Dementia Risk Factors Modify Hubs but Leave Other Connectivity Measures Unchanged in Asymptomatic Individuals: A Graph Theoretical Analysis.

Publisher: Mary Ann Liebert, Inc Country of Publication: United States NLM ID: 101550313 Publication Model: Print-Electronic Cited Medium: Internet ISSN: 2158-0022 (Electronic) Linking ISSN: 21580014 NLM ISO Abbreviation: Brain Connect Subsets: MEDLINE

Original Publication: New Rochelle, NY : Mary Ann Liebert, Inc.

Alzheimer Disease*/diagnostic imaging ; Alzheimer Disease*/genetics ; Alzheimer Disease*/pathology; Apolipoprotein E4/genetics ; Brain ; Humans ; Longitudinal Studies ; Magnetic Resonance Imaging/methods ; Risk Factors

Background: Alzheimer's disease (AD) is the most common form of dementia with genetic and environmental risk contributing to its development. Graph theoretical analyses of brain networks constructed from structural and functional magnetic resonance imaging (MRI) measurements have identified connectivity changes in AD and individuals with mild cognitive impairment. However, brain connectivity in asymptomatic individuals at risk of AD remains poorly understood. Methods: We analyzed diffusion-weighted MRI data from 161 asymptomatic individuals (38-71 years) from the Cardiff Ageing and Risk of Dementia Study (CARDS). We calculated white matter tracts and constructed whole-brain, default mode network (DMN) and visual structural brain networks that incorporate multiple structural metrics as edge weights. We then calculated the relationship of three AD risk factors, namely Apolipoprotein-E ɛ4 ( APOE4 ) genotype, family history of dementia (FH), and central obesity (Waist-Hip-Ratio [WHR]), on graph theoretical measures and hubs. Results: We observed no risk-related differences in clustering coefficients, characteristic path lengths, eccentricity, diameter, and radius across the whole-brain, DMN or visual system. However, a hub in the right paracentral lobule was present in all the high-risk groups (FH, APOE4 , obese), but absent in low-risk groups (no FH, APOE4 -ve, healthy WHR). Discussion: We identified no risk-related effects on graph theoretical metrics in the structural brain networks of cognitively healthy individuals. However, high risk was associated with a hub in the right paracentral lobule, a medial fronto-parietal cortical area with motor and sensory functions. This finding is consistent with accumulating evidence for right parietal cortex contributions in AD. If this phenotype is shown to predict symptom development in longitudinal studies, it could be used as an early biomarker of AD. Impact statement Alzheimer's disease (AD) is a common form of dementia that to date has no cure. Identifying early biomarkers will aid the discovery and development of treatments that may slow AD progression in the future. In this article, we report that asymptomatic individuals at heightened risk of dementia due to their family history, Apolipoprotein-E ɛ4 genotype, and central adiposity have a hub in the right paracentral lobule, which is absent in low-risk groups. If this phenotype were to predict the development of symptoms in a longitudinal study of the same cohort, it could provide an early biomarker of disease progression.

