Table 3 Summary of AD-relevant effects based on candidate imaging biomarkers and association studies
From: A review of brain imaging biomarker genomics in Alzheimer’s disease: implementation and perspectives
Author | Dataset | Genes included | Model | Methods | Imaging phenotypes | Neural location | Results |
|---|---|---|---|---|---|---|---|
Pathophysiological pathway: Brain Aβ accumulation (Aβ PET) | |||||||
2009 Drzezga et al. [70] | 32 AD | APOE | Univariate imaging—Univariate genetic | Candidate-based association | Aβ plaque deposition | Bilateral temporoparietal, frontal cortex | The ɛ4-positive patients with AD had higher levels of Aβ plaque deposition compared to age-matched ɛ4-negative patients with similar levels of cognitive impairment and brain atrophy |
2009 Reiman et al. [71] | 28 AD | APOE | Univariate imaging—Univariate genetic | Candidate-based association | PiB DVR fibrillar Aβ burden | Frontal, temporal, parietal, posterior cingulate-precuneus,basal ganglia ROIs | Fibrillar Aβ burden in cognitively normal older people was associated with APOE ɛ4 gene dose |
2011 Chibnik et al. [72] | n = 1666 | CR1, CLU, PICALM | Univariate imaging—Multivariate genetic | Candidate-based association | Pathology score of neuritic plaques | Whole brain cortex | Common variation at the CR1 locus had a broad impact on cognition and this effect was mediated by an individual’s amyloid plaque burden |
2012 Thambisetty et al. [73] | 57 HC | CR1, APOE | Univariate imaging—Multivariate genetic | Candidate-based association | PIB DVR | Orbitofrontal, prefrontal, superior frontal, posterior cingulate, lateral temporal, occipital cortices | There was a greater variability in brain amyloid deposition in the CLU rs3818361 noncarrier group relative to risk carriers, an effect explained partly by APOE genotype |
2012 Swaminathan et al. [74] | ADNI (22 HC, 25 AD, 56 MCI) | 15 amyloid candidate genes (DNCR24, NCSTN, SOAT1, BCHE, etc.) | Multivariate imaging—Multivariate genetic | Candidate-based association | Normalized PiB uptake value | Anterior cingulate, frontal cortex, parietal cortex, precuneus | The minor allele of an intronic SNP within DHCR24 was identified and associated with a lower average PiB uptake, and non-carriers of the minor allele had higher PiB uptake in frontal regions compared to carriers |
2013 Shulman et al. [75] | Multiple cohorts (n = 725/ 56/58) | ABCA7, MS4A6A/MS4A4E, EPHA1, CD3, CR1, CD2AP, CLU, BIN1, PICALM | Univariate imaging—Multivariate genetic | Candidate-based association | Pathology score of neuritic plaques | Midfrontal, middle temporal, inferior parietal, entorhinal, hippocampal cortex | Besides the previously reported APOE and CR1 loci, ABCA7 (rs3764650) and CD2AP (rs9349407) were associated with neuritic plaque burden |
2013 Shulman et al. [75] | Multiple cohorts (n = 725/ 56/58) | Genome-wide genotyping | Univariate imaging—Multivariate genetic | GWAS | Pathology score of neuritic plaques | Midfrontal, middle temporal, inferior parietal, entorhinal, hippocampal cortex | The finding discovered a novel variant near the amyloid precursor protein gene (APP, rs2829887) that is associated with neuritic plaques |
2013 Hohman et al. [76] | ADNI (174 HC, 64 AD, 292 MCI) | PICALM, BIN1, CR1, CLU, MS4A6A, EPHA1, CD33, ABCA7, CD2AP | Multivariate imaging—Univariate genetic | Candidate-based association | Aβ PET SUVR | Cingulate, frontal, temporal, lateral parietal cortices | Two SNP-SNP interactions (BIN1 (rs7561528, rs744373) × PICALM (rs7851179)) reached significance when correcting for multiple comparisons |
2014 Lehmann et al. [77] | 52 AD | APOE | Multivariate imaging—Univariate genetic | Candidate-based association | PIB DVR, FDG SUVR | Frontal, lateral parietal/temporal, occipital cortices, precuneus, posterior cingulate gyrus, hippocampus | APOE ε4+ AD patients showed lower global amyloid burden and greater medial temporal hypometabolism compared with matched APOE ε4- patients |
