Table 2 Comparison of PSEN1 Trp165Cys with all mutations, located in membrane associated TM-III domain

H163P

FLAIR, showing bilateral hippocampal, temporal lobe atrophy, and paraventricular hyperintensity.

PET, revealing moderate-to-severe hypometabolism in the diffuse cortical area.

Immunohistochemical stain revealed expression of amyloid beta in the senile plaque

34

No

↑Aβ42/Aβ40 ratio; ↑Aβ42; Aβ40.

[18] Kim et al., 2012

H163R

Data are limited, but neuropathology consistent with AD has been observed in at least one case.

42–47

Yes

↓Aβ42/Aβ total ratio in COS-1 cells; ↓Aβ42 and Aβ40 production in vitro. Involving γ-secretase- neurexin processing.

[51] Martin et al., 1995;

H163Y

Typical AD neuropathology (one case); decreased glucose metabolism in presymptomatic mutation carriers, especially in the thalamus. Widespread brain amyloid (PiB-PET) and shrunken hippocampi.

47

Yes

↓CSF Aβ42 and Aβ38 levels. ↑Aβ42/Aβ total ratio when expressed in COS-1 cells, and ↑Aβ42 production

[52] Clark et al., 1995

A164V

MRI revealed atrophy in brain involved anterior temporal lobe, and the hippocampus.

45–50

Yes

Possibly damaging via in silico.

[19] Roeber et al., 2015

W165C (G > C)

Not available

37–47

Yes

↑Aβ42 and ↓Aβ40; elevated Aβ42/Aβ40 ratio

[36] Campion et al., 1999

W165C (G > T)

EOAD, a severe form of atrophies and rapid deterioration in cerebral and cerebellar

45

Yes

↓Aβ42 and ↓Aβ40; elevated Aβ42/Aβ40 ratio

[37] Syama et al., 2018

W165G

Not available

34–38

Yes

Not available

[39] Higuchi et al., 2000

L166H

MRI: hippocampal atrophy and cortical atrophy. SPECT: bilateral hypometabolism in the parietal and frontal lobes.

30

Yes

Not available

[26] Pantieri et al., 2005

L166P

numerous Aβ-positive neuritic and cotton-wool plaques; abundant Aβ-positive amyloid cores in the cerebellar cortex.

↑Aβ42/Aβ ratio; ↓Aβ40, Aβ42, and AICD.↓cleavage of Notch and N-cadherin.

[53] Moehlmann et al., 2002

L166R

MRI revealed cortical atrophy;

PET revealed parietal hypoperfusion.

32–34

Yes

Not available

[27] Ezquerra et al., 2000

L166 V

SPECT indicated temporoparietal hypoperfusion. Advanced plaques and tangles

42–50

Yes

Possibly damaging by in silico

[20] Sassi et al., 2014

L166del

MRI strongly revealed symmetrical cerebral atrophy,

40–46

Yes

Predicted possibly damaging in silico

[21] Knight et al., 2007

I167del

Symptom was progressive memory loss, behavior variants and spastic paraparesis.

38–46

Pathogenic by in silico

[54] Jiao et al., 2014

I168del

Not available

Yes

Pathogenic by in silico

[9] Janssen et al., 2003

I168T

Neuropathology consistent with AD.

86–94

Yes

Pathogenic by in silico

[20] Sassi et al., 2014

S169del (ΔS169, Ser169del, ΔS170)

MRI revealed cerebral atrophy involvement of the ventricles and widening of the sulci.

40

Yes

Not available

[28] Guo et al., 2010

S169 L

Aβ deposition in the cerebellum and white matter

33–37

Yes

Not available

[29] Taddei et al., 1998

S169P

Numerous plaques and neurofibrillary tangles could be seen in brain of the case

35

Yes

Not available

[30] Ezquerra et al., 1999

S170F

Much Lewy bodies in the substantia nigra and had severe cerebellar pathology

Also, abundant amyloid deposition and loss of Purkinje cells reported.

27

Yes

↑Aβ42 and Aβ40, altering the ratio.

[31] Snider et al., 2005

S170P

MRI shown hypointensity, globus pallidus, and substantia nigra, as well as frontotemporal cortical atrophy.

SPECT revealed severe nigrostriatal dopaminergic deficit bilaterally, and 18F-FDG PET hypometabolism in striatal and posterior cingulate.

25

No

Pathogenic by in silico

[40] Carecchio et al., 2017

L171P

Not available

36–40

Yes

Not available

[41] Ramirez-Dueñas et al., 1998

L173F (G > T)

Not available

50.5

Yes

↑Aβ42; ↑Aβ42:Aβ40 ratio

[42] Jin et al., 2012

L173F (G > C)

MRI revealed atrophy of the medial temporal lobe. SPECT indicated hypoperfusion of the posterior cingulate gyri and other cortical areas.

40–42

Yes

↑Aβ42 than cells

↑Aβ42:Aβ40 ratio

[43] Kasuga et al., 2009

L173 W

Not available

24–29

Yes

Not available

[36] Campion et al., 1999

L174del

MRI shown slight temporal lobe atrophy.

53

Yes

↑Aβ40, and ↓Aβ42 and Aβ42/Aβ40

[44] Tiedt et al., 2013

L174 M

Neuropathology consistent with AD and CAA associated

58

No

↓Aβ40 and ↑ Aβ42/Aβ40 ratio

[45] Tedde et al., 2003

L174R

EOAD

46–56

Yes

Not available

[46] Klünemann et al., 2004

F175S

Not available

NA

Yes

Not available

[47] Colacicco et al., 2002

F176 L

Much abundant amyloid plaques and neurofibrillary tangles in the cortex.

51

Yes

Not available

[48] Müller et al., 2013

F177 L

Not available

60

Not available

Not available

[49] Rogaeva et al., 2001

F177S

Not available

60

Not available

Not available

[49] Rogaeva et al., 2001

S178P

Not available

60

Not available

Not available

[49] Rogaeva et al., 2001