Abstract
A number of Alzheimer’s disease (AD) susceptibility loci are expressed abundantly in microglia. We examined associations between AD risk variants in genes that are highly expressed in microglia and neuropathological outcomes, including cerebral amyloid angiopathy (CAA) and microglial activation, in 93 AD patients. We observed significant associations of CAA pathology with APOE ɛ4 and PTK2B rs28834970. Nominally significant associations with measures of microglial activation in white matter were observed for variants in PTK2B, PICALM, and CR1. Our findings suggest that several AD risk variants may also function as disease modifiers through amyloid-β metabolism and white matter microglial activity.
Get full access to this article
View all access options for this article.
References
1.Alzheimer’s Association (2015 ) 2015 Alzheimer’s disease facts and figures . Alzheimers Dement 11 , 332 –384 .
2.
Hyman
BT
,
Phelps
CH
,
Beach
TG
,
Bigio
EH
,
Cairns
NJ
,
Carrillo
MC
,
Dickson
DW
,
Duyckaerts
C
,
Frosch
MP
,
Masliah
E
,
Mirra
SS
,
Nelson
PT
,
Schneider
JA
,
Thal
DR
,
Thies
B
,
Trojanowski
JQ
,
Vinters
HV
,
Montine
TJ
(2012 ) National Institute on Aging-Alzheimer’s Association guidelines for the neuropathologic assessment of Alzheimer’s disease . Alzheimers Dement 8 , 1 –13 .
3.
Brenowitz
WD
,
Nelson
PT
,
Besser
LM
,
Heller
KB
,
Kukull
WA
(2015 ) Cerebral amyloid angiopathy and its co-occurrence with Alzheimer’s disease and other cerebrovascular neuropathologic changes . Neurobiol Aging 36 , 2702 –2708 .
4.
Mosher
KI
,
Wyss-Coray
T
(2014 ) Microglial dysfunction in brain aging and Alzheimer’s disease . Biochem Pharmacol 88 , 594 –604 .
5.
Tanzi
RE
,
Bertram
L
(2005 ) Twenty years of the Alzheimer’s disease amyloid hypothesis: A genetic perspective . Cell 120 , 545 –555 .
6.
Hollingworth
P
,
Harold
D
,
Sims
R
,
Gerrish
A
,
Lambert
JC
,
Carrasquillo
MM
,
Abraham
R
,
Hamshere
ML
,
Pahwa
JS
,
Moskvina
V
,
Dowzell
K
,
Jones
N
,
Stretton
A
,
Thomas
C
,
Richards
A
,
Ivanov
D
,
Widdowson
C
,
Chapman
J
,
Lovestone
S
,
Powell
J
,
Proitsi
P
,
Lupton
MK
,
Brayne
C
,
Rubinsztein
DC
,
Gill
M
,
Lawlor
B
,
Lynch
A
,
Brown
KS
,
Passmore
PA
,
Craig
D
,
McGuinness
B
,
Todd
S
,
Holmes
C
,
Mann
D
,
Smith
AD
,
Beaumont
H
,
Warden
D
,
Wilcock
G
,
Love
S
,
Kehoe
PG
,
Hooper
NM
,
Vardy
ER
,
Hardy
J
,
Mead
S
,
