Table 1 Major histocompatibility complex II (MHCII)
First Author | Brain bank | N | Sex | Age | AD genetic risk factors | AD histologically confirmed | Braak stage | C history of neurological or psychiatric disease | PMI (h) | Brain region | Technique | Marker | Results (AD vs C unless otherwise specified) |
|---|---|---|---|---|---|---|---|---|---|---|---|---|---|
Akiyama15 | NR | AD: 9 C: 6 | AD: 77 C: 69 | NR | NR | NR | NR | No neurological disease | All within 2–12 h | Temporal lobe | IHC | HLA-DR | ↑ |
Carpenter19 | NR | AD: 5 C: 5 | AD 4/1 C: 5/0 | AD: 75.4 C: 73.6 | NR | Khachaturian | NR | No history of neurological or systemic diseases affecting the brain | AD: 3.6 C: 2.4 | Grey matter of the middle temporal gyrus | IHC | HLA-DR (LN3) | ↑ Density of cells per mm, staining area and percent of area. Most cells of resting morphology in Cs vs activated in AD (not compared statistically) |
Dal Bianco20 | NR | AD: 9 C: 15 | AD: 0/9 C: 13/2 | AD: 81 C: 70 | NR | Braak, CERAD | AD: IV: 2, V: 4, VI: 3 | No neurological disease or brain lesions | NR | Cortical areas of the temporal lobe, including entorhinal cortex, hippocampus and temporal cortex | Immunocytochemistry | MHCII | ↑ MHCII |
Desai21 | Religious Orders Study | AD:8 C: 7 | AD: 3/5 C: 4/3 | AD: 85.2 C: 79.5 | NR | NIA-Reagan criteria | AD: III–VI | NR | AD: 5.4 C: 15.5 | Hippocampus, midfrontal cortex, locus ceruleus, substantia nigra pars compacta | IHC | HLA-DR-DQ- DP (Cr3/43) | ↑ In the midfrontal cortex, and locus ceruleus ↔ In density of HLA-DR microglia in hippocampus |
Dhawan22 | University of Washington ADRC | NR | NR | NR | NR | NR | NR | NR | NR | Temporal lobe | IHC | HLA-DR | ↑ HLA-DR+ microglia |
Mattiace49 | NR | AD: 15 C: 14 | AD: 2/13 C: 3/11 | AD: 76.6 C: 67.8 (as young as 6 months) | NR | Khachaturian | NR | Depressive psychosis, manic depressive psychosis (n=2), Parkinson’s disease (n=1) | AD: 6.4 C: 6.3 | Midfrontal cortex (BA9) | IHC | HLA-DR, double staining with Leu-M5 (CD11c) | ↑ Activated microglia (morphology) ↑ Proportion of HLA-1DR+ microglia in grey matter ↔ In white matter Results not compared statistically |
Egensperger48 | Institute of Neuropathology of the University of Munich | AD: 20 C: 5 | AD: 5/15 C: NR | AD: 75.9 C: 71.6 | APOE: AD: 3/3: 7 3/4: 10 4/4: 3 C: NR | Braak, CERAD | NR | No neurological or neuropathological disorder | NR | Frontal and temporal cortex | IHC | HLA-DR-DQ-DP (CR3/43) | ↑ Counts and area—Plaque-associated microglia demonstrate activated morphology—Microglia number correlates with neuritic plaques and NFT |
Flanary24 | BSHRI | AD: 4 HPC: 3 C: 4 | AD: 1/3 HPC: 2/1 C: 3/1 | AD: 82.0 HPC: 87.7 C: 81.5 | NR | Yes | NR | NR | AD: 2.4 HPC: 3.1 C: 2.6 | Superior frontal and temporal gyri | IHC | HLA-DR | ↑ Dystrophic microglia in AD vs C, HPC vs C and AD+HPC vs C ↑ HPC vs AD (not clear if statistically significant) |
Giulian25 | NR | AD: 6 C: 5 | NR | NR | NR | CERAD | NR | No neuropathological disorder | NR | Cerebellum, hippocampus, frontal, occipital, parietal cortices and neocortical white matter | IHC, confocal microscopy | HLA-DR | ↑ Hippocampus, frontal, occipital and parietal cortices ↔ Cerebellum, white matter |
