Ullg ene al. Molecula Neu odegene a ion (2023) 18:85
h ps://doi.o g/10.1186/s13024-023-00677-6
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Molecula Neu odegene a ion
Al e ed plasma p o ein p o iles ingene ic
FTD – aGENFI s udy
Abbe Ullg en1,2,3†, Linn Öije s ed 1,2,3†, Jennie Olo sson1,4, So ia Be gs öm1,4, Julia Remnes ål1,4,
John C. an Swie en5, Lize C. Jiskoo 5, Ha o Seelaa 5, Ba ba a Bo oni6, Raquel Sanchez‑Valle7,
Fe min Mo eno8,9, Robe La o ce10, Ma his Syno zik11,12, Daniela Galimbe i13,14, James B. Rowe15,
Ma io Masellis16, Ma ia Ca mela Ta aglia17, Elizabe h Finge 18, Rik Vandenbe ghe19,20,21,
Alexand e de Mendonça22, Pie o Ti abosch23, Isabel San ana24,25, Simon Ducha me26,27, Ch is R. Bu le 28,29,
Alexande Ge ha d30,31, Ma kus O o32, A abella Bouzigues33,34, Lucy Russell33,34, Imogen J. Swi 33,34,
Ai ana Sogo b‑Es e e33,34, Ca olin Helle 33,34, Jona han D. Roh e 33,34, Anna Månbe g1,4, Pe e Nilsson1,4,
Ca oline G a 1,2,3* and on behal o he Gene ic F on o empo al Demen ia Ini ia i e (GENFI)
Abs ac
Backg ound Plasma bioma ke s e lec ing he pa hology o on o empo al demen ia would add signi ican alue
o clinical p ac ice, o he design and implemen a ion o ea men ials as well as ou unde s anding o disease
mechanisms. The aim o his s udy was o explo e he le els o mul iple plasma p o eins in indi iduals om amilies
wi h gene ic on o empo al demen ia.
Me hods Blood samples om 693 pa icipan s in he GENe ic F on o empo al Demen ia Ini ia i e s udy we e ana‑
lysed using a mul iplexed an ibody a ay a ge ing 158 p o eins.
Resul s We ound 13 ele a ed p o eins in symp oma ic mu a ion ca ie s, when compa ing plasma le els om peo‑
ple diagnosed wi h gene ic FTD o heal hy non‑mu a ion con ols and 10 p o eins ha we e ele a ed compa ed
o p esymp oma ic mu a ion ca ie s.
Conclusion We iden i ied plasma p o eins wi h al e ed le els in symp oma ic mu a ion ca ie s compa ed o non‑
ca ie con ols as well as o p esymp oma ic mu a ion ca ie s. Fu he in es iga ions a e needed o elucida e hei
po en ial as luid bioma ke s o he disease p ocess.
Keywo ds F on o empo al demen ia, Plasma bioma ke s, GRN, C9o 72, MAPT, Neu odegene a ion
Backg ound
F on o empo al demen ia (FTD) is a g oup o neu ode-
gene a i e diseases whe e he mos common pheno ypes
a e beha iou al a ian FTD (b FTD) and p ima y p o-
g essi e aphasias (PPA). The e is a g ea he e ogenei y
in FTD, bo h in e ms o clinical symp oms, unde lying
gene ic causes, and neu opa hological indings. O e he
pas yea s, e o has been pu in o explaining he di e -
si y by sea ching o luid bioma ke s ha e lec di e en
aspec s o FTD [1]. Mos e o s ha e ocused on inding
bioma ke s in ce eb ospinal luid (CSF) and a ew p om-
ising candida es ha e been ound, such as neu o ilamen
ligh chain (NEFL) and neu onal pen axin 2 (NPTX2) [2,
3]. Howe e , he use o CSF bioma ke s is limi ed by he
in asi e na u e o he sampling p ocedu e and es ic ed
a ailabili y. The e o e, a eliable blood-based bioma ke
†Abbe Ullg en and Linn Öije s ed sha ed i s au ho .
*Co espondence:
Ca oline G a
ca oline.g a @ki.se
Full lis o au ho in o ma ion is a ailable a he end o he a icle
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Ullg ene al. Molecula Neu odegene a ion (2023) 18:85
would be ex emely aluable. A well-known blood-based
bioma ke in gene ic FTD is p og anulin (GRN), which
is educed in indi iduals wi h loss-o - unc ion mu a-
ions in he gene wi h he same name [4]. While se um
o plasma GRN le els can be used o con i m mu a ions
in GRN, hey do no co ela e wi h clinically impo an
me ics such as age a onse [4]. P e ious s udies ha e
also iden i ied glial ib illa y acidic p o ein (GFAP), au
and NEFL as possible plasma-based bioma ke s, whe e
GFAP is ele a ed in symp oma ic GRN mu a ion ca i-
e s, au is ele a ed in spo adic FTD and in symp oma ic
MAPT mu a ion ca ie s, and NEFL is ele a ed in bo h
gene ic and spo adic FTD [5–7]. Howe e , none o he
p o eins a e speci ic o FTD since inc eased le els ha e
been obse ed in o he neu ological diseases [8, 9]. A
la ge sc een o plasma p o eins in FTD and Alzheime
disease (AD) ound a panel o 12 p o eins ha disc imi-
na ed be ween he wo diseases. Howe e , hese p o eins
we e associa ed wi h AD pa hology and no di e ences
we e ound be ween FTD cases and con ols [10]. Fu -
he s udies a e he e o e needed o ind bioma ke s ha
a e FTD speci ic.
