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Topographical patterns of whole-brain structural alterations in association with genetic risk, cerebrospinal fluid, positron emission tomography biomarkers of Alzheimer’s disease, and neuropsychological measures

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Abstract

Purpose

This study aimed at investigating the topographical pattern of whole-brain structural alterations in association with apolipoprotein E ε4 (APOE ε4), cerebrospinal fluid (CSF) [amyloid-beta 42 (Aβ42), and neurofibrillary tau protein], positron emission tomography (PET) biomarkers [Aβ, tau, and 2-[18F]fluoro-2-deoxy-d-glucose (FDG)], and neuropsychological measures.

Methods

PubMed, Scopus, Ovid, and Cochrane databases were searched. Risk of bias (using a modified Newcastle–Ottawa Scale) and level of evidence were determined.

Results

One hundred and thirty-one studies met the inclusion criteria. APOE ε4 effect is exerted on the whole-brain. Still, the medial temporal lobe is the most affected, with moderate evidence observed across the lifespan (except late mid-life) and in the AD continuum. Moderate to strong evidence shows that atrophy of AD-vulnerable regions is associated with reduced CSF Aβ42, increased Aβ- and tau-PET, and increased CSF tau. No association between gray matter changes and FDG-PET measures in healthy late mid-life and older adults. Preliminary findings demonstrate a relationship between hippocampal atrophy and lower episodic memory in early life. Moderate evidence of an association between hippocampal atrophy and lower episodic memory is observed in late mid-life. In contrast, hippocampal atrophy is associated with reduced episodic memory and global cognition in older APOE ε4 carriers.

Conclusions

Strong evidence suggests that atrophy of the AD vulnerable regions is associated with CSF and PET biomarkers and cognitive measures. These relationships may be potentially helpful in characterizing the preclinical and clinical stages of MCI and AD and predicting AD progression.

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References

  1. Mueller SG, Weiner MW, Thal LJ, Petersen RC, Jack C, Jagust W, Trojanowski JQ, Toga AW, Beckett L (2005) The Alzheimer’s disease neuroimaging initiative. Neuroimaging Clin N Am 15(4):869–877

    Article  PubMed  PubMed Central  Google Scholar 

  2. Sperling RA, Aisen PS, Beckett LA, Bennett DA, Craft S, Fagan AM, Iwatsubo T, Jack CR Jr, Kaye J, Montine TJ, Park DC, Reiman EM, Rowe CC, Siemers E, Stern Y, Yaffe K, Carrillo MC, Thies B, Morrison-Bogorad M, Wagster MV, Phelps CH (2011) Toward defining the preclinical stages of Alzheimer’s disease: recommendations from the National Institute on Aging-Alzheimer’s Association workgroups on diagnostic guidelines for Alzheimer’s disease. Alzheimers Dement 7(3):280–292

    Article  PubMed  PubMed Central  Google Scholar 

  3. Suppiah S, Didier MA, Vinjamuri S (2019) The who, when, why, and how of PET amyloid imaging in management of Alzheimer’s disease-review of literature and interesting images. Diagnostics (Basel) 9(2):65

    Article  CAS  Google Scholar 

  4. Ou Y-N, Xu W, Li J-Q, Guo Y et al (2019) FDG-PET as an independent biomarker for Alzheimer’s biological diagnosis: a longitudinal study. Alzheimer’s Res Ther 11(1):1

    Google Scholar 

  5. Smailagic N, Vacante M, Hyde C, Martin S, Ukoumunne O, Sachpekidis C (2015) 18F-FDG PET for the early diagnosis of Alzheimer’s disease dementia and other dementias in people with mild cognitive impairment (MCI). Cochrane Database Syst Rev 1(1):CD010632

    PubMed  Google Scholar 

  6. Morbelli S, Garibotto V, Van De Giessen E, Arbizu J, Chételat G, Drezgza A, Hesse S, Lammertsma AA, Law I, Pappata S, Payoux P, Pagani M, European Association of Nuclear Medicine (2015) A Cochrane review on brain [18F]FDG PET in dementia: limitations and future perspectives. Eur J Nucl Med Mol Imaging 42(10):1487–1491

    Article  PubMed  Google Scholar 

  7. Botha H, Mantyh WG, Murray ME, Knopman DS, Przybelski SA, Wiste HJ, Graff-Radford J, Josephs KA, Schwarz CG, Kremers WK, Boeve BF, Petersen RC, Machulda MM, Parisi JE, Dickson DW, Lowe V, Jack CR Jr, Jones DT (2018) FDG-PET in tau-negative amnestic dementia resembles that of autopsy-proven hippocampal sclerosis. Brain 141(4):1201–1217

    Article  PubMed  PubMed Central  Google Scholar 

  8. Meramat A, Rajab NF, Shahar S, Sharif R (2015) Cognitive impairment, genomic instability and trace elements. J Nutr Health Aging 19(1):48–57

    Article  CAS  PubMed  Google Scholar 

  9. Hussin NM, Shahar S, Yahya HM, Din NC, Singh D, Omar MA (2019) Incidence and predictors of mild cognitive impairment (MCI) within a multi-ethnic Asian populace: a community-based longitudinal study. BMC Public Health 19(1):1159

    Article  PubMed  PubMed Central  Google Scholar 

  10. Rivan NFM, Shahar S, Rajab NF, Singh DKA, Che Din N, Mahadzir H, Mohamed Sakian NI, Ishak WS, Abd Rahman MH, Mohammed Z, You YX (2020) Incidence and predictors of cognitive frailty among older adults: a community-based longitudinal study. Int J Environ Res Public Health 17(5):1547

    Article  PubMed Central  Google Scholar 

  11. Shahar S, Lee LK, Rajab N, Lim CL, Harun NA, Noh MF, Mian-Then S, Jamal R (2013) Association between vitamin A, vitamin E and apolipoprotein E status with mild cognitive impairment among elderly people in low-cost residential areas. Nutr Neurosci 16(1):6–12

    Article  CAS  PubMed  Google Scholar 

  12. American Psychiatric Association (2013) Diagnostic and statistical manual of mental disorders (DSM–5), 5th edn. American Psychiatric Publishing, Washington, DC

    Book  Google Scholar 

  13. Liu Y, Yu JT, Wang HF, Han PR, Tan CC, Wang C, Meng XF, Risacher SL, Saykin AJ, Tan L (2015) APOE genotype and neuroimaging markers of Alzheimer’s disease: systematic review and meta-analysis. J Neurol Neurosurg Psychiatry 86(2):127–134

    Article  PubMed  Google Scholar 

  14. Emrani S, Arain HA, DeMarshall C, Nuriel T (2020) APOE4 is associated with cognitive and pathological heterogeneity in patients with Alzheimer’s disease: a systematic review. Alzheimer’s Res Ther 12(1):141

    Article  Google Scholar 

  15. Cherbuin N, Leach LS, Christensen H, Anstey KJ (2007) Neuroimaging and APOE genotype: a systematic qualitative review. Dement Geriatr Cogn Disord 24(5):348–362

    Article  PubMed  Google Scholar 

  16. Piersson AD, Mohamad M, Rajab F, Suppiah S (2020) Cerebrospinal fluid amyloid beta, tau levels, apolipoprotein, and 1H-MRS brain metabolites in Alzheimer’s disease: a systematic review. Acad Radiol. https://doi.org/10.1016/j.acra.2020.06.006

    Article  PubMed  Google Scholar 

  17. Liberati A, Altman DG, Tetzlaff J et al (2009) The PRISMA statement for reporting systematic reviews and meta-analyses of studies that evaluate healthcare interventions: explanation and elaboration. BMJ 339:b2700–b2700

    Article  PubMed  PubMed Central  Google Scholar 

  18. Coppieters I, Meeus M, Kregel J, Caeyenberghs K, De Pauw R, Goubert D, Cagnie B (2016) Relations between brain alterations and clinical pain measures in chronic musculoskeletal pain: a systematic review. J Pain 17(9):949–962

    Article  PubMed  Google Scholar 

  19. Cacciaglia R, Molinuevo JL, Falcón C, Brugulat-Serrat A, Sánchez-Benavides G, Gramunt N, Esteller M, Morán S, Minguillón C, Fauria K, Gispert JD, ALFA study (2018) Effects of APOE-ε4 allele load on brain morphology in a cohort of middle-aged healthy individuals with enriched genetic risk for Alzheimer’s disease. Alzheimers Dement 14(7):902–912

