Clinical, Biological, and Imaging Features of Monogenic Alzheimer’s Disease

Table 1

Atypical presentation of different PSEN1, PSEN2, and APP mutations.

Clinical phenotype	Mutations		Differential diagnosis
Very early onset (<30 y)	PSEN1	L85P P117L P117S L166P S169L M233L M233V L235P Y256S V272A A434C P436Q G206V	GE, MD, SD, PWMD, HD
Late onset (>65 y)	PSEN1	Uncommon, A79V M139V I143F H163R H163Y A231V K239N L271V E273A R377W C410Y	Sporadic AD, FTD, LBD, VaD, CJD
	PSEN2	Possible for all mutations, especially, M239I and M239V
Behavioral or psychiatric symptoms	PSEN1	Common at presentation V89L C92S P117L M139V M146I M146L H163R H163Y L166P L166R S169L F176L E184D I202F G206A G206V K239N L250S L250V Y256S R269G R269H V272A E280A L282VΔ9 R377W L392P C410Y L424P A434C	bvFTD, LBD, HD, WE, CJD
	PSEN2	Possible at presentation R71W A85V T122P T122R Y231C M239V M239I
	APP	Rare at presentation D694N A713T
“Pure” frontotemporal presentation	PSEN1	L113P P117R M139V M146V L174R G183V L226F M233L M233T P264V E280A V412I L424H
Prominent aphasia	PSEN1	E120D H163R H163Y L166R G209V L226F L235R A246E L250S A260V L262F P264L R278I E280A R377W L392V A431E A434C L435F	Sporadic PPA (svPPA, lvPPA, avPPA) FTD-MND, CJD
	PSEN2	Y231C
Epileptic seizures	PSEN1	Possible as first presentation; L113P L113Q intron4insTAC P117L E120D E120G N135S M139I M139V I143T M146I M146L H163P H163R H163Y L166R S169L S169P S170F E184D G206D G206V Q222H M233T M233V F237I A246E L250V A260V P264L R269G R269H E280A E280G L282R L282V L282VΔ9 R377W L392V L420R L424P A434C	GE, SD, MD, AE, CJD
	PSEN2	Rare at presentation, often seen during disease course M239V
	APP	Possible at presentation for D694N APP duplication (related or not to ICH)
Myoclonus	PSEN1	L113P 4insTAC P117R M139V I143T M146L M146I M146V L153V H163R H163Y S169P S169L L174M E184D G209V Q222H F237I L250V L250S A260V P264L R269H R269G E280A L286V L392V C410Y A434C	CBS, MD, GE, CJD
Parkinsonism, dystonia, or apraxia	PSEN1	C92S F105L L113P P117R E120D N135D M139V M146I M146L M146V H163P H163R H163Y L166R S170F E184D I202F G206A G209V G217D M233L M233T M233V F237I L250S Y256S G266S V272A R278I E280A P284L L286VΔ9 L381V L392V C410Y A431E L435F ΔT440	CBS, LBD, PSP, FTD, CJD
	PSEN2	Rare at presentation, possible during disease course A85V M239V
Spastic paraparesis	PSEN1	ΔI83/M84, L85P N135S Y154N InsF1 L166P G217D F237I V261F V261L P264L P264V G266S L271V R278K R278S R278T E280G E280Q P284L P284S L286R Δ9 Ins18 T291P L381V, N405S L424R P436Q	HSP, VaD, PWMD, MND, CJD
Cerebellar ataxia	PSEN1	P117A N135S M139V I143T H163P L166P S169L S170F Y256S E280A L282V P436Q	CJD, SCA, MSA-C, PNS
Leukoencephalopathy	APP	D694N A713T	VaD, PWMD, DD, V
CAA with or without ICH	PSEN1	Rare ΔE4 V89L 4insTAC E184D C217D L271V V272A E280G L282V S290C N405S ΔT440	Sporadic CAA, monogenic CAA (CYST C, TTR, ITM2B, PRNP mutations)
	PSEN2	Rare R71V N141I
	APP	Often present also without cognitive impairment A692G E693Q E693G E693K D694N A713T APP duplication

Abbreviations: AD: Alzheimer’s Disease, AE: autoimmune encephalitis, APP: Amyloid Precursor Protein gene, avPPA: agrammatic variant of primary progressive aphasia, bvFTD: behavioural variant of frontotemporal dementia, CAA: cerebral amyloid angiopathy, CBS: corticobasal syndrome, CJD: Creutzfeldt-Jacob Disease, CYST C: Cystatin C gene, DD: demyelinating Disease, FTD: frontotemporal dementia, GE: genetic epilepsy HD: Huntington’s Disease, HSP: hereditary spastic paraplegia, ITM2B: integral membrane protein 2B gene, LBD: Lewy Bodies Dementia, lvPPA: logopenic variant of primary progressive aphasia, MD: Mitochondrial Disease, MND: Motor-neuron Disease, MSA-C: cerebellar form of multisystem atrophy, PNS: paraneoplastic syndromes, PRNP: prion protein gene, PSEN1: Presenilin 1 gene, PSEN2: Presenilin 2 gene, PSP: progressive supranuclear palsy, PWMD: progressive white matter disease, SCA: spino cerebellar ataxia, SD: storage disorders, svPPA: semantic variant of primary progressive Aphasia, TTR: Transthyretin gene, VaD: Vascular dementia, V: Vasculitis, WE: Wernicke encephalopathy.