He e, we p esen an explo a o y plasma p o iling s udy
o 158 p o eins in 693 pa icipan s in he well-desc ibed
gene ic FTD coho . To ou knowledge, a plasma p o-
eomic analysis o his magni ude has no been done in
gene ic FTD be o e. We aimed o in es iga e di e ences
in plasma p o ein le els be ween bo h symp oma ic and
p esymp oma ic mu a ion ca ie s compa ed o non-
ca ie amily membe s who se e as con ols. Ou ind-
ings indica e al e a ions in plasma p o ein le els be ween
symp oma ic mu a ion ca ie s and non-ca ie con ols,
as well as gene speci ic di e ences in GRN mu a ion
ca ie s.
Ma e ials andme hods
Coho
All clinical da a and samples included in he s udy we e
collec ed wi hin he Gene ic on o empo al demen ia
ini ia i e (GENFI) be ween 2012 and 2019 [11]. Va i-
ables included we e age a sampling, sex, mu a ion g oup
(symp oma ic mu a ion ca ie s, SMC; p esymp oma ic
mu a ion ca ie s, PMC; o non-ca ie con ols, NC),
gene ic g oup (ch omosome 9 open eading ame 72,
C9o 72; p og anulin, GRN; o mic o ubule associa ed
p o ein au, MAPT), clinical pheno ype, and age a onse .
In o al, baseline plasma samples om 701 pa icipan s
we e collec ed including 141 SMC (63 C9o 72, 50 GRN,
and 28 MAPT), 283 PMC (97 C9o 72, 135 GRN and 51
MAPT) and 277 NC. Ca ie s o FTD-causing a ian s in
o he genes we e no included. Clinically, he SMC mos
equen ly p esen ed wi h b FTD (n = 102), ollowed by
PPA (n = 25), FTD wi h concomi an amyo ophic la e al
scle osis (ALS) (n = 5) and o he FTD- ela ed pheno ypes
(n = 5).
Sample collec ion acco ding oGENFI p o ocol
Blood samples (n = 701) we e collec ed a 20 di e en
si es in Eu ope and Canada in e hylenediamine e aace ic
acid (EDTA) ubes. Samples we e cen i uged a 2200 × g
o 5min a 22°C and he supe na an plasma was ans-
e ed o 0.5ml polyp opylene c yo ubes and s o ed a
-80°C un il analysis.
Suspension bead a ay assay
The plasma samples we e dilu ed and labelled wi h a en-
old mola excess o bio in (NHS-PEG4-bio in. 21329,
The mo Scien i ic), hea ea ed, and subsequen ly mixed
wi h an an ibody suspension bead a ay as desc ibed in
de ail p e iously [12, 13]. A s ep a idin conjuga ed luo-
opho e (S ep a idin R-Phycoe y h in Conjuga e, In -
i ogen) enabled he de ec ion o he p o eins, and he
eadou was pe o med on a Flexmap 3D ins umen
(Luminex co po a ion). Binding e en s we e displayed as
signal in ensi y. Published as well as in e nal unpublished
wo k we e used o guide he selec ion o a ge p o eins
(n = 163) which was based on p e iously iden i ied p om-
ising a ge s, p o eins in ol ed in sugges ed pa hologi-
cal p ocesses o neu odegene a ion and p o eins wi h
en iched exp ession in b ain compa ed o o he issue
[14–17]. The majo i y o he an ibodies (n = 156) we e
selec ed om he Human P o ein A las p ojec (www.
p o e ina l as. o g) and he emaining se en we e ob ained
om o he p o ide s (M067-3 om MBL In e na ional;
MA1-70053, PA5-34943, 34–1000 om In i ogen An i-
bodies; MAB2037-SP, AF2420, AF3154 om R&D Sys-
ems). The mean coe icien o a iance pe 384-well
pla e (n = 3) was less han 10%, and 97% o he an ibod-
ies had an indi idual coe icien o a iance below 20%.
The in e -assay co ela ions we e high ( ho > 0.8 o 154
an ibodies). A e quali y con ol analysis, i e an ibodies
we e excluded due o high co ela ion o a nega i e con-
ol ( ho > 0.6) esul ing in 158 p o ein a ge s o u he
analysis (Supplemen a y Table1).
S a is ical analysis
Da a p e‑p ocessing
All da a p e-p ocessing, analysis and illus a ions we e
pe o med in R S udio e sion 2022.2.3.492 using R e -
sion 4.2.1 [18]. The da a was no malised in wo s eps o
diminish he e ec s o ime delay du ing eadou and
po en ial di e ences be ween pla es [19]. P io o s a is-
ical analysis, he da a was log2- and z- ans o med ia
mean cen ing and uni a iance scaling. Ou lie samples
wi h a median p o ein le el h ee s anda d de ia ions
highe o lowe han he median o he whole coho
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Ullg ene al. Molecula Neu odegene a ion (2023) 18:85
we e excluded om he analysis (n = 8 samples emo ed).
A esidual adjus men app oach was used o deal wi h
he po en ial con ounding e ec o heal hy ageing on
p o ein le els [20]. The e ec o heal hy ageing on p o ein
le els was es ima ed in he NC ia linea mixed e ec
models using p o ein le els as he esponse a iable, age
as a ixed e ec and collec ion si e as a andom in e cep
(lme , lme4, [21]). Fo each subjec in he o e all coho
(including each o he NC, PMC, and SMC g oups), he
adjus ed p o ein le els we e hen ob ained h ough he
ollowing:
whe e P o einadj. is he age adjus ed p o ein le el, P o ein
is he o iginal p o ein le el, β is he age-associa ed be a
coe icien , Age is he subjec ’s age and
Age
is he mean
age in he en i e coho .
Demog aphic s a is ics
The pa icipan s’ ages ollowed a no mal dis ibu ion,
e alua ed by isual assessmen o no mal p obabili y plo
and his og am. Di e ences in age be ween SMC, PMC
and NC we e assessed by one-way ANOVA and Tukey’s
HSD pos hoc es . Pea son’s Chi-squa ed es was used
o in es iga e di e ences in sex be ween SMC, PMC and
NC. P- alues below 0.05 we e conside ed signi ican .