    Article  PubMed  Google Scholar 

  20. Groot C, Sudre CH, Barkhof F, Teunissen CE, van Berckel BNM, Seo SW, Ourselin S, Scheltens P, Cardoso MJ, van der Flier WM, Ossenkoppele R (2018) Clinical phenotype, atrophy, and small vessel disease in APOEε2 carriers with Alzheimer disease. Neurology 91(20):e1851–e1859

    Article  CAS  PubMed  Google Scholar 

  21. Kirsebom BE, Nordengen K, Selnes P, Waterloo K, Torsetnes SB, Gísladóttir B, Brix B, Vanmechelen E, Bråthen G, Hessen E, Aarsland D, Fladby T (2018) Cerebrospinal fluid neurogranin/β-site APP-cleaving enzyme 1 predicts cognitive decline in preclinical Alzheimer’s disease. Alzheimers Dement (N Y) 4:617–627

    Article  Google Scholar 

  22. Koval I, Schiratti JB, Routier A, Bacci M, Colliot O, Allassonnière S, Durrleman S (2018) Spatiotemporal propagation of the cortical atrophy: population and individual patterns. Front Neurol 9:235

    Article  PubMed  PubMed Central  Google Scholar 

  23. Wang R, Laveskog A, Laukka EJ, Kalpouzos G, Bäckman L, Fratiglioni L, Qiu C (2018) MRI load of cerebral microvascular lesions and neurodegeneration, cognitive decline, and dementia. Neurology 91(16):e1487–e1497

    Article  PubMed  PubMed Central  Google Scholar 

  24. Wang X, Zhou W, Ye T, Lin X, Zhang J, Alzheimer’s Disease Neuroimaging Initiative (2019) The relationship between hippocampal volumes and delayed recall is modified by APOE ε4 in mild cognitive impairment. Front Aging Neurosci 11:36

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  25. Mattsson N, Ossenkoppele R, Smith R, Strandberg O, Ohlsson T, Jögi J, Palmqvist S, Stomrud E, Hansson O (2018) Greater tau load and reduced cortical thickness in APOE ε4-negative Alzheimer’s disease: a cohort study. Alzheimers Res Ther 10(1):77

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  26. Moon SW, Lee B, Choi YC (2018) Changes in the hippocampal volume and shape in early-onset mild cognitive impairment. Psychiatry Investig 15(5):531–537

    Article  PubMed  PubMed Central  Google Scholar 

  27. Rane S, Donahue MJ, Claassen DO (2018) Amnestic mild cognitive impairment individuals with dissimilar pathologic origins show common regional vulnerability in the default mode network. Alzheimers Dement (Amst) 10:717–725

    Article  Google Scholar 

  28. Sundermann EE, Tran M, Maki PM, Bondi MW (2018) Sex differences in the association between apolipoprotein E ε4 allele and Alzheimer’s disease markers. Alzheimers Dement (Amst) 10:438–447

    Article  Google Scholar 

  29. Dong Q, Zhang W, Wu J, Li B, Schron EH, McMahon T, Shi J, Gutman BA, Chen K, Baxter LC, Thompson PM, Reiman EM, Caselli RJ, Wang Y (2019) Applying surface-based hippocampal morphometry to study APOE-E4 allele dose effects in cognitively unimpaired subjects. Neuroimage Clin 22:101744

    Article  PubMed  PubMed Central  Google Scholar 

  30. Barboriak DP, Doraiswamy PM, Krishnan KR, Vidyarthi S, Sylvester J, Charles HC (2000) Hippocampal sulcal cavities on MRI: relationship to age and apolipoprotein E genotype. Neurology 54(11):2150–2153

    Article  CAS  PubMed  Google Scholar 

  31. Lehtovirta M, Laakso MP, Soininen H, Helisalmi S, Mannermaa A, Helkala EL, Partanen K, Ryynänen M, Vainio P, Hartikainen P et al (1995) Volumes of hippocampus, amygdala and frontal lobe in Alzheimer patients with different apolipoprotein E genotypes. Neuroscience 67(1):65–72

    Article  CAS  PubMed  Google Scholar 

  32. Du AT, Schuff N, Chao LL, Kornak J, Jagust WJ, Kramer JH, Reed BR, Miller BL, Norman D, Chui HC, Weiner MW (2006) Age effects on atrophy rates of entorhinal cortex and hippocampus. Neurobiol Aging 27(5):733–740

    Article  PubMed  Google Scholar 

  33. Barber R, Ballard C, McKeith IG, Gholkar A, O’Brien JT (2000) MRI volumetric study of dementia with Lewy bodies: a comparison with AD and vascular dementia. Neurology 54(6):1304–1309

    Article  CAS  PubMed  Google Scholar 

  34. Boccardi M, Sabattoli F, Testa C, Beltramello A, Soininen H, Frisoni GB (2004) APOE and modulation of Alzheimer’s and frontotemporal dementia. Neurosci Lett 356(3):167–170

    Article  CAS  PubMed  Google Scholar 

  35. Reiman EM, Uecker A, Caselli RJ, Lewis S, Bandy D, de Leon MJ, De Santi S, Convit A, Osborne D, Weaver A, Thibodeau SN (1998) Hippocampal volumes in cognitively normal persons at genetic risk for Alzheimer’s disease. Ann Neurol 44(2):288–291

    Article  CAS  PubMed  Google Scholar 

  36. Schmidt H, Schmidt R, Fazekas F, Semmler J, Kapeller P, Reinhart B, Kostner GM (1996) Apolipoprotein E e4 allele in the normal elderly: neuropsychologic and brain MRI correlates. Clin Genet 50(5):293–299

    Article  CAS  PubMed  Google Scholar 

  37. Basso M, Gelernter J, Yang J, MacAvoy MG, Varma P, Bronen RA, van Dyck CH (2006) Apolipoprotein E epsilon4 is associated with atrophy of the amygdala in Alzheimer’s disease. Neurobiol Aging 27(10):1416–1424

    Article  CAS  PubMed  Google Scholar 

  38. Espeseth T, Greenwood PM, Reinvang I, Fjell AM, Walhovd KB, Westlye LT, Wehling E, Lundervold A, Rootwelt H, Parasuraman R (2006) Interactive effects of APOE and CHRNA4 on attention and white matter volume in healthy middle-aged and older adults. Cogn Affect Behav Neurosci 6(1):31–43

    Article  PubMed  Google Scholar 

  39. Tanaka S, Kawamata J, Shimohama S, Akaki H, Akiguchi I, Kimura J, Ueda K (1998) Inferior temporal lobe atrophy and APOE genotypes in Alzheimer’s disease. X-ray computed tomography, magnetic resonance imaging and Xe-133 SPECT studies. Dement Geriatr Cogn Disord 9(2):90–98

    Article  CAS  PubMed  Google Scholar 

  40. Bigler ED, Tate DF, Miller MJ, Rice SA, Hessel CD, Earl HD, Tschanz JT, Plassman B, Welsh-Bohmer KA (2002) Dementia, asymmetry of temporal lobe structures, and apolipoprotein E genotype: relationships to cerebral atrophy and neuropsychological impairment. J Int Neuropsychol Soc 8(7):925–933

    Article  CAS  PubMed  Google Scholar 

  41. Barber R, Gholkar A, Scheltens P, Ballard C, McKeith IG, Morris CM, O’Brien JT (1999) Apolipoprotein E epsilon4 allele, temporal lobe atrophy, and white matter lesions in late-life dementias. Arch Neurol 56(8):961–965

    Article  CAS  PubMed  Google Scholar 

  42. Carmelli D, DeCarli C, Swan GE, Kelly-Hayes M, Wolf PA, Reed T, Guralnik JM (2000) The joint effect of apolipoprotein E epsilon4 and MRI findings on lower-extremity function and decline in cognitive function. J Gerontol A Biol Sci Med Sci 55(2):103–109

    Article  Google Scholar 

  43. Pennanen C, Testa C, Boccardi M, Laakso MP, Hallikainen M, Helkala EL, Hänninen T, Kivipelto M, Könönen M, Nissinen A, Tervo S, Vanhanen M, Vanninen R, Frisoni GB, Soininen H (2006) The effect of apolipoprotein polymorphism on brain in mild cognitive impairment: a voxel-based morphometric study. Dement Geriatr Cogn Disord 22(1):60–66

    Article  PubMed  Google Scholar 

  44. Morra JH, Tu Z, Apostolova LG, Green AE, Avedissian C, Madsen SK, Parikshak N, Toga AW, Jack CR Jr, Schuff N, Weiner MW, Thompson PM, Initiative ADN (2009) Automated mapping of hippocampal atrophy in 1-year repeat MRI data from 490 subjects with Alzheimer’s disease, mild cognitive impairment, and elderly controls. Neuroimage 45(1 Suppl):S3-15

