Effectiveness of Apolipoprotein E Targeted Therapeutic Drugs for Alzheimer’s Disease: A Systematic Review and Meta-analysis
Ayush Halder1, Rahul Kashyap2, Faisal Nawaz3, Aroul Murugan1, Hamna Javed4, Smitesh Padte5, Sindhura Tadisetty6
1Jawaharlal Institute of Postgraduate Medical Education & Research, Puducherry, 2WellSpan Health, 3Psychiatry, Al Amal Psychiatric Hospital, 4Internal Medicine, Saint Agnes Medical Center, 5Global Remote Research Scholars Program, 6Radiology, University of Kentucky
Objective:
To determine the efficacy of Apolipoprotein E targeting drugs in the treatment of Alzheimer's disease (AD).
Background:
The APOE allele codes the protein apolipoprotein E (apoE), which plays a role in the pathogenesis of AD- the most prevalent neurodegenerative disease in aging. Thus, ApoE-targeted drugs can be seen as a possible treatment modality by reducing cognitive decline and improving the quality of life.
Design/Methods:
We included randomized and non-randomized, placebo-controlled clinical trials that evaluated ApoE-targeted drugs in people diagnosed with Dementia due to AD, Mild cognitive impairment (MCI) due to AD, or cognitively unimpaired subjects. Pubmed, Embase, and Scopus databases and Cochrane Library were searched from inception to February 2023. Other pertinent manuscripts were included and assessed for their suitability for inclusion. The results were pooled using a random-effects model. The continuous data were expressed as mean differences (MD) and standard deviation to assess the effectiveness of the novel therapeutics. PROSPERO ID: CRD42023397813.
Results:
Out of 2747, 12 RCTs were included in the meta-analysis. Two major classes of drugs were identified: RXR agonists and PPAR-γ agonists. Using the Alzheimer’s Disease Assessment Scale–Cognitive subscale (ADAS-Cog), Nine studies were analyzed, and ApoE-targeted drugs showed a significant but small size of effect (MD: -1.03, 95% CI: -1.90 to -0.16, p=0.02). However, significant results were seen in the ‘Pioglitazone’ subgroup, i.e. ADAS-Cog (MD: -3.36, 95% CI: -4.36 to -2.35, p<0.00001) and MMSE (MD: 1.25, 95% CI: 0.48 to 2.02, p=0.002) with low and very-low certainty of evidence respectively, which was not seen in other PPAR-γ agonists like Rosiglitazone. The Meta-analysis assessing the effect of ApoE-targeting drugs using ADCS-ADL, CDR-SoB, and NPI scores showed no difference in outcomes.
Conclusions:
Drugs targeting Apo-E show little to no efficacy in the treatment of AD. More large-scale trials with Pioglitazone would likely show no beneficial effects, as seen with the Rosiglitazone group.