P o ein p o ile analysis
Di e ences in p o ein le els be ween SMC and NC we e
examined ia binomial gene alised linea mixed e ec s
models using clinical s a us (i.e. SMC o NC) as he
esponse a iable, p o ein le els and sex as ixed e ec s
P o einadj
.=P o ein −β(Age −Age
)
wi h a andom in e cep based on collec ion si e (glme ,
lme4, [21]). One model pe p o ein was buil . The same
me hod was used o assess di e ences in p o ein le -
els be ween SMC and p esymp oma ic mu a ion ca i-
e s (PMC), PMC e sus NC, as well as o analyse gene
speci ic di e ences e.g., SMC ca ying a GRN mu a ion
(SMC-GRN) s NC. Log2 old changes we e calcula ed
by sub ac ing he median log2 ans o med p o ein le -
els in NC o PMC om he median log2 ans o med
p o ein le els in SMC. In con as , he e ec s o age and
sex on he p o ein le els in mu a ion ca ie s as well as in
non-ca ie s we e es ima ed ia gene alised linea mixed-
e ec s models using p o ein le els as he esponse; age
and sex as ixed e ec s wi h a andom in e cep based on
collec ion si e (lme , lme4, [21]). P- alues we e calcula ed
using he Sa e hwai e’s deg ees o eedom me hod
(lme Tes , [22]). Mul iple es ing co ec ions we e made
ia he Benjamini–Hochbe g me hod o con olling
alse-disco e y a es and an adjus ed p- alue o 0.05
was conside ed signi ican . Only adjus ed p- alues a e
epo ed unless clea ly s a ed o he wise. P o ein – p o-
ein co ela ions we e calcula ed using Spea man’s ank
co ela ion coe icien . P o ein clus e s a e based on hie -
a chical clus e ing using Wa d’s clus e ing c i e ion.
Resul s
Coho
In o al, plasma esul s om 693 pa icipan s we e
included in he s a is ical analysis, and demog aphic
da a o he coho is p esen ed in Table 1. The age
was no signi ican ly di e en be ween NC and PMC
(p- alue = 0.06), bu SMC we e olde han bo h NC
Table 1 Demog aphic da a o he coho
a One-way ANOVA (F(2,690) = 106.0, p = 7.13 × 10–41). Di e ences in age be ween NC s SMC and PMC s SMC (Tukey mul iple compa ison pos -hoc es ). No di e ence
be ween NC and PMC (p = 0.06)
b Pea son’s Chi-squa ed es . Mo e emales in NC and PMC compa ed o SMC (X2(1, N = 413) = 6.1, p = 1.3 × 10–2) and X2(1, N = 417) = 14.9, p = 1.1 × 10–4 espec i ely). No
di e ence be ween NC and PMC (X2(1, N = 556) = 2.6, p = 0.1)
Non-ca ie s (NC) P esymp oma ic mu a ion
ca ie s (PMC) Symp oma ic mu a ion
ca ie s (SMC) To al p- alue
No. o pa icipan s 276 280 137 693
Age, mean yea s (SD) 47 (14) 45 (12) 63 (9) 49 (14) < 0.001a
Females (%) 152 (55) 174 (62) 57 (42) 383 (55) < 0.001b
Mu a ed gene (%) 417 (60)
GRN 133 (48) 49 (36)
C9o 72 96 (34) 62 (45)
MAPT 51 (18) 26 (19)
Age a onse , mean yea s (SD)
GRN 61 (8)
C9o 72 60 (9)
MAPT 51 (8)
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Ullg ene al. Molecula Neu odegene a ion (2023) 18:85
and PMC (p- alue = 7.13 × 10–41). The e we e mo e
emales in NC (55%) and PMC (62%) compa ed o SMC
(42%) (NC s SMC: p- alue = 1.3 × 10–2; PMC s SMC:
p- alue = 1.1 × 10–4).
Al e ed plasma p o ein le els insymp oma ic mu a ion
ca ie s
When compa ing plasma p o ein le els in SMC o
NC, we ound ha 13 p o eins we e ele a ed in SMC
(Fig. 1A, Table 2 and Supplemen a y Fig. 1). In he
compa ison be ween SMC e sus PMC, we ound ha
10 p o eins we e ele a ed in SMC (Fig.1B, Table2).
The e we e six o e lapping p o eins i.e., six p o eins
had ele a ed le els in SMC bo h in he compa ison o
NC as well as in he compa ison o he p o ein le els in
PMC. An o e iew o how hese p o eins co ela e wi h
each o he can be ound in Fig.2. When s a i ying by
gene ic g oup, abphilin 3a (RPH3A) was inc eased in
SMC-GRN compa ed o NC (p- alue = 1.3 × 10–3, odds
a io = 1.915) whe eas p og anulin, as expec ed, was
dec eased (p- alue = 9.3 × 10–6, odds a io = 0.152). No
p o eins had signi ican ly di e en le els in he com-
pa ison be ween SMC-C9 and NC no in he compa i-
son be ween SMC-MAPT and NC (da a no shown).
Nex , we in es iga ed he co ela ion be ween age
and p o ein le els o he al e ed p o eins in mu a ion
ca ie s. Among he 17 unique p o eins wi h ele a ed
le els in SMC (SMC s NC o SMC s PMC), 13 had a
signi ican co ela ion wi h age (Table3).
When analysing sex di e ences o he 17 p o-
eins ele a ed in SMC, wo p o eins we e ound
o be inc eased in men compa ed o women in
he mu a ion ca ie s: apolipop o ein E (APOE,
p- alue = 1.73 × 10–2, β = 0.267) and apolipop o ein
C1 (APOC1, p- alue = 1.73 × 10–2, β = 0.235). No
sex di e ences we e ound among he NC o ei he
Fig. 1 Volcano plo s o plasma p o ein le els showing ‑log10 (p‑ alues) o he log2( old change) o compa isons be ween di e en g oups.