    Article  PubMed  Google Scholar 

  45. Goltermann J, Redlich R, Dohm K, Zaremba D, Repple J, Kaehler C, Grotegerd D, Förster K, Meinert S, Enneking V, Schlaghecken E, Fleischer L, Hahn T, Kugel H, Jansen A, Krug A, Brosch K, Nenadic I, Schmitt S, Stein F, Meller T, Yüksel D, Fischer E, Rietschel M, Witt SH, Forstner AJ, Nöthen MM, Kircher T, Thalamuthu A, Baune BT, Dannlowski U, Opel N (2019) Apolipoprotein E homozygous ε4 allele status: a deteriorating effect on visuospatial working memory and global brain structure. Front Neurol 10:552

    Article  PubMed  PubMed Central  Google Scholar 

  46. Konishi K, Joober R, Poirier J, MacDonald K, Chakravarty M, Patel R, Breitner J, Bohbot VD (2018) Healthy versus entorhinal cortical atrophy identification in asymptomatic APOE4 carriers at Risk for Alzheimer’s Disease. J Alzheimers Dis 61(4):1493–1507

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  47. Kelly DA, Seidenberg M, Reiter K, Nielson KA, Woodard JL, Smith JC, Durgerian S, Rao SM (2018) Differential 5-year brain atrophy rates in cognitively declining and stable APOE-ε4 elders. Neuropsychology 32(6):647–653

    Article  PubMed  PubMed Central  Google Scholar 

  48. Alemany S, Vilor-Tejedor N, García-Esteban R, Bustamante M, Dadvand P, Esnaola M, Mortamais M, Forns J, van Drooge BL, Álvarez-Pedrerol M, Grimalt JO, Rivas I, Querol X, Pujol J, Sunyer J (2018) Traffic-related air pollution, APOEε4 status, and neurodevelopmental outcomes among school children enrolled in the BREATHE project (Catalonia, Spain). Environ Health Perspect 126(8):87001

    Article  Google Scholar 

  49. Tosun D, Schuff N, Truran-Sacrey D, Shaw LM, Trojanowski JQ, Aisen P, Peterson R, Weiner MW, Initiative ADN (2010) Relations between brain tissue loss, CSF biomarkers, and the ApoE genetic profile: a longitudinal MRI study. Neurobiol Aging 31(8):1340–1354

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  50. Hua X, Leow AD, Parikshak N, Lee S, Chiang MC, Toga AW, Jack CR Jr, Weiner MW, Thompson PM, Initiative ADN (2008) Tensor-based morphometry as a neuroimaging biomarker for Alzheimer’s disease: an MRI study of 676 AD, MCI, and normal subjects. Neuroimage 43(3):458–469

    Article  PubMed  Google Scholar 

  51. Filippini N, Zarei M, Beckmann CF, Galluzzi S, Borsci G, Testa C, Bonetti M, Beltramello A, Ghidoni R, Benussi L, Binetti G, Frisoni GB (2009) Regional atrophy of transcallosal prefrontal connections in cognitively normal APOE epsilon4 carriers. J Magn Reson Imaging 29(5):1021–1026

    Article  PubMed  Google Scholar 

  52. Jak AJ, Houston WS, Nagel BJ, Corey-Bloom J, Bondi MW (2007) Differential cross-sectional and longitudinal impact of APOE genotype on hippocampal volumes in nondemented older adults. Dement Geriatr Cogn Disord 23(6):382–389

    Article  PubMed  Google Scholar 

  53. Doody RS, Azher SN, Haykal HA, Dunn JK, Liao T, Schneider L (2000) Does APO epsilon4 correlate with MRI changes in Alzheimer’s disease? J Neurol Neurosurg Psychiatry 69(5):668–671

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  54. Geroldi C, Laakso MP, DeCarli C, Beltramello A, Bianchetti A, Soininen H, Trabucchi M, Frisoni GB (2000) Apolipoprotein E genotype and hippocampal asymmetry in Alzheimer’s disease: a volumetric MRI study. J Neurol Neurosurg Psychiatry 68(1):93–96

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  55. Mishra S, Blazey TM, Holtzman DM, Cruchaga C, Su Y, Morris JC, Benzinger TLS, Gordon BA (2018) Longitudinal brain imaging in preclinical Alzheimer disease: impact of APOE ε4 genotype. Brain 141(6):1828–1839

    Article  PubMed  PubMed Central  Google Scholar 

  56. Bussy A, Snider BJ, Coble D, Xiong C, Fagan AM, Cruchaga C, Benzinger TLS, Gordon BA, Hassenstab J, Bateman RJ, Morris JC, Network DIA (2019) Effect of apolipoprotein E4 on clinical, neuroimaging, and biomarker measures in noncarrier participants in the dominantly inherited Alzheimer network. Neurobiol Aging 75:42–50

    Article  CAS  PubMed  Google Scholar 

  57. Taylor JL, Scanlon BK, Farrell M, Hernandez B, Adamson MM, Ashford JW, Noda A, Murphy GM Jr, Weiner MW (2014) APOE-epsilon4 and aging of medial temporal lobe gray matter in healthy adults older than 50 years. Neurobiol Aging 35(11):2479–2485

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  58. Kerchner GA, Berdnik D, Shen JC, Bernstein JD, Fenesy MC, Deutsch GK, Wyss-Coray T, Rutt BK (2014) APOE ε4 worsens hippocampal CA1 apical neuropil atrophy and episodic memory. Neurology 82(8):691–697

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  59. Fennema-Notestine C, Panizzon MS, Thompson WR, Chen CH, Eyler LT, Fischl B, Franz CE, Grant MD, Jak AJ, Jernigan TL, Lyons MJ, Neale MC, Seidman LJ, Tsuang MT, Xian H, Dale AM, Kremen WS (2011) Presence of ApoE ε4 allele associated with thinner frontal cortex in middle age. J Alzheimers Dis 26(Suppl 3):49–60

    Article  PubMed  PubMed Central  Google Scholar 

  60. Andrawis JP, Hwang KS, Green AE, Kotlerman J, Elashoff D, Morra JH, Cummings JL, Toga AW, Thompson PM, Apostolova LG (2012) Effects of ApoE4 and maternal history of dementia on hippocampal atrophy. Neurobiol Aging 33(5):856–866

    Article  CAS  PubMed  Google Scholar 

  61. Chang L, Douet V, Bloss C, Lee K, Pritchett A, Jernigan TL, Akshoomoff N, Murray SS, Frazier J, Kennedy DN, Amaral DG, Gruen J, Kaufmann WE, Casey BJ, Sowell E, Ernst T (2016) Gray matter maturation and cognition in children with different APOE ε genotypes. Neurology 87(6):585–594

    CAS  PubMed  PubMed Central  Google Scholar 

  62. Honea RA, Vidoni E, Harsha A, Burns JM (2009) Impact of APOE on the healthy aging brain: a voxel-based MRI and DTI study. J Alzheimers Dis 18(3):553–564

    Article  PubMed  PubMed Central  Google Scholar 

  63. Chang YL, Fennema-Notestine C, Holland D, McEvoy LK, Stricker NH, Salmon DP, Dale AM, Bondi MW (2014) Alzheimer’s disease neuroimaging initiative. APOE interacts with age to modify rate of decline in cognitive and brain changes in Alzheimer’s disease. Alzheimers Dement 10(3):336–348

    Article  PubMed  Google Scholar 

  64. Li B, Shi J, Gutman BA, Baxter LC, Thompson PM, Caselli RJ, Wang Y, Alzheimer’s Disease Neuroimaging Initiative (2016) Influence of APOE genotype on hippocampal atrophy over time—an N = 1925 surface-based ADNI study. PLoS ONE 11(4):e0152901

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  65. Okonkwo OC, Alosco ML, Jerskey BA, Sweet LH, Ott BR, Tremont G, Initiative ADN (2010) Cerebral atrophy, apolipoprotein E varepsilon4, and rate of decline in everyday function among patients with amnestic mild cognitive impairment. Alzheimers Dement 6(5):404–411

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  66. Tosun D, Schuff N, Shaw LM, Trojanowski JQ, Weiner MW, Alzheimer’s Disease NeuroImaging Initiative (2011) Relationship between CSF biomarkers of Alzheimer’s disease and rates of regional cortical thinning in ADNI data. J Alzheimers Dis 26(3):77–90