Fox
NC
,
Rossor
M
,
Collinge
J
,
Maier
W
,
Jessen
F
,
Ruther
E
,
Schurmann
B
,
Heun
R
,
Kolsch
H
,
van den Bussche
H
,
Heuser
I
,
Kornhuber
J
,
Wiltfang
J
,
Dichgans
M
,
Frolich
L
,
Hampel
H
,
Gallacher
J
,
Hull
M
,
Rujescu
D
,
Giegling
I
,
Goate
AM
,
Kauwe
JS
,
Cruchaga
C
,
Nowotny
P
,
Morris
JC
,
Mayo
K
,
Sleegers
K
,
Bettens
K
,
Engelborghs
S
,
De Deyn
PP
,
Van Broeckhoven
C
,
Livingston
G
,
Bass
NJ
,
Gurling
H
,
McQuillin
A
,
Gwilliam
R
,
Deloukas
P
,
Al-Chalabi
A
,
Shaw
CE
,
Tsolaki
M
,
Singleton
AB
,
Guerreiro
R
,
Muhleisen
TW
,
Nothen
MM
,
Moebus
S
,
Jockel
KH
,
Klopp
N
,
Wichmann
HE
,
Pankratz
VS
,
Sando
SB
,
Aasly
JO
,
Barcikowska
M
,
Wszolek
ZK
,
Dickson
DW
,
Graff-Radford
NR
,
Petersen
RC
,
van Duijn
CM
,
Breteler
MM
,
Ikram
MA
,
DeStefano
AL
,
Fitzpatrick
AL
,
Lopez
O
,
Launer
LJ
,
Seshadri
S
,
Berr
C
,
Campion
D
,
Epelbaum
J
,
Dartigues
JF
,
Tzourio
C
,
Alperovitch
A
,
Lathrop
M
,
Feulner
TM
,
Friedrich
P
,
Riehle
C
,
Krawczak
M
,
Schreiber
S
,
Mayhaus
M
,
Nicolhaus
S
,
Wagenpfeil
S
,
Steinberg
S
,
Stefansson
H
,
Stefansson
K
,
Snaedal
J
,
Bjornsson
S
,
Jonsson
PV
,
Chouraki
V
,
Genier-Boley
B
,
Hiltunen
M
,
Soininen
H
,
Combarros
O
,
Zelenika
D
,
Delepine
M
,
Bullido
MJ
,
Pasquier
F
,
Mateo
I
,
Frank-Garcia
A
,
Porcellini
E
,
Hanon
O
,
Coto
E
,
Alvarez
V
,
Bosco
P
,
Siciliano
G
,
Mancuso
M
,
Panza
F
,
Solfrizzi
V
,
Nacmias
B
,
Sorbi
S
,
Bossu
P
,
Piccardi
P
,
Arosio
B
,
Annoni
G
,
Seripa
D
,
Pilotto
A
,
Scarpini
E
,
Galimberti
D
,
Brice
A
,
Hannequin
D
,
Licastro
F
,
Jones
L
,
Holmans
PA
,
Jonsson
T
,
Riemenschneider
M
,
Morgan
K
,
Younkin
SG
,
Owen
MJ
,
O’Donovan
M
,
Amouyel
P
,
Williams
J
(2011 ) Common variants at ABCA7, MS4A6A/MS4A4E, EPHA1, CD33 and CD2AP are associated with Alzheimer’s disease . Nat Genet 43 , 429 –435 .
7.
Naj
AC
,
Jun
G
,
Beecham
GW
,
Wang
LS
,
Vardarajan
BN
,
Buros
J
,
Gallins
PJ
,
Buxbaum
JD
,
Jarvik
GP
,
Crane
PK
,
Larson
EB
,
Bird
TD
,
Boeve
BF
,
Graff-Radford
NR
,
De Jager
PL
,
Evans
D
,
Schneider
JA
,
Carrasquillo
MM
,
Ertekin-Taner
N
,
Younkin
SG
,
Cruchaga
C
,
Kauwe
JS
,
Nowotny
P
,
Kramer
P
,
Hardy
J
,
Huentelman
MJ
,
Myers
AJ
,
Barmada
MM
,
Demirci
FY
,
Baldwin
CT
,
Green
RC
,
Rogaeva
E
,
St George-Hyslop
P
,
Arnold
SE
,
Barber
R
,
Beach
T
,
Bigio
EH
,
Bowen
JD
,
Boxer
A
,
Burke
JR
,
Cairns
NJ
,
Carlson
CS
,
Carney
RM
,
Carroll
SL
,
Chui
HC
