# Natural Vitamins and Novel Synthetic Antioxidants Targeting Mitochondria in Cognitive Health: A Scoping Review of In Vivo Evidence

## TL;DR

This review explores how natural vitamins and synthetic antioxidants targeting mitochondria may help prevent or treat cognitive decline in Alzheimer's and dementia.

## Contribution

The study provides a comprehensive in vivo evidence-based comparison of natural vitamins and mitochondria-targeted antioxidants for cognitive health.

## Key findings

- Natural vitamins showed mixed efficacy, with Vitamin E demonstrating the most consistent neuroprotective effects.
- Mitochondria-targeted antioxidants improved mitochondrial function and cognitive outcomes more robustly than natural vitamins.
- Both types of antioxidants improved biomarkers in animal models, but mitochondria-targeted antioxidants showed greater promise.

## Abstract

Mitochondrial dysfunction and oxidative stress are crucial contributors to the pathogenesis of Alzheimer’s disease (AD) and dementia exhibiting cognitive decline at the early stage of neurodegeneration. Natural vitamin antioxidants (NVAs) and novel mitochondria-targeted antioxidants (MTAs) are proposed as potential therapeutics though conclusive evidence is lacking. Objectives were to examine in vivo evidence on NVAs and MTAs for preventing and/or treating cognitive decline leading to dementia, to identify the most promising antioxidants, and highlight translational gaps. Methods followed PRISMA-ScR guidelines. MEDLINE, EMBASE and Scopus were searched for English language in vivo experiments assessing NVAs or MTAs in AD and dementia. A total of 25 studies (13 NVAs; 12 MTAs) met inclusion criteria. NVAs (Vitamin A, B, C, E) demonstrated mixed efficacy in reducing oxidative stress and improving cognitive outcomes, with Vitamin E showing the most consistent neuroprotective effects. MTAs (MitoQ, MitoTEMPO, SS31, SkQ1) improved mitochondrial dynamics and cognitive performance and reduced dementia-related pathology. Both NVAs and MTAs improved biomarker profiles and cognitive outcomes in vivo animal models of AD and dementia, but MTAs showed more robust and consistent efficacy by directly targeting mitochondrial pathways. Given the favourable safety profiles of MTAs in other clinical conditions, early-phase human trials in dementia and AD are warranted to evaluate their long-term cognitive benefits.