2014 Ramanan et al. [78] | ADNI (n = 555) | Genome-wide genotyping | Univariate imaging—Multivariate genetic | GWAS | Aβ PET brain amyloid burden | Frontal, parietal, temporal, limbic, occipital lobes | A novel association with higher rates of amyloid load independent from APOE ε4 status was identified in IL1RAP (rs12053868-G) |
2018 Apostolova et al. [17] | ADNI (322 HC, 159 AD, 496 MCI) | The top 20 AD risk variants (ABCA7,CLU, SORL1, DSG2, etc.) | Univariate imaging—Multivariate genetic | Candidate-based association | Florbetapir mean SUVR | Frontal, anterior–posterior cingulate, lateral-parietal, lateral-temporal cortices | ABCA7 gene had the strongest association with amyloid deposition, after APOE ε4. FERMT2 gene had a stage-dependent association with brain amyloidosis |
2018 Scelsi et al. [79] | ADNI (226 HC, 125 AD, 92 SMC, 501 MCI) | Genome-wide genotyping | Multivariate imaging—Multivariate genetic | PGS-based association | Aβ PET SUVR, HV | Hippocampus | The finding identified a genome-wide significant locus implicating LCORL rs6850306. The possession of a minor allele at rs6850306 was protective against conversion from MCI to AD |
2019 Li et al. [80] | ADNI (155 HC, 125 AD, 72 SMC, 422 MCI) | Genome-wide genotyping | Univariate imaging—Multivariate genetic | GWAS | Florbetapir composite SUVR | Frontal, anterior/ posterior cingulate, lateral parietal/ temporal regions | The study identified 24 consensus modules enriched by robust genetic signals in a genome wide association analysis, including a few novel genes (ABL1, ABLIM2) |
2021 Kim et al [81] | Korean cohort (n = 1474) | Genome- wide genotyping | Univariate imaging—multivariate genetic | GWAS | Aβ PET SUVR | Whole brain | In addition to APOE, nine SNPs of FGL2 gene on chromosome 7 were identified, which were associated with a decreased risk of Aβ positivity at a genome-wide suggestive level |
2021 Liu et al. [82] | Multiple cohorts (n = 767/ 1373) | Summary statistics | Multivariate imaging—Multivariate genetic | PGS-based association | Aβ PET SUVR, HV, entorhinal, middle temporal gyrus volumes | Whole brain cortex, Hippocampus, entorhinal cortex | PGS was associated with the increased cortical amyloid burdens (PiB-PET and AV45-PET), but decreased hippocampus and entorhinal cortex volumes |
Pathophysiological pathway: Tau hyperphosphorylation (Tau PET) | |||||||
2016 Smith et al. [83] | 4 HC, 3 AD | MAPT | Univariate imaging—Univariate genetic | Candidate-based association | Tau PET SUVR, GM volume | Global AD pathology | 18F-AV1451 tau PET imaging correlated with tau pathology in MAPT mutation carriers |
2018 Mattsson et al. [84] | 65 Aβ + patients | APOE | Univariate imaging—Univariate genetic | Candidate-based association | Tau PET SUVR, GM volume | Parietal, entorhinal cortex | APOE ε4-negative patients had greater tau load and reduced cortical thickness, with the most pronounced effects for both in the parietal cortex |
2019 Shen et al. [85] | ADNI (90 HC) | MAPT rs242557 | Univariate imaging—Univariate genetic | Candidate-based association | Tau PET SUVR | Hippocampus | The finding confirmed the significant correlation of MAPT rs242557 risk variant with increased hippocampus tau burden in non-demented elders |
2019 Therriaultet al. [86] | Multiple cohorts (281 HC, 75 AD, 133 MCI) | APOE | Univariate imaging—Univariate genetic | Candidate-based association | Tau PET SUVR | Entorhinal cortex, hippocampus | The elevated risk of developing dementia conferred by APOE ε4 genotype involved mechanisms associated with both Aβ and tau aggregation |
2019 Franzmeier et al. [87] | ADNI (49 HC, 40 MCI) | BIN1 rs744373 | Univariate imaging—Univariate genetic | Candidate-based association | Global/stage- specific Tau PET SUVR | Brain Braak stage II–VI | BIN1 rs744373 SNP was associated with increased tau but not Aβ pathology, that is alterations in BIN1 may contribute to memory deficits via increased tau pathology |
