Peripheral apoE isoform levels in cognitively normal APOE ε3/ε4 individuals are associated with regional gray matter volume and cerebral glucose metabolism

BackgroundCarriers of the APOE ε4 allele are at increased risk of developing Alzheimer’s disease (AD), and have been shown to have reduced cerebral metabolic rate of glucose (CMRgl) in the same brain areas frequently affected in AD. These individuals also exhibit reduced plasma levels of apolipoprotein E (apoE) attributed to a specific decrease in the apoE4 isoform as determined by quantification of individual apoE isoforms in APOE ε4 heterozygotes. Whether low plasma apoE levels are associated with structural and functional brain measurements and cognitive performance remains to be investigated.MethodsUsing quantitative mass spectrometry we quantified the plasma levels of total apoE and the individual apoE3 and apoE4 isoforms in 128 cognitively normal APOE ε3/ε4 individuals included in the Arizona APOE cohort. All included individuals had undergone extensive neuropsychological testing and 25 had in addition undergone FDG-PET and MRI to determine CMRgl and regional gray matter volume (GMV).ResultsOur results demonstrated higher apoE4 levels in females versus males and an age-dependent increase in the apoE3 isoform levels in females only. Importantly, a higher relative ratio of apoE4 over apoE3 was associated with GMV loss in the right posterior cingulate and with reduced CMRgl bilaterally in the anterior cingulate and in the right hippocampal area. Additional exploratory analysis revealed several negative associations between total plasma apoE, individual apoE isoform levels, GMV and CMRgl predominantly in the frontal, occipital and temporal areas. Finally, our results indicated only weak associations between apoE plasma levels and cognitive performance which further appear to be affected by sex.ConclusionsOur study proposes a sex-dependent and age-dependent variation in plasma apoE isoform levels and concludes that peripheral apoE levels are associated with GMV, CMRgl and possibly cognitive performance in cognitively healthy individuals with a genetic predisposition to AD.

[1]  G. Alexander,et al.  Correlations between apolipoprotein E ε4 gene dose and brain-imaging measurements of regional hypometabolism , 2005 .

[2]  S. Estus,et al.  Soluble apoE/Aβ complex: mechanism and therapeutic target for APOE4-induced AD risk , 2014, Molecular Neurodegeneration.

[3]  A. Fagan,et al.  APOE predicts amyloid‐beta but not tau Alzheimer pathology in cognitively normal aging , 2010, Annals of neurology.

[4]  C. Jack,et al.  Association of hypometabolism and amyloid levels in aging, normal subjects , 2014, Neurology.

[5]  A. Fleisher,et al.  The neuropsychology of normal aging and preclinical Alzheimer's disease , 2014, Alzheimer's & Dementia.

[6]  S. Thibodeau,et al.  Preclinical evidence of Alzheimer's disease in persons homozygous for the epsilon 4 allele for apolipoprotein E. , 1996, The New England journal of medicine.

[7]  Margaret A. Pericak-Vance,et al.  Effects of age, sex, and ethnicity on the association between apolipoprotein E genotype and Alzheimer disease , 1997 .

[8]  G. Alexander,et al.  Declining brain activity in cognitively normal apolipoprotein E ɛ4 heterozygotes: A foundation for using positron emission tomography to efficiently test treatments to prevent Alzheimer's disease , 2001, Proceedings of the National Academy of Sciences of the United States of America.

[9]  A. M. Saunders,et al.  Protective effect of apolipoprotein E type 2 allele for late onset Alzheimer disease , 1994, Nature Genetics.

[10]  Sirkka Goebeler,et al.  Apolipoprotein E–dependent accumulation of Alzheimer disease–related lesions begins in middle age , 2009, Annals of neurology.

[11]  O Almkvist,et al.  Impaired cerebral glucose metabolism and cognitive functioning predict deterioration in mild cognitive impairment , 2001, Neuroreport.

[12]  N. Schuff,et al.  Reduced FDG-PET brain metabolism and executive function predict clinical progression in elderly healthy subjects☆☆☆ , 2013, NeuroImage: Clinical.

[13]  J. Baron,et al.  Mild cognitive impairment , 2003, Neurology.

