Table 2.

The spectrum of APP, PSEN1, and PSEN2 mutations found in Asian countries.

Gene	Exon	Codon, Mutation	Location in the Protein	Age of Onset, Clinical Characteristics	Pathogenic Nature	Country	References
APP	3	p.Glu145Lys	N-terminal	50s/Familial, EOAD	Located outside of the amyloid progressing region	Korea	This study
	4	p.Val225Ala	N-terminal	65/Familial, EOAD			This study
	7	pThr297Met	N-terminal	60s/Familial, EOAD			This study
	8	p. Pro484Ser	N-terminal	60s/Familial, EOAD			This study
	14	p.Val604Met	N-terminal	55/Familial, EOAD	Pathogenic	Thailand	This study
	16	p.Val669Leu	N-terminal	56 years; AD with a positive family history	Located nearby the β-secretase cleavage site of APP, right next to the Swedish APP (Lys, Met670/671Asn, Leu) mutation	Korea	This study
		p.Asp678Asn	N-terminal	59–65 years/familial, EOAD	Probably pathogenic, may enhance the toxic amyloid oligomer formation	Japan	Wakutani et al., 2004 [25]
	17	p.Glu693del	N-terminal	44 years/familial, EOAD/MCI	Enhances the toxic amyloid oligomer formation	Japan	Tomiyama et al., 2008 [26]
		p. Val710Gly	TM-I	65–82 years/Familial, AD, Parkinsonism	Probably pathogenic	China, Taiwan	Thajeb et al. 2009 [27]
		p. Thr714Ala	TM-I	47–55 years/Familial, EOAD, epilepsy	Probably pathogenic	Iran	Pasalar et al. 2002 [28]
		p.Val715Met	TM-I	41 years/ Familial EOAD	Expressed in HEK293 cells, revealed 2* decrease in Abeta 40 levels. Might destroy the cleavage of gamma secretase at site at Abeta40	Korea	Park et al., 2008 [29]
		p.Val717Ile	TM-I	53 years/Familial, EOAD	Increased Abeta42/Abeta40 ratio in CHO and HEK293 cells	Japan	Yoshioka et al., 1991 [30]
				54 years/unknown, EOAD		Thailand	Jiao et al., 2014 [31]
		p. Ile718Leu	TM-I	65–82 years/Familial, AD, Parkinsonism	Probably pathogenic	China, Taiwan	Thajeb et al., 2009 [27]
		p.Leu720Ser	TM-I	65–82 years/Familial, AD, Parkinsonism	Probably pathogenic	China, Taiwan	Thajeb et al. 2009 [27]
	4	p.Leu85Pro	TM-I	26 years, Juvenile EOAD	Abeta42/Abeta40 ratio increased in HEK293	Japan	Ataka et al. 2004 [54]
		p. Val96Phe	TM-I	EOAD, 49–60 years	2.1 * increased Abeta 42/40 ratio in COS-1 cells	Japan	Kamino et al. 1996 [32]
		p.Val97Leu	TM-I	EOAD	Higher beta secretase activity in human neuroblastoma cells	China	Fang et al. 2006 [33]
		p. Phe105Cys	HL-I	59 years/Familial, EOAD	Survival of mutant neuroblastoma cells dropped	China	Jiao et al., 2014 [31]
	5	p. Gly111Val	HL-I	EOAD; 59 years/Familial	Increased ratios of secreted Aβ42/Aβ40 in vitro study	China	Qiu et al., 2019 [53]
		p. Thr116Ile	HL-I	Late 30s–early-40s years; EOAD with a probable familial	Possible pathogenic mechanisms of mutation	Korea	This study
		p. Thr119Ile	HL-I	49–64 years; EOAD with a probable familial
		p.Glu120Lys	HL-I	40–65 years/Familial, EOAD	Probably pathogenic	Iran	Akbari et al., 2013 [34]
		p.Glu123Lys	HL-I	26–45 years, EOAD, myoclonus, epilepsy	Abeta42/total Abeta increased in COS-1 cells (2.7 *) and in HEK293 (4 *) cells	Japan	Yasuda et al. 1999 [35]
		p.Ala136Gly	TM-II	Unknown, EOAD	Survival of mutant neuroblastoma cells dropped, deleterious effects	China	Fang et al., 2007 [36]
		p.Met139Ile	TM-II	38 years/Familial, EOAD	Ratio of Abeta42/total Abeta increased in COS-1 cell lines.	Korea	Kim et al., 2010 [37]
		p. Ile143Thr	TM-II	26–45 years, EOAD, myoclonus, epilepsy	Abeta42/total Abeta increased in COS-1 cells (2.7 *) and in HEK293 (4 *) cells	Japan	Arai et al., 2008 [38]
		p.Tyr154Asn	TM-II	40–60 years, EOAD, spastic paraparesis	Pathogenic nature might be associated with the missing aromatic ring.	Japan	Hattori et al., 2004 [47]
	6	p.His163Arg	HL-II	43–50 years/5 Japanese families, both familial and de novo cases	Abeta42/Abeta40 ratio increased 2 * in COS1 cell lines	Japan	Kamino et al., 1996 [32]
