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Current Alzheimer Research

Editor-in-Chief

ISSN (Print): 1567-2050
ISSN (Online): 1875-5828

Research Article

Nuances in Alzheimer’s Genetic Risk Reveal Differential Predictions of Non-demented Memory Aging Trajectories: Selective Patterns by APOE Genotype and Sex

Author(s): G. Peggy McFall*, Lars Bäckman and Roger A. Dixon

Volume 16, Issue 4, 2019

Page: [302 - 315] Pages: 14

DOI: 10.2174/1567205016666190315094452

Price: $65

Abstract

Background: Apolipoprotein E (APOE) is a prominent genetic risk factor for Alzheimer’s disease (AD) and a frequent target for associations with non-demented and cognitively impaired aging. APOE offers a unique opportunity to evaluate two dichotomous comparisons and selected gradations of APOE risk. Some evidence suggests that APOE effects may differ by sex and emerge especially in interaction with other AD-related biomarkers (e.g., vascular health).

Methods: Longitudinal trajectories of non-demented adults (n = 632, 67% female, Mage = 68.9) populated a 40-year band of aging. Focusing on memory performance and individualized memory trajectories, a sequence of latent growth models was tested for predictions of (moderation between) APOE and pulse pressure (PP) as stratified by sex. The analyses (1) established robust benchmark PP effects on memory trajectories, (2) compared predictions of alternative dichotomous groupings (ε4- vs ε4+, ε2- vs ε2+), and (3) examined precision-based predictions by disaggregated APOE genotypes.

Results: Healthier (lower) PP was associated with better memory performance and less decline. Therefore, all subsequent analyses were conducted in the interactive context of PP effects and sex stratification. The ε4-based dichotomization produced no differential genetic predictions. The ε2-based analyses showed sex differences, including selective protection for ε2-positive females. Exploratory follow-up disaggregated APOE genotype analyses suggested selective ε2 protection effects for both homozygotic and heterozygotic females.

Conclusion: Precision analyses of AD genetic risk will advance the understanding of underlying mechanisms and improve personalized implementation of interventions.

Keywords: Apolipoprotein E, Alzheimer's disease, pulse pressure, memory aging, sex differences, trajectory analyses, Victoria Longitudinal Study.