2020 Yan et al. [88] | ADNI (57 AD) | APOE | Multivariate imaging—Univariate genetic | Candidate-based association | Tau PET SUVR, GM volume | Temporal, parietal, posterior cingulate, entorhinal cortex, amygdala, parahippocampal gyrus, etc | Among elderly individuals with AD, sex modified the effects of the APOE ε4 allele on region-specific tau deposition and GM volume |
2020 Neitzel et al. [89] | Multiple cohorts (n = 493) | APOE | Univariate imaging—Univariate genetic | Candidate-based association | Baseline Tau PET SUVR, annual change rates | MTL (entorhinal cortex, parahippocampus) | There was an amyloid-independent association between APOE ε4 and elevated tau PET specifically in medial temporal regions |
2021 Franzmeier et al. [90] | Multiple cohorts (n = 216) | BIN1 rs744373 | Univariate imaging—Univariate genetic | Candidate-based association | ROI Tau PET SUVR, annual change rates | Whole brain | BIN1-associated AD risk was potentially driven by accelerated tau accumulation in the face of Aβ |
2021 Neitzel et al. [91] | ADNI (347 HC, 48 AD, 156 MCI) | Klotho-VShet | Multivariate imaging—Univariate genetic | Candidate-based association | Global/ROI tau/Aβ PET SUVR | Whole brain; bilateral inferior temporal gyri | Findings proved a protective role of KL-VShet against amyloid-related tau pathology and tau-related memory impairments in elderly humans at risk of AD dementia |
2021 Sun et al. [92] | ADNI (n = 158) | Summary statistics | Multivariate imaging—Multivariate genetic | PGS-based association | Global tau SUVR for Braak stage ROIs | Whole brain | The association between PGS and tau pathology was significant when APOE was excluded, even among females |
Pathophysiological pathway: Neurodegeneration (sMRI) | |||||||
2007 Lunetta et al. [93] | 449 HC, 366 AD | APOE | Univariate imaging—Univariate genetic | Candidate-based association | Cerebral atrophy, MTA, WMH, CVR | Cerebral atrophy, MTA, WMH | A substantial proportion of the additive genetic variation in MRI traits was explained by other genes, and MRI traits were heritable |
2009 Potkin et al. [94] | ADNI (n = 381) | Genome-wide genotyping | Univariate imaging—Multivariate genetic | GWAS | GM voxels of hippocampal regions | The right and left hippocampal regions | The study identified candidate risk genes (EFNA5, CAND1, MAGI2, ARSB, and PRUNE2) for sporadic AD, involved in the regulation of protein degradation, apoptosis, neuronal loss and neurodevelopment |
2010 Wolk et al. [95] | ADNI (91 AD) | APOE | Univariate imaging—Univariate genetic | Candidate-based association | Cortical thickness, HV | Hippocampus, superior frontal gyrus,angular gyrus, MTL, precentral gyrus | The presence or absence of the APOE ε4 allele influenced the cognitive and anatomic phenotypic expression of AD in a dissociable manner |
2010 Biffi et al. [96] | Multiple cohorts (215 HC, 168 AD, 357 MCI) | GWAS-validated and GWAS-promising novel AD loci | Univariate imaging—Multivariate genetic | Candidate-based association | HV, amygdala volume, WM lesion volume, parahippocampal, entorhinal, temporal pole cortex thickness | Hippocampal, parahippocampal gyrus, amygdala, entorhinal, temporal pole cortex | Loci associated with AD influenced neuroimaging correlates of this disease. And neuroimaging analysis identified 2 additional loci (BIN1 and CNTN5) of high interest for further study |
2013 Meda et al. [97] | ADNI (156 HC, 140 AD, 281 MCI) | 151 million SNPs within 212 KEGG pathways | Univariate imaging—Multivariate genetic | Candidate-based association | 12-month regional structural atrophy rates | Hippocampus, entorhinal cortex | A total of 109 SNP-SNP interactions were associated with right hippocampus atrophy, and 125 were associated with right entorhinal cortex atrophy |
2013 Jahanshad et al. [98] | 366 HC | SPON1 gene | multivariate imaging—multivariate genetic | Candidate-based association | Heritable brain connections | Maps of the brain’s structural connectome | Rs2618516 was shown to affect brain structure in an elderly population with varying degrees of dementia |