Gouw26 | NBB and Vrije University Medical Centre | AD: 11 C: 7 | AD: 3/8 C: 3/4 | AD: 82.6 C: 78.3 | NR | Braak, CERAD | AD: V C: I | All had white matter hyperintensities (small vessel disease), other neurological diseases excluded | AD: 6.1 C: <24 h | Normal white matter and white matter hyperintensities in frontal, parietal and prefrontal lobes | IHC | HLA-DR | ↑ Overall than C ↑ Higher in white matter hyperintensities than normal white matter |
Halliday16 | Dementia clinics at the Repatriation General Hospital Concord and Lidcombe Hospital in Sydney, Australia | AD: 12 C: 10 | NR | AD: 79 C: 77 | APOE: AD: 3/4: 1 C: 3/4: 1 | CERAD, NIA-Reagan Criteria | NR | NR | All <45 h, mean 19 | Anterior cingulate, hippocampal, inferior temporal, parahippocampal and superior frontal regions | IHC | HLA-DR | ↑ In AD vs C ↔ AD patients taking NSAIDs and AD patients not taking NSAIDs |
Hensley27 | NR | AD: 3 C: 3 | Whole sample: AD: 9/13 C: 4/3 | Whole sample: AD: 78.1 C: 79.7 | NR | Khachaturian, Mirra | NR | No history of neurological and/or psychiatric disorders | Whole sample: AD: 4.6 C: 4.4 | Cerebellum, hippocampus, inferior parietal lobule | IHC | HLA-DR | ↑ In all regions |
Hoozemans17 | NBB | Braak stage 0: 5, I–II: 16, III–IV: 10, V–VI: 9 | Braak stage 0: 3/2, I–II: 6/10, III–IV: 0/10, V–VI: 3/6 | Braak stage 0: 62, I–II: 83, III–IV: 89, V–VI: 76 | NR | Braak | 0–VI (not divided into C and AD) | NR | Braak stage 0: 8, I–II: 7.5, III–IV: 6.5, V–VI: 5 | Temporal cortex | IHC | HLA-DR-DQ-DP (CR3/43) | ↑ With increasing Braak NFT or plaque stage (P<0.05 for trend), significant for NFT group V–VI vs O |
Hoozemans28 | Netherlands Brain Bank | AD: 19 C:19 | AD: 3/16 C: 8/11 | AD: 83.5 C: 76.8 | APOE4: AD: 12 C: 8 | Braak | AD: avg IV C: avg I | NR | AD: 5.1 C: 8.6 | Midtemporal cortex | IHC | HLA | ↑, ↑ In AD patients >80 years compared with those >80 years |
Imamura29 | NR | AD: 6 C: 6 | AD: 2/4 C: 2/4 | AD: 65.4 C: 62.8 | NR | Yes | NR | NR | NR | Temporal lobe | IHC | HLA-DR | ↑ |
Itagaki30 | NR | AD: 10 C: 5 | NR | NR | NR | Yes | NR | No neurological complications | All within 2–12 | Mixed: hippocampus and temporal cortex | IHC: semiquantitative scoring of staining | HLA-DR, LCA | ↑ |
Jantaratnotai31 | Kinsmen Laboratory Brain Bank at the University of British Columbia | AD severe: 9 AD mild: 6 C: 9 | NR | AD severe: 74.2 AD mild: 77.7 C: 83 | NR | Braak, NIA-Reagan criteria | NR | No neurological disorders | NR | Medial temporal cortex | IHC | HLA-DR | ↑ |
Kellner18 | NR | AD: 48 C: 48 | AD: 19/29 C: 24/24 | AD: 80.3 C: 77.5 | NR | Braak, CERAD | AD: II–VI (38>4) C: I–III (45=0) | NR | NR | Entorhinal, frontal cortex, temporal cortex | IHC | HLA-DR | ↑ |