[1]
Ward A, Crean S, Mercaldi CJ, Collins JM, Boyd D, Cook MN, et al. Prevalence of apolipoprotein E4 genotype and homozygotes (APOE e4/4) among patients diagnosed with Alzheimer’s disease: a systematic review and meta-analysis. Neuroepidemiology 38(1): 1-17. (2011).
[2]
Karch CM, Cruchaga C, Goate AM. Alzheimer’s disease genetics: from the bench to the clinic. Neuron 83(1): 11-26. (2014).
[3]
Michaelson DM. APOE ε4: the most prevalent yet understudied risk factor for Alzheimer’s disease. Alzheimers Dement 10(6): 861-8. (2014).
[4]
Conejero-Goldberg C, Gomar J, Bobes-Bascaran T, Hyde T, Kleinman J, Herman M, et al. APOE2 enhances neuroprotection against Alzheimer’s disease through multiple molecular mechanisms. Mol Psychiatry 19: 1243-50. (2014).
[5]
Khan W, Giampietro V, Banaschewski T, Barker GJ, Bokde AL, Büchel C, et al. A multi-cohort study of ApoE ε4 and amyloid-β effects on the hippocampus in Alzheimer’s Disease. J Alzheimers Dis 56(3): 1159-74. (2017).
[6]
Guerreiro RJ, Gustafson DR, Hardy J. The genetic architecture of Alzheimer’s disease: beyond APP, PSENs and APOE. Neurobiol Aging 33(3): 437-56. (2012).
[7]
Riedel BC, Thompson PM, Brinton RD. Age, APOE and sex: triad of risk of Alzheimer’s disease. J Steroid Biochem Mol Biol 160: 134-47. (2016).
[8]
Suri S, Heise V, Trachtenberg AJ, Mackay CE. The forgotten APOE allele: a review of the evidence and suggested mechanisms for the protective effect of APOE ε2. Neurosci Biobehav Rev 37(10): 2878-86. (2013).
[9]
McFall GP, Wiebe SA, Vergote D, Westaway D, Jhamandas J, Bäckman L, et al. ApoE and pulse pressure interactively influence level and change in the aging of episodic memory: protective effects among ε2 carriers. Neuropsychology 29(3): 388-401. (2015).
[10]
Podcasy JL, Epperson CN. Considering sex and gender in Alzheimer disease and other dementias. Dialogues Clin Neurosci 18(4): 437. (2016).
[11]
Carter CL, Resnick EM, Mallampalli M, Kalbarczyk A. Sex and gender differences in Alzheimer’s disease: recommendations for future research. J Womens Health 21(10): 1018-23. (2012).
[12]
Chêne G, Beiser A, Au R, Preis SR, Wolf PA, Dufouil C, et al. Gender and incidence of dementia in the Framingham Heart Study from mid-adult life. Alzheimers Dement 11(3): 310-20. (2015).
[13]
Snyder HM, Asthana S, Bain L, Brinton R, Craft S, Dubal DB, et al. Sex biology contributions to vulnerability to Alzheimer’s disease: a think tank convened by the Women’s Alzheimer’s Research Initiative. Alzheimers Dement 12(11): 1186-96. (2016).
[14]
Jefferson AL, Beiser AS, Seshadri S, Wolf PA, Au R. APOE and mild cognitive impairment: the Framingham Heart Study. Age Ageing 44(2): 307-11. (2015).
[15]
Jochemsen HM, Muller M, van der Graaf Y, Geerlings MI. APOE ε4 differentially influences change in memory performance depending on age. The SMART-MR study. Neurobiol Aging 33(4): 832.e15-22. (2012).
[16]
Luck T, Riedel-Heller S, Luppa M, Wiese B, Köhler M, Jessen F, et al. Apolipoprotein E epsilon 4 genotype and a physically active lifestyle in late life: analysis of gene-environment interaction for the risk of dementia and Alzheimer’s disease dementia. Psychol Med 44(06): 1319-29. (2014).
[17]
Verlinden VJ, van der Geest JN, de Bruijn RF, Hofman A, Koudstaal PJ, Ikram MA. Trajectories of decline in cognition and daily functioning in preclinical dementia. Alzheimers Dement 12(2): 144-53. (2016).
[18]
Schiepers O, Harris S, Gow A, Pattie A, Brett C, Starr J, et al. APOE E4 status predicts age-related cognitive decline in the ninth decade: longitudinal follow-up of the Lothian Birth Cohort 1921. Mol Psychiatry 17(3): 315-24. (2012).
[19]
Wilson R, Bienias J, Berry-Kravis E, Evans D, Bennett D. The apolipoprotein E ε2 allele and decline in episodic memory. J Neurol Neurosurg Psychiatry 73(6): 672-7. (2002).
[20]
Berlau DJ, Corrada MM, Head E, Kawas CH. APOE ε2 is associated with intact cognition but increased Alzheimer pathology in the oldest old. Neurology 72(9): 829-34. (2009).
[21]
Albert MS, DeKosky ST, Dickson D, Dubois B, Feldman HH, Fox NC, 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. Alzheimers Dement 7(3): 270-9. (2011).
[22]