2014 Morgen et al. [99] | 165 AD | PICALM, APOE | Univariate imaging—Multivariate genetic | Candidate-based association | GM volume | Prefrontal cortex | There was a synergistic adverse effect of homozygosity for the PICALM risk allele G in rs3851179 and APOE ε4 on prefrontal volume and performance on the Trail Making Test A, which is sensitive to processing speed and working memory function |
2014 Hohman et al. [100] | ADNI (388 HC, 228 AD, 764 MCI) | Genome-wide genotyping | Univariate imaging—multivariate genetic | GWAS | Baseline ICV | Whole brain | One intergenic SNP rs4866650 and one SNP rs7849530 within the SPTLC1 gene modified the association between amyloid positivity and neurodegeneration |
2015 Chauhan et al. [101] | 8175– 11,550 HC | 24 AD candidate loci (APOE, BIN1,HLA-DRB1,CR33,CR1,CLU, ABCA7, SORL1, etc.) | Multivariate imaging—Multivariate genetic | Meta- analysis | ICV, TBV, HV, WMH | Hippocampus | APOE rs2075650 was associated with smaller HV and CD33 rs3865444 with smaller ICV. There was associations of HLA-DRB1 with TBV and BIN1 with HV. A weighted AD genetic risk score was associated with smaller HV, even after excluding APOE locus |
2015 Desikan et al. [102] | 9386 HC, 6409 AD | Summary statistics | Univariate imaging—Multivariate genetic | PGS-based association | Longitudinal volume loss in MTL, entorhinal cortex, hippocampus | MTL, hippocampus, entorhinal cortex | Polygenic hazard scores predicted in vivo markers (volume loss in MTL, hippocampus, entorhinal cortex) |
2016 Yang et al. [103] | ADNI (194 HC, 168 AD, 337 MCI) | PICALM, CLU | Univariate imaging—Multivariate genetic | Candidate-based association | HV, hippocampal shape | Hippocampus | Common LOAD risk loci in CLU and PICALM exhibited significant interaction effects on hippocampal morphology in both young healthy adults and elderly individuals |
2016 Ramirez et al. [104] | 50 HC, 98 MCI | the top 10 AD non-APOE genes | Univariate imaging—Multivariate genetic | Candidate-based association | Cortical thickness, hippocampal radial distance | Hippocampus | MS4A6A rs610932 and ABCA7 rs3764650 demonstrated significant associations with cortical and hippocampal atrophy |
2016 Habes et al. [105] | n = 1472 | APOE | Univariate imaging—Univariate genetic | Candidate-based association | AD-related GM volume | Lateral frontal, lateral temporal, medial frontal cortex, hippocampus | Measurable APOE-related brain atrophy did not occur in early adulthood and midlife and such atrophy may only occur more proximal to the onset of clinical symptoms of dementia |
2016 Foley et al. [106] | n = 272 | APOE, summary statistics | Multivariate imaging—Multivariat genetic | PGS-based association | HV | Hippocampus | A significant association was found between AD PGS and left HV, with higher risk associated with lower left HV, although excluding the APOE gene |
2016 Harrison et al. [107] | n = 66 | Summary statistics | Univariate imaging—Multivariate genetic | PGS-based association | Thickness in hippocampal subregions | Hippocampus, entorhinal cortex | Polygenic AD risk scores may be especially sensitive to structural change over time in regions affected early in AD, like the hippocampus and adjacent entorhinal cortex |
2017 Wang et al. [108] | ADNI (281 HC, 48 AD, 483 MCI) | 12 SNPs in HLA | Univariate imaging—Multivariate genetic | Candidate-based association | Structural volumes | Hippocampus, parahippocampus, posterior cingulate, middle temporal, etc | TNF-α SNPs at rs2534672, rs2395488, HFE rs1800562 and RAGE rs2070600 were correlated with various structures on MRI |
2017 Wang et al. [109] | ADNI (281 HC, 48 AD, 483 MCI) | HLA-A2 | Univariate imaging—Univariate genetic | Candidate-based association | Hippocampal/ parahippocampal/ amygdala/ middle temporal/ posterior cingulate volume, entorhinal cortex thickness | Hippocampus, parahippocampus, posterior cingulate, precuneus, middle temporal, entorhinal cortex, amygdala | HLA-A2 in Caucasians contributed to the risk of AD by modulating the alteration of HV and HLA-A gene variants appeared to play a role in altering AD-related brain structures on MRI |
