Moving Beyond Amyloid and Tau to Capture the Biological Heterogeneity of Alzheimer's Disease

Overview

Journal Trends Neurosci

Specialty Neurology

Date 2023 Apr 5

PMID 37019812

Authors

Tracy L Young-Pearse

Hyo Lee

Yi-Chen Hsieh

Vicky Chou

Dennis J Selkoe

Affiliations

Soon will be listed here.

Abstract

Alzheimer's disease (AD) manifests along a spectrum of cognitive deficits and levels of neuropathology. Genetic studies support a heterogeneous disease mechanism, with around 70 associated loci to date, implicating several biological processes that mediate risk for AD. Despite this heterogeneity, most experimental systems for testing new therapeutics are not designed to capture the genetically complex drivers of AD risk. In this review, we first provide an overview of those aspects of AD that are largely stereotyped and those that are heterogeneous, and we review the evidence supporting the concept that different subtypes of AD are important to consider in the design of agents for the prevention and treatment of the disease. We then dive into the multifaceted biological domains implicated to date in AD risk, highlighting studies of the diverse genetic drivers of disease. Finally, we explore recent efforts to identify biological subtypes of AD, with an emphasis on the experimental systems and data sets available to support progress in this area.

Citing Articles

Discovery of Isobavachin, a Natural Flavonoid, as an Apolipoprotein E4 (ApoE4) Structure Corrector for Alzheimer's Disease.

Patil S, Kuehn B, McCullough C, Bates D, Hazim H, Diallo M Molecules. 2025; 30(4).

PMID: 40005250 PMC: 11858207. DOI: 10.3390/molecules30040940.

Critical role of Oas1g and STAT1 pathways in neuroinflammation: insights for Alzheimer's disease therapeutics.

Xie Z, Li L, Hou W, Fan Z, Zeng L, He L J Transl Med. 2025; 23(1):182.

PMID: 39953505 PMC: 11829366. DOI: 10.1186/s12967-025-06112-2.

Microglial Responses to Alzheimer's Disease Pathology: Insights From "Omics" Studies.

Reid A, Jayadev S, Prater K Glia. 2025; 73(3):519-538.

PMID: 39760224 PMC: 11801359. DOI: 10.1002/glia.24666.

Assessing the Benefit of Dietary Choline Supplementation Throughout Adulthood in the Ts65Dn Mouse Model of Down Syndrome.

Tallino S, Etebari R, McDonough I, Leon H, Sepulveda I, Winslow W Nutrients. 2024; 16(23).

PMID: 39683562 PMC: 11644426. DOI: 10.3390/nu16234167.

Disease Modifying Monoclonal Antibodies and Symptomatic Pharmacological Treatment for Alzheimer's Disease.

Qi X, Nizamutdinov D, Yi S, Wu E, Huang J Biomedicines. 2024; 12(11).

PMID: 39595200 PMC: 11592475. DOI: 10.3390/biomedicines12112636.

References

Frost B, Hemberg M, Lewis J, Feany M . Tau promotes neurodegeneration through global chromatin relaxation. Nat Neurosci. 2014; 17(3):357-66. PMC: 4012297. DOI: 10.1038/nn.3639. View

Andreone B, Przybyla L, Llapashtica C, Rana A, Davis S, van Lengerich B . Alzheimer's-associated PLCγ2 is a signaling node required for both TREM2 function and the inflammatory response in human microglia. Nat Neurosci. 2020; 23(8):927-938. DOI: 10.1038/s41593-020-0650-6. View

Lemere C, Blusztajn J, Yamaguchi H, Wisniewski T, Saido T, Selkoe D . Sequence of deposition of heterogeneous amyloid beta-peptides and APO E in Down syndrome: implications for initial events in amyloid plaque formation. Neurobiol Dis. 1996; 3(1):16-32. DOI: 10.1006/nbdi.1996.0003. View

Lei P, Ayton S, Moon S, Zhang Q, Volitakis I, Finkelstein D . Motor and cognitive deficits in aged tau knockout mice in two background strains. Mol Neurodegener. 2014; 9:29. PMC: 4141346. DOI: 10.1186/1750-1326-9-29. View

Hark T, Rao N, Castillon C, Basta T, Smukowski S, Bao H . Pulse-Chase Proteomics of the App Knockin Mouse Models of Alzheimer's Disease Reveals that Synaptic Dysfunction Originates in Presynaptic Terminals. Cell Syst. 2020; 12(2):141-158.e9. PMC: 7897324. DOI: 10.1016/j.cels.2020.11.007. View

