Impact of apolipoprotein E ε4 and HIV on cognition and brain atrophy: Antagonistic pleiotropy and premature brain aging

OBJECTIVE The apolipoprotein E (APOE) ε4 allele may accelerate the progression of HIV disease, and increase the risk for developing HIV-associated neurocognitive disorder (HAND). Whether APOEε4 allele(s) and age may influence brain atrophy in HIV patients is unknown and was evaluated. METHODS Automated morphometry on magnetic resonance images, using FreeSurfer analyses, neuropsychological testing and APOE genotyping were performed in 139 subjects [70 seronegative controls (SN); 69 clinically-stable HIV subjects]. RESULTS Compared to SN, HIV subjects had smaller volumes throughout the brain regardless of their HAND status. Compared to APOEε4- subjects, SN controls with APOEε4 had better memory and larger global brain volumes (cerebral white matter and cortex) while HIV subjects with the APOEε4 allele(s) had poorer cognition (verbal fluency, learning, executive function and memory) and smaller cerebral and cerebellar white matter and subcortical structures. Further stratification of age showed that younger (<50 years) APOEε4+SN subjects had larger putamen and cerebral white matter, while younger APOEε4+HIV subjects had poorer performance on verbal fluency and smaller brain volumes [3-way (HIV-status×APOEε4×Age) interaction-p-values=0.005 to 0.03]. INTERPRETATION These findings suggest that APOEε4 allele(s) may show antagonistic pleiotropy on cognition and brain atrophy in SN controls, but may lead to premature aging with neurodegeneration in younger HIV patients prior to the development of HAND. Potential mechanisms for such interactions may include stronger neuro-inflammation or greater amyloid deposition in younger HIV subjects with APOEε4 allele(s). Early screening for the APOEε4 allele and brain atrophy with morphometry may guide neuroprotective intervention of cognitively normal HIV subjects prior to the development of HAND. Longitudinal follow-up studies and larger sample sizes are needed to validate these cross-sectional results.

[1]  Michael W Weiner,et al.  Abnormal contingent negative variation in HIV patients receiving antiretroviral therapy , 2003, Neuroreport.

[2]  Jianhui Zhong,et al.  Effects of Nadir Cd4 Count and Duration of Human Immunodeficiency Virus Infection on Brain Volumes in the Highly Active Antiretroviral Therapy Era , 2022 .

[3]  Thomas Ernst,et al.  Decreased brain dopamine transporters are related to cognitive deficits in HIV patients with or without cocaine abuse , 2008, NeuroImage.

[4]  T. Ernst,et al.  A multicenter in vivo proton-MRS study of HIV-associated dementia and its relationship to age , 2004, NeuroImage.

[5]  D. Tomasi,et al.  Adaptation of the attention network in human immunodeficiency virus brain injury , 2004, Annals of neurology.

[6]  G. D. Pearlson,et al.  Reduced basal ganglia volume in HIV‐1‐associated dementia , 1993, Neurology.

[7]  U Seligsohn,et al.  Improved method for genotyping apolipoprotein E polymorphisms by a PCR-based assay simultaneously utilizing two distinct restriction enzymes. , 1997, Clinical chemistry.

[8]  Linda Chang,et al.  Lower brain glutamate is associated with cognitive deficits in HIV patients: A new mechanism for HIV‐associated neurocognitive disorder , 2010, Journal of magnetic resonance imaging : JMRI.

[9]  Y. Liu,et al.  Age, apolipoprotein E4, and the risk of HIV dementia: the Hawaii Aging with HIV Cohort , 2004, Journal of Neuroimmunology.

[10]  J. M. Gatt,et al.  The contribution of apolipoprotein E alleles on cognitive performance and dynamic neural activity over six decades , 2007, Biological Psychology.

[11]  J. Gilbert,et al.  Human Apolipoprotein E Isoform‐Specific Differences in Neuronal Sprouting in Organotypic Hippocampal Culture , 1999, Journal of neurochemistry.