2017 Xiao et al. [110] | n = 231 | APOE, summary statistics | Univariate imaging—Multivariate genetic | PGS-based association | Activation in hippocampus ROI | Hippocampus | There was a cumulative deleterious effect of LOAD risk genes on hippocampal function even in healthy volunteers |
2018 Axelrud et al. [111] | Multiple cohorts | Summary statistics | Univariate imaging—Multivariate genetic | PGS-based association | HV | Left and right hippocampus | Genetic risk for AD may affect early-life cognition and HV |
2018 Li et al. [112] | Multiple cohorts (n = 683) | Summary statistics | Univariate imaging—Multivariate genetic | PGS-based association | GM volume | Precuneal cortex | An elevated AD PGR was associated with a smaller precuneal volume, and the effect remained after excluding the APOE genotype |
2019 Lancaster et al. [113] | Multiple cohorts | AD SNPs within a microglia-mediated immunity network | Univariate imaging—Multivariate genetic | PGS-based association | HV | Hippocampus | The observations suggested that the relationship between AD and HV was partially explained by genes within an AD-linked microglia-mediated immunity network |
2020 Lyall et al. [114] | UK Biobank (n = 8539) | APOE | Multivariate imaging—Univariate genetic | Candidate-based association | FA, MD, left/right HV, total GM, total WM and log WMHV | Left or right Hippocampus, total GM and WM | There was association between APOE ε4 and WMHV, but not TBV or WM integrity |
2020 Cong et al. [115] | ADNI (41 HC, 26 AD, 67 MCI) | Genome- wide genotyping | Univariate imaging—Multivariate genetic | GWAS | 14 MTL substructures | MTL | A novel association with right Brodmann area 36 volume was discovered in an ERC1 SNP rs2968869. And rs2968869 was associated with GM density and glucose metabolism in the right hippocampus and disease status |
2020 De Marco et al. [116] | ADNI (317 HC, 562 MCI) | Summary statistics | Univariate imaging—Multivariate genetic | PGS-based association | GM and WM volumes | Whole brain | PGS predicted volume in sensorimotor regions in ε3ε3 Aβ + participants. The link between polygenic hazard and neurocognitive variables varies depending on APOE ε4 allele status |
2020 van der Meer et al. [117] | Multiple cohorts (n = 21,297) | Genome-wide genotyping | Univariate imaging—multivariate genetic | GWAS | Hippocampal and subfield volumes | Hippocampus | GWAS of whole HV identified eight whole-genome significant loci, including three novel loci, namely, TFDP2 SNP rs7630893, FAM175B rs2303611, and PARP11 rs1419859 |
2021 Foo et al. [118] | UK Biobank (n = 17,161) | Summary statistics | Univariate imaging—Multivariate genetic | PGS-based association | Volumes in hippocampal subregions | Multiple hippocampal regions | PGSAD had differential effects on the hippocampal subfield volumes |
2021 Tank et al. [119] | UK Biobank (n = 32,790) | APOE, summary statistics | Univariate imaging—Multivariate genetic | PGS-based association | Volumes of total GM, WM, WMH, whole brain, left/ right hippocampus | Left hippocampus | LOAD-PGR was associated with smaller HV and aspects of cognitive ability in healthy adults and could supplement APOE status in risk stratification of cognitive impairment/LOAD |
Pathophysiological pathway: Neurodegeneration (FDG PET) | |||||||
2010 Corneveaux et al. [120] | Multiple cohort (n = 1728) | KIBRA rs17070145 | Univariate imaging—Univariate genetic | Candidate-based association | Glucose metabolism | Entorhinal cortex, hippocampus, middle temporal gyrus, posterior cingulate cortex, superior frontal gyrus, primary visual cortex | Non-carriers of the KIBRA rs17070145-T had increased risk of LOAD in an association study of 702 neuropathologically verified expired subjects and in a combined analysis of 1026 additional living and expired subjects |
