstrated, the clinical relevance is limited because the efficacy is lower than that of choline esterase inhibitors.ApoE is a lipoprotein that has genetic polymorphisms (ApoE2, ApoE3, and ApoE4). 19,20) The wild-type ApoE3 constitutes 50-90% of individuals, whereas ApoE4 that constitutes 5-35% of individuals is known to be a genetic risk factor of AD. 19) A clinical trial using intranasal insulin for AD showed improved cognitive function in ApoE4-negative AD patients following short-term intranasal insulin treatment, 8) suggesting tha...

ApoE3 vs. ApoE4 Astrocytes: A Detailed Analysis Provides New Insights into Differences in Cholesterol Homeostasis

“…Since AD is also characterized by alterations of brain insulin signaling, studies on AD mouse models and AD patients have been carried out to investigate the potential of these drugs in AD treatment; however, contrasting results have been obtained so far [ 85 , 86 ]. In particular, a lower effectiveness of PPARγ-targeting therapies has been observed in ApoE4 carriers and may be due to the impairment of PPARγ signaling mediated by ApoE4 through still unknown mechanisms [ 87 ]. Overall, these data suggest that PPARγ down-regulation could be one of the leading causes of the alterations in cholesterol metabolism that we observed in ApoE4 astrocytes.…”

Antidiabetic Drugs in Alzheimer’s Disease and Mild Cognitive Impairment: A Systematic Review

“…A recent meta-analysis addressed this question synthesizing results of 4 rosiglitazone clinical trials [39, 41, 45] and obtained that, compared to placebo, rosiglitazone significantly improved ADAS-Cog in apoE4− patients and significantly worsened it in apoE4+ participants. Although the number of studies was small, this meta-analysis suggests that apoE4 status affects the efficacy of glitazones [65]. Future clinical trials with pioglitazone should explore this possibility.…”

Mapping new pharmacological interventions for cognitive function in Alzheimer’s disease: a systematic review of randomized clinical trials

“…However, drugs of this type are still in phase I, and their efficacy is unknown ( Silverman et al, 2022 ). The effectiveness of thiazolidinediones in treating AD is influenced by APOE gene polymorphisms ( Iketani et al, 2018 ). Finally, cannabis-based drugs may inhibit the progression of AD by modulating Aβ modifications.…”