Plasma p o ein le el di e ences be ween A) all SMC and NC, B) all SMC and all PMC. Each p o ein is ep esen ed by a g ay do and a e colou ed
ed i he p o ein le els a e inc eased in he SMC compa ed o he compa ison g oup (NC, o PMC). Do ed ho izon al line = adjus ed p‑ alue 0.05,
do ed e ical line = log2 old change 0
Page 5 o 12
Ullg ene al. Molecula Neu odegene a ion (2023) 18:85
p o ein (p- alue = 1.49 × 10–1 and p- alue = 7.4 × 10–1,
espec i ely).
Finally, we explo ed i any o he 158 p o eins included
in his s udy we e ound a di e en le els in SMC wi h
b FTD compa ed o SMC wi h PPA bu ound no signi i-
can di e ences (da a no shown).
Plasma p o ein le els in hep esymp oma ic s age
We also in es iga ed he possibili y o de ec di e ences
in p o ein le els al eady a he p esymp oma ic s age o
FTD by i s compa ing PMC o NC and hen s a i y-
ing by gene. The only di e ence ound in hese com-
pa isons was dec eased le els o GRN in PMC-GRN
compa ed o NC (p- alue = 4.44 × 10–3). Howe e , he
p o eins neu o ilamen medium chain (NEFM), neu onal
pen axin 2 (NPTX2) and chi inase 3 like 1 (CHI3L1)
showed ends o being ele a ed in PMC-GRN com-
pa ed o NC (unadjus ed p- alue = 3.1 × 10–3, unadjus ed
p- alue = 4.8 × 10–3 and unadjus ed p- alue = 4.6 × 10–3,
espec i ely), hough hese di e ences we e no signi i-
can a e adjus men o mul iple es ing. None o he
h ee p o eins showed any co ela ion wi h age when
analysed in PMC-GRN alone o in PMC-GRN oge he
wi h SMC-GRN (Supplemen a y Table2). NPTX2 was,
howe e , ele a ed in SMC compa ed o NC and CHI3L1
was jus abo e he signi icance h eshold in he same
compa ison (p- alue = 5.1 × 10–2). Nei he we e signi i-
can in he compa ison be ween SMC and PMC (bo h
p- alues > 0.3).
Discussion
We pe o med ex ensi e p o ein p o iling o plasma om
a gene ic FTD coho , collec ed wi hin he GENFI s udy.
We ound 13 signi ican ly inc eased plasma p o eins in
pa ien s wi h gene ic FTD compa ed o non-ca ie con-
ols and 10 p o eins ha we e signi ican ly inc eased
compa ed o p esymp oma ic mu a ion ca ie s. Six o
hese p o eins we e signi ican ly di e en in bo h com-
pa isons, indica ing ha hey likely a e associa ed wi h
symp om onse a he han he p esence o one o he
pa hogenic mu a ions. These six p o eins we e also sig-
ni ican ly co ela ed wi h inc eased age in mu a ion ca -
ie s, a e co ec ing o heal hy ageing, which u he
s eng hens hei associa ion wi h symp om onse .
In con as , ou p o eins, inc eased in SMC s NC,
we e no co ela ed wi h age, no ele a ed in he SMC s
PMC compa ison, sugges ing ha hey may be ele a ed
al eady be o e symp om onse . One o hese p o eins
NPTX2, is o pa icula in e es . NPTX2, a synap ic p o-
ein, which has p e iously been shown o be educed in
CSF om pa ien s wi h FTD and is po en ially one o he
i s p o ein bioma ke s o become abno mal in gene ic
Table 2 Compa ison o plasma p o ein le els in symp oma ic mu a ion ca ie s e sus non‑ca ie s and p esymp oma ic mu a ion
ca ie s
P o eins wi h s a is ically signi ican di e en plasma le els in he compa ison be ween symp oma ic mu a ion ca ie s (SMC) and non-ca ie s (NC) o in he
compa ison be ween SMC and p esymp oma ic mu a ion ca ie s (PMC), including p- alues and odds a ios wi h 95% con idence in e als. All p- alues a e adjus ed
o mul iple es ing. Non-signi ican p- alues a e in i alics. An as e isk indica es p o eins wi h signi ican ly di e en plasma le els in bo h compa isons
P o ein SMC s NC SMC s PMC
p- alue Odds a io p- alue Odds a io
RPH3A* 2.68 × 10–2 1.535 (1.228—1.919) 2.27 × 10–21.46 (1.177—1.811)
NPTX2 2.93 × 10–2 1.499 (1.2—1.874) 3.52 × 10–1 1.176 (0.964—1.433)
XPO5 3.73 × 10–2 1.598 (1.216—2.1) 1.29 × 10–1 1.322 (1.056—1.656)
RGS7BP* 3.73 × 10–2 1.504 (1.181 – 1.915) 2.27 × 10–2 1.619 (1.246 – 2.103)
APOE* 3.73 × 10–2 1.532 (1.179—1.992) 3.94 × 10–2 1.516 (1.165—1.972)
S100A12* 3.73 × 10–2 1.5 (1.173—1.919) 3.94 × 10–2 1.394 (1.126—1.725)
GLA 3.87 × 10–2 1.605 (1.194—2.158) 4.25 × 10–1 1.185 (0.938—1.498)
APOC1* 4.06 × 10–2 1.627 (1.194—2.218) 3.94 × 10–2 1.651 (1.2—2.271)
EIF4ENIF1 4.60 × 10–2 1.503 (1.144—1.976) 3.31 × 10–1 1.264 (0.976—1.636)
LCAT 4.60 × 10–2 1.414 (1.128—1.773) 8.46 × 10–2 1.336 (1.075—1.662)
C7 4.60 × 10–2 1.49 (1.14—1.948) 3.08 × 10–1 1.277 (0.981—1.663)
CHGA 4.60 × 10–2 1.458 (1.132—1.877) 5.96 × 10–2 1.436 (1.111—1.855)
ADAMTS1* 5.00 × 10–2 1.404 (1.113—1.77) 3.11 × 10–2 1.564 (1.198—2.04)
TFEB 7.47 × 10–2 1.362 (1.082—1.715) 2.27 × 10–2 1.555 (1.229—1.967)
LRRFIP2 7.47 × 10–2 1.344 (1.079—1.674) 3.94 × 10–2 1.44 (1.141—1.818)
LAMA2 9.31 × 10–2 1.327 (1.057—1.667) 2.27 × 10–2 1.57 (1.219—2.022)
IL1B 1.69 × 10–1 1.308 (1.018—1.681) 3.94 × 10–2 1.576 (1.173—2.117)

Page 6 o 12
Ullg ene al. Molecula Neu odegene a ion (2023) 18:85
FTD [3, 23, 24]. We ha e, as o ye , no explana ion o why
NPTX2 is educed in CSF and ele a ed in plasma, o i
he NPTX2 de ec ed in plasma is b ain de i ed. How-
e e , inding ele a ed le els o NPTX2 in plasma om
SMC sugges s ha NPTX2 could wo k as a plasma-based
bioma ke .
