{"paper_id":"00cd7a97-7255-459a-832b-6e90d8bb0286","body_text":"Effect of reduction in brain amyloid levels on change in cognitive and functional decline in \nrandomized clinical trials: an updated instrumental variable meta-analysis  \n \n \nAuthors : \n \nMeng l an  Pan g , PhD 1,7   \nLing  Zh u , P hD\n1,7\n \nAu dr e y G ab el l e, MD,  Ph D\n1,7\n  \nAri e  R.  G a fs o n ,  MD , P h D\n1,7\n  \nRob ert  W  P l att ,  Ph D\n2\n  \nJam es E G al v in , MD , M PH  3,4  \nP ie r re Kro l a k-S alm o n , MD ,  Ph D 5-6  \nIv a n a  R u bi n o , P h D 7  \nC a rl  de  Moor ,  Ph D 1,7   \nS hib e s h ih  B elach ew ,  MD ,  Ph D 1,7 \nC ha ngyu  Sh en , P h D 1,7  \n \nAffiliations :  \n1 Bi o g e n  Di g it al He al t h,  Biog en, C a mb r id ge ,  M A, US A  \n2 McGill  U ni versit y,  D e part m e nt  of Epide m i ol ogy ,  Bi o s t at is tics,  an d Occ upa ti onal  He alt h ,  Montr eal, Q C, Canada  \n3 Ch arl e s  E.  S c hmi dt  Coll ege of  M e d icin e , F l orida Atl a n tic U ni vers i t y,  B oca  R a t o n, FL, U S A \n4 Co m pre h e n si v e C e nt er f o r Br ai n  H ea l t h, Depart ment  of N e ur ol ogy ,  U ni versit y  o f  M iami Mill e r Sc ho o l  of  \nMe dici ne , B o c a  R at o n , F L , U SA  \n5\nCl in ical  and  Re s e arc h  Me mory  Ce nt e r  of L yon ( CM RR L y on) , L yo n In sti t ute  F or Agi n g , Un iv ersit y  h os pit a l  of \nLyon (H os pi c es  C i vils d e L y o n),  L yo n, Fra n c e \n6\nNeu ro s cienc e  Re s e arc h Centr e of L y o n,  I nse rm 1 0 4 8 ,  CN R S  5 292,  L yo n,  Fra n c e   \n7\nB i oge n,  C a mb ri dg e , MA , US A \n \nC orres p on d i n g  a ut hor: C han gy u Shen, PhD  \nAd d r es s:  225  Bi n ne y  S t,  C am b r i dg e ,  M A 02 142 ,  U SA \nEmai l : ch ang yu.s he n@b io gen. c om  \n \nWord count:  28 7 5  \n \nKeywords : Al z h e i me r’s  d ise a s e ,  a myl o i d, c ausa l e ffect, cl in i c a l trial s , c og nit ive d ecline  \n \nAll rights reserved. No reuse allowed without permission. \n(which was not certified by peer review) is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity. \nThe copyright holder for this preprintthis version posted April 5, 2022. ; https://doi.org/10.1101/2022.04.01.22273253doi: medRxiv preprint \nNOTE: This preprint reports new research that has not been certified by peer review and should not be used to guide clinical practice.\n\n \n \n \n \nABST RA CT  \n \nObjec t iv e: To upd ate a rec e ntly publ i s he d analy s i s  ex ploring th e cau sal a ssocia t i o n betwe e n po s i tro n  \ne mission t o mography ( PET) -mea s ur ed chan ge i n brain β -amylo id pla que and c ognitiv e de cline  i n  \npa tien t s  w ith Alzh eimer’s di s ea se ( AD) e nr o lled in  r a ndomized c linic al trial s ( RCT s ) .   \nDesign: Updat ed in s trum enta l variabl e meta -ana ly si s .  \nSe t t i n g:  Sixtee n  RCT s  w ere  includ ed  in thi s upda t e d  met a- analy s i s  ver su s 14  i n  the  orig in al  \npu blica t i on by Ackl ey et al. 1  Dat a s o urc e s  we r e  Cl inica lTrial s.o rg, Alz heime r Re se arch Fo rum  \n(a lzforum. org) , PubMe d and  cl inica l s tu dy report s  f rom 2 015 t o  Marc h 1,  202 2. Three r e sea r c he r s \ne xtract ed da ta  fr om the da ta sourc e s  in d epend ently  and sub sequ ently  re s olv ed a ny  discrep an cy.  \nPo pulation: RCT s  that  eva lu ate d β - a m y lo i d  ta r g e ti n g  t he r a pi es  a n d  e n r o l l e d  a du l t  p at i e nts  wi th  AD  \nde menti a or mild co gnitive  i mpairmen t due to A D  w it h  da t a  on β - a myloi d a s  m ea s ured by  P ET and  \nc linic al o ut c ome me a s u re s.  \nMai n outcom e me as ures : An in st r um e ntal variabl e me ta -analy s i s was pe rfo rmed  to compu t e  tr ial  \na nd drug - s pe ci fic  e stima te s  an d  pool ed es timat e s o f  the  e f f e ct o f ch ang e in  PET  β -a myloid st andar d  \nup t a ke v alue r atio (S UVR) on c ogni tiv e a nd fun ction al decli ne wi t h 95% c onfi den c e interval s  ( CI s ) and  \na ssoci a ted p -val ue s. T his  analy s i s upda te d a nd exp anded a  pr i o r  me t a -an aly s i s by  Ac kley  et al . 1  u s i n g  \nthe s ame  me thodol og y and c linic al o ut c ome mea s ure s : Clini cal Dem e ntia R ating –Sum of Box e s (C D R -\nS B), Al zheime r's D i s ea se A s s e ssment Sc a le– Cog nitive Su bsc a le (AD AS- Cog ),  and  Mini-M ent al Sta t e  \nE xamin ation (MMSE ).  \nR e su l t s:  The reduc tion o f PE T-me as ure d β -amy loid induce d a sta t i s tica lly s ig n ifica nt r educ t i on  in  \nc ognitiv e and func t i o nal dec lin e. T h e e ff ect s i z e w a s c ha rac te r iz ed by  a n e stima te d chang e (95% CI )  \nof 0 .09 (0 .034 , 0.15 ) o n th e  CD R -S B ; 0.33  (0.1 2,  0.55 ) on the  ADAS -Cog ; and  0. 13 (0.017,  0 .24) on th e  \nMMSE  for eac h dec rea s e o f 0.1 -unit in P ET β -amy loid S U VR.  \nCo nclusion : This updated in strumen tal  va r i able meta -a n alysi s o f 16 RCTs p rovide s stati s tica lly  \nsign ific ant e videnc e of a cau sal r el a tion sh ip betwe e n the reduc t i on in b rain β - a m yloid  plaque  and t he  \nredu ctio n in cogni t i ve an d f unction a l dec line in  pati ent s with Alz heime r’s dis ea se .  \n \n \n  \nAll rights reserved. No reuse allowed without permission. \n(which was not certified by peer review) is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity. \nThe copyright holder for this preprintthis version posted April 5, 2022. ; https://doi.org/10.1101/2022.04.01.22273253doi: medRxiv preprint \n\n \n \n \n \nINTRODUCTION \n \nAlzheim e r ’s dis ea se ( AD ) is de fin ed pathologi call y by t he  pre s e n ce of β -a myloid deposi ts, tau -\nc ontainin g n euro fibrill ary  ta ngle s, neur o nal injury and  d egen era tion. 2  C l i n i c a l l y ,  t h e  d i s e as e  c o u r s e  i s  \nc harac t e r ized by progre s s iv e cogni t i ve  decl ine, behav ior al chan ge s, i ncrea s ed depend e ncy in  \nac t i v it ies  o f  d a i ly  l i v i ng  a n d  i n c r e a s e d bu r d e n f or  c a r e gi v e rs  an d  s o ci et y . 3 4  Genetic da t a , prec linic a l  \nmo dels , biomark er s, and c linic a l ob serva tion s 5-8  have  highlig hted that r e moval o f  brai n par enchy mal  \nβ -am yloid rema ins a  rel ev ant targe t f or s l owing dise a s e  p rogre ssio n. N one t hele ss, r andomize d  \nc linic al tri al s (RCT s) o f d r ug s  t hat  ta r g et  the  r educ tion  in  pr od uc tion  or  remov a l of  β -amyloi d h av e  \ng enera ted incon si ste nt  r e s ul ts, a n d the l ink betwe en cha nge i n β -amyloid pa thology  an d  \nc ognitiv e/fun ctio nal per fo r ma nce i s  ho t l y  deba t e d . 9  \n  \nOne po s sibl e r ea son for  the  inc on s i s t ent ev idenc e t hat β - a m y l oi d  is  a  c li n i c all y  va l i d  t ar get  i n  A D  m ay \nbe  tha t pa tien t-l ev el c or r el a tion an a lys es b etwee n c hang e in β -am yloid a nd ch ang e i n cog nition u sin g  \nda ta fr om a  si ngl e trial  may hav e in su ffi c ient sta t i stica l power and/ or con foundi n g bias . To add re s s \nthe se  limita tio n s , Ack ley et al. 1  publi sh ed a m eta -an al ysi s  u sing  an in s t rumen ta l v ariabl e  a pp r oa ch  \ntha t  i n t e gra ted 14 RCT s wi t h dat a ava ila bl e up until April 3 0, 2020. T he RCT s wer e sel ec te d using th e  \nAlzheim e r  R e sea r c h Fo rum ( al z f orum.o rg) and f rom Cl inica lTri als .gov  and r e quired qu anti tativ e  \nme asu r e men t s  o f cha nge i n  a c ognitiv e sco re a nd bra in β -amyloi d data u s i n g the s t anda r di ze d  \nup t a ke v alu e r atio ( S UVR ) ob ta ine d f rom  β -amyl oid posi tr o n emis s i on  to mograph y ( P ET) .  The  autho r s \nthen  u sed r and omiz a t i on  to  t r ea t m e nt g r ou p s  a s the  in stru ment al va r i a ble to eli mi nate co n f o unding  \nbi as,  permi tting va lid c au s al inf er enc e on  the  ef fec t of  a verag e PET -mea sur ed \nβ -amy loid reduc tion  o n  \na verage  c ogni tive  and  func tiona l  dec lin e within and acr o ss multipl e s tudi e s . I n the  Ackl ey et al. \nstu dy, 1  the po oled e stima te s cha nge s we re 0.058 (95 % CI:  − 0.031 to 0 .15) an d 0. 034 (95%  CI: − 0.05 6  \nto 0 .12) on the C li nica l Dem enti a Rat ing S cale –Sum o f  Boxe s (C DR - S B) a nd  Mini -M e nt a l S tat e  \nE xamin ation (MMSE ) score s, re spec tiv ely, for e a ch 0 .1 -unit r eductio n in the PE T \nβ - amyl oid SUVR.  \n \nI n  t h e i r  o r i g i n a l  w o r k ,  A c k l e y  et al . 1  provided  a  publ icly  ava ilabl e  web in te rf a ce  c ont ainin g a n  \ni nt e ra ctive  ver s i on of t heir ana ly tic  approac h to enc ou r a ge rec alc ul ation o f thei r  r es ult s  whe n  \nup date d o r n e w da ta b ec ame  av ailab l e.  The autho r s a l s o  a cknow ledg e d t ha t th ey  d id n ot ha ve ful l  \na cc ess to the  sou r c e  dat a for c e r t ain  t ria l s , a nd po ten tial err or s  in  input  dat a mig h t  ha ve oc curre d in  \nthei r  an aly s i s. I n r e s pon se to t he  invi ta t i on to t he re s earc h commu nity, w e revi ewed t h e da t a  \ni nclude d in the ir met a- a naly sis and ide n ti fied seve ral incon si ste ncie s and  s om e  limitation s a s s oc i ate d  \nw ith the dat a re trieval  pr oc e ss for the 14  RCT s . In additi on, th ere wer e t ri a ls  not i nclude d i n th e  \ni nitial a naly si s, par tially  due to da ta  not being a vail able i n the public  do mai n at the time o f  \nAll rights reserved. No reuse allowed without permission. \n(which was not certified by peer review) is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity. \nThe copyright holder for this preprintthis version posted April 5, 2022. ; https://doi.org/10.1101/2022.04.01.22273253doi: medRxiv preprint \n\n \n \n \n \npu blica t i on , whic h coul d potentially  imp rove the ac curac y of th e pooled  e stimat e. In  thi s ar ticle , we  \nprov ided an  upd a ted ve r s i on o f t hi s in s t r ume nt a l  variab l e me ta -ana ly si s  by  p e r f orming  sev eral  dat a  \nup date s and  by  ad ding da ta fr o m two addi t i on al R CTs . Ou r up d ate d analy s i s demon st r ate s  tha t  a  \nredu ctio n in β -amyloi d pl aque  is  c au sall y an d c on si s t ently  a ss ocia te d w ith  a  s ta tistic ally  sign i fican t  \nredu ctio n in  c ognitiv e  a nd fun c tional  d ec line as  me a s u red  by ch ange s  i n the  CDR -SB , A l z hei me r ' s \nDi sea se A sse s sment Sc al e– Cog nitive Su b scale  (ADAS -C og ), and MMS E.   \n \nMETHODS \nF or trial s inc lude d in the initial  pu blic a t i o n by  Ackle y et al. 1 , t h r e e au tho r s ind e pe nden tly revie wed  \nthe s ou rc e da ta for β -am yloid PET S UVR, CD R-S B,  A D AS -Co g and MMS E f ro m cli nica ltr ia l s . gov ,  \npu blish ed articl e s an d  clini cal s tudy r epo rt s , a nd s u b seque n tly r e s o lved a ny di scr epan cy. In  a ddition ,  \non e a u t h or appl ie d t h e  same se arch st rategy  an d selec t i on c ri t e r ia  a s  the  orig inal pape r\n1  t o  s eek  \nsuppl e ment al trial  da ta  elig ible to be  i ncl uded in  thi s  upda t e d  anal y s i s , e xce pt t ha t  trial s  w e re  fu rt h e r \nrequ ire d to h ave  a “ Las t Upda ted Po st ed ” da te at c linic al tr i als .gov b etwe en 3 0 Ap ril 2020  (t h e dat e o f  \nda ta cut o f t h e  initi al public ati on) and 1 March 2 022.  \n \nUpdated da t a  fr o m the or ig inal ana lysis \nF o r  1 2  o f  t h e  1 4  s t u d i e s  f o r  w h i c h  Ack le y et al .  re trieve d t h e  da t a  en tir ely fr om t h e o r ig inal sou rc e  \n(Cl inica lTr ial s.gov , p e er revie we d public ation s, or othe r publ icly  a vail a ble ma te rial s) ,  w e ide nti fie d  \nan d  e l i m i nat e d  s e ver a l  i n c ons i st e n c ie s  be t w ee n t he  da t a us ed b y  A c k le y  et al .  a nd th e sou r c e d at a  \n( Ta ble A1 in t he Appe ndi x 1) .  F o r  e x a m p l e ,  t he inpu tte d sta nda rd err o r s (SEs ) f or SUVR and MMS E  \nme asu r e s f rom fou r of th e se tri als w er e  inc on s i st ent wi t h t h e  data sou rce,  incl uding standa rd  \nd e v i a t i o n s  ( S D s )  o f  t h e  S U V R  b e i n g  u s e d  i n  p l a c e  o f  t h e  S E s  i n  t w o  t r i a l s  ( b a p i n e u z u m a b - 1  \n[ N CT005 75055\n] and  g ant ener umab (Sc a rlet Roa d) [ NCT012241 06 ]) . In addition , da t a  for the cha ng e  \ni n CD R- S B and ADA S- Cog in s ol a nezumab  1&2 10  (s o la ne z u m a b- 1 & 2  i n c lu d e d  da t a f r o m  an i n te g r a ted \npo pulati on o f mild AD  f rom bo th sol a nezumab (E XPED ITIO N )  [ NCT00 905372 ]  a nd s o l anezumab  \n(E XPEDIT IO N 2) [ NCT009 04683 ])  w e r e in c o r r e c t l y r e v e rs ed  be t w een  t h e t r e at m en t  a nd  p l ace bo \ng r ou ps. Final ly, the o r i ginal s ourc e  data o f aduc an umab-1 (EMERGE ) [ NCT 0248454 7 ]  a nd \na duca numab -2 (E NG AG E ) [ N CT024 77800 ] t rial s w e r e  b a sed on pa r tia l  da ta, w hich  were u pda te d wit h  \nthe la te st  da ta from Cli ni calT r ia l s . gov.  \n \nF or t h e o ther two RCT s, Ack ley e t al . obt aine d a t  l ea s t  p a rt  of  t h e  d at a t hr o u gh  es t im at i n g  a lg o r it h ms  \nrath er than di rec tly f rom t h e s ou rce  dat a ( T a b l e  A 2  i n  t h e  A p p e n d i x  1 ) .  S p e ci f i cal l y ,  M M S E  ch a n g e s  \ni n t he  l eca n emab [ NCT01767 311 ]  and  ve r ube c es ta t- 2  ( APE CS)  [ N CT 0195360 1 ]  t rial s wer e e s timat e d  \nba se d on th e cha nge s in th e Alzh ei mer’s D i se a se C ompo sit e Score (AD C O MS) an d C DR- SB,  \nAll rights reserved. No reuse allowed without permission. \n(which was not certified by peer review) is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity. \nThe copyright holder for this preprintthis version posted April 5, 2022. ; https://doi.org/10.1101/2022.04.01.22273253doi: medRxiv preprint \n\n \n \n \n \nre spec t i vely . We upd at ed MMSE cha ng e s c o re s  u s i ng s ourc e d a t a  fr om a c linic al study  repo rt f o r  \nl ecan emab a n d a public ati on fo r v eru bece sta t -2 (A PECS ). 11  W e  al so id e nti fie d a nd co r rec t e d a n  \ni nconsi s t e ncy i n  th e SE valu e s  for  ve rube ce sta t - 2  (AP ECS ) PET  β -amylo id SUVR  i n  t h e  o r i g i n a l  \npu blica t i on  ( Table A 1  in the Appen dix  1 ).  \n \nInc lusion of two additiona l RCTs  \nWe e xpan de d t h e  initi al m e t a -analy s i s b y i ncludi ng two ad d ition al R CT s o f β -amy loid targ eting  d r ug s \n(a ducan umab -3 (P RIME ) [ N CT01 677572 ] and don a nemab  (TRA ILBL AZER-ALZ ) [ N CT033 67403 ] ),  w i t h \nda ta o n c hange  in  PE T β -a myloid SUVR  and cli nical  outc ome mea sure s  a t wee k  5 4 for PRIME and  \nw eek 76 for dona ne mab (TRAIL BLAZE R - A L Z)  av aila ble in t he  public  dom ai n . 12  \n \nS t a t istical  analy s is  \nA prog r a m i n th e R  c ompu tat ion e nv ir o nment  ( A p pendix 2) w a s writ t e n  b as ed on the s ame  \nme t h odol ogy  describ ed in the o r ig inal  public ation 1  and r e plica te d the ou tpu t from the public ly  \na vail able web inte rf ac e. A  new  progra m wa s  written beca use the public ly ava ilabl e w eb inte rfa c e  \non ly permitt ed the inclu sio n of on e add i t io nal R CT. We compu ted  bo th trial - an d drug- speci f i c and  \npo oled e s timat e s of the e f fec t  of a  reduc tion i n PET β -a myloid SU V R  on the cha ng e of CDR -SB , A D AS -\nCo g, and MMSE t ogeth e r  wi t h  9 5% conf id ence i nte r v al s ( CI s) a nd the a s s oc i ated  p-va lue s. We  u se d  \nthe s am e repre s en ta t i o n o f th e e ff ec t  e st ima t e s a s in t he  o riginal  met a- ana ly si s , w here i t w a s  de fined  \na s th e chang e in  c linic al en dpoin t s  p e r  0 . 1-unit  ch ange  i n PET β -a myloid SU V R ( a  0.1-uni t reduc ti on in  \nP ET β - a m yl o i d  S U VR  is  a  m a t he m at i cal  r ep r es en t a t io n t o m e as ur e t h e eff ect  of  a c o n t in uo us  \ne xposur e wh e r e  the c h oic e o f u ni t ch a nge i s  dr i ven  by c onven ienc e ; i t do e s n ot  con fe r to thi s \na r bi t r ary unit any  act ual  cli nical  meani ng fulne s s).  \n \nS olanezuma b-1 &2 (EXPE DITI ON E XT) ( NCT0 1127633\n)  w as  an  ex t en s i on o f  s olan ezumab -1&2 with a  \nl onger follow -up  p e r i o d f o r  c ontinu ed sa fe ty monit oring.  