Korvatska32 | University of Washington Neuropathology Core Brain Bank | AD (normal TREM2): 6 AD (with TREM2 R47H variant): 7 C: 3 | NR | Whole sample: 84.9 | NR | CERAD | AD: III: 1, V: 4, VI: 1, AD R47H: V: 6, VI: 1, C: 0: 1, I: 1, III: 1 | NR, One C CERAD score A and one B | Whole sample: 4.5 | Frontal lobe: grey and white matter Hippocampus: CA1, hilus, parahippocampal gyrus and white matter | IHC | MHCII | ↑ Staining in hippocampus CA1, hilus, parahippocampal gyrus and white matter ↑ Activated counts in hippocampus white matter |
Lopes33 | BSHRI | AD: 7 young C: 3 Aged C: 7 HPC: 7 | AD: 4/3 young C: 2/3 Aged C: 6/1 HPC: 5/2 | AD: 80.3 young C: 36.3 aged C: 80.0 HPC: 83.4 | NR | Yes | NR | NR | AD: 2.3 young C: 2.8 aged C: 2.5 HPC: 2.90 | Amygdala, hippocampus, superior frontal gyrus, superior, middle, and inferior temporal gyri | IHC and morphometric analyses | HLA-DR | Microglia counts HLA-DR: ↑ vs all other groups Dystrophic microglia HLA-DR: ↑ vs C, ↔ vs HPC |
Lue7 | NR | AD: 6 HPC: 6 C: 6 | AD: 3/3 HPC: 5/1 C: 2/4 | AD: 81 HPC: 78 C: 77 | NR | Markesbery | NR | NR, Cs had minimal AD pathology or sufficient plaques or tangles to qualify for AD diagnosis | AD: 3.2 HPC: 3.2 C: 1.9 | Entorhinal cortex, superior frontal gyrus | IHC | HLA-DR (LN3) | ↑ AD>HPC>C |
Lue34 | BSHRI | AD:11 C:10 | AD: 5/6 C: 4/6 | AD: 80.8C: 80.5 | APOE: AD: 3/4: 4 4/4: 4 C: 3/4: 3 4/4: 1 | Braak, CERAD | AD: IV–VI C: I–III | NR | AD: 2.6 C: 2.3 | Hippocampus, cerebellum, superior frontal gyrun | IHC | HLA-DR (LN3) | ↑ In the hippocampus, parahippocampal gyrus and superior frontal gyrus ↔Cerebellum |
Matsuo35 | NR | AD: 8 C: 5 | NR | NR | NR | Yes | NR | Neurologically normal | All 2–24 | Angular, entorhinal, hippocampus, occipitotemporal cortices | IHC | HLA-DR | ↑ HLA-DR (more intense staining in more severe AD cases) |
McGeer38 | Pathology Department of the University of British Columbia | NR | NR | NR | NR | NR | NR | NR | NR | Hippocampus | PCR | HLA-DR | ↑ |
McGeer36 | Autopsy Service of the University of British Columbia | AD: 9 C: 7 | AD: 5/4 C: NR | AD: 77.2 C: 73.4 | NR | NR | NR | No neurological disorders | All >3 days, most >10 h | Hippocampus, substantia nigra | IHC | HLA-DR | ↑ |
McGeer37 | NR | AD: 6 C: 5 | NR | AD: 78, C: 73 | NR | NR | NR | No neurological disease | All within 2-12 | Hippocampus | IHC | HLA-DR | ↑ |
Minett56 | Medical Research Council Cognitive Function and Ageing Study—six centres in UK | AD: 83 C: 130 | AD: 30/53 C: 64/66 | AD: 89 C: 84 | NR | CERAD | NR | NR | NR | Middle frontal gyrus | IHC | HLA-DR | ↔ |
Narayan39 | Neurological Foundation of New Zealand Human Brain Bank (Centre for Brain Research, University of Auckland) | AD: 14 C: 17 | AD: 6/8 C: 10/7 | AD: 74.1 C: 58.9 | NR | Braak or CERAD | NR | Neurologically normal, four have high plaque load | AD: 16.7 C: 16.7 | Inferior temporal gyrus | IHC | HLA-DP-DQ-DR | ↑ HLA-DP, DQ, DR-positive cells correlate with Iba1-positive cells in C but not AD |
Overmyer52 | Kuopio University Hospital | AD: 73 C: 22 | AD: 12/61, C: 12/10 | AD: 84 C: 78 | APOE4 carriers: AD: 31 C: 7 | CERAD Patients with possible AD and vascular dementia included | NR | NR—55% demonstrated plaque and tangles, 32% enough for diagnosis of possible AD | All within 48 | Grey and white matter of frontal, temporal and parietal cortices | IHC | HLA-DR | ↔ With dementia diagnosis (trend) ↑ With CERAD in grey matter ↔ White matter (counts and area) ↔ With plaque burden but ↑ correlation with NFT |
