Progress and challenges in drug delivery for the treatment of Alzheimer's disease.

INTRODUCTION: Alzheimer's disease (AD) is a neurodegenerative disorder marked by declining memory and cognitive function. Despite recent advances to slowdown early-stage progression, no curative therapies exist due to challenges in delivering neuroregenerative agents to the brain. AREAS COVERED: This review examines recent research on strategies to modulate the blood-brain barrier (BBB) to enhance the delivery of small-to-large molecules through the paracellular pathway into the brain for potential treatments of AD. A literature search was conducted using PubMed and Scopus covering studies published between 2016 and 2026. EXPERT OPINION: BBB modulation technologies are advancing rapidly and offer real potential to improve delivery of therapeutics in AD patients. Hyperosmotic method has been successfully used to deliver anticancer drugs to treat brain tumor patients and can be used for AD. Recently, focused ultrasound (FUS) has been used to disrupt the BBB at a targeted brain region to enhance paracellular permeation of drug molecules to the brain. Finally, drug permeation through the BBB paracellular pathway can also be enhanced by modulating the protein-protein interactions in the intercellular junctions using BBB modulators (BBBMs). This review covers the mechanisms, advantages, and limitations of these methods as well as recent studies that showcase their ability to deliver therapeutic agents for AD and other brain diseases.