Cataldo A, Peterhoff C, Troncoso J, Gomez-Isla T, Hyman B, Nixon R . Endocytic pathway abnormalities precede amyloid beta deposition in sporadic Alzheimer's disease and Down syndrome: differential effects of APOE genotype and presenilin mutations. Am J Pathol. 2000; 157(1):277-86. PMC: 1850219. DOI: 10.1016/s0002-9440(10)64538-5. View

Griciuc A, Serrano-Pozo A, Parrado A, Lesinski A, Asselin C, Mullin K . Alzheimer's disease risk gene CD33 inhibits microglial uptake of amyloid beta. Neuron. 2013; 78(4):631-43. PMC: 3706457. DOI: 10.1016/j.neuron.2013.04.014. View

Bellenguez C, Kucukali F, Jansen I, Kleineidam L, Moreno-Grau S, Amin N . New insights into the genetic etiology of Alzheimer's disease and related dementias. Nat Genet. 2022; 54(4):412-436. PMC: 9005347. DOI: 10.1038/s41588-022-01024-z. View

Colom-Cadena M, Spires-Jones T, Zetterberg H, Blennow K, Caggiano A, DeKosky S . The clinical promise of biomarkers of synapse damage or loss in Alzheimer's disease. Alzheimers Res Ther. 2020; 12(1):21. PMC: 7053087. DOI: 10.1186/s13195-020-00588-4. View

10.

Naj A, Jun G, Beecham G, Wang L, Vardarajan B, Buros J . Common variants at MS4A4/MS4A6E, CD2AP, CD33 and EPHA1 are associated with late-onset Alzheimer's disease. Nat Genet. 2011; 43(5):436-41. PMC: 3090745. DOI: 10.1038/ng.801. View

11.

Chou V, Pearse 2nd R, Aylward A, Ashour N, Taga M, Terzioglu G . INPP5D regulates inflammasome activation in human microglia. Nat Commun. 2023; 14(1):7552. PMC: 10684891. DOI: 10.1038/s41467-023-42819-w. View

12.

Jack Jr C, Bennett D, Blennow K, Carrillo M, Dunn B, Budd Haeberlein S . NIA-AA Research Framework: Toward a biological definition of Alzheimer's disease. Alzheimers Dement. 2018; 14(4):535-562. PMC: 5958625. DOI: 10.1016/j.jalz.2018.02.018. View

13.

Lambert J, Ibrahim-Verbaas C, Harold D, Naj A, Sims R, Bellenguez C . Meta-analysis of 74,046 individuals identifies 11 new susceptibility loci for Alzheimer's disease. Nat Genet. 2013; 45(12):1452-8. PMC: 3896259. DOI: 10.1038/ng.2802. View

14.

Johnson E, Dammer E, Duong D, Ping L, Zhou M, Yin L . Large-scale proteomic analysis of Alzheimer's disease brain and cerebrospinal fluid reveals early changes in energy metabolism associated with microglia and astrocyte activation. Nat Med. 2020; 26(5):769-780. PMC: 7405761. DOI: 10.1038/s41591-020-0815-6. View

15.

Montagne A, Barnes S, Sweeney M, Halliday M, Sagare A, Zhao Z . Blood-brain barrier breakdown in the aging human hippocampus. Neuron. 2015; 85(2):296-302. PMC: 4350773. DOI: 10.1016/j.neuron.2014.12.032. View

16.

Perez M, Jara C, Quintanilla R . Contribution of Tau Pathology to Mitochondrial Impairment in Neurodegeneration. Front Neurosci. 2018; 12:441. PMC: 6041396. DOI: 10.3389/fnins.2018.00441. View

17.

Muratore C, Rice H, Srikanth P, Callahan D, Shin T, Benjamin L . The familial Alzheimer's disease APPV717I mutation alters APP processing and Tau expression in iPSC-derived neurons. Hum Mol Genet. 2014; 23(13):3523-36. PMC: 4049307. DOI: 10.1093/hmg/ddu064. View

18.

Harada A, Oguchi K, Okabe S, KUNO J, Terada S, Ohshima T . Altered microtubule organization in small-calibre axons of mice lacking tau protein. Nature. 1994; 369(6480):488-91. DOI: 10.1038/369488a0. View

19.

James B, Wilson R, Boyle P, Trojanowski J, Bennett D, Schneider J . TDP-43 stage, mixed pathologies, and clinical Alzheimer's-type dementia. Brain. 2016; 139(11):2983-2993. PMC: 5091047. DOI: 10.1093/brain/aww224. View

20.

Bell R, Sagare A, Friedman A, Bedi G, Holtzman D, Deane R . Transport pathways for clearance of human Alzheimer's amyloid beta-peptide and apolipoproteins E and J in the mouse central nervous system. J Cereb Blood Flow Metab. 2006; 27(5):909-18. PMC: 2853021. DOI: 10.1038/sj.jcbfm.9600419. View