Altmann A, Tian L, Henderson VW, Greicius MD. Sex modifies the APOE‐related risk of developing Alzheimer disease. Ann Neurol 75(4): 563-73. (2014).
[23]
Dixon RA, DeCarlo CA, MacDonald SW, Vergote D, Jhamandas J, Westaway D. APOE and COMT polymorphisms are complementary biomarkers of status, stability, and transitions in normal aging and early mild cognitive impairment Front Aging Neurosci 6: 236- 1- 11 (2014).
[24]
Small BJ, Rosnick CB, Fratiglioni L, Bäckman L. Apolipoprotein E and cognitive performance: a meta-analysis. Psychol Aging 19(4): 592-600. (2004).
[25]
Wisdom NM, Callahan JL, Hawkins KA. The effects of apolipoprotein E on non-impaired cognitive functioning: a meta-analysis. Neurobiol Aging 32(1): 63-74. (2011).
[26]
Alexopoulos P, Richter-Schmidinger T, Horn M, Maus S, Reichel M, Sidiropoulos C, et al. Hippocampal volume differences between healthy young apolipoprotein E e2 and e4 carriers. J Alzheimers Dis 26: 207-10. (2011).
[27]
Deary IJ, Whiteman MC, Pattie A, Starr JM, Hayward C, Wright AF, et al. Apolipoprotein E gene variability and cognitive functions at age 79: a follow-up of the Scottish mental survey of 1932. Psychol Aging 19(2): 367-71. (2004).
[28]
Lindahl-Jacobsen R, Tan Q, Mengel-From J, Christensen K, Nebel A, Christiansen L. Effects of the APOE ε2 allele on mortality and cognitive function in the oldest old. J Gerontol A Biol Sci Med Sci 68(4): 389-94. (2013).
[29]
Bangen KJ, Beiser A, Delano-Wood L, Nation DA, Lamar M, Libon DJ, et al. APOE genotype modifies the relationship between midlife vascular risk factors and later cognitive decline. J Stroke Cerebrovasc Dis 22(8): 1361-9. (2013).
[30]
Kolovou G, Daskalova D, Mikhailidis DP. Apolipoprotein E polymorphism and atherosclerosis. Angiology 54(1): 59-71. (2003).
[31]
Sperling RA, Aisen PS, Beckett LA, Bennett DA, Craft S, Fagan AM, et al. 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): 280-92. (2011).
[32]
Burkhardt M, Foster J, Laws S, Baker L, Craft S, Gandy S, et al. Oestrogen replacement therapy may improve memory functioning in the absence of APOE ε4. J Alzheimers Dis 6(3): 221-8. (2004).
[33]
Jacobs EG, Kroenke C, Lin J, Epel ES, Kenna HA, Blackburn EH, et al. Accelerated cell aging in female APOE-ε4 carriers: implications for hormone therapy use. PLoS One 8(2): e54713. (2013).
[34]
Bertram L, Lill CM, Tanzi RE. The genetics of Alzheimer disease: back to the future. Neuron 68(2): 270-81. (2010).
[35]
Belsky J, Jonassaint C, Pluess M, Stanton M, Brummett B, Williams R. Vulnerability genes or plasticity genes? Mol Psychiatry 14(8): 746-54. (2009).
[36]
Bender AR, Raz N. Age-related differences in episodic memory: a synergistic contribution of genetic and physiological vascular risk factors. Neuropsychology 26(4): 442-50. (2012).
[37]
Caselli RJ, Dueck A, Locke D, Sabbagh M, Ahern GL, Rapcsak SZ, et al. Cerebrovascular risk factors and preclinical memory decline in healthy APOE ε4 homozygotes. Neurology 76(12): 1078-84. (2011).
[38]
McFall GP, Wiebe SA, Vergote D, Anstey KJ, Dixon RA. Alzheimer’s genetic risk intensifies neurocognitive slowing associated with diabetes in nondemented older adults. Alzheimer’s & Dement: Diagn. Assess Dis Monit 1(4): 395-402. (2015).
[39]
Zade D, Beiser A, McGlinchey R, Au R, Seshadri S, Palumbo C, et al. Interactive effects of apolipoprotein E type 4 genotype and cerebrovascular risk on neuropsychological performance and structural brain changes. J Stroke Cerebrovasc Dis 19(4): 261-8. (2010).
[40]
Andrews S, Das D, Anstey KJ, Easteal S. Interactive effect of APOE genotype and blood pressure on cognitive decline: the PATH through life study. J Alzheimers Dis 44(4): 1087-98. (2015).
[41]
Nation DA, Edland SD, Bondi MW, Salmon DP, Delano-Wood L, Peskind ER, et al. Pulse pressure is associated with Alzheimer biomarkers in cognitively normal older adults. Neurology 81(23): 2024-7. (2013).
[42]
Pase MP, Beiser A, Himali JJ, Tsao C, Satizabal CL, Vasan RS, et al. Aortic stiffness and the risk of incident mild cognitive impairment and dementia. Stroke 47(9): 2256-61. (2016).
[43]
Singer J, Trollor JN, Baune BT, Sachdev PS, Smith E. Arterial stiffness, the brain and cognition: a systematic review. Ageing Res Rev 15: 16-27. (2014).