2014 Lehmann et al. [77] | 52 AD | APOE | Multivariate imaging—Univariate genetic | Candidate-based association | PIB DVR, FDG SUVR | Lateral temporoparietal cortex, precuneus, posterior cingulate cortex, middle frontal gyrus, etc | APOE ε4+ AD patients showed lower global amyloid burden and greater medial temporal hypometabolism compared with matched APOE ε4- patients |
2018 Miller et al. [121] | ADNI (n = 695) | EXOC3L4 | Univariate imaging—Multivariate genetic | WGS | Global cortical glucose metabolism | Whole brain cortex | EXOC3L4 gene, was identified as significantly associated with global cortical glucose metabolism. Three loci that may affect splicing within EXOC3L4 helped to the association |
2018 Kong et al. [122] | ADNI (37 HC, 59 AD, 126 MCI) | Genome-wide genotyping | Univariate imaging—Univariate genetic | GWAS | ROI glucose metabolic uptake | Left and right angular, temporal gyri, bilateral posterior cingulate | A genome-wide significant SNP rs12444565 in the RBFOX1, four suggestive loci (rs235141, rs79037, rs12526331 and rs12529764) were associated with 18F-FDG |
2020 Seo et al. [123] | KBASE (336 HC, 84 AD, 136 MCI) | 132 AD candidate genes | Multivariate imaging—Multivariate genetic | Candidate-based association | Aβ deposition, region cerebral glucose metabolism/ cortical thickness, HV | AD-signature cortical, hippocampus | Several novel loci for common variants were associated with AD pathology (PIWIL1, NME8 and PSEN2, PSEN1, CASS4). Cases carrying rare variants in LPL, FERMT2, NFAT5, DSG2, and ITPR1 displayed associations with the neuroimaging features |
2021 Wang et al. [124] | ADNI (n = 586) | Genome- wide genotyping | Univariate imaging—Multivariate genetic | GWAS | Glucose metabolic uptake in ROIs | Left angular gyri, bilateral posterior cingulate gyrus, right /left middle/inferior temporal gyrus | Two genome-wide significant SNPs (rs4819351, rs13387360) in AGPAT3 and LOC101928196 served as protective sites to regulate the decline of glucose metabolism |
2019 Li et al. [80] | ADNI (37 HC, 86 AD, 188 MCI) | Genome-wide genotyping | Univariate imaging—Multivariate genetic | GWAS | Glucose metabolic uptake in ROIs | Frontal, lateral parietal, lateral temporal regions, anterior/posterior cingulate regions | Indirect genetic effects on certain chemical compound or protein translocation were reflected in the PET scans and may be associated with AD |
Pathophysiological pathway: Neurodegeneration (fMRI) | |||||||
2000 Bookheimer et al. [125] | 30 HC | APOE | Univariate imaging—Univariate genetic | Candidate-based association | Patterns of brain activation | Left hippocampal, parietal, prefrontal cortices | Both the magnitude and the extent of brain activation during memory-activation tasks in regions of the left hippocampal, parietal, and prefrontal regions, were greater among the carriers of the APOE ε4 allele than among the carriers of the APOE ɛ3 allele |
2011 Erk et al. [126] | 109 HC | CLU rs11136000 | Univariate imaging—Univariate genetic | Candidate-based association | FC | Hippocampus, prefrontal cortex | Healthy carriers of the variant exhibited altered coupling between hippocampus and prefrontal cortex during memory processing |
2011 Lancaster et al. [127] | 43 HC | CLU rs11136000 | Univariate imaging—Univariate genetic | Candidate-based association | Working memory values based on brain activity | Frontal, posterior cingulate cortex, hippocampus | Participants with the CLU risk genotype had higher activity than participants with the protective allele in frontal and posterior cingulate cortex and hippocampus |
2014 Green et al. [128] | 131 HC | APOE, CLU | Univariate imaging—Multivariate genetic | Candidate-based association | ROI BOLD signal change | Hippocampus, MTL | APOE ε4 and CLU-C had an additive effect on brain activity, that is, increased combined genetic risk was associated with decreased brain activity during executive attention, including in the MTL |