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  67. Tang X, Holland D, Dale AM, Miller MI, Initiative ADN (2015) APOE affects the volume and shape of the amygdala and the hippocampus in mild cognitive impairment and Alzheimer’s disease: age matters. J Alzheimers Dis 47(3):645–660

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  68. Burggren AC, Zeineh MM, Ekstrom AD, Braskie MN, Thompson PM, Small GW, Bookheimer SY (2008) Reduced cortical thickness in hippocampal subregions among cognitively normal apolipoprotein E e4 carriers. Neuroimage 41(4):1177–1183

    Article  CAS  PubMed  Google Scholar 

  69. Reiter K, Nielson KA, Durgerian S, Woodard JL, Smith JC, Seidenberg M, Kelly DA, Rao SM (2017) Five-year longitudinal brain volume change in healthy elders at genetic risk for Alzheimer’s disease. J Alzheimers Dis 55(4):1363–1377

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  70. Lampert EJ, Roy Choudhury K, Hostage CA et al (2014) Brain atrophy rates in first degree relatives at risk for Alzheimer’s. NeuroImage Clin 6:340–346

    Article  PubMed  PubMed Central  Google Scholar 

  71. Bender AR, Raz N (2012) Age-related differences in memory and executive functions in healthy APOE ɛ4 carriers: the contribution of individual differences in prefrontal volumes and systolic blood pressure. Neuropsychologia 50(5):704–714

    Article  PubMed  PubMed Central  Google Scholar 

  72. Mueller SG, Weiner MW (2009) Selective effect of age, Apo e4, and Alzheimer’s disease on hippocampal subfields. Hippocampus 19(6):558–564

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  73. Mueller SG, Schuff N, Raptentsetsang S, Elman J, Weiner MW (2008) Selective effect of Apo e4 on CA3 and dentate in normal aging and Alzheimer’s disease using high resolution MRI at 4 T. Neuroimage 42(1):42–48

    Article  CAS  PubMed  Google Scholar 

  74. Donix M, Burggren AC, Suthana NA, Siddarth P, Ekstrom AD, Krupa AK, Jones M, Rao A, Martin-Harris L, Ercoli LM, Miller KJ, Small GW, Bookheimer SY (2010) Longitudinal changes in medial temporal cortical thickness in normal subjects with the APOE-4 polymorphism. Neuroimage 53(1):37–43

    Article  CAS  PubMed  Google Scholar 

  75. Ferencz B, Laukka EJ, Lövdén M, Kalpouzos G, Keller L, Graff C, Wahlund LO, Fratiglioni L, Bäckman L (2013) The influence of APOE and TOMM40 polymorphisms on hippocampal volume and episodic memory in old age. Front Hum Neurosci 7:198

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  76. Spampinato MV, Rumboldt Z, Hosker RJ, Mintzer JE, Initiative ADN (2011) Apolipoprotein E and gray matter volume loss in patients with mild cognitive impairment and Alzheimer disease. Radiology 258(3):843–852

    Article  PubMed  Google Scholar 

  77. Ma C, Zhang Y, Li X, Zhang J, Chen K, Liang Y, Chen Y, Liu Z, Zhang Z (2016) Is there a significant interaction effect between apolipoprotein E rs405509 T/T and ε4 genotypes on cognitive impairment and gray matter volume? Eur J Neurol 23(9):1415–1425

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  78. Lu PH, Thompson PM, Leow A, Lee GJ, Lee A, Yanovsky I, Parikshak N, Khoo T, Wu S, Geschwind D, Bartzokis G (2011) Apolipoprotein E genotype is associated with temporal and hippocampal atrophy rates in healthy elderly adults: a tensor-based morphometry study. J Alzheimers Dis 23(3):433–442

    Article  PubMed  PubMed Central  Google Scholar 

  79. Dean DC 3rd, Jerskey BA, Chen K, Protas H, Thiyyagura P, Roontiva A, O’Muircheartaigh J, Dirks H, Waskiewicz N, Lehman K, Siniard AL, Turk MN, Hua X, Madsen SK, Thompson PM, Fleisher AS, Huentelman MJ, Deoni SC, Reiman EM (2014) Brain differences in infants at differential genetic risk for late-onset Alzheimer disease: a cross-sectional imaging study. JAMA Neurol 71(1):11–22

    Article  PubMed  PubMed Central  Google Scholar 

  80. Wolk DA, Dickerson BC, Initiative ADN (2010) Apolipoprotein E (APOE) genotype has dissociable effects on memory and attentional-executive network function in Alzheimer’s disease. Proc Natl Acad Sci USA 107(22):10256–10261

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  81. Soldan A, Pettigrew C, Lu Y, Wang MC, Selnes O, Albert M, Brown T, Ratnanather JT, Younes L, Miller MI, BIOCARD Research Team (2015) Relationship of medial temporal lobe atrophy, APOE genotype, and cognitive reserve in preclinical Alzheimer’s disease. Hum Brain Mapp 36(7):2826–2841

    Article  PubMed  PubMed Central  Google Scholar 

  82. Fan M, Liu B, Zhou Y, Zhen X, Xu C, Jiang T, Initiative ADN (2010) Cortical thickness is associated with different apolipoprotein E genotypes in healthy elderly adults. Neurosci Lett 479(3):332–336

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  83. Banks SJ, Miller JB, Rissman RA, Bernick CB (2017) Lack of influence of apolipoprotein E status on cognition or brain structure in professional fighters. J Neurotrauma 34(2):380–384

    Article  PubMed  PubMed Central  Google Scholar 

  84. Walsh B, Slater S, Nair B, Attia J (2013) The relationship between the apolipoprotein E e4 allele and hippocampal magnetic resonance imaging volume in community-dwelling individuals with mild Alzheimer’s disease. Degener Neurol Neuromuscul Dis 3:11–14

    CAS  PubMed  PubMed Central  Google Scholar 

  85. Li C, Loewenstein DA, Duara R, Cabrerizo M, Barker W, Adjouadi M, Alzheimer’s Disease Neuroimaging Initiative (2017) The relationship of brain amyloid load and APOE status to regional cortical thinning and cognition in the ADNI cohort. J Alzheimers Dis 59(4):1269–1282

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  86. Chen K, Ayutyanont N, Langbaum JB, Fleisher AS, Reschke C, Lee W, Liu X, Alexander GE, Bandy D, Caselli RJ, Reiman EM (2012) Correlations between FDG PET glucose uptake-MRI gray matter volume scores and apolipoprotein E ε4 gene dose in cognitively normal adults: a cross-validation study using voxel-based multi-modal partial least squares. Neuroimage 60(4):2316–2322

    Article  CAS  PubMed  Google Scholar 

  87. Hostage CA, Choudhury KR, Murali Doraiswamy P, Petrella JR, Initiative ADN (2014) Mapping the effect of the apolipoprotein E genotype on 4-year atrophy rates in an Alzheimer disease-related brain network. Radiology 271(1):211–219

    Article  PubMed  Google Scholar 

  88. Donix M, Burggren AC, Scharf M, Marschner K, Suthana NA, Siddarth P, Krupa AK, Jones M, Martin-Harris L, Ercoli LM, Miller KJ, Werner A, von Kummer R, Sauer C, Small GW, Holthoff VA, Bookheimer SY (2013) APOE associated hemispheric asymmetry of entorhinal cortical thickness in aging and Alzheimer’s disease. Psychiatry Res 214(3):212–220

    Article  PubMed  Google Scholar 

  89. Shi J, Leporé N, Gutman BA, Thompson PM, Baxter LC, Caselli RJ, Wang Y, Initiative ADN (2014) Genetic influence of apolipoprotein E4 genotype on hippocampal morphometry: an N = 725 surface-based Alzheimer’s disease neuroimaging initiative study. Hum Brain Mapp 35(8):3903–3918

    Article  PubMed  PubMed Central  Google Scholar 

  90. Hafsteinsdottir SH, Eiriksdottir G, Sigurdsson S, Aspelund T, Harris TB, Launer LJ, Gudnason V (2012) Brain tissue volumes by APOE genotype and leisure activity-the AGES-Reykjavik study. Neurobiol Aging 33(4):829.e1–8

    Article  CAS  Google Scholar 

  91. Novellino F, López ME, Vaccaro MG, Miguel Y, Delgado ML, Maestu F (2019) Association between hippocampus, thalamus, and caudate in mild cognitive impairment APOEε4 carriers: a structural covariance MRI study. Front Neurol 10:1303

