Sid Byrapaneni

Background:   Alzheimer’s disease (AD) affects an estimated 55 million people worldwide and is projected to reach 152 million by 2050, with an annual economic burden approaching 1 trillion dollars.¹,² Despite extensive research focused on amyloid‑β plaques and tau neurofibrillary tangles, current therapies are only symptomatic and do not prevent or reverse neurodegeneration.¹ Data from human tissue, cellular models, and animal studies suggest mitochondrial dysfunction and impaired mitophagy as early, upstream events in AD pathogenesis rather than mere downstream consequences of amyloid and tau pathology.³‑⁵ The emerging literature motivates investigation of the PINK1/Parkin mitophagy pathway as a disease‑modifying target in AD.⁴,⁵

Objective:  The objective of this narrative review is to synthesize evidence that impaired PINK1/Parkin‑mediated mitophagy is a mechanistic driver of AD and to evaluate whether restoring mitophagy can reverse amyloid and tau pathology and improve outcomes.⁴‑⁸,¹⁰

 Search Methods: Studies were identified through online searches of PubMed published between January 1, 2017, and December 31, 2024, using keywords including “Alzheimer disease,” “mitophagy,” “mitochondria,” “PINK1,” “Parkin,” and “cell-penetrating peptides.

Results:  Familial AD iNSCs demonstrate that APP C‑terminal fragments (APP‑CTFs) accumulate within mitochondria, causing membrane depolarization and ATP depletion. This is mediated by stalling of the PINK1/Parkin mitophagy pathway, inconsistent PINK1/Parkin recruitment, and failed mitochondria‑lysosome fusion.⁵ Inhibiting γ‑secretase with DAPT reproduces these mitophagy defects in PSEN‑knockout cells despite preventing amyloid‑β production, implicating that APP‑CTFs themselves are directly toxic to mitochondria.⁵ Cross‑species studies show that pharmacologic stimulation of mitophagy, including via NAD⁺ precursors and other agents, reduces both amyloid‑β and tau pathology and reverses cognitive deficits in worm and mouse AD models, providing proof that restoring mitophagy can improve outcomes in AD.⁷  Machine learning guided screening has identified natural compounds such as kaempferol and rhapontigenin as PINK1/Parkin‑targeting mitophagy inducers with strong efficacy, demonstrating the ability of AI‑driven drug discovery in this pathway.⁸,⁹ Translational work using a cell‑penetrating peptide (aMTD) to deliver Parkin protein demonstrates rescue of neurons and mitigation of mitochondrial damage in Parkinson’s disease models, and subsequent AAV‑aMTD‑Parkin gene therapy achieves sustained restoration of mitophagy with a single dose, improving motor and cognitive outcomes in rodent models of both Parkinson’s disease and AD.⁶,¹⁰

Conclusion:  Recent evidence supports a model in which impaired PINK1/Parkin‑mediated mitophagy is an early, mechanistically upstream driver of AD, and restoring mitophagy reverses both amyloid‑β and tau pathology across species, drug classes, and delivery platforms.⁵‑⁸,¹⁰  The findings suggest that targeting mitochondrial function may offer a disease‑modifying strategy that complements or surpasses current amyloid‑centric approaches.⁴‑⁸,¹⁰  However, critical gaps remain, including the lack of large‑animal data, unvalidated human blood–brain barrier transport for AAV‑aMTD‑Parkin, and absence of long‑term safety and immunogenicity data for Parkin‑based gene therapies.³,⁶,¹⁰

Works Cited

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2. Fu H, Huang H, Liao S, Dai Z. Global burden of Alzheimer’s disease and other dementias (1990–2021). Front Aging Neurosci. 2025;17:1637029.
3. Faria R, Boisguérin P, Sousa Â, Costa D. Delivery systems for mitochondrial gene therapy: a review. Pharmaceutics. 2023;15(2):572.
4. Checler F, Alves da Costa C. Parkin as a molecular bridge linking Alzheimer’s and Parkinson’s diseases? Biomolecules. 2022;12(4):559.
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9. Liu Z, Zhuang W, Cai M, et al. Kaempferol protects dopaminergic neurons by promoting mTOR‑mediated autophagy. Neurochem Res. 2023;48(5):1395‑1411.
10. Lee S, Kang M, Lee S, et al. AAV‑aMTD‑Parkin, a therapeutic gene delivery cargo, enhances motor and cognitive functions in Parkinson’s and Alzheimer’s diseases. Pharmacol Res. 2024;208:107326.