		p.His163Arg	HL-II	43–50 years/5 Japanese families, both familial and de novo cases	Abeta42/Abeta40 ratio increased 2 * in COS1 cell lines	Korea	Hong et al., 1997 [48]
		p.His163Pro	HL-II	35 years/de novo EOAD, parkinsonism	The rigid proline might result abnormalities in the border of HL-II and TM-III	Korea	This study
		p.Trp165Gly	TM-III	34–38 years; EOAD with strong familiar	The small glycine is a rare amino acid in the helix	Japan	Higuchi et al., 2000 [55]
		p.Trp165Cys	TM-III	55 years; memory decline, followed by difficulty in finding ways and had a strong family history of dementia	Increased Aβ42 and decreased Aβ40 production in vitro; elevated Aβ42/Aβ40 ratio	Korea	This study
				45 years; EOAD, a severe form of the illness, with cerebral and cerebellar atrophies and rapid deterioration		India	Syama et al., 2018 [49]
		p.Ile167del	TM-III	38 years/familial; EOAD, spastic paraparesis	Deletion might result abnormal conformation in TM-III	China	Jiao et al., 2014 [31]
		p.Ser169del	TM-III	EOAD, 42–50 years/familial	Missing –OH group might result a missing H-bound in the TM-III	China	Guo et al., 2010 [43]
		p.Leu173Phe	TM-III	47–50/familial; EOAD with parkinsonism	Elevated Abeta42 levels and Abeta42/Abeta40 ration in neuroblastoma cells	Japan	Kasuga et al. 2009 [50]
	7	p.Glu184Asp	HL-III	40s years; EOAD, DLB-like phenotype	The smaller asparatic acid might change the loop conformation	Japan	Yasuda et al. 1997 [35]
		p.Glu184Gly	HL-III	40s years; probable autosomal dominant EOAD, frontal variant form	Resulting potential functional alterations; may also disturb the splicing near exon 7	Thailand	This study
		p.Gly206Ser	TM-IV	30–35 years/familial, EOAD	Probably pathogenic	Korea	Park et al., 2008 [29]
		p.Gly209Arg	TM-IV	46–53 years, EOAD	Arginine might result extra stress inside the helix and form abnormal hydrogen bonds	Japan	Sugiyama et al., 1999 [44]
		p.Gly209Ala	TM-IV	54 years; MCI with depression, followed by progressive deterioration in verbal and visual memory	The extra –CH3 group in alanine might result extra stress inside the TM-IV region	Korea	This study
		p.Ile213Thr	TM-IV	42–47 years, EOAD	Increased (1.7 * Abeta)	Japan	Kamino et al., 1996 [32]
		p.Gly217Asp	HL-IV	42–47 years/familial, EOAD	Increased (1.7 * Abeta)	Japan	Takao et al., 2002 [52]
		p.Leu226Phe	TM-V	37 years; de novo, Aβ plaques observed	Results elevated Abeta42/Abeta40 ratio in HEK293 cells	Korea	This study
		p.Leu226Arg	TM-V	60 years/familial, EOAD	Probably pathogenic	China	Ma et al., 2019 [41]
		p.Glu311Arg	TM-V	> 65 years, familial, LOAD	Overproducing toxic Aβ species and enhancing tau phosphorylation	China	Dong et al., 2017 [56]
		p.Leu232Pro	TM-V	37 years/familial; EOAD	The rigid proline might result serious torsion in the TM-V since proline is helix breaker	Korea	This study
		p.Met233Thr	TM-V	34 years/de novo, EOAD, rapid progressive memory impairment	Elevated (3.2 *) Abeta42/Abeta40 levels in CHO cells	Korea	Park HK et al., 2008 [29]
		p.Phe237Ile	TM-V	35 years/de novo, EOAD, spastic paraparesis	Probably pathogenic	Japan	Sodeyama et al. 2001 [57]
		p.Leu248Pro	TM-VI	42 years/familial, EOAD	Proline is a helix breaker, resulting in torsion in TM-IV	China	Jiao et al., 2014 [31]
		p.Leu250Val	TM-VI	40–51 years/Familial, EOAD, myoclonus, seizures	Probably pathogenic	Japan	Furuya t al., 2003 [58]
	8	p.Ala260Val	TM-VI	27–46 years/Familial, EOAD, Pick inclusions	1.5 * Increased Abeta42/total Abeta in COS1 cells	Japan	Ikeda et al., 1996 [59]
		p.Gly266Ser	HL-VI(a)	35–44 years, EOAD, spastic paraparesis, aphasia	Probably pathogenic	Japan	Matsubara-Tsutsui et al., 2002 [60]
		p.Arg 269His	HL-VI(a)	46–67 years/Familial, EOAD, myoclonus	Unknown	Japan	Kamimura el al., 1998 [61]
		p.Glu273Ala	HL-VI(a)	46–67 years/Familial, EOAD, myoclonus	Unknown	Japan	Kamimura el al., 1998 [61]