,
Clark
DG
,
Corneveaux
J
,
Cotman
CW
,
Cummings
JL
,
DeCarli
C
,
DeKosky
ST
,
Diaz-Arrastia
R
,
Dick
M
,
Dickson
DW
,
Ellis
WG
,
Faber
KM
,
Fallon
KB
,
Farlow
MR
,
Ferris
S
,
Frosch
MP
,
Galasko
DR
,
Ganguli
M
,
Gearing
M
,
Geschwind
DH
,
Ghetti
B
,
Gilbert
JR
,
Gilman
S
,
Giordani
B
,
Glass
JD
,
Growdon
JH
,
Hamilton
RL
,
Harrell
LE
,
Head
E
,
Honig
LS
,
Hulette
CM
,
Hyman
BT
,
Jicha
GA
,
Jin
LW
,
Johnson
N
,
Karlawish
J
,
Karydas
A
,
Kaye
JA
,
Kim
R
,
Koo
EH
,
Kowall
NW
,
Lah
JJ
,
Levey
AI
,
Lieberman
AP
,
Lopez
OL
,
Mack
WJ
,
Marson
DC
,
Martiniuk
F
,
Mash
DC
,
Masliah
E
,
McCormick
WC
,
McCurry
SM
,
McDavid
AN
,
McKee
AC
,
Mesulam
M
,
Miller
BL
,
Miller
CA
,
Miller
JW
,
Parisi
JE
,
Perl
DP
,
Peskind
E
,
Petersen
RC
,
Poon
WW
,
Quinn
JF
,
Rajbhandary
RA
,
Raskind
M
,
Reisberg
B
,
Ringman
JM
,
Roberson
ED
,
Rosenberg
RN
,
Sano
M
,
Schneider
LS
,
Seeley
W
,
Shelanski
ML
,
Slifer
MA
,
Smith
CD
,
Sonnen
JA
,
Spina
S
,
Stern
RA
,
Tanzi
RE
,
Trojanowski
JQ
,
Troncoso
JC
,
Van Deerlin
VM
,
Vinters
HV
,
Vonsattel
JP
,
Weintraub
S
,
Welsh-Bohmer
KA
,
Williamson
J
,
Woltjer
RL
,
Cantwell
LB
,
Dombroski
BA
,
Beekly
D
,
Lunetta
KL
,
Martin
ER
,
Kamboh
MI
,
Saykin
AJ
,
Reiman
EM
,
Bennett
DA
,
Morris
JC
,
Montine
TJ
,
Goate
AM
,
Blacker
D
,
Tsuang
DW
,
Hakonarson
H
,
Kukull
WA
,
Foroud
TM
,
Haines
JL
,
Mayeux
R
,
Pericak-Vance
MA
,
Farrer
LA
,
Schellenberg
GD
(2011 ) Common variants at MS4A4/MS4A6E, CD2AP, CD33 and EPHA1 are associated with late-onset Alzheimer’s disease . Nat Genet 43 , 436 –441 .
8.
Lambert
JC
,
Ibrahim-Verbaas
CA
,
Harold
D
,
Naj
AC
,
Sims
R
,
Bellenguez
C
,
DeStafano
AL
,
Bis
JC
,
Beecham
GW
,
Grenier-Boley
B
,
Russo
G
,
Thorton-Wells
TA
,
Jones
N
,
Smith
AV
,
Chouraki
V
,
Thomas
C
,
Ikram
MA
,
Zelenika
D
,
Vardarajan
BN
,
Kamatani
Y
,
Lin
CF
,
Gerrish
A
,
Schmidt
H
,
Kunkle
B
,
Dunstan
ML
,
Ruiz
A
,
Bihoreau
MT
,
Choi
SH
,
Reitz
C
,
Pasquier
F
,
Cruchaga
C
,
Craig
D
,
Amin
N
,
Berr
C
,
Lopez
OL
,
De Jager
PL
,
Deramecourt
V
,
Johnston
JA
,
Evans
D
,
Lovestone
S
,
Letenneur
L
,
Moron
FJ
,
Rubinsztein
DC
,
Eiriksdottir
G
,
Sleegers
K
,
Goate
AM
,
Fievet
N
,
Huentelman
MW
,
Gill
M
,
Brown
K
,
Kamboh
MI
,
Keller
L
,
Barberger-Gateau
P
,
McGuiness
B
,
Larson
EB
,
Green
R
,
Myers
AJ
,
Dufouil
C
,
Todd
S
,
Wallon
D
,
Love
S
,
Rogaeva
E
,
Gallacher
J
,
St George-Hyslop
P
,
Clarimon
J
