Abstract
Alzheimer's disease is a major cause of dementia, that affects approximately 7-8% of people aged 65 years and older (according to WHO & Alzheimer's Disease International) and thus is a major concern in public health world-wide. This review chronicles the foundational research and translational trajectory leading to the development of donanemab, a monoclonal antibody targeting pyroglutamyl amyloid-β (Aβ3pE-X) peptides, recently approved for the treatment of early Alzheimer's disease (AD). We trace a 30-year arc from the biochemical identification of Aβ species to the recognition of Aβ3pE-42 as a predominant pathological isoform in AD and Down syndrome brains-a fact still underrecognized among clinicians and researchers. We highlight key breakthroughs in antibody generation, Aβ peptide biochemistry, and resistance to enzymatic degradation. Mechanistic distinctions between donanemab (Kisunla®), and lecanemab (Leqembi®) are also explored, along with therapeutic implications for targeting specific Aβ species at preclinical stages of disease. The review emphasizes how persistent biochemical research, fueled by intellectual curiosity, serendipity, and rigorous experimentation, has culminated in clinical proof-of-concept for the amyloid hypothesis. In addition to its molecular specificity, donanemab's development underscores a critical shift toward precision medicine in Alzheimer's care. Its clinical validation, though limited in scope, reinforces the need for scalable and affordable interventions that can address the growing global burden of dementia. We expect these therapeutic antibodies to contribute to reducing the global burden by ceasing the disease progression in a preclinical stage now that new methods for fluid biomarkers are becoming available. As the global population ages, understanding and addressing AD has become a top priority in neuroscience and public health.