In  ord er to m axi miz e  t he  fol low- up p erio d  \na nd s im ila rly to th e original  stu dy,\n1  we  i nclude d t he  d ata fr om sola ne z uma b -1 &2 (EXPE D IT I O N EXT)  \n(ra ther  t h an  f rom s o lan ezumab -1&2 and  sola nezum ab-1 & 2  (EXPE DIT ION E XT)) in a ll p oole d  \ne stimat e s as w ell a s the dr ug -spec ific  e s timate for s ola n ez u mab. For A D AS -Co g, the aduc anumab - 3  \n(PR IME ) trial  wa s no t incl uded in the p o oled e stim ate s no r in th e drug -s pecific  e st i ma te b ec au s e  t h i s \ne ndpoin t w a s  no t mea s u red i n thi s tri al. Final ly,  Bexaro ten e (BEAT -AD) [ NCT 01 782742\n] wa s no t  \ni nclude d in the p ooled es timat e f or C DR - SB a s  no CDR-S B sou r c e da ta wer e av aila ble.  \n \nAll rights reserved. No reuse allowed without permission. \n(which was not certified by peer review) is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity. \nThe copyright holder for this preprintthis version posted April 5, 2022. ; https://doi.org/10.1101/2022.04.01.22273253doi: medRxiv preprint \n\n \n \n \n \nW e  p e r f o r m e d  s i m i l a r  s e n s i t i v i t y  a n a l y s e s  a s  i n  A c k l e y  et al . 1  by (1) inc ludi ng  a l l publish ed da ta,  (2 )  \non ly inc luding  all  anti body da ta,  an d  (3) only incl uding a ll published  antib o dy  data . Not e t hat  \nl ecan emab w a s  the  only t rial w ith  u npublish ed d a ta i n our  ana ly se s ,  whe rea s in the  orig inal  \nma nuscrip t, bot h lec anem ab and  th e two a ducan umab trial s (E MERGE a nd ENGAGE) rel i ed o n  \nun publis hed da ta . W e  al so p erf ormed th e foll owing  addi tiona l se ns i tiv ity an aly se s:  \n(a ) In clud ed  on ly th e mo st r ec en t β -a myloid ta rge t i ng  anti bodie s ,  i. e.  g ant ener umab (S ca rle t R oad) ,  \na duca numab (EMER GE, ENGA GE, and  PR IME), lec anema b , and donan ema b ( TR AI LBL AZER-ALZ ).  \n(b) Exc luded t he  two RCT s  evalu a ti ng v erubece s ta t (E PO CH & A PECS ) [ NCT01739348  &  \nNCT01 953601 ]  a s  ev idenc e  of  t r ea t m ent - a ssoci a ted c og nitive w o r s enin g 13  du e  to  t h e  inhibi tion o f β -\nsec re ta se 1  whic h may  indic ate of f -t arge t ef fec ts.  \n(c ) Ap pl ied d ata u pdat e s (term ed “ initial trials with data updates ” in  Fi g ur e  1 )  a s  d e s c r i b e d  i n  t h e  \nme t h od s  withou t inc luding  the tw o ne w  addition al RCT s  d at a s et s  (aduc a nu mab-3 ( PRI M E ) and  \ndo nanemab  (TRAILBL AZER -ALZ ) ) .   \n(d) Ex clud ed t h e  leca n emab t rial mon th  12 data t o addr e ss  the lim i t a t i on o f no t ac coun t in g for  the  \nc orr e la tion be tw ee n da t a  fr om  we ek  53 (month 1 2) and w e ek 79 (month 18) .  \n(e )  Ex clude d don an emab  (TRA IL BLAZER- AL Z)  trial  dat a,  bec au se t he  S UVR val ues  in thi s  t rial wer e  \nc onve r ted  f rom th e Cen tilo id sca l e u s in g  a n e qua tion .\n14  T his s en sitivity an al ysi s wa s  p er for m e d t o  \ne liminat e pote ntial in a cc ur a cie s r e sulting  from thi s co nver s i on.  \n( f)  E xc l ud e d  bo t h l e ca ne m ab  t r i al  month  12  and d ona nema b  (T RA I LBLAZ ER -ALZ)  t rial da ta  fo r re a son s \nspec i fied i n (d) a nd (e ).  \n \nRESULTS \nF or the pool e d e stima te s o n “ All Data , ”  t hi s  updat ed meta -a n alysi s showe d st ati s tic ally  s igni fican t  \ne videnc e o f a  cau s al  r e l ation shi p be t we en th e r educ ti on in  b r a in  β - a m y l o i d  p l a q u e  l e v e l s  a n d  \nredu ctio n in  cog nitive and func ti onal de c line a s m ea sure d b y CDR-S B (0. 09 p oin t p e r  ea ch 0 .1-uni t  \nredu ctio n in PET β - a m y l o i d  S U V R ;  9 5 %  C I :  0 . 0 3 4 ,  0 . 1 5 ;  w i t h  a  p - v a l u e  o f  0 . 0 0 1 6 )  ( Fi gu r e  1A ).  T he \nup date d poin t e st i m ate  is a ppro ximatel y  1.5 time s t he o r i ginal  e stimat e (0 .0 58 with 95%  CI:  -0 .031,  \n0 .15) (Tab l e  1 ). 1  Multipl e  sen sit ivity ana lyse s  we re per fo rmed t o  ex clude  the i nfluen c e of sp ec ifi c  \ntrial s a f fec te d by inh e r e n t  l imit ation s  a s des c ribed in  th e Me thod s . The se  s en siti vity a nalys es  ( Figu re  \n1 A  a nd Fig ur e A 2  in the  Appendix 3 ) yiel ded similar  poi n t  e stima te s for  C DR -SB,  w it h  p-valu e s  <  0.05 ,  \ne xce pt fo r  “ initial trials with data updates .” \n \n \n \n \nAll rights reserved. No reuse allowed without permission. \n(which was not certified by peer review) is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity. \nThe copyright holder for this preprintthis version posted April 5, 2022. ; https://doi.org/10.1101/2022.04.01.22273253doi: medRxiv preprint \n\n \n \n \n \nTa b l e  1 . Compari so n of t he ma in r esul ts betw ee n the o rig inal a nd upd ate d analy sis on th e e ffe ct o f a \nredu ctio n in β-a myloi d SUV R on c hange i n cog nitive endpoin t s. P o sitive v alue s o f the e ffe ct \ne stimat e— for e ac h 0.1 -uni t  r edu ctio n in PET S U VR—i ndic at e tha t β -amy loid red u c tion sl ows \nc ognitiv e dec line .  \n \n \nADAS - Cog , Alz he im er’s  D i se a se A s s e ss ment Sc al e– Co gnitive  Sub scal e; C DR- S B, Cli nical  Deme ntia  \nRa t i ng–Su m o f Boxe s; CI , c onfid enc e i nterva l ; MMSE, Mini -M ent al  Sta te Ex a mination ; N A, n ot  \nav a i la b l e .   \n \nT he updated  me ta- analy s i s fur ther s h ow ed a sta ti st i call y signi fic an t ca usa l ef fect o f β -amy loid \nredu ctio n on reductio n in  c ognitiv e dec line as mea su red by ADAS - Cog (0.33 poi n t  per ea ch 0.1 -uni t  \nredu ctio n in PET β -amyl oid SUVR ; 95 % CI: 0 .12, 0.55 ; w ith a  p -v alue o f 0.0025 )  ( Fig ur e  1B ), w hich  \nr e m ai n e d t he  cas e in  a l l  se ns i t i v i t y  ana l y s es  pe rf or me d ( Fi g ur e  1 B  and Fi g ur e  A 2  in the  Appendix 3 ) \ne xce pt f or “initial trials with data updates.” W e w ere n ot abl e to co mp are t he upda ted po oled  \ne s t i m a t e  w i t h  t h e  o r i g i n a l  e s t i m a t e  f o r  A D A S - C o g  a s  t h i s  w a s  n o t  p r o v i d e d  i n  t h e  o r i g i n a l  w o r k  f r o m  \nAc kley  et al. 1  \n \nT he upd a ted  met a- an alys is  al so  s howe d a stati s t i cal ly signi fica nt c au sal re la ti onship  be tw een  β -\na myloid  reduc t i on an d r educ ed de clin e  as me a s u r e d  by the M MS E (0.1 3 poi n t  per e ach 0.1 -unit  \nredu ctio n in PE T \nβ -amy loid SUVR; 95 % CI : 0.0 17, 0 .24; w ith a  p-va lu e of 0.02 4) ( Fig ur e  1C ).  T h e \npo oled e s tima t e  i n  th e upd ated  ana ly si s  wa s  fou r time s th e orig in al e s t i mat e (0 .034 with 95% CI :  \n− 0.056, 0.12) ( Ta b l e  1 ). 1  W h e n we p erf or me d only  dat a upda te s a s de scri bed in the Meth od s \nw ithout i ncludi ng t h e tw o ne w addi tion a l RCT s  da ta se t s  (a duc anumab -3  [PR IM E] and do na nema b  \n[TR A I LBLAZ ER -ALZ] ) , the  up da ted  met a -ana ly si s  als o d emon strat ed a  sub s t an tial  s hi ft f rom the  \norig inal re s ul t s on  the MMS E en dp oint  (0.10  poin t pe r ea ch 0 .1- unit r edu cti o n i n PE T β -amy loid \nS U VR; 95% C I:  − 0.023 , 0.23 ), a l though th is w a s  n ot  s t ati sti call y signi fic ant .  \n \nF inall y, a s e n s i tiv ity ana lysi s incl uding only the  most r ec en t β - a m y l o i d  t a r g e t i n g  a n t i b o d i e s  ( i . e .  \ng anten erumab,  a duc anumab,  l ec anema b , and donan ema b) , s howed over all  n umeric ally  stronge r \ne ffe ct s  a cro ss all  thr ee en dpoi nt s : C DR- S B (0.0 95 point  per  eac h 0 .1- unit reduc ti on  in PET \nβ -amy loid \nC ognitive en dpoi nt s  \nOriginal  analysi s  \n(“All data” )  \nU pdated analysis \n(“All data”) \nEff ec t  ( 95% CI)  Effect (95% CI)  P-V a lu e  \nCDR - S B  0 .058 ( − 0 .031, 0. 15 )  0.09 (0.0 34, 0.1 5 )  0. 0016 \nAD AS -Co g  NA  0.33 (0 .12, 0.5 5 ) 0. 0025 \nMMSE 0 .034 ( − 0 .056, 0. 12 )  0.13 (0.0 17, 0.2 4 )  0 .024 \nAll rights reserved. No reuse allowed without permission. \n(which was not certified by peer review) is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity. \nThe copyright holder for this preprintthis version posted April 5, 2022. ; https://doi.org/10.1101/2022.04.01.22273253doi: medRxiv preprint \n\n \n \n \n \nS U VR;  95% C I : 0.039 , 0.15;  with a  p-v alu e o f 0.0 008 ), AD AS- Cog (0 .41 poi nt  p er eac h 0.1 -uni t  \nredu ctio n in PE T β -amyl oid SUV R; 95%  C I: 0.2 , 0.61 ; w it h  a p -val ue  o f 0.00 01 ), a n d MMSE  (0.16 p oint  \npe r  ea ch 0.1 -uni t reduct ion in PE T β -a myloid S U VR; 95%  CI:  0. 054 , 0.27; wi t h  a p-va lue of 0 .0032)  \nw ith con s i s tent stati s tica l s i gnific anc e  ( Fi gure 1).  \n \nT r i al- a nd d r ug -spec i fic e s tima t e s  for C D R-SB,  AD AS -Cog,  and MM SE are  pre se nte d in Fi g u r e  A 1  in the \nAppendix  3. T he RCTs inc luded in thi s up dated a nalysi s a re summariz ed in Appendi x 4 .  \n \nDISCUSSION  \nI n t h i s  s tudy, w e up dat ed a previou sly  p ublish ed in st r u men tal va r i able me t a - a n a lysis 1  o f  t h e ef fe c t  of \na  redu ctio n in β -amyloi d pl aque as mea sure d b y PET on cha nge in cog nitive dec line, by  c orr e ctin g  \na nd improvi ng t he o rigi nal d a t a  input s a nd inc rea sing the  num be r  o f R CTs  incl ud ed. In c on tra st t o th e  \ni nitial an aly s i s, our study d emon st r at es  that a r e duc tion in β - a m y l o i d  i s  c a u s a l l y  a n d  c o n s i s t e n t l y  \na ssoci a ted with a  stati s tical ly signi fic ant reduc t i o n in c ognitive  and func t i onal d e cline  as me a sured b y  \nc hang es  in CDR -SB , AD AS -Cog, a nd MMS E.  \n \nS t reng t hs and l imitat i ons \nA unique stre ngth o f t he  me thodol og y de velope d  in t h e  origin a l publi ca tion\n1  is  t h e us e of  t he \ni ns t rumen tal va r i able appro ac h t o ad dre ss th e i ssue  of  pot enti al c on foun ding bia s  f ound i n  \nc orr e la tion anal y s i s. I n addi tion,  the  int egratio n o f da ta from m ul tiple tr ia l s s u bs t an t i a lly improve s \nst ati stic al p r ec i sion r ela tiv e to any  indiv i dual trial .  \n \nDe spit e be ing c atego rized a s  l evel  1 ev idenc e wi t h multiple adva ntag es , met a-a n alys es a re no t  \nw ithout l imi tati on s, 15  s om e o f whi ch h ave alr ea dy be en highli gh ted in  th e o ri gina l p ublica ti on. 1 16  \nAddi t i on al poi nts o f c aut ion in  int erpre t a t i on s h ould be e mpha siz e d .  \n \nF irst, subjec t s  i nclude d in thi s me t a - a nalysi s ar e a t di ff eren t s t a ge s o f A D, from mild cog nitive  \ni mpairment d ue t o A D  to mod era te st age o f A D demen tia . In a d dition , β - a m y lo i d  p os it iv i t y \n(me a s ur ed w ith visu al scal e or P ET SU V R t h r e shol d) w a s  not a p rer equi sit e inc lusion cri teri on in th e  \nma jority of i nc luded s tudie s (9 o f 16  st udie s ). I t i s  bi ol ogic ally  plau sible tha t  subjec t s  i n  t h i s \nhe t e r og en eou s p opula t i on may  d erive  d i ffe r e n t  l evel s o f b e ne fi t in c ognitive  func tion from  β -amy loid \nredu ctio n. In  thi s c on text, comb ining t hose indiv idual s with p r od r om a l, mi ld, o r  moder at e AD, in  \nw hich  the und er l ying pa t h o logy ( β -amy l oid loa d a nd downs tre am proce s s e s) may  v ary, co uld caus e  \ndi ff i cul ty in inte rpre ting th e re sul ts. 16  \nAll rights reserved. No reuse allowed without permission. \n(which was not certified by peer review) is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity. \nThe copyright holder for this preprintthis version posted April 5, 2022. ; https://doi.org/10.1101/2022.04.01.22273253doi: medRxiv preprint \n\n \n \n \n \n \nS e c o n d ,  w h i l e  w e  a s s u m e  a  l i n e a r i t y  b e t w e e n  β -am yloid depo si tion and c ogn itiv e a nd func tiona l  \nde clin e, the pr eci s e t empor al and spa ti al dynam ic of thi s r el a tion s h ip i s  no t w ell under stood . For  \ne xampl e, a lt hough a chang e i n SU VR may be a g ene ralizabl e  met ric,  it m ay not op tima lly re flec t  \nspa tia lly and  t emporally  h ete r o gen ou s prope rtie s  of  th e und erly ing pa tholog y assoc ia ted  with a nd  \nr e l e v a n t  t o  A D  a n d  i t s  c l i n i c a l  m a n i f e s t a t i o n s ,  p a r t i c u l a r l y  a t  t h e  e a r l y  s t a g e  o f  t h e  d i s e a s e .  A s  s u c h ,  \nrec en t finding s  u sing  r e gion al  SUV R data ha ve de mon s tr at ed promi se . 17 18  \n \nT hird, t he  in s trum ent al v ariable an aly si s requ i r e s the ab s ence  o f  o ff - targe t  eff ect s from the  \nther ap eu tic a gent s. In ou r pre s e n t stu dy , w e partial ly a ddre ssed t h i s  limit ati on b y pe r forming  a  \nsen si tivity  ana ly sis  incl udi ng only tr ia l s with antibody  th erapi e s tha t, due to their spec i ficity an d  \ndi r e ct impac t on \nβ -amylo id, may  pr ov ide  more a ccu r a t e  e s tima te s o f t his r e la tion ship . Howev er , thi s \nw ould not have ad dr e sse d t h e h ighly  c omplex  temp or a l rel ati on s h ip tha t  lik ely ex ists betwe en  th e  \ni mpact of a myloid  pl aque remo val a nd t he dec line i n cog ni t i on and func ti on th at  is inhe ren tly  limited  \nb y  t h e  s h o r t - t e r m  s e t t i n g  o f  m o s t  t y p i c a l  c l i n i c a l  t r i a l s  a n d  w h e r e  a  p o t e n t i a l l y  d e l a y e d - o n s e t  e f f e c t  \nc annot be  cap tur ed.  \n \nF ourt h ,  th e v ariou s r adiot race rs  u sed i n trial s inc lud ed in thi s an aly si s di ff er in their  s en s i t i vity ,  \nspec i fici t y , va ria bili ty, d ynamic  rang e s,  an d o the r pe rfo r ma nce  me t r ic s\n19-23 . The r e for e, al though  \ndi ffe re nt  a myloid trac er s produc e highl y  con s i s ten t an d hig hly c orrela t e d  r e s ul t s,  SUVR  de rived from  \ndi ffe re nt  t rac e r s  are  no t equi val en t  a nd sh ould b e co mp ared  or c ombin ed w ith som e c auti on.  \nF urt he r more , al thoug h  a myloid PET  ha s  been  s how n to  be robu st agai n st di f fe r e nt qua n t ifi c atio n  \nme t h od s 24 , dif fe ren t an aly si s pipeli n es  m ay a ls o have re sult ed i n s m a ll dif fe renc e s  betwee n studie s .  \n \nF inall y, th e a ss e ss m ent  o f chang e  in A D -rel at ed impa i r m ent  o f co gni tion and fu nction a t the  ea rly  \nph ase s  o f AD i s no t fully a dd r e ssed  by t he c linic al sco re s  u til iz e d i n t he se c linic a l tr i al s , in par t i cula r \nthe MM SE , due to i ts l imited se n s itiv ity to cap ture p rogre s s i on  in cog nitive d e cli ne . Thi s wa s fu r th er  \nem p h as i z ed i n  ou r  c ur r e nt  st u d y  b y t he d e m o ns t ra t i o n of  h ig he r  p- v a l ues  fo r  MM S E  c o mp a re d  w i t h \nCDR -SB a nd AD AS -Cog e n dpoint s  (Figu re 1) .  \n \nIm plications  \n \nT hat a st ati s tic ally  s ig ni fica nt cau sal a sso cia t i on be twee n dec rea s ing  PET -mea s ur ed \nβ -am yloid p laqu e  \na nd r eduction  o f c ogni tiv e and  f unc tion a l dec line  wa s con si ste nt l y demon st r a te d on all thr ee  c linic al  \nAll rights reserved. No reuse allowed without permission. \n(which was not certified by peer review) is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity. \nThe copyright holder for this preprintthis version posted April 5, 2022. ; https://doi.org/10.1101/2022.04.01.22273253doi: medRxiv preprint \n\n \n \n \n \ne ndpoin ts d e s pit e som e of the a for eme nt i oned limi t a t i o n s  hig hlight s the po ten t ial of β -amy loid as a  \nv iable  bio logic al t a r g et in  A D. A s more  data  ac cumu la te i n th e fu ture , w e hop e t ha t  som e of the  \nl imitation s can  b e addr e s s e d by a naly si s of da ta w ith longe r fo ll ow-up p eriod s . In a ddition , the a bility  \nto harmo nize the d ata  on β -a myloid  lo a d by us i ng Cen tiloid s will fur ther  a cco u nt  f or t he  di f fer ent  \nprope rtie s o f β - a m y l o i d  r a d i o t r a c e r s .  T h e s e  e f f o r t s  w i l l  s h e d  m o r e  l i g h t  o n  t h e  e f f e c t  o f  β -amy loid \nredu ctio n on c ognitiv e  and f u nctio nal  decli ne and  guide futu re dr ug devel o pment a nd c linic al  \na pplic ation s.  \n \nCONCLUSIONS  \n \nT his  upda ted i ns tr u m ental va r i able m e t a - a naly si s, whi ch i s ba s ed on 16 r andomiz ed c linic al tr ial s an d  \ne xpands  on the o rig inal w or k  by Ack ley et al ., 1  d e m on st r a t ed a  c o ns ist e n t a n d  st at is t i ca l l y  s i g nif i c a n t \ni mpact of PET β -amyloi d S U VR ch ange on thr e e commonly  u s ed c linic al outco me mea s u re s. Mo r e  \nda ta a nd re s earc h a re need e d to fu rt h e r  cha r a ct eriz e the pr eci se sp atial /t em poral prop ert i e s  and  \npo t e n t i al he ter oge nei ty of the c au sa tive rel ati on s h ip betw ee n β -amylo id cl earanc e  and c ognitiv e and  \nfunc tio nal t r aje ctory w it h in the A D con t i nu um.  \n \nPATI EN T  A N D P UB L IC INV O L V E M E N T:   \n \nP ati ent s  o r  the  public  we re no t  i nvolv ed in the  de sign, o r c onduct, o r repo rting,  o r dissemina t i on \npl ans o f thi s  re sea rc h.  \n \nACKNOWL EDGMEN TS:   \n \nWe would l ike to tha nk Ta mmy Jian g for quali t y -ch ec king  t h e inpu t da t a ; Joh n O’G orman,  S ama nth a \nBu dd Haeb erlein ,  Tuck er War d, Kathl ee n  Gr obb e n, Anni e Racine  an d P r iy a Si nghal  f o r  r ev iewi ng the \nma nuscrip t and pr ov iding h elpful c omme nts .  \n \nCOM PETIN G INT ERESTS :  \n \nCh angyu  Sh en, Menglan  P ang, Ling  Zh u, Aud rey  Gabel le ,  Ar i e Ga fson,  Ivana  Rubino,  Shib es hih  \nBe lach ew an d Ca rl de Moor a re emp loye es and sha rehol d ers of Bi og en inc . Jim E.  Galv in MD, MPH  i s \na  P rof e ss or  of Neu r o logy a t Unive rsi ty of Mi a mi, con sul tan t f or Bio gen,  Alpha  Cogn ition , Ei sai,  and  \nCo gnivue , and h a s  re s earch f u nding f ro m NIH, and c linic al inc om e f rom pati e nt  c are. R obe rt W . Pla t t ,  \nP hD, ha s an ong oing c on s u lting a rrange ment with Bi ogen .  \n \nFU ND I N G :   \n \nT his  work w as funde d by  Biogen .  \n \nRE FERENCES: \n \nAll rights reserved. No reuse allowed without permission. \n(which was not certified by peer review) is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity. \nThe copyright holder for this preprintthis version posted April 5, 2022. ; https://doi.org/10.1101/2022.04.01.22273253doi: medRxiv preprint \n\n \n \n \n \n1. Ack le y SF , Zimmerman SC, Br enowitz W D, e t  al. Ef fect of reduc t ions  in amyloid levels  on \nc ognit iv e change in randomized tr ials : instrumental var iable me ta-analysis .  Bmj  \n2021;37 2:n156 . doi: 10.113 6/bmj.n1 56 [publis hed Online First: 2021 /02/ 2 7] \n2. Karran E, Merc k en  M, De Str ooper B. The amyloid ca scade hypothes i s f or Alzheime r's \ndis ease: an apprai s al fo r the deve lop ment  of ther apeu tics . Nat Rev Dr ug Disc ov  \n2011;10(9): 698 -712. doi: 10 .103 8/nr d3505 [pu blished Online Fir s t : 20 11/08/20]  \n3. Mc Khann G M , Knopman DS, Chertkow H, e t  al. The diagnosi s of dement ia due to \nAlz heimer's  diseas e:  r e c ommendatio n s  fr om the National Institute on  Agin g-\nAlz heimer's  As socia t ion workgroups  on diagnostic guidelin e s for  Alz heime r's disease. \nAlz heimer s  D em ent  2011;7(3) :2 63-9. doi: 10.1016/j .jalz .2 011. 03.00 5 [publis hed \nO nline First: 2011/04/26] \n4. Jack CR,  J r., Knopma n  DS , Jagus t  WJ, et  a l. Hypothetic al model o f dynamic biomar kers of \nthe Alzheimer's pathological c a s c ade.  Lancet Ne ur ol  2010;9(1): 11 9-28. doi: \n10.1016 /s147 4-4422( 09)70 299-6 [pu blished Online Fir s t : 2010 / 01 /20] \n5. Karran E, De St rooper  B. The amyloid hy pothesis  in Alzheimer diseas e: n ew insight s f rom \nnew t herapeut ic s. N a t Rev Drug D iscov  2022 doi: 10.1 038/ s41573-0 22 -003 91-w \n[published O nline First: 2022/0 2/19]  \n6. Thal DR, Rüb U, O r antes M, et al. Phas e s of A bet a-d eposition in the human brain and its \nrelevanc e fo r th e development  of AD. N eur ology 200 2;5 8(12):179 1- 800. do i: \n10.1212 / wnl.58 .12.1 791 [ publis hed Online First: 2002 /06/27]  \n7. Ingels son M, Fukumoto H, Ne well KL, et al. Early Abeta accumulation and pr ogressive \nsynaptic los s, glios i s, and tan gle for m ation in AD brain. Neurology 2004;62(6):9 25-31. \ndoi: 10.1212/01 .w nl.0 000 11 5115 .989 60.37 [published On line  Fir s t:  20 0 4/ 0 3/24] \n8. G oate A, Chartier -Ha r lin MC, Mulla n M, et al. S egr egation of a miss ense mutat ion in the \namyloid precursor pr otein gene with familia l A lzheimer's dis ea se. Natu re  \n1991;34 9(6311): 7 04-6. doi: 10.1 038/ 349704a 0 [publis hed O nline First: 19 91/02/21 ] \n9. Karlawis h J, Grill JD. T he approval o f Aduhe lm r is ks eroding public tr us t  i n Alz heimer  \nresea r ch and the FDA. Nat R e v Neurol  2021;17(9) : 523-24. doi: 10. 1038/ s41 582- 021-\n00540-6 [published Online F ir s t : 20 21 / 07/17]  \n10. S ieme r s  ER, Sundell KL, Carlson C, et al. Phase 3 solanezumab tr ials: Secon dary outcomes \nin mild Alz heimer's  disea s e pat ien ts. A l zh e i m e r s D em en t  2016;12(2) : 110-2 0. doi: \n10.1016 / j.jalz .2015 .06.1 893 [publishe d Onlin e Fir s t : 2 015 / 08/0 5] \n11. E g an MF, Kos t  J, Vos s  T , et al. Randomized Trial of Ver ub eces t at for Pr odromal \nAlz heimer's  Dis ease. N  Engl J M ed  2 019;380(15): 1408- 20. doi: \n10.1056 /NEJMoa181 2840 [published O nline First: 2019 /04/ 11] \n12. S evigny J, Chiao P, Bus sièr e T, et a l. The  an t ibody aduca numab reduce s Aβ plaqu es  in  \nAlz heimer's  diseas e. Natur e 2016 ;537 (7618):5 0-6. doi: 10.1 038/nature193 23 \n[published O nline First: 2016/0 9/02]  \n13. W e s s els AM, Lines C, St ern RA, et  al. Cognitive outcomes in t rials  of  two  BACE inhibit o rs \nin Alz heime r 's  diseas e. A l zheimer s De ment  2020;16(11): 148 3-92. doi: \n10.1002 / alz. 12164 [published Onlin e  