    Article  PubMed  PubMed Central  Google Scholar 

  92. Juottonen K, Lehtovirta M, Helisalmi S, Riekkinen PJ Sr, Soininen H (1998) Major decrease in the volume of the entorhinal cortex in patients with Alzheimer’s disease carrying the apolipoprotein E epsilon4 allele. J Neurol Neurosurg Psychiatry 65(3):322–327

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  93. Wilhelm J, Frieling H, von Ahsen N, Hillemacher T, Kornhuber J, Bleich S (2008) Apolipoprotein E polymorphism, homocysteine serum levels and hippocampal volume in patients with alcoholism: an investigation of a gene-environment interaction. Pharmacogenomics J 8(2):117–121

    Article  CAS  PubMed  Google Scholar 

  94. Cherbuin N, Anstey KJ, Sachdev PS, Maller JJ, Meslin C, Mack HA, Wen W, Easteal S (2008) Total and regional gray matter volume is not related to APOE*E4 status in a community sample of middle-aged individuals. J Gerontol A Biol Sci Med Sci 63(5):501–504

    Article  PubMed  Google Scholar 

  95. Biffi A, Anderson CD, Desikan RS, Sabuncu M, Cortellini L, Schmansky N, Salat D, Rosand J, Alzheimer’s Disease Neuroimaging Initiative (ADNI) (2010) Genetic variation and neuroimaging measures in Alzheimer disease. Arch Neurol 67(6):677–685

    Article  PubMed  PubMed Central  Google Scholar 

  96. Ystad MA, Lundervold AJ, Wehling E, Espeseth T, Rootwelt H, Westlye LT, Andersson M, Adolfsdottir S, Geitung JT, Fjell AM, Reinvang I, Lundervold A (2009) Hippocampal volumes are important predictors for memory function in elderly women. BMC Med Imaging 22(9):17

    Article  Google Scholar 

  97. Schuff N, Woerner N, Boreta L, Kornfield T, Shaw LM, Trojanowski JQ, Thompson PM, Jack CR Jr, Weiner MW, Initiative ADN (2009) MRI of hippocampal volume loss in early Alzheimer’s disease in relation to ApoE genotype and biomarkers. Brain 132(Pt 4):1067–1077

    CAS  PubMed  PubMed Central  Google Scholar 

  98. Stewart R, Godin O, Crivello F, Maillard P, Mazoyer B, Tzourio C, Dufouil C (2011) Longitudinal neuroimaging correlates of subjective memory impairment: 4-year prospective community study. Br J Psychiatry 198(3):199–205

    Article  PubMed  Google Scholar 

  99. Protas HD, Chen K, Langbaum JB, Fleisher AS, Alexander GE, Lee W, Bandy D, de Leon MJ, Mosconi L, Buckley S, Truran-Sacrey D, Schuff N, Weiner MW, Caselli RJ, Reiman EM (2013) Posterior cingulate glucose metabolism, hippocampal glucose metabolism, and hippocampal volume in cognitively normal, late-middle-aged persons at 3 levels of genetic risk for Alzheimer disease. JAMA Neurol 70(3):320–325

    Article  PubMed  PubMed Central  Google Scholar 

  100. Hoogendam YY, van der Geest JN, van der Lijn F, van der Lugt A, Niessen WJ, Krestin GP, Hofman A, Vernooij MW, Breteler MM, Ikram MA (2012) Determinants of cerebellar and cerebral volume in the general elderly population. Neurobiol Aging 33(12):2774–2781

    Article  PubMed  Google Scholar 

  101. Geroldi C, Pihlajamäki M, Laakso MP, DeCarli C, Beltramello A, Bianchetti A, Soininen H, Trabucchi M, Frisoni GB (1999) APOE-epsilon4 is associated with less frontal and more medial temporal lobe atrophy in AD. Neurology 53(8):1825–1832

    Article  CAS  PubMed  Google Scholar 

  102. Lehtovirta M, Soininen H, Laakso MP, Partanen K, Helisalmi S, Mannermaa A, Ryynänen M, Kuikka J, Hartikainen P, Riekkinen PJ Sr (1996) SPECT and MRI analysis in Alzheimer’s disease: relation to apolipoprotein E epsilon 4 allele. J Neurol Neurosurg Psychiatry 60(6):644–649

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  103. O’Dwyer L, Lamberton F, Matura S, Tanner C, Scheibe M, Miller J, Rujescu D, Prvulovic D, Hampel H (2012) Reduced hippocampal volume in healthy young ApoE4 carriers: an MRI study. PLoS ONE 7(11):e48895

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  104. Sabuncu MR, Buckner RL, Smoller JW, Lee PH, Fischl B, Sperling RA, Initiative ADN (2012) The association between a polygenic Alzheimer score and cortical thickness in clinically normal subjects. Cereb Cortex 22(11):2653–2661

    Article  PubMed  Google Scholar 

  105. Bunce D, Anstey KJ, Cherbuin N, Gautam P, Sachdev P, Easteal S (2012) APOE genotype and entorhinal cortex volume in non-demented community-dwelling adults in midlife and early old age. J Alzheimers Dis 30(4):935–942

    Article  PubMed  Google Scholar 

  106. Hostage CA, Roy Choudhury K, Doraiswamy PM, Petrella JR, Alzheimer’s Disease Neuroimaging Initiative (2013) Dissecting the gene dose-effects of the APOE ε4 and ε2 alleles on hippocampal volumes in aging and Alzheimer’s disease. PLoS ONE 8(2):e54483

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  107. DiBattista AM, Stevens BW, Rebeck GW, Green AE (2014) Two Alzheimer’s disease risk genes increase entorhinal cortex volume in young adults. Front Hum Neurosci 8:779

    Article  PubMed  PubMed Central  Google Scholar 

  108. Manning EN, Barnes J, Cash DM, Bartlett JW, Leung KK, Ourselin S, Fox NC, Alzheimer’s Disease NeuroImaging Initiative (2014) APOE ε4 is associated with disproportionate progressive hippocampal atrophy in AD. PLoS ONE 9(7):e104482

    Article  CAS  Google Scholar 

  109. Khan W, Giampietro V, Ginestet C, Dell’Acqua F, Bouls D, Newhouse S, Dobson R, Banaschewski T, Barker GJ, Bokde AL, Büchel C, Conrod P, Flor H, Frouin V, Garavan H, Gowland P, Heinz A, Ittermann B, Lemaître H, Nees F, Paus T, Pausova Z, Rietschel M, Smolka MN, Ströhle A, Gallinat J, Westman E, Schumann G, Lovestone S, Simmons A, IMAGEN consortium (2014) No differences in hippocampal volume between carriers and non-carriers of the ApoE ε4 and ε2 alleles in young healthy adolescents. J Alzheimers Dis 40(1):37–43

    Article  CAS  PubMed  Google Scholar 

  110. Holland D, Desikan RS, Dale AM, McEvoy LK, Initiative ADN (2015) Higher rates of decline for women and apolipoprotein E epsilon4 carriers. AJNR Am J Neuroradiol 36(10):E67

    Google Scholar 

  111. Lyall DM, Royle NA, Harris SE, Bastin ME, Maniega SM, Murray C, Lutz MW, Saunders AM, Roses AD, del Valdés Hernández MC, Starr JM, Porteous DJ, Wardlaw JM, Deary IJ (2013) Alzheimer’s disease susceptibility genes APOE and TOMM40, and hippocampal volumes in the Lothian birth cohort 1936. PLoS ONE 8(11):e80513

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  112. Morgen K, Schneider M, Frölich L, Tost H, Plichta MM, Kölsch H, Rakebrandt F, Rienhoff O, Jessen F, Peters O, Jahn H, Luckhaus C, Hüll M, Gertz HJ, Schröder J, Hampel H, Teipel SJ, Pantel J, Heuser I, Wiltfang J, Rüther E, Kornhuber J, Maier W, Meyer-Lindenberg A (2015) Apolipoprotein E-dependent load of white matter hyperintensities in Alzheimer’s disease: a voxel-based lesion mapping study. Alzheimers Res Ther 7(1):27

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  113. Risacher SL, Kim S, Nho K, Foroud T, Shen L, Petersen RC, Jack CR Jr, Beckett LA, Aisen PS, Koeppe RA, Jagust WJ, Shaw LM, Trojanowski JQ, Weiner MW, Saykin AJ, Initiative ADN, (ADNI), (2015) APOE effect on Alzheimer’s disease biomarkers in older adults with significant memory concern. Alzheimers Dement 11(12):1417–1429