,
Lleo
A
,
Bayer
A
,
Tsuang
DW
,
Yu
L
,
Tsolaki
M
,
Bossu
P
,
Spalletta
G
,
Proitsi
P
,
Collinge
J
,
Sorbi
S
,
Sanchez-Garcia
F
,
Fox
NC
,
Hardy
J
,
Deniz Naranjo
MC
,
Bosco
P
,
Clarke
R
,
Brayne
C
,
Galimberti
D
,
Mancuso
M
,
Matthews
F
, European Alzheimer’s Disease Initiative (EADI); Genetic and Environmental Risk in Alzheimer’s Disease; Alzheimer’s Disease Genetic Consortium; Cohorts for Heart and Aging Research in Genomic Epidemiology ,
Moebus
S
,
Mecocci
P
,
Del Zompo
M
,
Maier
W
,
Hampel
H
,
Pilotto
A
,
Bullido
M
,
Panza
F
,
Caffarra
P
,
Nacmias
B
,
Gilbert
JR
,
Mayhaus
M
,
Lannefelt
L
,
Hakonarson
H
,
Pichler
S
,
Carrasquillo
MM
,
Ingelsson
M
,
Beekly
D
,
Alvarez
V
,
Zou
F
,
Valladares
O
,
Younkin
SG
,
Coto
E
,
Hamilton-Nelson
KL
,
Gu
W
,
Razquin
C
,
Pastor
P
,
Mateo
I
,
Owen
MJ
,
Faber
KM
,
Jonsson
PV
,
Combarros
O
,
O’Donovan
MC
,
Cantwell
LB
,
Soininen
H
,
Blacker
D
,
Mead
S
,
Mosley
TH
Jr.
,
Bennett
DA
,
Harris
TB
,
Fratiglioni
L
,
Holmes
C
,
de Bruijn
RF
,
Passmore
P
,
Montine
TJ
,
Bettens
K
,
Rotter
JI
,
Brice
A
,
Morgan
K
,
Foroud
TM
,
Kukull
WA
,
Hannequin
D
,
Powell
JF
,
Nalls
MA
,
Ritchie
K
,
Lunetta
KL
,
Kauwe
JS
,
Boerwinkle
E
,
Riemenschneider
M
,
Boada
M
,
Hiltuenen
M
,
Martin
ER
,
Schmidt
R
,
Rujescu
D
,
Wang
LS
,
Dartigues
JF
,
Mayeux
R
,
Tzourio
C
,
Hofman
A
,
Nothen
MM
,
Graff
C
,
Psaty
BM
,
Jones
L
,
Haines
JL
,
Holmans
PA
,
Lathrop
M
,
Pericak-Vance
MA
,
Launer
LJ
,
Farrer
LA
,
van Duijn
CM
,
Van Broeckhoven
C
,
Moskvina
V
,
Seshadri
S
,
Williams
J
,
Schellenberg
GD
,
Amouyel
P
(2013 ) Meta-analysis of 74,046 individuals identifies 11 new susceptibility loci for Alzheimer’s disease . Nat Genet 45 , 1452 –1458 .
9.
Beecham
GW
,
Hamilton
K
,
Naj
AC
,
Martin
ER
,
Huentelman
M
,
Myers
AJ
,
Corneveaux
JJ
,
Hardy
J
,
Vonsattel
JP
,
Younkin
SG
,
Bennett
DA
,
De Jager
PL
,
Larson
EB
,
Crane
PK
,
Kamboh
MI
,
Kofler
JK
,
Mash
DC
,
Duque
L
,
Gilbert
JR
,
Gwirtsman
H
,
Buxbaum
JD
,
Kramer
P
,
Dickson
DW
,
Farrer
LA
,
Frosch
MP
,
Ghetti
B
,
Haines
JL
,
Hyman
BT
,
Kukull
WA
,
Mayeux
RP
,
Pericak-Vance
MA
,
Schneider
JA
,
Trojanowski
JQ
,
Reiman
EM
, Alzheimer’s Disease Genetics Consortium (ADGC) ,
Schellenberg
GD
,
Montine
TJ
(2014 ) Genome-wide association meta-analysis of neuropathologic features of Alzheimer’s disease and related dementias . PLoS Genet 10 , e1004606 .
10.