Fir s t:  20 20 / 10/ 14] \n14. N avitsk y  M , Joshi AD, Kennedy I , et al. Standar diz ation  of amyloid qua ntitation wit h \nflorbe t apir s t andardized uptake value  ratios to the  Cent iloid s cale. Alzheimers \nDement 2018 ;14(1 2):1565- 71 . doi: 10 .1016/ j .jalz.2 018.0 6.135 3 [published Onlin e \nF ir s t : 2018 / 07/ 15] \n15. E ysenc k HJ. Me t a-analys i s and its pr oblems. Bmj  1994;30 9(6957) :7 89-9 2. doi: \n10.1136 / bmj.309 .6957 .789 [publishe d O nlin e First:  199 4 / 09/2 4] \nAll rights reserved. No reuse allowed without permission. \n(which was not certified by peer review) is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity. \nThe copyright holder for this preprintthis version posted April 5, 2022. ; https://doi.org/10.1101/2022.04.01.22273253doi: medRxiv preprint \n\n \n \n \n \n16. Mangiala sche F, S olomon A, Winblad B, et al. Alz heimer's  disease :  clinic al t rials  and dr ug \ndev elopment. Lancet N eur ol  2010;9(7 ):702- 16. doi: 10.10 16/s14 74-4422( 1 0)70119-8 \n[published O nline First: 2010/0 7/09]  \n17. F ar rell ME, Chen X, Rundle MM, e t  a l. Regional amyloid acc umulation a nd cognitive \ndec line in initially amyloid-negativ e a dults. Neur ology  201 8;91(19):e18 09- e21 . d oi: \n10.1212 / wnl.00 00000 000 0 06469 [publis hed O nline First: 2018 /10/12 ] \n18. G r othe MJ , Barthel H, S epulc r e J, et al. In vivo staging of regional amylo id deposition. \nN eur ology  2017; 8 9(20):20 31-38.  d oi: 10.1212 / wnl.00 00000 0000 04 643 [pu blis h e d  \nO nline First: 2017/10/20] \n19. Yeo JM, Waddell B, Khan Z, et al. A s y stematic review and meta-analysis  of 18F-labeled \namyloid ima ging in Alzheime r's dise as e. Alzheimers Dem ent. D iagn. As s e s s . Dis. \nMonit. 2015; 1(1):5-13. doi: ht tps:/ /doi.or g /10.101 6/j.dadm.2 014.1 1.004 [ publis hed \nO nline First: 2015/03/01] \n20. L andau SM, Thomas  BA, Thurfjell L, et al. Amyloid PET imaging in Alz heimer ’s  disea s e: a \nc o mp a r is o n o f th re e  ra d i o tra c e rs . Eur . J . N ucl. Med. M ol .  Im aging . 2014;41 (7):139 8-\n407. doi: http s :// dx .doi.or g/ 10. 1007 %2F s00 259-014-275 3 -3 [published Online First: \n2014/0 3/20]  \n21. Krishnada s  N, Villemagne VL, Doré V, e t  al. Advanc es in Brain Amyloid Imag ing. Semin. \nN ucl. Med. 20 21;51( 3): 2 41–252. doi: 10.1053 /j. s emnu c lmed.20 20 .12. 005 [published \nO nline First: 2021/01/19] \n22. Cho SH, Choe Y S, Kim YJ, et  al. He ad-to- head c ompar ison of 18F-flor be t aben and 18F-\nflutem et amo l in the  cortical and s t riatal regions. J. Alzheimers Di s . 20 20;76 (1):281 -90. \ndoi: 10.3233/ J AD-200079 [published O nlin e Fir s t:  202 0 / 06/ 30] \n23. W olk DA, Z ha n g  Z , Boudhar S, et al. Amyloid imaging in Alz heimer 's  diseas e: compar is on \nof flo rbetapir and Pitt s burgh compound- B pos it ron e mission tomogr a phy. J . N eur ol. \nN eur o s ur g. P s y chiatry . 2012;83( 9): 92 3-6. doi: 10.1136/ jnnp-2012 -3025 48 [published \nO nline First: 2012/07/11] \n24. L andau SM, Breault C, J os hi AD, et al. Amyloid -β imaging with Pit tsburg h compound B \nand florbe t apir: comparing r a diot racers and quantif ication  meth ods. J. Nuc l . M e d.  \n2013;54(1): 70- 7. doi: 10.29 67/ jn ume d.112.10 9009 [pub lished Online F ir s t : \n2012/1 1/19]  \n \n \n  \nAll rights reserved. No reuse allowed without permission. \n(which was not certified by peer review) is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity. \nThe copyright holder for this preprintthis version posted April 5, 2022. ; https://doi.org/10.1101/2022.04.01.22273253doi: medRxiv preprint \n\n \n \nFigure 1  \n \n \n \n  \nAll rights reserved. No reuse allowed without permission. \n(which was not certified by peer review) is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity. \nThe copyright holder for this preprintthis version posted April 5, 2022. ; https://doi.org/10.1101/2022.04.01.22273253doi: medRxiv preprint \n\n \n \n \n \nFigure Legend \nFi g u r e  1.  Fore st pl ot s of t he  poo le d e stima te s r epre s enting the  e ff ec t  o f a d ec r e a se in br a in β -\na myloid  as  me asured b y PET on  cha ng e in A) C DR-S B, B) ADAS - Cog , and C) M MS E. P o s itiv e val u e s  of  \nthe e f fect  e s tima t e — f or e ach 0.1 -unit  redu ctio n i n PET  SU VR —indic at e t hat β -a myloid r e duction  \nredu ce s cog ni tive decl in e. Cen t er a nd wi dt h  of dia mond s  re pres ent  poo le d es timat e s and 95%  \nc onfidenc e in terva l s ,  r e spectiv ely.  T he  tria l o f l eca nemab  i s unp ubl i s he d  and  wa s ex clude d from th e  \n“ All published data”  a nd “ All published antibody data ” c at egorie s i n the sen s i t i v ity anal ys e s. Mo s t  \nrec en t β -amy loid t arge ting  antibod i e s  i nclu ded ga nte neruma b, a duca numa b ( ENGA G E , EMERGE,  \nP RIME ), leca n emab, a nd don anema b t rial s . A DAS - Cog, Alzh eime r ’s Di se a s e  As se ssm ent Sc ale –\nCo gnitive  S ub s c al e; C DR -SB, Cl inica l D e mentia Ra ting– Sum o f Boxe s; CI, con fi d ence i nte r v al; MMSE ,  \nM i ni - M en t al  S t at e  Ex a m in a t i o n.   \n \n \n \n \n \n  \n \n \n \nAll rights reserved. No reuse allowed without permission. \n(which was not certified by peer review) is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity. \nThe copyright holder for this preprintthis version posted April 5, 2022. ; https://doi.org/10.1101/2022.04.01.22273253doi: medRxiv preprint","source_license":"Public-Domain","license_restricted":false}