We ound wo p o eins, GRN and RPH3A, ha di -
e ed in SMC-GRN compa ed o NC, while no p o eins
we e obse ed a di e en le els in nei he SMC-MAPT
no SMC-C9, compa ed o NC. A educ ion o GRN in
p og anulin mu a ion ca ie s is o cou se expec ed since
all known pa hogenic FTD- ela ed GRN mu a ions lead
o haploinsu iciency. On he o he hand, RPH3A was
ele a ed in SMC-GRN. RPH3A is in ol ed in p esynap ic
esicle a icking and has been implica ed o play a ole
in synap ic dys unc ion in o he neu odegene a i e dis-
eases [25, 26]. In addi ion o he indings in SMC-GRN,
we obse ed some indica ions o di e ences al eady
in he p esymp oma ic s ages in GRN mu a ion ca i-
e s. While no s a is ically signi ican a e adjus men
o mul iple es ing, he di e ences a e s ill no ewo hy
since he p o eins, NEFM, NPTX2 and CHI3L1, all ha e
been epo ed as bioma ke candida es in CSF [16, 27].
NPTX2 was also ele a ed in all SMC compa ed o NC
and CHI3L1 was jus abo e he h eshold o signi icance
while nei he o hese wo p o eins we e ele a ed in SMC
when compa ed o PMC. Taken oge he his indica es
ha hese wo p o eins migh be up egula ed al eady a
he p esymp oma ic s age. Howe e , u he s udies a e
needed o es ablish i hese p o eins indeed a e ela ed o
p esymp oma ic changes in GRN mu a ion ca ie s o i
i is a spu ious inding.
Biological sex is a known isk ac o o se e al ypes
o demen ia, wi h emale sex being a isk ac o o AD
and male sex being mo e common in FTD [28, 29]. In
ligh o his, we analysed i any o he p o eins iden i ied
in he cu en s udy exhibi ed any sex speci ic pa e ns.
While we could no de e mine any signi ican in e ac-
ions be ween sex and mu a ion s a us o hese p o eins
(da a no shown), wo p o eins we e signi ican ly co e-
la ed wi h sex in he mu a ion ca ie g oup, bu no in
con ols, sugges ing a po en ial biological e ec .
We acknowledge se e al limi a ions in his s udy. The
ocus was on gene ic FTD and samples om pa ien s
Fig. 2 Plo s o p o ein – p o ein co ela ions. P o ein o de is based on hie a chical clus e ing. Co ela ion plo o he 17 p o eins wi h ele a ed
le els in symp oma ic mu a ion ca ie s (SMC) compa ed o non‑ca ie s (NC) o p esymp oma ic mu a ion ca ie s (PMC). The colou scale indica es
Spea man’s ank co ela ion coe icien om da k blue (‑1) o b igh ed (1)
Page 7 o 12
Ullg ene al. Molecula Neu odegene a ion (2023) 18:85
wi h o he neu odegene a i e diseases we e no
included in he analysis. Follow-up s udies wi h com-
pa isons o o example AD and ALS will elucida e he
impo ance o al e ed plasma p o eins in FTD in ela-
ion o o he diseases as well as spo adic FTD. The sus-
pension bead a ay echnique is a me hod o analysing
mul iple p o eins simul aneously, which is use ul in an
explo a o y s udy like his. Howe e , a high- h oughpu
an ibody-based single-binde assay can ha e educed
sensi i i y, which may limi he de ec ion o low abun-
dan p o eins and equi e u he alida ion o an ibody
speci ici y. In addi ion, we used a a ge ed app oach,
and he p o ein analysis was hus limi ed by he p o ein
selec ion as well as he a ailabili y o an ibodies.
Conclusions
To ou knowledge, his is he i s la ge scale plasma
p o ein p o iling speci ically in gene ic FTD. A eli-
able luid bioma ke could aid o example in diagnos-
ing FTD a an ea ly s age o in selec ing indi iduals
o upcoming clinical ials. Blood-based bioma ke s
would ha e he ad an age o being easy o access and
widely a ailable compa ed o CSF-bioma ke s. He e, we
ha e p esen ed an explo a o y s udy p o iding p o eins,
including a p e ious CSF-bioma ke , ha a e o in e es
o u u e in es iga ions as po en ial bioma ke s.
Supplemen a y In o ma ion
The online e sion con ains supplemen a y ma e ial a ailable a h ps:// doi.
o g/ 10. 1186/ s13024‑ 023‑ 00677‑6.
Addi ional ile1: Supplemen a y Table1. An ibodies used in he
suspension bead a ay plasma analysis. Supplemen a y Table2. P o eins
wi h di e en le els in PMC compa ed o NC. Supplemen a y Figu e1.