Lambert
JC
,
Heath
S
,
Even
G
,
Campion
D
,
Sleegers
K
,
Hiltunen
M
,
Combarros
O
,
Zelenika
D
,
Bullido
MJ
,
Tavernier
B
,
Letenneur
L
,
Bettens
K
,
Berr
C
,
Pasquier
F
,
Fievet
N
,
Barberger-Gateau
P
,
Engelborghs
S
,
De Deyn
P
,
Mateo
I
,
Franck
A
,
Helisalmi
S
,
Porcellini
E
,
Hanon
O
, European Alzheimer’s Disease Initiative Initiative ,
de Pancorbo
MM
,
Lendon
C
,
Dufouil
C
,
Jaillard
C
,
Leveillard
T
,
Alvarez
V
,
Bosco
P
,
Mancuso
M
,
Panza
F
,
Nacmias
B
,
Bossu
P
,
Piccardi
P
,
Annoni
G
,
Seripa
D
,
Galimberti
D
,
Hannequin
D
,
Licastro
F
,
Soininen
H
,
Ritchie
K
,
Blanche
H
,
Dartigues
JF
,
Tzourio
C
,
Gut
I
,
Van Broeckhoven
C
,
Alperovitch
A
,
Lathrop
M
,
Amouyel
P
(2009 ) Genome-wide association study identifies variants at CLU and CR1 associated with Alzheimer’s disease . Nat Genet 41 , 1094 –1099 .
11.
Seshadri
S
,
Fitzpatrick
AL
,
Ikram
MA
,
DeStefano
AL
,
Gudnason
V
,
Boada
M
,
Bis
JC
,
Smith
AV
,
Carassquillo
MM
,
Lambert
JC
,
Harold
D
,
Schrijvers
EM
,
Ramirez-Lorca
R
,
Debette
S
,
Longstreth
WT
Jr.
,
Janssens
AC
,
Pankratz
VS
,
Dartigues
JF
,
Hollingworth
P
,
Aspelund
T
,
Hernandez
I
,
Beiser
A
,
Kuller
LH
,
Koudstaal
PJ
,
Dickson
DW
,
Tzourio
C
,
Abraham
R
,
Antunez
C
,
Du
Y
,
Rotter
JI
,
Aulchenko
YS
,
Harris
TB
,
Petersen
RC
,
Berr
C
,
Owen
MJ
,
Lopez-Arrieta
J
,
Varadarajan
BN
,
Becker
JT
,
Rivadeneira
F
,
Nalls
MA
,
Graff-Radford
NR
,
Campion
D
,
Auerbach
S
,
Rice
K
,
Hofman
A
,
Jonsson
PV
,
Schmidt
H
,
Lathrop
M
,
Mosley
TH
,
Au
R
,
Psaty
BM
,
Uitterlinden
AG
,
Farrer
LA
,
Lumley
T
,
Ruiz
A
,
Williams
J
,
Amouyel
P
,
Younkin
SG
,
Wolf
PA
,
Launer
LJ
,
Lopez
OL
,
van Duijn
CM
,
Breteler
MM
, CHARGE Consortium; GERAD1 Consortium; EADI1 Consortium (2010 ) Genome-wide analysis of genetic loci associated with Alzheimer disease . JAMA 303 , 1832 –1840 .
12.