Parachikova40 | Institute for Brain Aging and Dementia Tissue Repository, and the BSHRI | AD: 10 HPC: 10 C: 4 | AD: 6/4 HPC: 4/6 C: 3/1 | AD: 85.3 HPC: 86.6 C: 76.3 | NR | Braak | AD: IV–V HPC: 1–V | NR | AD: 2.6 HPC: 2.8 C: 3.0 | Hippocampus and prefrontal cortex (gene chip only) | Gene chip, western, IHC | GeneChip: MHCII western: HLA-DR- DQ-DP IHC: CD4/43 | GeneChip and western: ↑ vs HPC+C (pooled) IHC: ↑ MHCII (not quantified) |
Pugliese53 | Neurological Tissue Bank (Serveis Cientifico-Tècnics), Universitat de Barcelona | AD: 7 C: 3 | AD: 2/5 C: 1/2 | AD: 84.0 C: 63.3 | NR | Braak, Newell Criteria | AD: II: 3, V: 1, VI: 3 | NR | AD: 8.8 C: 5.1 | Subventricular zone of the lateral ventricle | IHC | HLA-DR | ↔ Number of microglia ↑ Activated microglia |
Rezaie41 | MRC London Neurodegenerative Diseases Brain Bank | AD: 10 C: 10 | AD: 4/6 C:7/3 | AD: 79.3 C: 70.2 | Not reported | CERAD | NR | No history of neurological disease or neuropathology | AD: 20.9, C: 43.2 | Frontal blocks included agranular- intermediate frontal cortex (BA 6/8), cingulate cortex (BA 24/32) Occipital blocks included the calcarine sulcus (BA 17) and striate cortex) | IHC | HLA-DR-DP-DQ (CR3/43) | ↑ In frontal white matter, occipital white matter, plaque associated frontal grey matter, plaque associated occipital grey matter ↔ In MHCII in frontal grey matter, or occipital grey matter |
Serrano-Pozo54 | Massachusetts ADRC Brain Bank | AD: 40 C: 32 | AD: 14/26 C: 13/19 | AD: 77.3 C: 81.3 | APOE4: AD: 21/40 C: 5/27 | NIA—Reagan criteria | NR | No clinical history of neurological disorders and did not meet the pathological criteria for any neurodegenerative disease | AD: 14.1 C: 17.9 | Temporal polar association cortex (BA38) | IHC, stereology | HLA-DR-DQ-DP | ↔ Total microglia ↓Iba1+/MHC2- microglia ↑Iba1-/MHC2+ microglia ↔Iba1+/MHC2+ microglia ↑ Iba1+/MHC2+ microglia in APOE4+ ↔with microglia by genotype |
Shepherd42 | Collected brains from a regional brain donor program for neurodegenerative diseases in 1993 | AD:10 C: 11 | NR | AD:76 C: 71 | NR | CERAD | AD: V or VI | No history of neurological disease or neuropathology | AD: 16 C: 21 | Cortex and hippocampus (grey and white matter) | IHC | HLA-DR | ↑ White and grey matter |
Szpak23 | NR | AD: 18 (7 had Lewy body variant of AD) C: 6 | NR | Whole sample: 63–86 years old | NR | CERAD | NR | No neuropathological abnormality | NR | Cortical layers of limbic, cingulate cortex and temporal association cortex | IHC | CR 3/43 clone HLA-DP-DQ-DR | ↑ |
Thal43 | Pathological Institute of the University of Leipzig and University of Frankfurt | 159 participants (68 non-demented, 24 and 19 in GDS scores 6 and 7) | NR | Ages 46–93 (most between 71 and 90) | NR | Braak | Whole sample: 0: 23, I: 23, II: 42, III: 36, IV: 16, V: 13, VI: 6 | No confounding neurological diagnosis | All within 12–72 | Entorhinal cortex, hippocampus (CA1, CA4), occipital region (BA 17), temporal cortex | IHC | HLA-DR | ↑ |