2014 Guerini et al. [129] | n = 1680 | SNAP-25 SNP | Univariate imaging—Univariate genetic | Candidate-based association | FMRI task accuracy | Cingulate cortex, frontal, temporoparietal cortices | FMRI analyses indicated that SNAP-25 genotypes correlated with a significantly decreased brain activity in the cingulate cortex and in the frontal (middle, superior gyri) and the temporo-parietal (angular gyrus) area |
2014 Liu et al. [130] | Han Chinese (21 HC, 46 MCI) | TOMM40 rs157581 | Univariate imaging—Univariate genetic | Candidate-based association | ALFF | Bilateral superior frontal gyrus, bilateral lingual gyrus, right calcarine sulcus, left cerebellar | TOMM40 rs157581 polymorphism may modulate regional spontaneous brain activity and relate to the progression of aMCI |
2015 Lancaster et al. [131] | 85 HC | CLU rs11136000 | Multivariate imaging—Univariate genetic | Candidate-based association | Working memory task accuracy, GM density | Hippocampus, prefrontal, limbic areas | Young individuals with the CLU rs11136000-C had higher activation levels in prefrontal and limbic areas during a working memory task. And there were subtle reductions in GM in the right hippocampal formation in carriers of the risk variant |
2015 Zhang et al. [132] | 360 HC | BIN1 rs744373 | Multivariate imaging—Univariate genetic | Candidate-based association | Working memory, GM volume, FC | Whole brain | Healthy homozygous carriers of the rs744373 risk allele exhibited worse high-load working memory performance, larger HV and lower FC between the bilateral hippocampus and right dorsolateral prefrontal cortex |
2017 Sun et al. [133] | 32 HC, 32 MCI | PICALM rs3851179 | Univariate imaging—Univariate genetic | Candidate-based association | FC | DMN | The PICALM rs3851179 polymorphism significantly affected the DMN network in MCI |
2017 Xiao et al. [110] | n = 231 | APOE, summary statistics | Univariate imaging—Multivariate genetic | PGS-based association | Activation in hippocampus ROI | Hippocampus | There was a cumulative deleterious effect of LOAD risk genes on hippocampal function even in healthy volunteers |
2017 Su et al. [134] | 131 HC, 87 MCI | APOE, summary statistics | Univariate imaging—Multivariate genetic | PGS-based association | FC in ROIs of DMN | Temporal cortex | The pMCIs exhibited tremendous decrements in DMN connections that were partially determined by the AD-related risk alleles |
2018 Korthauer et al. [135] | 76 HC | APOE | Multivariate imaging—Univariate genetic | Candidate-based association | Graph analysis of network efficiency | Whole brain functional-structural network | ε4 carriers had significantly lower global and local efficiency of the integrated resting-state structural connectome compared to non-carriers |
2021 Franzmeier et al. [136] | Multiple cohort (n = 378) | BDNFVal66Met SNP | Univariate imaging—Univariate genetic | Candidate-based association | FC | DMN, DAN, SAL, CON | BDNFVal66Met was associated with a higher vulnerability of hippocampus-frontal connectivity to primary AD pathology |
2019 Chandler et al. [137] | n = 75 | APOE, summary statistics | Univariate imaging—Multivariate genetic | PGS-based association | Whole-brain gmCBF | Frontal cortex | The results found a reduction in gmCBF in APOE ε4 carriers, a negative relationship between AD-PGS and gmCBF, and regional reductions in gmCBF in individuals with higher AD-PGS across the frontal cortex |
2019 Axelrud et al. [138] | Multiple cohorts (n = 636) | APOE, summary statistics | Univariate imaging—Multivariate genetic | PGS-based association | FC among main nodes for 10 tau pathology networks | Precuneus, superior temporal gyrus | The PGS was associated with the connectivity between the right precuneus and the right superior temporal gyrus |