Harold
D
,
Abraham
R
,
Hollingworth
P
,
Sims
R
,
Gerrish
A
,
Hamshere
ML
,
Pahwa
JS
,
Moskvina
V
,
Dowzell
K
,
Williams
A
,
Jones
N
,
Thomas
C
,
Stretton
A
,
Morgan
AR
,
Lovestone
S
,
Powell
J
,
Proitsi
P
,
Lupton
MK
,
Brayne
C
,
Rubinsztein
DC
,
Gill
M
,
Lawlor
B
,
Lynch
A
,
Morgan
K
,
Brown
KS
,
Passmore
PA
,
Craig
D
,
McGuinness
B
,
Todd
S
,
Holmes
C
,
Mann
D
,
Smith
AD
,
Love
S
,
Kehoe
PG
,
Hardy
J
,
Mead
S
,
Fox
N
,
Rossor
M
,
Collinge
J
,
Maier
W
,
Jessen
F
,
Schurmann
B
,
Heun
R
,
van den Bussche
H
,
Heuser
I
,
Kornhuber
J
,
Wiltfang
J
,
Dichgans
M
,
Frolich
L
,
Hampel
H
,
Hull
M
,
Rujescu
D
,
Goate
AM
,
Kauwe
JS
,
Cruchaga
C
,
Nowotny
P
,
Morris
JC
,
Mayo
K
,
Sleegers
K
,
Bettens
K
,
Engelborghs
S
,
De Deyn
PP
,
Van Broeckhoven
C
,
Livingston
G
,
Bass
NJ
,
Gurling
H
,
McQuillin
A
,
Gwilliam
R
,
Deloukas
P
,
Al-Chalabi
A
,
Shaw
CE
,
Tsolaki
M
,
Singleton
AB
,
Guerreiro
R
,
Muhleisen
TW
,
Nothen
MM
,
Moebus
S
,
Jockel
KH
,
Klopp
N
,
Wichmann
HE
,
Carrasquillo
MM
,
Pankratz
VS
,
Younkin
SG
,
Holmans
PA
,
O’Donovan
M
,
Owen
MJ
,
Williams
J
(2009 ) Genome-wide association study identifies variants at CLU and PICALM associated with Alzheimer’s disease . Nat Genet 41 , 1088 –1093 .
13.
Bettens
K
,
Sleegers
K
,
Van Broeckhoven
C
(2013 ) Genetic insights in Alzheimer’s disease . Lancet Neurol 12 , 92 –104 .
14.
Mhatre
SD
,
Tsai
CA
,
Rubin
AJ
,
James
ML
,
Andreasson
KI
(2015 ) Microglial malfunction: The third rail in the development of Alzheimer’s disease . Trends Neurosci 38 , 621 –636 .
15.
Chibnik
LB
,
Shulman
JM
,
Leurgans
SE
,
Schneider
JA
,
Wilson
RS
,
Tran
D
,
Aubin
C
,
Buchman
AS
,
Heward
CB
,
Myers
AJ
,
Hardy
JA
,
Huentelman
MJ
,
Corneveaux
JJ
,
Reiman
EM
,
Evans
DA
,
Bennett
DA
,
De Jager
PL
(2011 ) CR1 is associated with amyloid plaque burden and age-related cognitive decline . Ann Neurol 69 , 560 –569 .
16.
Shulman
JM
,
Chen
K
,
Keenan
BT
,
Chibnik
LB
,
Fleisher
A
,
Thiyyagura
P
,
Roontiva
A
,
McCabe
C
,
Patsopoulos
NA
,
Corneveaux
JJ
,
Yu
L
,
Huentelman
MJ
,
Evans
DA
,
Schneider
JA
,
Reiman
EM
,
De Jager
PL
,
Bennett
DA
(2013 ) Genetic susceptibility for Alzheimer disease neuritic plaque pathology . JAMA Neurol 70 , 1150 –1157 .
17.
Carrasquillo
MM
,
Zou
F
,
Pankratz
VS
,
Wilcox
SL
,
Ma
L
,
Walker
LP
,
Younkin
SG
,
Younkin
CS
,
Younkin
LH
,
Bisceglio
GD
,
Ertekin-Taner
N
,
Crook
JE
,
Dickson
DW
,
Petersen
RC
,
Graff-Radford
NR
,
Younkin
SG
(2009 ) Genetic variation in PCDH11X is associated with susceptibility to late-onset Alzheimer’s disease . Nat Genet 41 , 192 –198 .
18.
Braak
H
,
Braak
E
(1991 ) Neuropathological stageing of Alzheimer-related changes . Acta Neuropathol 82 , 239 –259 .
19.
Thal
DR
,
Rub
U
,
Orantes
M
,
Braak
H
(2002 ) Phases of A beta-deposition in the human brain and its relevance for the development of AD . Neurology 58 , 1791 –1800 .
20.
Shinohara
M
,
Murray
ME
,
Frank
RD
,
Shinohara
M
,
DeTure
M
,
Yamazaki
Y
,
Tachibana
M
,
Atagi
Y
,
Davis
MD
,
Liu
CC
,
Zhao
N
,
Painter
MM
,
Petersen
RC
,
Fryer
JD
,
Crook
JE
,
Dickson
DW
,
Bu
G
,
Kanekiyo
T
(2016 ) Impact of sex and APOE4 on cerebral amyloid angiopathy in Alzheimer’s disease . Acta Neuropathol 132 , 225 –234 .