    Article  PubMed  PubMed Central  Google Scholar 

  114. Yokoyama JS, Lee AK, Takada LT, Busovaca E, Bonham LW, Chao SZ, Tse M, He J, Schwarz CG, Carmichael OT, Matthews BR, Karydas A, Weiner MW, Coppola G, DeCarli CS, Miller BL, Rosen HJ (2015) Apolipoprotein ε4 is associated with lower brain volume in cognitively normal Chinese but not white older adults. PLoS ONE 10(3):e0118338

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  115. Sampedro F, Vilaplana E, de Leon MJ, Alcolea D, Pegueroles J, Montal V, Carmona-Iragui M, Sala I, Sánchez-Saudinos MB, Antón-Aguirre S, Morenas-Rodríguez E, Camacho V, Falcón C, Pavía J, Ros D, Clarimón J, Blesa R, Lleó A, Fortea J, Alzheimer’s Disease Neuroimaging Initiative (2015) APOE-by-sex interactions on brain structure and metabolism in healthy elderly controls. Oncotarget 6(29):26663–26674

    Article  PubMed  PubMed Central  Google Scholar 

  116. Khan W, Giampietro V, Banaschewski T, Barker GJ, Bokde AL, Büchel C, Conrod P, Flor H, Frouin V, Garavan H, Gowland P, Heinz A, Ittermann B, Lemaître H, Nees F, Paus T, Pausova Z, Rietschel M, Smolka MN, Ströhle A, Gallinat J, Vellas B, Soininen H, Kloszewska I, Tsolaki M, Mecocci P, Spenger C, Villemagne VL, Masters CL, Muehlboeck JS, Bäckman L, Fratiglioni L, Kalpouzos G, Wahlund LO, Schumann G, Lovestone S, Williams SC, Westman E, Simmons A, Alzheimer’s Disease Neuroimaging Initiative; AddNeuroMed Consortium, Australian, Imaging, Biomarkers, and Lifestyle Study Research Group, IMAGEN consortium (2017) A multi-cohort study of ApoE ɛ4 and amyloid-β effects on the hippocampus in Alzheimer’s disease. J Alzheimers Dis 56(3):1159–1174

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  117. Falahati F, Ferreira D, Muehlboeck JS, Eriksdotter M, Simmons A, Wahlund LO, Westman E (2017) Monitoring disease progression in mild cognitive impairment: associations between atrophy patterns, cognition, APOE and amyloid. Neuroimage Clin 16:418–428

    Article  PubMed  PubMed Central  Google Scholar 

  118. Rogne S, Vangberg T, Eldevik P, Wikran G, Mathiesen EB, Schirmer H (2016) Magnetic resonance volumetry: prediction of subjective memory complaints and mild cognitive impairment, and associations with genetic and cardiovascular risk factors. Dement Geriatr Cogn Dis Extra 6(3):529–540

    Article  PubMed  PubMed Central  Google Scholar 

  119. Konishi K, Bhat V, Banner H, Poirier J, Joober R, Bohbot VD (2016) APOE2 is associated with spatial navigational strategies and increased gray matter in the hippocampus. Front Hum Neurosci 13(10):349

    Google Scholar 

  120. Habes M, Toledo JB, Resnick SM, Doshi J, Van der Auwera S, Erus G, Janowitz D, Hegenscheid K, Homuth G, Völzke H, Hoffmann W, Grabe HJ, Davatzikos C (2016) Relationship between APOE genotype and structural MRI measures throughout adulthood in the study of health in pomerania population-based cohort. AJNR Am J Neuroradiol 37(9):1636–1642

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  121. Fang Y, Du N, Xing L, Duo Y, Zheng L (2019) Evaluation of hippocampal volume and serum brain-derived neurotrophic factor as potential diagnostic markers of conversion from amnestic mild cognitive impairment to Alzheimer disease: a STROBE-compliant article. Med (Baltim) 98(30):16604

    Article  CAS  Google Scholar 

  122. Lupton MK, Strike L, Hansell NK, Wen W, Mather KA, Armstrong NJ, Thalamuthu A, McMahon KL, de Zubicaray GI, Assareh AA, Simmons A, Proitsi P, Powell JF, Montgomery GW, Hibar DP, Westman E, Tsolaki M, Kloszewska I, Soininen H, Mecocci P, Velas B, Lovestone S, Initiative ADN, Brodaty H, Ames D, Trollor JN, Martin NG, Thompson PM, Sachdev PS, Wright MJ (2016) The effect of increased genetic risk for Alzheimer’s disease on hippocampal and amygdala volume. Neurobiol Aging 40:68–77

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  123. Hobel Z, Isenberg AL, Raghupathy D, Mack W, Pa J, Alzheimer’s Disease Neuroimaging Initiative and the Australian Imaging Biomarkers and Lifestyle flagship study of ageing (2019) APOEɛ4 gene dose and sex effects on Alzheimer’s disease MRI biomarkers in older adults with mild cognitive impairment. J Alzheimers Dis 71(2):647–658

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  124. Schreiber S, Schreiber F, Lockhart SN, Horng A, Bejanin A, Landau SM, Jagust WJ, Alzheimer’s Disease Neuroimaging Initiative (2017) Alzheimer disease signature neurodegeneration and APOE genotype in mild cognitive impairment with suspected non-Alzheimer disease pathophysiology. JAMA Neurol 74(6):650–659

    Article  PubMed  PubMed Central  Google Scholar 

  125. Haller S, Montandon ML, Rodriguez C, Ackermann M, Herrmann FR, Giannakopoulos P (2017) APOE*E4 is associated with gray matter loss in the posterior cingulate cortex in healthy elderly controls subsequently developing subtle cognitive decline. AJNR Am J Neuroradiol 38(7):1335–1342

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  126. Nao J, Sun H, Wang Q, Ma S, Zhang S, Dong X, Ma Y, Wang X, Zheng D (2017) Adverse effects of the apolipoprotein E ε4 allele on episodic memory, task switching and gray matter volume in healthy young adults. Front Hum Neurosci 11:346

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  127. Li Z, Yang N, Lei X, Lin C, Li N, Jiang X, Wei X, Xu B (2019) The association between the ApoE polymorphisms and the MRI-defined intracranial lesions in a cohort of southern China population. J Clin Lab Anal 33(7):e22950

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  128. Hays CC, Zlatar ZZ, Meloy MJ, Bondi MW, Gilbert PE, Liu TT, Helm JL, Wierenga CE (2019) APOE modifies the interaction of entorhinal cerebral blood flow and cortical thickness on memory function in cognitively normal older adults. Neuroimage 202:116162

    Article  CAS  PubMed  Google Scholar 

  129. Herrmann FR, Rodriguez C, Haller S, Garibotto V, Montandon ML, Giannakopoulos P (2019) Gray matter densities in limbic areas and APOE4 independently predict cognitive decline in normal brain aging. Front Aging Neurosci 11:157

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  130. Foley SF, Tansey KE, Caseras X, Lancaster T, Bracht T, Parker G, Hall J, Williams J, Linden DE (2017) Multimodal brain imaging reveals structural differences in Alzheimer’s disease polygenic risk carriers: a study in healthy young adults. Biol Psychiatry 81(2):154–161

    Article  PubMed  PubMed Central  Google Scholar 

  131. Ghisays V, Goradia DD, Protas H, Bauer RJ 3rd, Devadas V, Tariot PN, Lowe VJ, Knopman DS, Petersen RC, Jack CR Jr, Caselli RJ, Su Y, Chen K, Reiman EM (2020) Brain imaging measurements of fibrillar amyloid-β burden, paired helical filament tau burden, and atrophy in cognitively unimpaired persons with two, one, and no copies of the APOE ε4 allele. Alzheimers Dement 16(4):598–609

    Article  PubMed  PubMed Central  Google Scholar 

  132. Cotta Ramusino M, Altomare D, Bacchin R, Ingala S, Bnà C, Bonetti M, Costa A, Barkhof F, Nicolosi V, Festari C, Frisoni GB, Boccardi M (2019) Medial temporal lobe atrophy and posterior atrophy scales normative values. Neuroimage Clin 24:101936

    Article  PubMed  PubMed Central  Google Scholar 

  133. Lyall DM, Cox SR, Lyall LM, Celis-Morales C, Cullen B, Mackay DF, Ward J, Strawbridge RJ, McIntosh AM, Sattar N, Smith DJ, Cavanagh J, Deary IJ, Pell JP (2020) Association between APOE e4 and white matter hyperintensity volume, but not total brain volume or white matter integrity. Brain Imaging Behav 14(5):1468–1476