[14]  J. Haines,et al.  Effects of age, sex, and ethnicity on the association between apolipoprotein E genotype and Alzheimer disease. A meta-analysis. APOE and Alzheimer Disease Meta Analysis Consortium. , 1997, JAMA.

[15]  J C Mazziotta,et al.  Apolipoprotein E type 4 allele and cerebral glucose metabolism in relatives at risk for familial Alzheimer disease. , 1995, JAMA.

[16]  Karl J. Friston,et al.  Neuroanatomical correlates of externally and internally generated human emotion. , 1997, The American journal of psychiatry.

[17]  Nick C Fox,et al.  The Diagnosis of Mild Cognitive Impairment due to Alzheimer’s Disease: Recommendations from the National Institute on Aging-Alzheimer’s Association Workgroups on Diagnostic Guidelines for Alzheimer’s Disease , 2011 .

[18]  Xue Hua,et al.  Brain differences in infants at differential genetic risk for late-onset Alzheimer disease: a cross-sectional imaging study. , 2014, JAMA neurology.

[19]  J. Morris,et al.  The diagnosis of dementia due to Alzheimer’s disease: Recommendations from the National Institute on Aging-Alzheimer’s Association workgroups on diagnostic guidelines for Alzheimer's disease , 2011, Alzheimer's & Dementia.

[20]  Richard J. Caselli,et al.  Higher serum total cholesterol levels in late middle age are associated with glucose hypometabolism in brain regions affected by Alzheimer's disease and normal aging , 2010, NeuroImage.

[21]  M. Torrens.  Co-Planar Stereotaxic Atlas of the Human Brain—3-Dimensional Proportional System: An Approach to Cerebral Imaging, J. Talairach, P. Tournoux. Georg Thieme Verlag, New York (1988), 122 pp., 130 figs. DM 268 , 1990 .

[22]  Huaxi Xu,et al.  Apolipoprotein E and Alzheimer disease: risk, mechanisms and therapy , 2013, Nature Reviews Neurology.

[23]  G. Bu,et al.  Apolipoprotein E lipoprotein particles inhibit amyloid-β uptake through cell surface heparan sulphate proteoglycan , 2016, Molecular Neurodegeneration.

[24]  E. Diamandis,et al.  Total apolipoprotein E levels and specific isoform composition in cerebrospinal fluid and plasma from Alzheimer’s disease patients and controls , 2014, Acta Neuropathologica.

[25]  Guojun Bu,et al.  Apolipoprotein E and its receptors in Alzheimer's disease: pathways, pathogenesis and therapy , 2009, Nature Reviews Neuroscience.

[26]  Harald Hampel,et al.  Reduced Hippocampal Volume in Healthy Young ApoE4 Carriers: An MRI Study , 2012, PloS one.

[27]  Andre Altmann,et al.  Sex modifies the APOE‐related risk of developing Alzheimer disease , 2014, Annals of neurology.

[28]  P. Sachdev,et al.  Plasma Apolipoprotein Levels Are Associated with Cognitive Status and Decline in a Community Cohort of Older Individuals , 2012, PloS one.

[29]  D. Holtzman,et al.  In Vivo Human Apolipoprotein E Isoform Fractional Turnover Rates in the CNS , 2012, PloS one.

[30]  G. Utermann,et al.  Changes of genetic apolipoprotein phenotypes caused by liver transplantation. Implications for apolipoprotein synthesis. , 1989, The Journal of clinical investigation.

[31]  R. Honea,et al.  Impact of APOE on the healthy aging brain: a voxel-based MRI and DTI study. , 2009, Journal of Alzheimer's disease : JAD.

[32]  Mary F. Lopez,et al.  Assessment of peptide chemical modifications on the development of an accurate and precise multiplex selected reaction monitoring assay for apolipoprotein e isoforms. , 2014, Journal of proteome research.

[33]  Daniel Bandy,et al.  Hippocampal volumes in cognitively normal persons at genetic risk for Alzheimer's disease , 1998, Annals of neurology.

[34]  J. Mazziotta,et al.  Cerebral metabolic and cognitive decline in persons at genetic risk for Alzheimer's disease. , 2000, Proceedings of the National Academy of Sciences of the United States of America.