21.
Verbeeck
C
,
Carrano
A
,
Chakrabarty
P
,
Jankowsky
JL
,
Das
P
(2017 ) Combination of Abeta suppression and innate immune activation in the brain significantly attenuates amyloid plaque deposition . Am J Pathol 187 , 2886 –2894 .
22.
Mattiace
LA
,
Davies
P
,
Dickson
DW
(1990 ) Detection of HLA-DR on microglia in the human brain is a function of both clinical and technical factors . Am J Pathol 136 , 1101 –1114 .
23.
Murray
ME
,
Vemuri
P
,
Preboske
GM
,
Murphy
MC
,
Schweitzer
KJ
,
Parisi
JE
,
Jack
CR
Jr
,
Dickson
DW
(2012 ) A quantitative postmortem MRI design sensitive to white matter hyperintensity differences and their relationship with underlying pathology . J Neuropathol Exp Neurol 71 , 1113 –1122 .
24.
Huynh
TV
,
Davis
AA
,
Ulrich
JD
,
Holtzman
DM
(2017 ) Apolipoprotein E and Alzheimer’s disease: The influence of apolipoprotein E on amyloid-beta and other amyloidogenic proteins . J Lipid Res 58 , 824 –836 .
25.
Yu
L
,
Boyle
PA
,
Nag
S
,
Leurgans
S
,
Buchman
AS
,
Wilson
RS
,
Arvanitakis
Z
,
Farfel
JM
,
De Jager
PL
,
Bennett
DA
,
Schneider
JA
(2015 ) APOE and cerebral amyloid angiopathy in community-dwelling older persons . Neurobiol Aging 36 , 2946 –2953 .
26.
Rannikmae
K
,
Kalaria
RN
,
Greenberg
SM
,
Chui
HC
,
Schmitt
FA
,
Samarasekera
N
,
Al-Shahi Salman
R
,
Sudlow
CL
(2014 ) APOE associations with severe CAA-associated vasculopathic changes: Collaborative meta-analysis . J Neurol Neurosurg Psychiatry 85 , 300 –305 .
27.
Liu
CC
,
Liu
CC
,
Kanekiyo
T
,
Xu
H
,
Bu
G
(2013 ) Apolipoprotein E and Alzheimer disease: Risk, mechanisms and therapy . Nat Rev Neurol 9 , 106 –118 .
28.
Banerjee
G
,
Carare
R
,
Cordonnier
C
,
Greenberg
SM
,
Schneider
JA
,
Smith
EE
,
Buchem
MV
,
Grond
JV
,
Verbeek
MM
,
Werring
DJ
(2017 ) The increasing impact of cerebral amyloid angiopathy: Essential new insights for clinical practice . J Neurol Neurosurg Psychiatry 88 , 982 –994 .
29.
Rosenberg
GA
(2017 ) Extracellular matrix inflammation in vascular cognitive impairment and dementia . Clin Sci (Lond) 131 , 425 –437 .
30.
Gorelick
PB
,
Scuteri
A
,
Black
SE
,
Decarli
C
,
Greenberg
SM
,
Iadecola
C
,
Launer
LJ
,
Laurent
S
,
Lopez
OL
,
Nyenhuis
D
,
Petersen
RC
,
Schneider
JA
,
Tzourio
C
,
Arnett
DK
,
Bennett
DA
,
Chui
HC
,
Higashida
RT
,
Lindquist
R
,
Nilsson
PM
,
Roman
GC
,
Sellke
FW
,
Seshadri
S
, American Heart Association Stroke Council, Council on Epidemiology and Prevention, Council on Cardiovascular Nursing, Council on Cardiovascular Radiology and Intervention, and Council on Cardiovascular Surgery and Anesthesia (2011 ) Vascular contributions to cognitive impairment and dementia: A statement for healthcare professionals from the american heart association/american stroke association . Stroke 42 , 2672 –2713 .
31.
Kapasi
A
,
Schneider
JA
(2016 ) Vascular contributions to cognitive impairment, clinical Alzheimer’s disease, and dementia in older persons . Biochim Biophys Acta 1862 , 878 –886 .