		p.Glu280Ala	HL-VI (MA)	48–57 years/Familial, EOAD, parkinsonism	Probably pathogenic	Japan	Tanahashi et al., 1996 [62]
		p.Glu280Lys	HL-VI (MA)	48–57; EOAD	Probably pathogenic	Malaysia	This study
		p.Leu282Phe	HL-VI (MA)	51 years, familial, EOAD	Probably pathogenic	Japan	Hamaguchi et al., 2009 [63]
		p.Pro284Leu	HL-VI (MA)	32 years, cotton-wool plaques and neurofibrillary tangles or amyloid angiopathy in brain	Probably pathogenic	Japan	Tabira et al., 2002 [64]
		p.Ala285Val	HL-VI (MA)	46 year/de novo, EOAD	The Abeta42/total Abeta ratio increased; Abeta40/total Abeta and Abeta38/total Abeta ratios decreased	Korea	This study
				50.5 years, two families		Japan	Ikeuchi et al., 2008 [65]
		p.Leu286Val	HL-VI (MA)	47 years	Increases in the Abeta42/total Abeta ratio (1.5 *) and Abeta42/Abeta40 ratio (2.1 *)	Japan	Ikeuchi et al., 2008 [65]
	Intron 8	Exon9 del	-	47.5 years, in EOAD with spastic paraparesis	elevated Abeta42 levels and Abeta42/40 ratio were observed	Japan	Tabira et al., 2002 [64]
	10	p.Arg352Cys	HL-VI (b)	56–62 years, EOAD, psychiatric, behavioral symptoms	Cysteine could result intramolecular disulfide bound	China	Jiang et al., 2015 [66]
	11	p.Gly378Glu	TM-VII	37 years, EOAD, familiar positive	Abeta42/Abeta40 ratio increased (3.2 *)	Japan	Ikeda et al., 1996 [59]
		p.Leu381Val	TM-VII	30s years, AD and spastic paraparesis	Abeta42/Abeta40 ratio increased (1.9 *)	Japan	Ikeuchi et al., 2008 [65]
		p.Gly384Ala	TM-VII	31–37 years, EOAD, senile plaques and tangles inside proband’s brain	Beta40 and the Abeta42/Abeta40 ratio decreased and increased significantly. Abeta42/total Abeta ratio increased (3.8 *)	Japan	Kamimura et al. 1998 [61]
		p.Leu392Val	TM-VII	42 years, EOAD	Abeta42/Abeta40 ratio (2.4*). An increase in the Abeta42/Abeta40 ratio (2.9 *)	Japan	Ikeuchi et al. 2008 [65]
		p.Asn405Ser	HL-VII	EOAD, the patient has several senile plaques and tangles in the brain	It caused disturbances in the motor neuronal systems, leading to spastic paraparesis	Japan	Yasuda et al., 2000 [46]
		p.Gly417Ala	HL-VIII	37 years; EOAD, parkinsonism, positive familiar	Pathogenic mechanism	Korea	This study
	12	p.Ala431Val	HL-VIII	16 months, t-tau and phospho-Tau levels increased in the CSF, and metabolic deficits were detected in several parts of the brain	Possibly pathogenic	Japan	Matsushita et al., 2002 [45]
		p.Ala434Thr	HL-VIII	38 years, EOAD, Hallucinations, delusions	Threonine might result extramolecular or intramolecular hydrogen bound	China	Jiao et al., 2014 [31]
		p.Thr440del	HL-VIII	52 years, strong familiar history, EOAD and parkinsonism	Probably pathogenic, may alter the normal amyloid production	Japan	Ishikawa et al., 2005 [42]
PSEN2	4	p.Arg62Cys	N-term	49 years, EOAD	Possibly pathogenic, may alter the normal amyloid production.	Korea	This study
				40–65 years, EOAD		Iran	Akbari et al., 2013 [34]
	5	p.Asn141Tyr	TM-II	43–49 years, EOAD	No functional data	China	Niu et al., 2014 [39]
	6	p.His169Asn	TM-III	50 years; de novo	It may result in major helix torsion due to histidine to asparagine substitution	Korea	This study
				62 years; AD, de novo		China	Shi Z et al., 2015 [40]
				68 years; FTD, progressive nonfluent aphasia, Familial
				63 years/Familial, LOAD		China	Ma et al., 2018 [41]
	7	p.Val214Leu	TM-IV	56–70 years; AD	The extra CH3 group in leucine could result extra stress in the TM-IV region	Korea	This study

Abbreviation: APP, amyloid precursor protein; PSEN1, presenilin-1; PSEN2, presenilin-2; AD, Alzheimer’s disease; EOAD, early-onset Alzheimer’s disease; LOAD, late-onset Alzheimer’s disease; MCI, mild cognitive impairment; DLB, dementia with Lewy bodies; FTD, frontotemporal dementia; HEK293, human embryonic kidney 293; CHO, Chinese hamster ovary; COS-1, cercopithecus aethiops kidney; TM, transmembrane domain; * multiplication sign.