2020 Chandler et al. [139] | n = 608 | APOE, summary statistics | Univariate imaging—Multivariate genetic | PGS-based association | Bilateral hippocampus bold parameters | Hippocampus | AD-PGS, not APOE, selectively influenced activity within the HC in response to scenes, while other perceptual nodes remained intact |
Pathophysiological pathway: Neurodegeneration (DTI) | |||||||
2010 Smith et al. [140] | 23 HC, 42 AD | APOE | Univariate imaging—Univariate genetic | Candidate-based association | FA | Inferior temporal lobe, amygdala/ hippocampal head region | Reduced FA was observed in the fronto-occipital and inferior temporal fasciculi (particularly posteriorly), the splenium of the corpus callosum, subcallosal white matter and the cingulum bundle |
2005 Nierenberg et al. [141] | 29 HC | APOE | Univariate imaging—Univariate genetic | Candidate-based association | FA, axD, radD | Parahippocampal region | The APOE ε4 carriers showed significantly lower fractional anisotropy and higher radial diffusivity in the parahippocampal WM 15 mm below the anterior commissure-posterior commissure plane than noncarriers |
2014 Warstadt et al. [142] | n = 481 | Genome-wide genotyping | multivariate imaging—multivariate genetic | GWAS | Diffusion tensor, FA | Corpus callosum, fornix, internal capsule, inferior fronto-occipital fasciculus | A follow-up analysis detected WM associations with rs5882 in the opposite direction |
2015 Liang et al. [143] | 126 HC | SORL1 rs2070045 | Univariate imaging—Univariate genetic | Candidate-based association | FA, MD, axD, radD | Bilateral cingulum, cingulum hippocampal area | Sex moderated the effects of the SOR1 gene rs2070045 polymorphism on cognitive impairment and disruption of the cingulum hippocampal integrity in healthy elderly |
2016 Foley et al. [106] | n = 197 | APOE, summary statistics | Multivariate imaging—Multivariat genetic | PGS-based association | FA | Right cingulum | Fractional anisotropy of the right cingulum was inversely correlated with AD polygenic risk scores |
2017 Cavedo et al. [144] | 74 HC | APOE | Univariate imaging—Univariate genetic | Candidate-based association | FA, MD, radD, axD | Cingulum, corpus callosum, inferior fronto-occipital, inferior longitudinal fasciculi, internal, external capsule | These findings indicated a modulatory role of APOE ε4 on WM microstructure in elderly individuals at risk for AD suggesting early vulnerability and/or reduced resilience of WM tracts involved in AD |
2018 Rutten-Jacobs et al. [145] | UK Biobank (n = 8448) | Genome-wide genotyping | Univariate imaging—Multivariate genetic | GWAS | FA, MD, WMHV | White matter hyperintensity | A novel genome-wide significant locus VCAN rs13164785 on chr5q14 was identified, which may work in the mechanisms underlying microstructural integrity of the WM measured as FA and MD |
2019 Gu et al. [146] | GWAS Summary Statistics | PSEN1 | Multivariate imaging—Univariate genetic | Meta- analysis | WM integrity, cerebral amyloid deposition and brain metabolism | Whole brain | PSEN1 mutation associated with WM changes and amyloid deposition occurred in AD. Increased MD was observed and showed significant increase with amyloid deposition |
2020 Yan et al. [147] | ADNI (34 HC, 36 AD, 49 MCI) | 34 GWAS AD risk SNPs | Univariate imaging—Multivariate genetic | Candidate-based association | Fibre anisotropy, fibre length and density | 278 brain ROIs | Rs10498633 in SLC24A4 was found to be significantly associated with anisotropy, total number and length of fibres. APOE rs429358 showed nominal significance of association with the density of fibres between subcortical and cerebellum regions |
2020 Horgusluoglu-Moloch et al. [148] | ADNI (34 HC, 15 AD, 56 MCI) | 23 AD genes | Univariate imaging—Multivariate genetic | Candidate-based association | FA, MD, radD, axD, LIN, SPH, PLA, MOD | Hippocampus, cingulum, parahippocampal gyrus right, sagittal stratum, etc | A SNP rs2203712 in CELF1 was most significantly associated with several DTI-derived features in the hippocampus, the top ranked brain region |