[44]
Sun X, Rundek T. Does increased arterial stiffness herald cognitive impairment? Stroke 47: 2171-2. (2016).
[45]
van Sloten TT, Protogerou AD, Henry RM, Schram MT, Launer LJ, Stehouwer CD. Association between arterial stiffness, cerebral small vessel disease and cognitive impairment: a systematic review and meta-analysis. Neurosci Biobehav Rev 53: 121-30. (2015).
[46]
Raz N, Dahle CL, Rodrigue KM, Kennedy KM, Land S. Effects of age, genes, and pulse pressure on executive functions in healthy adults. Neurobiol Aging 32(6): 1124-37. (2011).
[47]
Al Hazzouri AZ, Yaffe K. Arterial stiffness and cognitive function in the elderly. J Alzheimers Dis 42(s4): S503-14. (2014).
[48]
Bérard E, Bongard V, Ruidavets J, Amar J, Ferrieres J. Pulse wave velocity, pulse pressure and number of carotid or femoral plaques improve prediction of cardiovascular death in a population at low risk. J Hum Hypertens 27(9): 529-34. (2013).
[49]
Jochemsen HM, Muller M, Bots ML, Scheltens P, Vincken KL, Mali WP, et al. Arterial stiffness and progression of structural brain changes: the SMART-MR study. Neurology 84(5): 448-55. (2015).
[50]
Riba-Llena I, Nafría C, Filomena J, Tovar JL, Vinyoles E, Mundet X, et al. High daytime and nighttime ambulatory pulse pressure predict poor cognitive function and mild cognitive impairment in hypertensive individuals. J Cereb Blood Flow Metab 36: 1-7. (2015).
[51]
Montagne A, Barnes SR, Sweeney MD, Halliday MR, Sagare AP, Zhao Z, et al. Blood-brain barrier breakdown in the aging human hippocampus. Neuron 85(2): 296-302. (2015).
[52]
Fratiglioni L, Viitanen M, von Strauss E, Tontodonati V, Herlitz A, Winblad B. Very old women at highest risk of dementia and Alzheimer’s Disease incidence data from the Kungsholmen Project, Stockholm. Neurology 48(1): 132-8. (1997).
[53]
Katz MJ, Lipton RB, Hall CB, Zimmerman ME, Sanders AE, Verghese J, et al. Age and sex specific prevalence and incidence of mild cognitive impairment, dementia and Alzheimer’s dementia in blacks and whites: a report from the Einstein Aging Study. Alzheimer Dis Assoc Disord 26(4): 335. (2012).
[54]
Deak F, Freeman WM, Ungvari Z, Csiszar A, Sonntag WE. Recent developments in understanding brain aging: implications for Alzheimer’s Disease and vascular cognitive impairment. J Gerontol A Biol Sci Med Sci 71(1): 13-20. (2016).
[55]
Holland D, Desikan RS, Dale AM, McEvoy LK. Higher rates of decline for women and apolipoprotein E ε4 carriers. Am J Neuroradiol 34(12): 2287-93. (2013).
[56]
Hua X, Hibar DP, Lee S, Toga AW, Jack CR, Weiner MW, et al. Sex and age differences in atrophic rates: an ADNI study with n= 1368 MRI scans. Neurobiol Aging 31(8): 1463-80. (2010).
[57]
Seshadri S, Wolf P, Beiser A, Au R, McNulty K, White R, et al. Lifetime risk of dementia and Alzheimer’s disease: the impact of mortality on risk estimates in the Framingham Study. Neurology 49(6): 1498-504. (1997).
[58]
Herlitz A, Nilsson L-G, Bäckman L. Gender differences in episodic memory. Mem Cognit 25(6): 801-11. (1997).
[59]
Herlitz A, Rehnman J. Sex differences in episodic memory. Curr Dir Psychol Sci 17(1): 52-6. (2008).
[60]
Tierney MC, Curtis AF, Chertkow H, Rylett RJ. Integrating sex and gender into neurodegeneration research: a six-component strategy. Alzheimer’s & Demen. Trans Res Clin Interven 3(4): 660-7. (2017).
[61]
Weber D, Skirbekk V, Freund I, Herlitz A. The changing face of cognitive gender differences in Europe. Proc Natl Acad Sci USA 111(32): 11673-8. (2014).
[62]
Jiao S-S, Bu X-L, Liu Y-H, Zhu C, Wang Q-H, Shen L-L, et al. Sex dimorphism profile of Alzheimer’s Disease-type pathologies in an APP/PS1 mouse model. Neurotox Res 29(2): 256-66. (2016).
[63]
Zhao L, Mao Z, Woody SK, Brinton RD. Sex differences in metabolic aging of the brain: insights into female susceptibility to Alzheimer’s disease. Neurobiol Aging 42: 69-79. (2016).
[64]
Yang H, Lyutvinskiy Y, Herukka S-K, Soininen H, Rutishauser D, Zubarev RA. Prognostic polypeptide blood plasma biomarkers of Alzheimer’s disease progression. J Alzheimers Dis 40(3): 659-66. (2014).
[65]
Dixon RA, de Frias CM. The victoria longitudinal study: from characterizing cognitive aging to illustrating changes in memory compensation. Aging Neuropsychol Cogn 11(2-3): 346-76. (2004).