    Article  PubMed  Google Scholar 

  134. Kim DH, Payne ME, Levy RM, MacFall JR, Steffens DC (2002) APOE genotype and hippocampal volume change in geriatric depression. Biol Psychiatry 51(5):426–429

    Article  CAS  PubMed  Google Scholar 

  135. Agosta F, Vossel KA, Miller BL, Migliaccio R, Bonasera SJ, Filippi M, Boxer AL, Karydas A, Possin KL, Gorno-Tempini ML (2009) Apolipoprotein E epsilon4 is associated with disease-specific effects on brain atrophy in Alzheimer’s disease and frontotemporal dementia. Proc Natl Acad Sci USA 106(6):2018–2022

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  136. Jack CR Jr, Petersen RC, Xu YC, O’Brien PC, Waring SC, Tangalos EG, Smith GE, Ivnik RJ, Thibodeau SN, Kokmen E (1998) Hippocampal atrophy and apolipoprotein E genotype are independently associated with Alzheimer’s disease. Ann Neurol 43(3):303–310

    Article  PubMed  PubMed Central  Google Scholar 

  137. Zhang C, Kong M, Wei H, Zhang H, Ma G, Ba M, lzheimer’s Disease Neuroimaging Initiative (2020) The effect of ApoE ε 4 on clinical and structural MRI markers in prodromal Alzheimer’s disease. Quant Imaging Med Surg 10(2):464–474

    Article  PubMed  PubMed Central  Google Scholar 

  138. Julkunen V, Niskanen E, Koikkalainen J, Herukka SK, Pihlajamäki M, Hallikainen M, Kivipelto M, Muehlboeck S, Evans AC, Vanninen R, Hilkka S (2010) Differences in cortical thickness in healthy controls, subjects with mild cognitive impairment, and Alzheimer’s disease patients: a longitudinal study. J Alzheimers Dis 21(4):1141–1151

    Article  PubMed  Google Scholar 

  139. Shaw P, Lerch JP, Pruessner JC, Taylor KN, Rose AB, Greenstein D, Clasen L, Evans A, Rapoport JL, Giedd JN (2007) Cortical morphology in children and adolescents with different apolipoprotein E gene polymorphisms: an observational study. Lancet Neurol 6(6):494–500

    Article  CAS  PubMed  Google Scholar 

  140. Thomann PA, Roth AS, Dos Santos V, Toro P, Essig M, Schröder J (2008) Apolipoprotein E polymorphism and brain morphology in mild cognitive impairment. Dement Geriatr Cogn Disord 26(4):300–305

    Article  CAS  PubMed  Google Scholar 

  141. Gutiérrez-Galve L, Lehmann M, Hobbs NZ, Clarkson MJ, Ridgway GR, Crutch S, Ourselin S, Schott JM, Fox NC, Barnes J (2009) Patterns of cortical thickness according to APOE genotype in Alzheimer’s disease. Dement Geriatr Cogn Disord 28(5):476–485

    Article  PubMed  Google Scholar 

  142. Yan S, Zheng C, Paranjpe MD, Li J, Benzinger TLS, Lu J, Zhou Y (2020) Association of sex and APOE ε4 with brain tau deposition and atrophy in older adults with Alzheimer’s disease. Theranostics 10(23):10563–10572

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  143. Lee YM, Ha JK, Park JM, Lee BD, Moon E, Chung YI, Kim JH, Kim HJ, Mun CW, Kim TH, Kim YH (2016) Impact of Apolipoprotein E4 polymorphism on the gray matter volume and the white matter integrity in subjective memory impairment without white matter hyperintensities: voxel-based morphometry and tract-based spatial statistics study under 3-tesla MRI. J Neuroimaging 26(1):144–149

    Article  PubMed  Google Scholar 

  144. Goñi J, Cervantes S, Arrondo G, Lamet I, Pastor P, Pastor MA (2013) Selective brain gray matter atrophy associated with APOE ε4 and MAPT H1 in subjects with mild cognitive impairment. J Alzheimers Dis 33(4):1009–1019

    Article  PubMed  CAS  Google Scholar 

  145. Grau-Rivera O, Operto G, Falcón C, Sánchez-Benavides G, Cacciaglia R, Brugulat-Serrat A, Gramunt N, Salvadó G, Suárez-Calvet M, Minguillon C, Iranzo Á, Gispert JD, Molinuevo JL (2020) Association between insomnia and cognitive performance, gray matter volume, and white matter microstructure in cognitively unimpaired adults. Alzheimers Res Ther 12(1):4

    Article  PubMed  PubMed Central  Google Scholar 

  146. Pievani M, Rasser PE, Galluzzi S, Benussi L, Ghidoni R, Sabattoli F, Bonetti M, Binetti G, Thompson PM, Frisoni GB (2009) Mapping the effect of APOE epsilon4 on gray matter loss in Alzheimer’s disease in vivo. Neuroimage 45(4):1090–1098

    Article  CAS  PubMed  Google Scholar 

  147. Hashimoto M, Yasuda M, Tanimukai S, Matsui M, Hirono N, Kazui H, Mori E (2001) Apolipoprotein E epsilon 4 and the pattern of regional brain atrophy in Alzheimer’s disease. Neurology 57(8):1461–1466

    Article  CAS  PubMed  Google Scholar 

  148. Rowe CC, Ellis KA, Rimajova M, Bourgeat P, Pike KE, Jones G, Fripp J, Tochon-Danguy H, Morandeau L, O’Keefe G, Price R, Raniga P, Robins P, Acosta O, Lenzo N, Szoeke C, Salvado O, Head R, Martins R, Masters CL, Ames D, Villemagne VL (2010) Amyloid imaging results from the Australian imaging, biomarkers and lifestyle (AIBL) study of aging. Neurobiol Aging 31(8):1275–1283

    Article  PubMed  Google Scholar 

  149. Mori E, Lee K, Yasuda M, Hashimoto M, Kazui H, Hirono N, Matsui M (2002) Accelerated hippocampal atrophy in Alzheimer’s disease with apolipoprotein E epsilon4 allele. Ann Neurol 51(2):209–214

    Article  CAS  PubMed  Google Scholar 

  150. Pievani M, Galluzzi S, Thompson PM, Rasser PE, Bonetti M, Frisoni GB (2011) APOE4 is associated with greater atrophy of the hippocampal formation in Alzheimer’s disease. Neuroimage 55(3):909–919

    Article  CAS  PubMed  Google Scholar 

  151. Huttenlocher PR (1979) Synaptic density in human frontal cortex—developmental changes and effects of aging. Brain Res 163(2):195–205

    Article  CAS  PubMed  Google Scholar 

  152. Cotter D, Mackay D, Chana G, Beasley C, Landau S, Everall IP (2002) Reduced neuronal size and glial cell density in area 9 of the dorsolateral prefrontal cortex in subjects with major depressive disorder. Cereb Cortex 12(4):386–394

    Article  PubMed  Google Scholar 

  153. Lehmann M, Rohrer JD, Clarkson MJ, Ridgway GR, Scahill RI, Modat M, Warren JD, Ourselin S, Barnes J, Rossor MN, Fox NC (2010) Reduced cortical thickness in the posterior cingulate gyrus is characteristic of both typical and atypical Alzheimer’s disease. J Alzheimers Dis 20(2):587–598

    Article  PubMed  Google Scholar 

  154. Scheltens NME, van der Weijden K, Adriaanse SM, van Assema D, Oomen PP, Krudop WA, Lammertsma AA, Barkhof F, Koene T, Teunissen CE, Scheltens P, van der Flier WM, Pijnenburg YAL, Yaqub M, Ossenkoppele R, van Berckel BNM (2018) Hypometabolism of the posterior cingulate cortex is not restricted to Alzheimer’s disease. Neuroimage Clin 19:625–632

    Article  PubMed  PubMed Central  Google Scholar 

  155. Voevodskaya O, Sundgren PC, Strandberg O, Zetterberg H, Minthon L, Blennow K, Wahlund LO, Westman E, Hansson O, Swedish BioFINDER study group (2016) Myo-inositol changes precede amyloid pathology and relate to APOE genotype in Alzheimer disease. Neurology 86(19):1754–1761

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  156. Suri S, Emir U, Stagg CJ, Near J, Mekle R, Schubert F, Zsoldos E, Mahmood A, Singh-Manoux A, Kivimäki M, Ebmeier KP, Mackay CE, Filippini N (2017) Effect of age and the APOE gene on metabolite concentrations in the posterior cingulate cortex. Neuroimage 152:509–516

