A manifesto for Alzheimer’s disease drug discovery in the era of disease-modifying therapies
Abstract After decades of disappointment, three disease-modifying therapies for Alzheimer’s disease (AD) have been approved since 2021. Burgeoning clinical data on these amyloid β-protein (Aβ) targeting drugs validate the amyloid cascade hypothesis as a molecular roadmap for the development of yet m...
Saved in:
| Main Authors: | , , , , , , |
|---|---|
| Format: | Article |
| Language: | English |
| Published: |
BMC
2025-08-01
|
| Series: | Molecular Neurodegeneration |
| Subjects: | |
| Online Access: | https://doi.org/10.1186/s13024-025-00872-7 |
| Tags: |
Add Tag
No Tags, Be the first to tag this record!
|
| _version_ | 1849761273927958528 |
|---|---|
| author | Heike Hering Thierry Bussiere Chia-Chen Liu Kelly E. Glajch Andreas Weihofen Jane Grogan Dominic M. Walsh |
| author_facet | Heike Hering Thierry Bussiere Chia-Chen Liu Kelly E. Glajch Andreas Weihofen Jane Grogan Dominic M. Walsh |
| author_sort | Heike Hering |
| collection | DOAJ |
| description | Abstract After decades of disappointment, three disease-modifying therapies for Alzheimer’s disease (AD) have been approved since 2021. Burgeoning clinical data on these amyloid β-protein (Aβ) targeting drugs validate the amyloid cascade hypothesis as a molecular roadmap for the development of yet more effective therapeutics and offer a template for drugging other AD-associated aggregation-prone proteins. While there remains much to be learned about the molecular pathology of AD, the current state of knowledge is sufficient to expedite the delivery of new drugs. Mindful of the urgent need of patients, we recommend prioritizing efforts in four directions: finishing the job on Aβ, accelerating and diversifying efforts on tau, and expanding discovery on apolipoprotein E and ⍺-synuclein. For each target, we explain the scientific premise, current efforts, and possible new approaches. In the short- and medium-term, we advocate focusing on the technical innovations required to better drug these already well validated targets. While the focus of this review is on expediating development of monotherapies, the subsequent approval of such agents will enable add-on or combination approaches best suited to individual patients. |
| format | Article |
| id | doaj-art-bb37bdcd89384e88abdd6e8c75f347f4 |
| institution | DOAJ |
| issn | 1750-1326 |
| language | English |
| publishDate | 2025-08-01 |
| publisher | BMC |
| record_format | Article |
| series | Molecular Neurodegeneration |
| spelling | doaj-art-bb37bdcd89384e88abdd6e8c75f347f42025-08-20T03:06:05ZengBMCMolecular Neurodegeneration1750-13262025-08-0120112910.1186/s13024-025-00872-7A manifesto for Alzheimer’s disease drug discovery in the era of disease-modifying therapiesHeike Hering0Thierry Bussiere1Chia-Chen Liu2Kelly E. Glajch3Andreas Weihofen4Jane Grogan5Dominic M. Walsh6Neurodegeneration Research UnitNeurodegeneration Research UnitNeurodegeneration Research UnitNeurodegeneration Research UnitNeurodegeneration Research UnitNeurodegeneration Research UnitNeurodegeneration Research UnitAbstract After decades of disappointment, three disease-modifying therapies for Alzheimer’s disease (AD) have been approved since 2021. Burgeoning clinical data on these amyloid β-protein (Aβ) targeting drugs validate the amyloid cascade hypothesis as a molecular roadmap for the development of yet more effective therapeutics and offer a template for drugging other AD-associated aggregation-prone proteins. While there remains much to be learned about the molecular pathology of AD, the current state of knowledge is sufficient to expedite the delivery of new drugs. Mindful of the urgent need of patients, we recommend prioritizing efforts in four directions: finishing the job on Aβ, accelerating and diversifying efforts on tau, and expanding discovery on apolipoprotein E and ⍺-synuclein. For each target, we explain the scientific premise, current efforts, and possible new approaches. In the short- and medium-term, we advocate focusing on the technical innovations required to better drug these already well validated targets. While the focus of this review is on expediating development of monotherapies, the subsequent approval of such agents will enable add-on or combination approaches best suited to individual patients.https://doi.org/10.1186/s13024-025-00872-7Aggregation inhibitors⍺-synucleinAmyloid β-proteinAntisense oligonucleotidesApolipoprotein EBrain shuttles |
| spellingShingle | Heike Hering Thierry Bussiere Chia-Chen Liu Kelly E. Glajch Andreas Weihofen Jane Grogan Dominic M. Walsh A manifesto for Alzheimer’s disease drug discovery in the era of disease-modifying therapies Molecular Neurodegeneration Aggregation inhibitors ⍺-synuclein Amyloid β-protein Antisense oligonucleotides Apolipoprotein E Brain shuttles |
| title | A manifesto for Alzheimer’s disease drug discovery in the era of disease-modifying therapies |
| title_full | A manifesto for Alzheimer’s disease drug discovery in the era of disease-modifying therapies |
| title_fullStr | A manifesto for Alzheimer’s disease drug discovery in the era of disease-modifying therapies |
| title_full_unstemmed | A manifesto for Alzheimer’s disease drug discovery in the era of disease-modifying therapies |
| title_short | A manifesto for Alzheimer’s disease drug discovery in the era of disease-modifying therapies |
| title_sort | manifesto for alzheimer s disease drug discovery in the era of disease modifying therapies |
| topic | Aggregation inhibitors ⍺-synuclein Amyloid β-protein Antisense oligonucleotides Apolipoprotein E Brain shuttles |
| url | https://doi.org/10.1186/s13024-025-00872-7 |
| work_keys_str_mv | AT heikehering amanifestoforalzheimersdiseasedrugdiscoveryintheeraofdiseasemodifyingtherapies AT thierrybussiere amanifestoforalzheimersdiseasedrugdiscoveryintheeraofdiseasemodifyingtherapies AT chiachenliu amanifestoforalzheimersdiseasedrugdiscoveryintheeraofdiseasemodifyingtherapies AT kellyeglajch amanifestoforalzheimersdiseasedrugdiscoveryintheeraofdiseasemodifyingtherapies AT andreasweihofen amanifestoforalzheimersdiseasedrugdiscoveryintheeraofdiseasemodifyingtherapies AT janegrogan amanifestoforalzheimersdiseasedrugdiscoveryintheeraofdiseasemodifyingtherapies AT dominicmwalsh amanifestoforalzheimersdiseasedrugdiscoveryintheeraofdiseasemodifyingtherapies AT heikehering manifestoforalzheimersdiseasedrugdiscoveryintheeraofdiseasemodifyingtherapies AT thierrybussiere manifestoforalzheimersdiseasedrugdiscoveryintheeraofdiseasemodifyingtherapies AT chiachenliu manifestoforalzheimersdiseasedrugdiscoveryintheeraofdiseasemodifyingtherapies AT kellyeglajch manifestoforalzheimersdiseasedrugdiscoveryintheeraofdiseasemodifyingtherapies AT andreasweihofen manifestoforalzheimersdiseasedrugdiscoveryintheeraofdiseasemodifyingtherapies AT janegrogan manifestoforalzheimersdiseasedrugdiscoveryintheeraofdiseasemodifyingtherapies AT dominicmwalsh manifestoforalzheimersdiseasedrugdiscoveryintheeraofdiseasemodifyingtherapies |