Modeling Alzheimer’s Disease with Induced Pluripotent Stem Cells: Current Challenges and Future Concerns

Table 1

Causative and risk variants of AD.

Gene	Variant	Effect allele frequency	Odds ratio	Function	AD-related pathways
APP	—	—	—	Aβ peptide precursor, neurite outgrowth, adhesion, and axonogenesis	APP processing, produce Aβ
PSEN1	—	—	—	Component of γ-secretase complex that cleaves APP into Aβ fragments	APP amyloidogenic pathway, cleaves APP
PSEN2	—	—	—	Component of γ-secretase complex that cleaves APP into Aβ fragments	APP amyloidogenic pathway, cleaves APP
Frequent variants
APOE	—	—	—	Component of lipoproteins, transports lipids and cholesterols, mediates synaptogenesis, synaptic plasticity, and neuroinflammation	Aβ clearance
CR1	rs6656401	0.197	1.18	Bind C3b and C4b, and moderate the activity of the complement system	Aβ clearance
BIN1	rs6733839	0.409	1.22	Participant in Clathrin-mediated endocytosis, intracellular trafficking, apoptosis, and interacting with the microtubule cytoskeleton	Mediate tau toxicity
CD2AP	rs10948363	0.266	1.10	Cytoskeletal organization, endocytosis	Mediate tau toxicity
EPHA1	rs11771145	0.338	0.9	Mediate brain development, particularly axonal guidance	Immune response, neural development
CLU	rs9331896	0.375	0.86	extracellular chaperone, inhibits formation of amyloid fibrils by APP	Aβ clearance
MS4A6A	rs983392	0.403	0.9	Signal transduction	unknown
PLCALM	rs10792832	0.358	0.87	Clathrin-mediated endocytosis	Aβ clearance
CD33	rs3865444	0.307	0.94	Inhibition of cell activity	Aβ42 uptake
HLA-DRB5–; HLA-DRB1	rs9271192	0.276	1.11	Histocompatibility antigen, peptide antigen binding	Immune response
PTK2B	rs28834970	0.366	1.10	Induce long term potentiation in hippocampus	Synapse function and neural development
SLC24A4; and RIN3	rs10498633	0.217	0.91	Calcium transport, brain and neural development	Neural development
DSG2	rs8093731	0.017	0.73	Component of intercellular desmosome junctions	unknown
INPP5D	rs35349669	0.488	1.08	Regulate cell proliferation and survival	Immune response
MEF2C	rs190982	0.408	0.93	Participant in hippocampal-dependent learning and memory by suppressing the number of excitatory synapses,and neuronal development and distribution	Neural development, synapse function
NME8	rs2718058	0.373	0.93	Spermatogenesis, ciliary functions	unknown
ZCWPW1; and NYAP1	rs1476679	0.278	0.91	Epigenetic regulation (ZCWPW1); brain and neural development (NYAP1)	Neural development
CELF1	rs10838725	0.316	1.08	mRNA splicing	unknown
FERMT2	rs17125944	0.092	1.14	Cell adhesion, cell shape and Wnt signaling pathway	Mediates tau toxicity
CASS4	rs7274581	0.083	0.88	cell adhesion and cell spreading	Cytoskeleton and axonal transport
SORL1	rs11218343	0.039	0.77	Lipoprotein uptake, APP trafficking to and from Golgi apparatus	APP trafficking
ABCA7	rs115550680	0.09	1.79	lipid metabolism, phagocytosis of apoptotic cells	Aβ clearance
Rare variants
ADAM10	Q170H and R181G	—	—	Constitute and regulate α-secretase activities	APP nonamyloidogenic pathway
APP	rs63750847	0.0045	0.24	Inhibit β-secretase activities	APP processing
TREM2	rs75932628	0.0063	2.26	Aβ clearance	Immune response
UNC5C	rs137875858	0.0003298	2.15	Increase susceptibility to neuronal cell death	Inflammatory response
PLD3	rs145999145	0.003077	2.1	APP trafficking and cleavage	APP processing
AKAP9	rs144662445	0.0006298	2.75	unknown	unknown
	rs149979685	0.000432	3.61