    Article  CAS  PubMed  Google Scholar 

  157. Leech R, Sharp DJ (2014) The role of the posterior cingulate cortex in cognition and disease. Brain 137(Pt 1):12–32

    Article  PubMed  Google Scholar 

  158. Yokoi T, Watanabe H, Yamaguchi H, Bagarinao E, Masuda M, Imai K, Ogura A, Ohdake R, Kawabata K, Hara K, Riku Y, Ishigaki S, Katsuno M, Miyao S, Kato K, Naganawa S, Harada R, Okamura N, Yanai K, Yoshida M, Sobue G (2018) Involvement of the precuneus/posterior cingulate cortex is significant for the development of Alzheimer’s disease: a PET (THK5351, PiB) and resting fMRI study. Front Aging Neurosci 10:304

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  159. Braak H, Braak E (1991) Neuropathological stageing of Alzheimer-related changes. Acta Neuropathol 82(4):239–259

    Article  CAS  PubMed  Google Scholar 

  160. Han SD, Bondi MW (2008) Revision of the apolipoprotein E compensatory mechanism recruitment hypothesis. Alzheimer’s Dement 4(4):251–254

    Article  CAS  Google Scholar 

  161. Smith MZ, Esiri MM, Barnetson L, King E, Nagy Z (2001) Constructional apraxia in Alzheimer’s disease: association with occipital lobe pathology and accelerated cognitive decline. Dement Geriatr Cogn Disord 12(4):281–288

    Article  CAS  PubMed  Google Scholar 

  162. Huang X, Pu W, Li X, Greenshaw AJ, Dursun SM, Xue Z, Liu H, Liu Z (2017) Decreased left putamen and thalamus volume correlates with delusions in first-episode schizophrenia patients. Front Psychiatry 8:245

    Article  PubMed  PubMed Central  Google Scholar 

  163. Salgado S, Kaplitt MG (2015) The nucleus accumbens: a comprehensive review. Stereotact Funct Neurosurg 93(2):75–93

    Article  PubMed  Google Scholar 

  164. Mattsson N, Insel PS, Donohue M, Landau S, Jagust WJ, Shaw LM, Trojanowski JQ, Zetterberg H, Blennow K, Weiner MW, Alzheimer’s Disease Neuroimaging Initiative (2015) Independent information from cerebrospinal fluid amyloid-β and florbetapir imaging in Alzheimer’s disease. Brain 138(Pt 3):772–783

    Article  PubMed  Google Scholar 

  165. Palmqvist S, Zetterberg H, Mattsson N, Johansson P, Minthon L, Blennow K, Olsson M, Hansson O, Alzheimer’s Disease Neuroimaging Initiative, Swedish BioFINDER Study Group (2015) Detailed comparison of amyloid PET and CSF biomarkers for identifying early Alzheimer disease. Neurology 85(14):1240–1249

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  166. Hansson O, Seibyl J, Stomrud E, Zetterberg H, Trojanowski JQ, Bittner T, Lifke V, Corradini V, Eichenlaub U, Batrla R, Buck K, Zink K, Rabe C, Blennow K, Shaw LM, BioFINDER S, study group, Alzheimer’s Disease Neuroimaging Initiative, (2018) CSF biomarkers of Alzheimer’s disease concord with amyloid-β PET and predict clinical progression: a study of fully automated immunoassays in BioFINDER and ADNI cohorts. Alzheimers Dement 14(11):1470–1481

    Article  PubMed  PubMed Central  Google Scholar 

  167. De Santi S, de Leon MJ, Rusinek H, Convit A, Tarshish CY, Roche A, Tsui WH, Kandil E, Boppana M, Daisley K, Wang GJ, Schlyer D, Fowler J (2001) Hippocampal formation glucose metabolism and volume losses in MCI and AD. Neurobiol Aging 22(4):529–539

    Article  PubMed  Google Scholar 

  168. de Prado BP, Mercader EMH, Pujol J, Sunyer J, Mortamais M (2018) The effects of air pollution on the brain: a review of studies interfacing environmental epidemiology and neuroimaging. Curr Environ Health Rep 5(3):351–364

    Article  CAS  Google Scholar 

  169. Herting MM, Younan D, Campbell CE, Chen JC (2019) Outdoor air pollution and brain structure and function from across childhood to young adulthood: a methodological review of brain MRI studies. Front Public Health 7:332

    Article  PubMed  PubMed Central  Google Scholar 

  170. Clifford A, Lang L, Chen R, Anstey KJ, Seaton A (2016) Exposure to air pollution and cognitive functioning across the life course—a systematic literature review. Environ Res 147:383–398

    Article  CAS  PubMed  Google Scholar 

  171. Donohue MC, Sperling RA, Salmon DP, Rentz DM, Raman R, Thomas RG, Weiner M, Aisen PS, Australian Imaging, Biomarkers, and Lifestyle Flagship Study of Ageing; Alzheimer’s Disease Neuroimaging Initiative; Alzheimer’s Disease Cooperative Study (2014) The preclinical Alzheimer cognitive composite: measuring amyloid-related decline. JAMA Neurol 71(8):961–970

    Article  PubMed  PubMed Central  Google Scholar 

  172. Lancaster C, Tabet N, Rusted J (2017) The elusive nature of APOE ε4 in mid-adulthood: understanding the cognitive profile. J Int Neuropsychol Soc 23(3):239–253

    Article  PubMed  Google Scholar 

  173. Frost GR, Longo V, Li T, Jonas LA, Judenhofer M, Cherry S et al (2020) Hybrid PET/MRI enables high-spatial resolution, quantitative imaging of amyloid plaques in an Alzheimer’s disease mouse model. Sci Rep 10(1):1–8

    CAS  Google Scholar 

  174. Zhang XY, Yang ZL, Lu GM, Yang GF, Zhang LJ (2017) PET/MR imaging: new frontier in Alzheimer’s disease and other dementias. Front Mol Neurosci 10:343

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  175. Landau SM, Lu M, Joshi AD, Pontecorvo M, Mintun MA, Trojanowski JQ, Shaw LM, Jagust WJ, Initiative ADN (2013) Comparing positron emission tomography imaging and cerebrospinal fluid measurements of β-amyloid. Ann Neurol 74(6):826–836

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  176. Palmqvist S, Mattsson N, Hansson O, Alzheimer’s Disease Neuroimaging Initiative (2016) Cerebrospinal fluid analysis detects cerebral amyloid-β accumulation earlier than positron emission tomography. Brain 139(Pt 4):1226–1236

    Article  PubMed  PubMed Central  Google Scholar 

  177. Sala A, Nordberg A, Rodriguez-Vieitez E (2020) Longitudinal pathways of cerebrospinal fluid and positron emission tomography biomarkers of amyloid-β positivity. Mol Psychiatry. https://doi.org/10.1038/s41380-020-00950-w

    Article  PubMed  PubMed Central  Google Scholar 

  178. La Joie R, Visani AV, Lesman-Segev OH, Baker SL, Edwards L, Iaccarino L, Soleimani-Meigooni DN, Mellinger T, Janabi M, Miller ZA, Perry DC, Pham J, Strom A, Gorno-Tempini ML, Rosen HJ, Miller BL, Jagust WJ, Rabinovici GD (2021) Association of APOE4 and clinical variability in Alzheimer disease with the pattern of tau- and amyloid-PET. Neurology 96(5):e650–e661

    Article  PubMed  PubMed Central  Google Scholar 

  179. La Joie R, Visani AV, Baker SL, Brown JA, Bourakova V, Cha J, Chaudhary K, Edwards L, Iaccarino L, Janabi M, Lesman-Segev OH, Miller ZA, Perry DC, O’Neil JP, Pham J, Rojas JC, Rosen HJ, Seeley WW, Tsai RM, Miller BL, Jagust WJ, Rabinovici GD (2020) Prospective longitudinal atrophy in Alzheimer’s disease correlates with the intensity and topography of baseline tau-PET. Sci Transl Med 12(524):5732

    Article  CAS  Google Scholar 

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Conception and study design (ADP), data collection (ADP), interpretation of results (ADP, MM, and SS); drafting the manuscript work (ADP), revising manuscript (ADP, MM, SS, and NFR); approval of final version to be published and agreement to be accountable for the integrity and accuracy of all aspects of the work (ADP, MM, SS, and NFR).

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Piersson, A.D., Mohamad, M., Suppiah, S. et al. Topographical patterns of whole-brain structural alterations in association with genetic risk, cerebrospinal fluid, positron emission tomography biomarkers of Alzheimer’s disease, and neuropsychological measures. Clin Transl Imaging 9, 439–497 (2021). https://doi.org/10.1007/s40336-021-00440-1

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