Boxplo s o he 13 p o eins ha di e ed be ween SMC and NC. Sup-
plemen a y Figu e2. Boxplo s o he 10 p o eins ha di e ed be ween
SMC and PMC.
Acknowledgemen s
Fi s , we would like o hank all he pa icipan s and hei amilies o con ib‑
u ing o he s udy. We would also like o hank he GENFI esea ch coo dina‑
o s who helped wi h a anging he isi s and he en i e s a o he Human
P o ein A las o hei e o s.
Gene ic F on o empo al Demen ia Ini ia i e (GENFI) collabo a ion g oup
Au ho A ilia ion
Sónia A onso Ins i u o Ciencias Nuclea es Aplica‑
das a Saude. Uni e sidade de Coimb a.
Coimb a. Po ugal
Ma ia Rosa io Almeida Facul y o Medicine. Uni e si y
o Coimb a. Coimb a. Po ugal
Sa ah Ande l‑S aub Depa men o Neu ology. Uni e si y
o Ulm. Ulm. Ge many
Ch is in Ande sson Depa men o Clinical Neu oscience.
Ka olinska Ins i u e . S ockholm.
Sweden
Anna An onell Alzheime ’s disease and O he Cogni‑
i e Diso de s Uni . Neu ology Se ice.
Hospi al Clínic. Ba celona. Spain
And ea A ighi Fondazione IRCCS
Ca’ G anda Ospedale Maggio e Poli‑
clinico. Neu odegene a i e Diseases
Uni . Milan. I aly; Uni e si y o Milan.
Cen o Dino Fe a i. Milan. I aly
Mi cea Balasa Alzheime ’s disease and O he Cogni‑
i e Diso de s Uni . Neu ology Se ice.
Hospi al Clínic. Ba celona. Spain
My iam Ba andia an Cogni i e Diso de s Uni . Depa men
o Neu ology. Donos ia Uni e si y Hos‑
pi al. San Sebas ian. Gipuzkoa. Spain;
Neu oscience A ea. Biodonos ia Heal h
Resea ch Insi u e. San Sebas ian.
Gipuzkoa. Spain
Nu ia Ba galló Imaging Diagnos ic Cen e . Hospi‑
al Clínic. Ba celona. Spain
Roba Ba ha Depa men o Medical Biophysics.
The Uni e si y o Wes e n On a io.
London. On a io. Canada; Cen e
o Func ional and Me abolic Map‑
ping. Roba s Resea ch Ins i u e. The
Uni e si y o Wes e n On a io. London.
On a io. Canada
Benjamin Bende Depa men o Diagnos ic and In e ‑
en ional Neu o adiology. Uni e si y
o Tübingen. Tübingen. Ge many
Emanuele Bu a i ICGEB T ies e, I aly
Luisa Benussi Is i u o di Rico e o e Cu a a Ca a ‑
e e Scien i ico Is i u o Cen o San
Gio anni di Dio Fa ebene a elli.
B escia. I aly
Maxime Be oux Inse m 1172. Lille. F ance
Table 3 Co ela ions be ween age and p o ein le els in
mu a ion ca ie s
Co ela ions be ween p o ein le els and age in all mu a ion ca ie s (MC)
including p- alues and be a coe icien s wi h 95% con idence in e als. All
p- alues a e adjus ed o mul iple es ing. Non-signi ican p- alues a e in i alics
P o ein p‑ alue β
RPH3A 9.98 × 10–7 0.019 (0.013—0.026)
IL1B 2.16 × 10–4 0.012 (0.006—0.017)
RGS7BP 5.35 × 10–4 0.012 (0.006—0.018)
TFEB 5.35 × 10–4 0.013 (0.006—0.019)
S100A12 1.04 × 10–3 0.013 (0.006—0.02)
GLA 4.18 × 10–3 0.01 (0.004—0.016)
EIF4ENIF1 5.22 × 10–3 0.008 (0.003—0.014)
APOE 5.22 × 10–3 0.009 (0.003—0.015)
CHGA 5.22 × 10–3 0.009 (0.003—0.015)
LRRFIP2 5.22 × 10–3 0.011 (0.004—0.018)
ADAMTS1 5.25 × 10–3 0.009 (0.003—0.015)
LAMA2 2.15 × 10–2 0.008 (0.002—0.014)
APOC1 3.09 × 10–2 0.006 (0.001—0.011)
XPO5 1.19 × 10–1 0.006 (-0.001—0.013)
LCAT 1.57 × 10–1 0.005 (-0.002—0.012)
NPTX2 1.68 × 10–1 0.005 (-0.002—0.013)
C7 3.73 × 10–1 0.003 (-0.003—0.008)
Page 8 o 12
Ullg ene al. Molecula Neu odegene a ion (2023) 18:85
Giuliano Bine i Is i u o di Rico e o e Cu a a Ca a ‑
e e Scien i ico Is i u o Cen o San
Gio anni di Dio Fa ebene a elli.
B escia. I aly
Sand a Black Sunnyb ook Heal h Sciences Cen e.
Sunnyb ook Resea ch Ins i u e. Uni e ‑
si y o To on o. To on o. Canada
Ma ina Bocche a Depa men o Neu odegene a i e
Disease. Demen ia Resea ch Cen e.
UCL Ins i u e o Neu ology. Queen
Squa e. London. UK
Se gi Bo ego‑Ecija Alzheime ’s disease and O he Cogni‑
i e Diso de s Uni . Neu ology Se ice.
Hospi al Clínic. Ba celona. Spain
Jose B as Cen e o Neu odegene a i e Science.
Van Andel Ins i u e. G and Rapids.
Michigan. MI 49503. USA
Rose B u ae s Labo a o y o Cogni i e Neu ology.