[12]  Matthias Orth,et al.  Expression of Human Apolipoprotein E3 or E4 in the Brains ofApoe−/− Mice: Isoform-Specific Effects on Neurodegeneration , 1999, The Journal of Neuroscience.

[13]  P. Perschler,et al.  Impairments in memory and hippocampal function in HIV-positive vs HIV-negative women , 2009, Neurology.

[14]  Dan J Stein,et al.  Association between apolipoprotein E4 genotype and human immunodeficiency virus-associated dementia in younger adults starting antiretroviral therapy in South Africa , 2010, Journal of NeuroVirology.

[15]  R. Mahley,et al.  Astrocytes synthesize apolipoprotein E and metabolize apolipoprotein E-containing lipoproteins. , 1987, Biochimica et biophysica acta.

[16]  M W Weiner,et al.  Brain atrophy in HIV infection is more strongly associated with CDC clinical stage than with cognitive impairment , 1997, Journal of the International Neuropsychological Society.

[17]  Michael Watters,et al.  Lowest ever CD4 lymphocyte count (CD4 nadir) as a predictor of current cognitive and neurological status in human immunodeficiency virus type 1 infection—The Hawaii Aging with HIV Cohort , 2006, Journal of NeuroVirology.

[18]  R. Simes,et al.  An improved Bonferroni procedure for multiple tests of significance , 1986 .

[19]  G D Pearlson,et al.  Magnetic resonance imaging measurement of gray matter volume reductions in HIV dementia. , 1995, The American journal of psychiatry.

[20]  Ming-Chang Chiang,et al.  Mapping cerebellar degeneration in HIV/AIDS , 2008, Neuroreport.

[21]  E. Weeber,et al.  ApoE4 Decreases Spine Density and Dendritic Complexity in Cortical Neurons In Vivo , 2009, The Journal of Neuroscience.

[22]  J. Conomy,et al.  The neurology of AIDS. , 1989, Singapore medical journal.

[23]  Yulin Ge,et al.  Whole brain imaging of HIV-infected patients: quantitative analysis of magnetization transfer ratio histogram and fractional brain volume. , 2003, AJNR. American journal of neuroradiology.

[24]  Paul M. Matthews,et al.  Differential effects of the APOE genotype on brain function across the lifespan , 2011, NeuroImage.

[25]  Paul M. Thompson,et al.  3 D pattern of brain atrophy in HIV / AIDS visualized using tensor-based morphometry , 2006 .

[26]  Abraham Z. Snyder,et al.  A unified approach for morphometric and functional data analysis in young, old, and demented adults using automated atlas-based head size normalization: reliability and validation against manual measurement of total intracranial volume , 2004, NeuroImage.

[27]  Jeff E. Mold,et al.  Apolipoprotein (apo) E4 enhances HIV-1 cell entry in vitro, and the APOE ε4/ε4 genotype accelerates HIV disease progression , 2008, Proceedings of the National Academy of Sciences.

[28]  H. Christensen,et al.  APOE genotype and cognitive functioning in a large age-stratified population sample. , 2007, Neuropsychology.

[29]  Simon Easteal,et al.  Does possession of apolipoprotein E ɛ4 benefit cognitive function in healthy young adults? , 2011, Neuropsychologia.

[30]  D. Butterfield,et al.  Apolipoprotein E modulates Alzheimer’s Aβ(1–42)-induced oxidative damage to synaptosomes in an allele-specific manner , 2002, Brain Research.

[31]  P. Doraiswamy,et al.  Learning and recall in subjects at genetic risk for Alzheimer's disease. , 2002, The Journal of neuropsychiatry and clinical neurosciences.

[32]  E. Masliah,et al.  Brain deposition of beta-amyloid is a common pathologic feature in HIV positive patients , 2005, AIDS.

[33]  K. Liestøl,et al.  HIV dementia and apolipoprotein E , 1997, Acta neurologica Scandinavica.