Valente55 | Hospital Clinic-University of Barcelona | AD: 7 AD with diabetes: 7 C: 6 | AD: 2/5 AD with diabetes: 5/2 C:3/3 | AD: 83.9 AD with Diabetes: 73.0 C: 70.0 | NR | Braak | AD: VI AD with diabetes: VI | NR | AD: 8.9 AD with diabetes: 11.5 C: 9.6 | Hippocampus | IHC | HLA | ↔ AD vs C ↑ AD+diabetes vs C |
Van Everbroeck44 | NR | AD: 10 C: 10 | NR | NR | NR | Braak | AD: at least III–IV C: 0, Av or A 1 | Some had protein deposition and some had core containing plaques (numbers not given) | NR | Cerebellum, hippocampus (CA1, CA4, subiculum), frontal, temporal and occipital neocortices | IHC | HLA-DR | ↑ In grey matter and hippocampus ↔ In white matter and cerebellum |
Vehmas45 | Johns Hopkins University ADRC and Baltimore Longitudinal Study of Aging | AD: 9 HPC: 15 C: 11 | AD: 3/6 HPC: 10/5 C: 11/0 | AD: 83.2 HPC: 86.3C: 81.7 | NR | Braak, CERAD | AD: II–V HPC: I–IV C: 0–III | NR, free of plaque | NR | Mixed: middle frontal gyrus, middle and superior temporal gyrus | IHC | HLA-DR | ↑ Than C ↔ high pathology C |
Verwer50 | NBB | AD: 14 C: 7 | AD: 4/10 C: 2/5 | AD: 83.9 C: 79.0 | NR | Braak | AD: IV: 3 V: 8 VI: 2 NA: 1 C: 0: 3 I: 1 II: 1 III: 1 NA: 1 | No neurological causes of death | AD: 4.6 C: 4.6 | Neocortex | IHC | HLA-DR-DQ-DP | ↔ P=0.08 |
Wilcock46 | Irvine ADRC, the Maryland Developmental Disorders Brain Bank and the University of Kentucky Alzheimer's Disease Center. | AD: 9 C: 9 | IHC: AD: 6/2 C: 3/6 qPCR+western: AD: 6/4 C: 12/4 | IHC: AD: 81.3, C: 81.6 qPCR+western: AD: 80 C: 81.6 | NR | NR | NR | NR | IHC: AD: 5.5, C: 3.3 qPCR+western: AD: 6.8 C: 3.3 | Frontal cortex | IHC for HLA-DR staining, RT-qPCR and western for expression of M2 and M1 markers | HLA-DR M1 markers: IL-1B, IL-6, IL-12, TNF-α M2a markers: CH13L1, IL1Ra, IL-10, MRc1, M2b markers: CD86, FCGR1B M2c markers: TGFB | ↑ HLA-DR in AD vs C ↑ HLA-DR in AD vs. AD+DS (in grey and white matter)—Pattern of increases in both M1 and M2 markers: IL6, IL-12, IL-10, CHI3L1, TGFB1 in AD vs C |
Wojtera51 | NR | AD: 4 C: 2 | NR | NR | NR | NIA-Reagan criteria | NR | NR | NR | Mixed: cerebellum, cerebral cortex | IHC | HLA-DR | ↔, ↔ in HLA-DR/CD68 ratio between AD and C (activation) |
Xiang47 | ADRC of the Mount Sinai School of Medicine | AD: 26 with clinical dementia rating 0.5–5, 6 rated 5 (very severe) C: 5 | AD: 7/19 C: 0/5 | AD: 88.7 C: 83.2 | NR | CERAD | NR | NR | AD: 4.2 C: 4.2 | Entorhinal cortex and dorsal hippocampus (CA1 pyramidal cell layer, DG granule cell layer and upper molecular layer) | IHC | HLA-DR | Entorhinal cortex: ↑ In grey and white matter at CDR 5, in grey matter only at CDR 2 ↔ For CDR scores of 0.5 to 1 vs 0 Hippocampus: ↑ In all regions for CDR >2 vs 0, for CA1 pyramidal layer and upper molecular layer for CDR 1 and for the upper molecular layer only for CDR 0.5—HLA-DR score correlates with plaque and tangle scores in various regions |