[35]  G. Alexander,et al.  Longitudinal modeling of age-related memory decline and the APOE epsilon4 effect. , 2009, The New England journal of medicine.

[36]  A. Shah,et al.  ApoE influences amyloid-β (Aβ) clearance despite minimal apoE/Aβ association in physiological conditions , 2013, Proceedings of the National Academy of Sciences.

[37]  E M Wijsman,et al.  Gender difference in apolipoprotein E-associated risk for familial Alzheimer disease: a possible clue to the higher incidence of Alzheimer disease in women. , 1996, American journal of human genetics.

[38]  Kewei Chen,et al.  Correlations between apolipoprotein E epsilon4 gene dose and brain-imaging measurements of regional hypometabolism. , 2005, Proceedings of the National Academy of Sciences of the United States of America.

[39]  Early-life stress leads to impaired spatial learning and memory in middle-aged ApoE4-TR mice , 2016, Molecular Neurodegeneration.

[40]  J. Haines,et al.  Effects of Age, Sex, and Ethnicity on the Association Between Apolipoprotein E Genotype and Alzheimer Disease: A Meta-analysis , 1997 .

[41]  G. Alexander,et al.  Longitudinal PET Evaluation of Cerebral Metabolic Decline in Dementia: A Potential Outcome Measure in Alzheimer's Disease Treatment Studies. , 2002, The American journal of psychiatry.

[42]  A. Fagan,et al.  Cerebrospinal fluid APOE levels: an endophenotype for genetic studies for Alzheimer's disease. , 2012, Human molecular genetics.

[43]  K. Blennow,et al.  The apolipoprotein E ε4 allele plays pathological roles in AD through high protein expression and interaction with butyrylcholinesterase , 2011, Neurobiology of Aging.

[44]  Michael W. Weiner,et al.  Low Plasma ApoE Levels Are Associated with Smaller Hippocampal Size in the Alzheimer's Disease Neuroimaging Initiative Cohort , 2014, Dementia and Geriatric Cognitive Disorders.

[45]  M. Blankenstein,et al.  Apolipoproteins E and J interfere with amyloid‐beta uptake by primary human astrocytes and microglia in vitro , 2014, Glia.

[46]  G. Alexander,et al.  Functional brain abnormalities in young adults at genetic risk for late-onset Alzheimer's dementia , 2003, Proceedings of the National Academy of Sciences of the United States of America.

[47]  D. Aarsland,et al.  Apolipoprotein E ε2 genotype delays onset of dementia with Lewy bodies in a Norwegian cohort , 2014, Journal of Neurology, Neurosurgery & Psychiatry.

[48]  P. Vemuri,et al.  Sex and gender differences in the causes of dementia: a narrative review. , 2014, Maturitas.

[49]  M. Pangalos,et al.  Impact of Apolipoprotein E (ApoE) Polymorphism on Brain ApoE Levels , 2008, The Journal of Neuroscience.

[50]  S. Rapcsak,et al.  Longitudinal modeling of frontal cognition in APOE ε4 homozygotes, heterozygotes, and noncarriers , 2011, Neurology.

[51]  J. Haines,et al.  Gene dose of apolipoprotein E type 4 allele and the risk of Alzheimer's disease in late onset families. , 1993, Science.

[52]  Edu,et al.  Molecular Neurodegeneration Apolipoprotein E Levels in Cerebrospinal Fluid and the Effects of Abca1 Polymorphisms , 2022 .

[53]  B. Nordestgaard,et al.  Plasma levels of apolipoprotein E and risk of dementia in the general population , 2015, Annals of neurology.

[54]  D. Holtzman,et al.  Apolipoprotein E in Alzheimer's disease and other neurological disorders , 2011, The Lancet Neurology.

[55]  R. Veerhuis,et al.  Astrocytic Aβ1‐42 uptake is determined by Aβ‐aggregation state and the presence of amyloid‐associated proteins , 2010, Glia.

[56]  Paul M. Thompson,et al.  Age, APOE and sex: Triad of risk of Alzheimer’s disease , 2016, The Journal of Steroid Biochemistry and Molecular Biology.