[34]  Tuula Tyry,et al.  APOE ε4 ALLELE IS ASSOCIATED WITH COGNITIVE IMPAIRMENT IN PATIENTS WITH MULTIPLE SCLEROSIS , 2008 .

[35]  Kiralee M. Hayashi,et al.  Thinning of the cerebral cortex visualized in HIV/AIDS reflects CD4+ T lymphocyte decline , 2005, Proceedings of the National Academy of Sciences of the United States of America.

[36]  Susan Swindells,et al.  The Neurology of AIDS , 1998 .

[37]  Chuan Shi,et al.  APOE ϵ4 and MBL-2 O/O genotypes are associated with neurocognitive impairment in HIV-infected plasma donors , 2010, AIDS.

[38]  H. Brewer,et al.  Amyloid-associated proteins α1-antichymotrypsin and apolipoprotein E promote assembly of Alzheimer β-protein into filaments , 1994, Nature.

[39]  J Vincent Filoteo,et al.  Apolipoprotein E and traumatic brain injury in a military population: evidence of a neuropsychological compensatory mechanism? , 2007, Journal of Neurology, Neurosurgery, and Psychiatry.

[40]  J. Kissel,et al.  Cerebellar atrophy associated with human immunodeficiency virus infection. , 2010, Archives of neurology.

[41]  Peter Boesiger,et al.  Better memory and neural efficiency in young apolipoprotein E epsilon4 carriers. , 2007, Cerebral cortex.

[42]  Peter Boesiger,et al.  Better Memory and Neural Efficiency in Young Apolipoprotein E ε4 Carriers , 2007 .

[43]  J. Detre,et al.  Caudate blood flow and volume are reduced in HIV+ neurocognitively impaired patients , 2006, Neurology.

[44]  J. Ma,et al.  Amyloid-associated proteins alpha 1-antichymotrypsin and apolipoprotein E promote assembly of Alzheimer beta-protein into filaments. , 1994, Nature.

[45]  Chantal E. Stern,et al.  Compromised fronto-striatal functioning in HIV: An fMRI investigation of semantic event sequencing , 2008, Behavioural Brain Research.

[46]  Lars Lannfelt,et al.  HIV-infected subjects with the E4 allele for APOE have excess dementia and peripheral neuropathy , 1998, Nature Medicine.

[47]  Mohammad Husain,et al.  Human immunodeficiency virus downregulates podocyte apoE expression. , 2009, American journal of physiology. Renal physiology.

[48]  Linda Chang,et al.  Declined neural efficiency in cognitively stable human immunodeficiency virus patients , 2009, Annals of neurology.

[49]  Richard B Buxton,et al.  HIV infection and aging independently affect brain function as measured by functional magnetic resonance imaging. , 2010, The Journal of infectious diseases.

[50]  C. Studholme,et al.  Evidence for ongoing brain injury in human immunodeficiency virus-positive patients treated with antiretroviral therapy , 2009, Journal of NeuroVirology.

[51]  T. Vollmer,et al.  APOE epsilon 4 allele is associated with cognitive impairment in patients with multiple sclerosis. , 2008, Neurology.

[52]  Linda Chang,et al.  The human immunodeficiency virus reduces network capacity: Acoustic noise effect , 2006, Annals of neurology.

[53]  Christine Fennema-Notestine,et al.  Effects of methamphetamine dependence and HIV infection on cerebral morphology. , 2005, The American journal of psychiatry.

[54]  T. Ernst,et al.  Neural correlates of attention and working memory deficits in HIV patients , 2001, Neurology.

[55]  Carol A. Colton,et al.  APOE genotype-specific differences in the innate immune response , 2009, Neurobiology of Aging.

[56]  John J. Sidtis,et al.  The apolipoprotein E ɛ4 allele and memory performance in HIV-1 seropositive subjects: differences at baseline but not after acute oral lorazepam challenge , 2008, Psychopharmacology.

[57]  J. Becker,et al.  Updated research nosology for HIV-associated neurocognitive disorders , 2007, Neurology.