Depa men o Neu osciences. KU
Leu en. Leu en. Belgium
Ma a Cañada CITA Alzheime . San Sebas ian. Gipuz‑
koa. Spain
Valen ina Can oni Cen e o Neu odegene a i e
Diso de s. Neu ology Uni . Depa ‑
men o Clinical and Expe imen al
Sciences. Uni e si y o B escia.
B escia. I aly
Paola Ca oppo Fondazione IRCCS Is i u o Neu o‑
logico Ca lo Bes a. Milano. I aly
Da id Cash Depa men o Neu odegene a i e
Disease. Demen ia Resea ch Cen e.
UCL Ins i u e o Neu ology. Queen
Squa e. London. UK
Miguel Cas elo‑B anco Facul y o Medicine. Uni e si y
o Coimb a. Coimb a. Po ugal
Rhian Con e y Depa men o Neu odegene a i e
Disease. Demen ia Resea ch Cen e.
UCL Ins i u e o Neu ology. Queen
Squa e. London. UK
Thomas Cope Depa men o Clinical Neu oscience.
Uni e si y o Camb idge. Camb idge.
UK
Vincen De amecou Uni Lille. F ance
Giuseppe Di Fede Fondazione IRCCS Is i u o Neu o‑
logico Ca lo Bes a. Milano. I aly
Alina Díez Neu oscience A ea. Biodonos ia Heal h
Resea ch Insi u e. San Sebas ian.
Gipuzkoa. Spain
Chia a Fenoglio Fondazione IRCCS
Ca’ G anda Ospedale Maggio e Poli‑
clinico. Neu odegene a i e Diseases
Uni . Milan. I aly; Uni e si y o Milan.
Cen o Dino Fe a i. Milan. I aly
Ca a ina B. Fe ei a Labo a o y o Neu osciences. Ins i u e
o Molecula Medicine. Facul y
o Medicine. Uni e si y o Lisbon.
Lisbon. Po ugal
Nick Fox Depa men o Neu odegene a i e
Disease. Demen ia Resea ch Cen e.
UCL Ins i u e o Neu ology. Queen
Squa e. London. UK
Mo is F eedman Bayc es Heal h Sciences. Ro ‑
man Resea ch Ins i u e. Uni e si y
o To on o. To on o. Canada
Gio gio Fumagalli Fondazione IRCCS
Ca’ G anda Ospedale Maggio e Poli‑
clinico. Neu odegene a i e Diseases
Uni . Milan. I aly; Uni e si y o Milan.
Cen o Dino Fe a i. Milan. I aly
Au élie Funkiewiez Cen e de é é‑
ence des démences a es ou p é‑
coces. IM2A. Dépa emen de Neu ol‑
ogie. AP‑HP—Hôpi al Pi ié‑Salpê iè e.
Pa is. F ance
Alazne Gabilondo Neu oscience A ea. Biodonos ia Heal h
Resea ch Insi u e. San Sebas ian.
Gipuzkoa. Spain
Robe o Gaspa o i Neu o adiology Uni . Uni e si y
o B escia. B escia. I aly
Se ge Gau hie Alzheime Disease Resea ch
Uni . McGill Cen e o S udies
in Aging. Depa men o Neu ology
& Neu osu ge y. McGill Uni e si y.
Mon eal. Québec. Canada
An onella Albe ici Cen e o Neu odegene a i e
Diso de s, Depa men o Clinical
and Expe imen al Sciences, Uni e si y
o B escia, B escia, I aly
Gio gio Giaccone Fondazione IRCCS Is i u o Neu o‑
logico Ca lo Bes a. Milano. I aly
Ana Go os idi Neu oscience A ea. Biodonos ia Heal h
Resea ch Insi u e. San Sebas ian.
Gipuzkoa. Spain
Ca oline G ea es Depa men o Neu odegene a i e
Disease. Demen ia Resea ch Cen e.
UCL Ins i u e o Neu ology. Queen
Squa e. London. UK
Ri a Gue ei o Cen e o Neu odegene a i e Science.
Van Andel Ins i u e. G and Rapids.
Michigan. MI 49503. USA
Ca olin Helle Depa men o Neu odegene a i e
Disease. Demen ia Resea ch Cen e.
UCL Ins i u e o Neu ology. Queen
Squa e. London. UK
Begoña Indakoe xea Cogni i e Diso de s Uni . Depa men
o Neu ology. Donos ia Uni e si y Hos‑
pi al. San Sebas ian. Gipuzkoa. Spain;
Neu oscience A ea. Biodonos ia Heal h
Resea ch Insi u e. San Sebas ian.
Gipuzkoa. Spain
Vesna Jelic Di ision o Clinical Ge ia ics. Ka olin‑
ska Ins i u e . S ockholm. Sweden
Hans‑O o Ka na h Di ision o Neu opsychology. He ie‑
Ins i u e o Clinical B ain Resea ch
and Cen e o Neu ology. Uni e si y
o Tübingen. Tübingen. Ge many
Ron Ke en The Uni e si y Heal h Ne wo k.
To on o Rehabili a ion Ins i u e.
To on o. Canada
G ego y Kuchcinski Uni Lille. F ance
Tobias Langhein ich Di ision o Neu oscience and Expe i‑
men al Psychology. Wol son Molecula
Imaging Cen e. Uni e si y o Man‑
ches e . Manches e . UK
Thibaud Lebou ie Uni Lille. F ance
Ma ia João Lei ão Cen e o Neu osciences and Cell
Biology. Uni e sidade de Coimb a.
Coimb a. Po ugal
Page 9 o 12
Ullg ene al. Molecula Neu odegene a ion (2023) 18:85
Albe Lladó Alzheime ’s disease and O he Cogni‑
i e Diso de s Uni . Neu ology Se ice.
Hospi al Clínic. Ba celona. Spain
Ca olina Ma u a Labo a o y o Language Resea ch.
Cen o de Es udos Egas Moniz. Facul y
o Medicine. Uni e si y o Lisbon.