[66]
Dixon RA, Small BJ, MacDonald SWS, McArdle JJ. Yes, memory declines with aging-but when, how, and why? In: Naveh-Benjamin M, Ohta N, editors. Memory and aging: Current issues and future directions. New York, NY: Psychology Press; 2012. p. 325-47.
[67]
Anstey K. Biomarkers and memory aging: a life-course perspective. In: Naveh-Benjamin M, Ohta N, Eds. Memory and aging: Current issues and future directions. New York, NY: Psychology Press, Taylor & Francis, p. 349-72 (2012)
[68]
Dixon RA, Wahlin Å, Maitland SB, Hultsch DF, Hertzog C, Bäckman L. Episodic memory change in late adulthood: generalizability across samples and performance indices. Mem Cognit 32(5): 768-78. (2004).
[69]
Josefsson M, Luna X, Pudas S, Nilsson LG, Nyberg L. Genetic and lifestyle predictors of 15‐Year longitudinal change in episodic memory. J Am Geriatr Soc 60(12): 2308-12. (2012).
[70]
Kalpouzos G, Nyberg L. Multimodal neuroimaging in normal aging. In: Naveh-Benjamin M, Ohta N, Eds. Memory and aging: Current issues and future directions. New York, NY: Psychology Press, Taylor & Francis; 2012. p. 273-304.
[71]
MacDonald SW, DeCarlo CA, Dixon RA. Linking biological and cognitive aging: toward improving characterizations of developmental time. J Gerontol B Psychol Sci Soc Sci 66(Suppl. 1): i59-70. (2011).
[72]
McFall GP, McDermott KL, Dixon RA. Modifiable risk factors discriminate memory trajectories in non-demented aging: precision factors and targets for promoting healthier brain aging and preventing dementia? J Alzheimers Dis (2019).
[http://dx.doi.org/10.3233/JAD-180571]
[73]
Muthén LK, Muthén BO. Mplus user's guide Los Angeles, CA: Muthén & Muthén; 1998 - 2017 DOI: 103233/JAD-180571
[74]
Enders CK. Analyzing longitudinal data with missing values. Rehabil Psychol 56(4): 267-88. (2011).
[75]
Little TD. Longitudinal structural equation modeling New York, NY: Guilford Press (2013); 2013.
[76]
Cribbie RA. Multiplicity control in structural equation modeling. Struct Equ Modeling 14(1): 98-112. (2007).
[77]
Liu C-C, Kanekiyo T, Xu H, Bu G. Apolipoprotein E and Alzheimer disease: risk, mechanisms and therapy. Nat Rev Neurol 9(2): 106-18. (2013).
[78]
Neu SC, Pa J, Kukull W, Beekly D, Kuzma A, Gangadharan P, et al. Apolipoprotein E genotype and sex risk factors for Alzheimer disease: a meta-analysis. JAMA Neurol 74(10): 1178-89. (2017).
[79]
Caselli RJ, Dueck AC, Locke DE, Baxter LC, Woodruff BK, Geda YE. Sex-based memory advantages and cognitive aging: a challenge to the cognitive reserve construct? J Int Neuropsychol Soc 21(02): 95-104. (2015).
[80]
Klosinski LP, Yao J, Yin F, Fonteh AN, Harrington MG, Christensen TA, et al. White matter lipids as a ketogenic fuel supply in aging female brain: implications for Alzheimer’s disease. EBioMedicine 2(12): 1888-904. (2015).
[81]
Du Y, Chen X, Wei X, Bales KR, Berg DT, Paul SM, et al. NF-κB mediates amyloid β peptide-stimulated activity of the human apolipoprotein E gene promoter in human astroglial cells. Mol Brain Res 136(1-2): 177-88. (2005).
[82]
Maloney B, Ge YW, Petersen RC, Hardy J, Rogers JT, Pérez‐Tur J, et al. Functional characterization of three single‐nucleotide polymorphisms present in the human APOE promoter sequence: differential effects in neuronal cells and on DNA–protein interactions. American J Med Genetics Part B: Neuropsychiatric Genetics 153(1): 185-201. (2010).
[83]
Lewin C, Wolgers G, Herlitz A. Sex differences favoring women in verbal but not in visuospatial episodic memory. Neuropsychology 15(2): 165. (2001).
[84]
Smith JD. Apolipoproteins and aging: emerging mechanisms. Ageing Res Rev 1(3): 345-65. (2002).
[85]
Shaw P, Lerch JP, Pruessner JC, Taylor KN, Rose AB, Greenstein D, et al. Cortical morphology in children and adolescents with different apolipoprotein E gene polymorphisms: an observational study. The Lancet Neurol 6(6): 494-500. (2007).
[86]
Pfefferbaum A, Sullivan EV. Cross-sectional versus longitudinal estimates of age-related changes in the adult brain: overlaps and discrepancies. Neurobiol Aging 36(9): 2563-7. (2015).

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