If Amyloid Drives Alzheimer Disease, Why Have Anti-amyloid Therapies Not Yet Slowed Cognitive Decline?

Overview

Journal PLoS Biol

Specialty Biology

Date 2022 Jul 21

PMID 35862308

Authors

Christian Haass

Dennis Selkoe

Affiliations

Soon will be listed here.

Abstract

Strong genetic evidence supports an imbalance between production and clearance of amyloid β-protein (Aβ) in people with Alzheimer disease (AD). Microglia that are potentially involved in alternative mechanisms are actually integral to the amyloid cascade. Fluid biomarkers and brain imaging place accumulation of Aβ at the beginning of molecular and clinical changes in the disease. So why have clinical trials of anti-amyloid therapies not provided clear-cut benefits to patients with AD? Can anti-amyloid therapies robustly decrease Aβ in the human brain, and if so, could this lowering be too little, too late? These central questions in research on AD are being urgently addressed.

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References

Keren-Shaul H, Spinrad A, Weiner A, Matcovitch-Natan O, Dvir-Szternfeld R, Ulland T . A Unique Microglia Type Associated with Restricting Development of Alzheimer's Disease. Cell. 2017; 169(7):1276-1290.e17. DOI: 10.1016/j.cell.2017.05.018. View

Lewcock J, Schlepckow K, Paolo G, Tahirovic S, Monroe K, Haass C . Emerging Microglia Biology Defines Novel Therapeutic Approaches for Alzheimer's Disease. Neuron. 2020; 108(5):801-821. DOI: 10.1016/j.neuron.2020.09.029. View

Selkoe D, Hardy J . The amyloid hypothesis of Alzheimer's disease at 25 years. EMBO Mol Med. 2016; 8(6):595-608. PMC: 4888851. DOI: 10.15252/emmm.201606210. View

Scheuner D, Eckman C, Jensen M, Song X, Citron M, Suzuki N . Secreted amyloid beta-protein similar to that in the senile plaques of Alzheimer's disease is increased in vivo by the presenilin 1 and 2 and APP mutations linked to familial Alzheimer's disease. Nat Med. 1996; 2(8):864-70. DOI: 10.1038/nm0896-864. View

Yang Y, Arseni D, Zhang W, Huang M, Lovestam S, Schweighauser M . Cryo-EM structures of amyloid-β 42 filaments from human brains. Science. 2022; 375(6577):167-172. PMC: 7612234. DOI: 10.1126/science.abm7285. View

Wolfe M, Xia W, Ostaszewski B, Diehl T, Kimberly W, Selkoe D . Two transmembrane aspartates in presenilin-1 required for presenilin endoproteolysis and gamma-secretase activity. Nature. 1999; 398(6727):513-7. DOI: 10.1038/19077. View

Castellano J, Kim J, Stewart F, Jiang H, DeMattos R, Patterson B . Human apoE isoforms differentially regulate brain amyloid-β peptide clearance. Sci Transl Med. 2011; 3(89):89ra57. PMC: 3192364. DOI: 10.1126/scitranslmed.3002156. View

Salloway S, Farlow M, McDade E, Clifford D, Wang G, Llibre-Guerra J . A trial of gantenerumab or solanezumab in dominantly inherited Alzheimer's disease. Nat Med. 2021; 27(7):1187-1196. PMC: 8988051. DOI: 10.1038/s41591-021-01369-8. View

Xu H, Gelyana E, Rajsombath M, Yang T, Li S, Selkoe D . Environmental Enrichment Potently Prevents Microglia-Mediated Neuroinflammation by Human Amyloid β-Protein Oligomers. J Neurosci. 2016; 36(35):9041-56. PMC: 5005718. DOI: 10.1523/JNEUROSCI.1023-16.2016. View

10.

Cullen N, Janelidze S, Palmqvist S, Stomrud E, Mattsson-Carlgren N, Hansson O . Association of CSF Aβ Levels With Risk of Alzheimer Disease-Related Decline. Neurology. 2021; 98(9):e958-e967. PMC: 8901176. DOI: 10.1212/WNL.0000000000013228. View

11.

Kaeser S, Hasler L, Lambert M, Bergmann C, Bottelbergs A, Theunis C . CSF p-tau increase in response to Aβ-type and Danish-type cerebral amyloidosis and in the absence of neurofibrillary tangles. Acta Neuropathol. 2021; 143(2):287-290. PMC: 8742811. DOI: 10.1007/s00401-021-02400-5. View

12.

Chartier-Harlin M, Crawford F, Houlden H, Warren A, Hughes D, Fidani L . Early-onset Alzheimer's disease caused by mutations at codon 717 of the beta-amyloid precursor protein gene. Nature. 1991; 353(6347):844-6. DOI: 10.1038/353844a0. View

13.

Prasher V, Farrer M, Kessling A, Fisher E, West R, Barber P . Molecular mapping of Alzheimer-type dementia in Down's syndrome. Ann Neurol. 1998; 43(3):380-3. DOI: 10.1002/ana.410430316. View

14.

Nilsberth C, Westlind-Danielsson A, Eckman C, Condron M, Axelman K, Forsell C . The 'Arctic' APP mutation (E693G) causes Alzheimer's disease by enhanced Abeta protofibril formation. Nat Neurosci. 2001; 4(9):887-93. DOI: 10.1038/nn0901-887. View

15.

Schenk D, Barbour R, Dunn W, Gordon G, Grajeda H, Guido T . Immunization with amyloid-beta attenuates Alzheimer-disease-like pathology in the PDAPP mouse. Nature. 1999; 400(6740):173-7. DOI: 10.1038/22124. View

16.

Goate A, Chartier-Harlin M, Mullan M, Brown J, Crawford F, Fidani L . Segregation of a missense mutation in the amyloid precursor protein gene with familial Alzheimer's disease. Nature. 1991; 349(6311):704-6. DOI: 10.1038/349704a0. View

17.

Mintun M, Lo A, Evans C, Wessels A, Ardayfio P, Andersen S . Donanemab in Early Alzheimer's Disease. N Engl J Med. 2021; 384(18):1691-1704. DOI: 10.1056/NEJMoa2100708. View

18.

Alzheimer A, Stelzmann R, SCHNITZLEIN H, Murtagh F . An English translation of Alzheimer's 1907 paper, "Uber eine eigenartige Erkankung der Hirnrinde". Clin Anat. 1995; 8(6):429-31. DOI: 10.1002/ca.980080612. View

19.

Kang J, Lemaire H, Unterbeck A, Salbaum J, Masters C, Grzeschik K . The precursor of Alzheimer's disease amyloid A4 protein resembles a cell-surface receptor. Nature. 1987; 325(6106):733-6. DOI: 10.1038/325733a0. View

20.

Citron M, Oltersdorf T, Haass C, McConlogue L, Hung A, Seubert P . Mutation of the beta-amyloid precursor protein in familial Alzheimer's disease increases beta-protein production. Nature. 1992; 360(6405):672-4. DOI: 10.1038/360672a0. View