Neurobiol Aging. 2019 Mar;75:71-82. (PMID: 30553155)
AJNR Am J Neuroradiol. 2008 May;29(5):843-52. (PMID: 18339719)
Neuroimage. 2019 Apr 1;189:793-803. (PMID: 30735826)
Magn Reson Med. 1999 Sep;42(3):515-25. (PMID: 10467296)
Brain Struct Funct. 2017 Mar;222(2):923-942. (PMID: 27357309)
Sci Rep. 2020 Nov 13;10(1):19787. (PMID: 33188215)
Lancet. 2020 Aug 8;396(10248):413-446. (PMID: 32738937)
Neuroimage. 2010 Sep;52(3):1059-69. (PMID: 19819337)
Neuroimage. 2019 Oct 1;199:495-511. (PMID: 31176831)
Neurol Sci. 2019 Nov;40(11):2333-2342. (PMID: 31243597)
Neuroimage. 2010 Jan 15;49(2):1446-58. (PMID: 19781650)
Mol Neurobiol. 2017 Nov;54(9):6999-7007. (PMID: 27785756)
Netw Neurosci. 2021 Jun 03;5(2):477-504. (PMID: 34189374)
J Neurosci. 2010 Dec 15;30(50):16876-85. (PMID: 21159959)
J Neurol Neurosurg Psychiatry. 2004 Mar;75(3):370-6. (PMID: 14966149)
Gen Psychiatr. 2019 Apr 16;32(2):e100005. (PMID: 31179429)
Annu Rev Clin Psychol. 2011;7:113-40. (PMID: 21128784)
Neurology. 2013 May 7;80(19):1778-83. (PMID: 23390181)
J Psychiatr Res. 1975 Nov;12(3):189-98. (PMID: 1202204)
J Neurosci. 2015 Jan 28;35(4):1423-31. (PMID: 25632120)
Neuroimage. 2015 Sep;118:313-33. (PMID: 25982515)
Sci Rep. 2019 Jan 31;9(1):1060. (PMID: 30705365)
Brain Neurosci Adv. 2020 Jan 22;4:2398212819899316. (PMID: 32219177)
Front Neurosci. 2017 Dec 19;11:694. (PMID: 29311775)
Neuroimage Clin. 2019;22:101795. (PMID: 30991617)
Hum Brain Mapp. 2021 Sep;42(13):4261-4280. (PMID: 34170066)
Neuroimage. 2002 Jan;15(1):273-89. (PMID: 11771995)
Brain Connect. 2017 Dec;7(10):661-670. (PMID: 28891322)
Neurobiol Aging. 2020 Oct;94:298-310. (PMID: 32736120)
Neuroimage. 2012 May 15;61(1):275-88. (PMID: 22401760)
J Neurosci. 2009 Feb 11;29(6):1860-73. (PMID: 19211893)
Elife. 2019 Apr 30;8:. (PMID: 31038453)
Nat Rev Neurosci. 2009 Mar;10(3):186-98. (PMID: 19190637)
ISRN Geriatr. 2013;2013:. (PMID: 25414852)
Neuroimage. 2020 May 1;211:116443. (PMID: 31927129)
Magn Reson Med. 2002 Oct;48(4):577-82. (PMID: 12353272)
Alzheimers Dement (Amst). 2017 Apr 18;8:73-85. (PMID: 28560308)
J Neurosci Methods. 2010 Oct 30;193(1):145-55. (PMID: 20817039)
Hum Brain Mapp. 2005 May;25(1):165-73. (PMID: 15846812)
Neuron. 2011 Nov 17;72(4):665-78. (PMID: 22099467)
Proc Natl Acad Sci U S A. 2011 Dec 20;108(51):20760-5. (PMID: 22106308)
Magn Reson Med. 2000 Oct;44(4):625-32. (PMID: 11025519)
Ann Neurol. 2012 Oct;72(4):571-7. (PMID: 23109152)
AJNR Am J Neuroradiol. 2008 Apr;29(4):632-41. (PMID: 18339720)
Neuroimage. 2019 Jul 1;194:68-81. (PMID: 30844506)
Trends Cogn Sci. 2013 Dec;17(12):683-96. (PMID: 24231140)
J Gen Intern Med. 2001 Sep;16(9):606-13. (PMID: 11556941)

208 United Kingdom ALZS_ Alzheimer's Society; 108891/B/15/Z United Kingdom WT_ Wellcome Trust; MR/K004360/1 United Kingdom MRC_ Medical Research Council; 204824/Z/16/Z United Kingdom WT_ Wellcome Trust

Keywords: Alzheimer's disease; graph theoretical analysis; hubs; risk factors

0 (Apolipoprotein E4)

Date Created: 20210525 Date Completed: 20220503 Latest Revision: 20220503

20240105

PMC8867081

10.1089/brain.2020.0935

34030485