Lisbon. Po ugal
Simon Mead MRC P ion Uni . Depa men o Neu‑
odegene a i e Disease. UCL Ins i u e
o Neu ology. Queen Squa e. London.
UK
Lieke Mee e Depa men o Neu ology. E as‑
mus Medical Cen e . Ro e dam.
Ne he lands
Gab iel Mil enbe ge Facul y o Medicine. Uni e si y o Lis‑
bon. Lisbon. Po ugal
Rick an Minkelen Depa men o Clinical Gene ics.
E asmus Medical Cen e . Ro e dam.
Ne he lands
Sa a Mi chell Sunnyb ook Heal h Sciences Cen e.
Sunnyb ook Resea ch Ins i u e. Uni e ‑
si y o To on o. To on o. Canada
Ka ina Moo e Depa men o Neu odegene a i e
Disease. Demen ia Resea ch Cen e.
UCL Ins i u e o Neu ology. Queen
Squa e. London. UK
Jenni e Nicholas Depa men o Medical S a is ics.
London School o Hygiene and T opi‑
cal Medicine. London. UK
Jaume Oli es Alzheime ’s disease and O he Cogni‑
i e Diso de s Uni . Neu ology Se ice.
Hospi al Clínic. Ba celona. Spain
Sebas ien Ou selin School o Biomedical Enginee ing
& Imaging Sciences. King’s College
London. London. UK
Alessand o Pado ani Cen e o Neu odegene a i e Diso de s.
Depa men o Clinical and Expe imen‑
al Sciences. Uni e si y o B escia. I aly
Jessica Panman Depa men o Neu ology. E as‑
mus Medical Cen e . Ro e dam.
Ne he lands
Janne M. Papma Depa men o Neu ology. E as‑
mus Medical Cen e . Ro e dam.
Ne he lands
Geo gia Peakman Depa men o Neu odegene a i e
Disease. Demen ia Resea ch Cen e.
UCL Ins i u e o Neu ology. Queen
Squa e. London. UK
Michela Pie ani Is i u o di Rico e o e Cu a a Ca a ‑
e e Scien i ico Is i u o Cen o San
Gio anni di Dio Fa ebene a elli.
B escia. I aly
Yolande Pijnenbu g Ams e dam Uni e si y Medical Cen e.
Ams e dam VUmc. Ams e dam.
Ne he lands
En ico P emi S oke Uni . ASST B escia Hospi al.
B escia. I aly
Sa a P ioni Fondazione IRCCS Is i u o Neu o‑
logico Ca lo Bes a. Milano. I aly
Rosa Rademake s Depa men o Neu osciences. Mayo
Clinic. Jackson ille. Flo ida. USA
Ve onica Redaelli Fondazione IRCCS Is i u o Neu o‑
logico Ca lo Bes a. Milano. I aly
Daisy Rinaldi Cen e de é é‑
ence des démences a es ou p é‑
coces. IM2A. Dépa emen de Neu ol‑
ogie. AP‑HP—Hôpi al Pi ié‑Salpê iè e.
Pa is. F ance
Tim Ri man Depa men o Clinical Neu osciences.
Uni e si y o Camb idge. Camb idge.
UK
Eka e ina Rogae a Tanz Cen e o Resea ch in Neu o‑
degene a i e Diseases. Uni e si y
o To on o. To on o. Canada
Adeline Rollin CHU. CNR‑MAJ. Labex Dis‑
alz. LiCEND Lille. F ance
Ped o Rosa‑Ne o T ansla ional Neu oimaging
Labo a o y. McGill Cen e o S udies
in Aging. McGill Uni e si y. Mon eal.
Québec. Canada
Giacomina Rossi Fondazione IRCCS Is i u o Neu o‑
logico Ca lo Bes a. Milano. I aly
Ma in Rosse Depa men o Neu odegene a i e
Disease. Demen ia Resea ch Cen e.
UCL Ins i u e o Neu ology. Queen
Squa e. London. UK
Elio Sca pini Fondazione IRCCS
Ca’ G anda Ospedale Maggio e Poli‑
clinico. Neu odegene a i e Diseases
Uni . Milan. I aly; Uni e si y o Milan.
Cen o Dino Fe a i. Milan. I aly
Elisa Semle Depa men o Neu ology. Uni e si y
o Ulm. Ulm
Rachelle Sha ei Depa men o Neu odegene a i e
Disease. Demen ia Resea ch Cen e.
UCL Ins i u e o Neu ology. Queen
Squa e. London. UK
Ch is en Shoesmi h Depa men o Clinical Neu ologi‑
cal Sciences. Uni e si y o Wes e n
On a io. London. On a io. Canada
Miguel Tábuas‑Pe ei a Neu ology Depa men . Cen o Hos‑
pi ala e Uni e si a io de Coimb a.
Coimb a. Po ugal; Facul y o Medi‑
cine, Uni e si y o Coimb a, Coimb a,
Po ugal
Mikel Tain a Neu oscience A ea. Biodonos ia Heal h
Resea ch Insi u e. San Sebas ian.
Gipuzkoa. Spain
Rica do Taipa Neu opa hology Uni and Depa men
o Neu ology. Cen o Hospi ala do
Po o—Hospi al de San o An ónio.
Opo o. Po ugal
Da id Tang‑Wai The Uni e si y Heal h Ne wo k. K em‑
bil Resea ch Ins i u e. To on o. Canada
Da id L Thomas Neu oimaging Analysis Cen e.
Depa men o B ain Repai and Reha‑
bili a ion. UCL Ins i u e o Neu ology.
Queen Squa e. London. UK
Paul Thompson Di ision o Neu oscience and Expe i‑
men al Psychology. Wol son Molecula
Imaging Cen e. Uni e si y o Man‑
ches e . Manches e . UK
Håkan Thonbe g Cen e o Alzheime Resea ch. Di i‑
sion o Neu oge ia ics. Ka olin‑
ska Ins i u e . S ockholm. Sweden