Table 2.

Spheroid and organoid models of AD.

Observed AD Phenotype	Method	AD Source	Experimental Time Point, Days	Reference
Neurofibrillary tanglelike inclusions	Dual SMAD inhibition and Matrigel (Corning Life Sciences)—embedded 3D maturation	Application of recombinant human tau (K18) to P301L overexpressed neurons differentiated from NPCs	>28	[116]
Extracellular deposition of Aβ, including Aβ plaques Aggregates of pTau in the soma and neurites and filamentous tau	Matrigel-embedded differentiation [137]	Lentiviral overexpression of FAD-related mutations in APP and PSEN1 of ReNcell VM (ReNeuron Group plc)	49–100	[118]
Aβ42/Aβ40-correlated increase of pTau and cell death	Matrigel-embedded differentiation [138]	Lentiviral overexpression of FAD-related mutations in APP and PSEN1 of ReNcell VM and FACS purification	35–84	[119]
Aβ accumulation and elevated pTau	Matrigel-embedded self-organized differentiation	FAD (APP and PSEN1) patient HiPSCs	60–90	[121]
Aβ oligomers and Aβ aggregation	Hydrogel-embedded dual SMAD-inhibited differentiation [108]	FAD (APP and PSEN1) patient fibroblasts	>14	[122]
Aβ plaques Aggregated and abnormal pTau	Component- and environment-controlled differentiation of cerebral organoids	FAD (PSEN1) and Down syndrome patient HiPSCs	110	[123]
↑ Tau fragmentation and mislocalization Impaired axonal transport and functionality that can be improved by microtubule stabilization	Matrigel-embedded self-organized differentiation	Familial frontotemporal dementia patient derived HiPSC with R406W mutation and isogenic control	60	[124]
Accelerated neuronal differentiation ↑ Synaptic markers ↑ Total tau and pTau	Matrigel-embedded growth factor–directed differentiation of HiPSCs in spinning bioreactor	apoE4+ LOAD patient–derived fibroblasts and gene-edited (apoE4) healthy control–derived fibroblasts	46	[128]
Early neuronal differentiation Aβ accumulation and elevated pTau	Matrigel-embedded self-organized differentiation	HiPSCs from LOAD patients with apoE4 mutation	>180	[89]
↑ Secretion of long Aβ peptides (Aβ40, Aβ42, and Aβ43)	Matrigel-embedded growth factor–directed differentiation of HiPSCs in spinning bioreactor	Fibroblasts from FAD patients with FAD-linked mutations in APP or PSEN1	100	[125]
Increased Aβ42/Aβ40 peptide ratios and decreased synaptic protein levels	Matrigel-embedded differentiation in suspension	FAD (APP and PSEN1) patient HiPSCs	35	[130]

Aβ, amyloid-β; AD, Alzheimer’s disease; apoE4, apolipoprotein E4; APP, amyloid precursor protein; FACS, fluorescence-activated cell sorting; FAD, familial AD; HiPSC, human induced pluripotent stem cell; LOAD, late-onset AD; NPC, neural progenitor cell; PSEN1, presenilin 1; pTau, phosphorylated tau; SMAD, an acronym from the fusion of the Caenorhabditis elegans and Drosophila genes, Sma and Mad (mothers against decapentaplegic); 3D, 3-dimensional.