Abstract
The study of individuals with autosomal dominant Alzheimer’s disease affords one of the best opportunities to characterize the biological and cognitive changes of Alzheimer’s disease that occur over the course of the preclinical and symptomatic stages. Unifying the knowledge gained from the past three decades of research in the world’s largest single-mutation autosomal dominant Alzheimer’s disease kindred — a family in Antioquia, Colombia with the E280A mutation in the Presenilin1 gene — will provide new directions for Alzheimer’s research and a framework for generalizing the findings from this cohort to the more common sporadic form of Alzheimer’s disease. As this specific mutation is virtually 100% penetrant for the development of the disease by midlife, we use a previously defined median age of onset for mild cognitive impairment for this cohort to examine the trajectory of the biological and cognitive markers of the disease as a function of the carriers’ estimated years to clinical onset. Studies from this cohort suggest that structural and functional brain abnormalities — such as cortical thinning and hyperactivation in memory networks — as well as differences in biofluid and in vivo measurements of Alzheimer’s-related pathological proteins distinguish Presenilin1 E280A mutation carriers from noncarriers as early as childhood, or approximately three decades before the median age of onset of clinical symptoms. We conclude our review with discussion on future directions for Alzheimer’s disease research, with specific emphasis on ways to design studies that compare the generalizability of research in autosomal dominant Alzheimer’s disease to the larger sporadic Alzheimer’s disease population.
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References
Stelzmann RA, Norman Schnitzlein H, Reed Murtagh F. An English translation of Alzheimer’s 1907 paper,“Über eine eigenartige Erkankung der Hirnrinde.” Clin. Anat. 1995;8, 429–431.
Dubois B, Feldman HH, Jacova C, Hampel H, Molinuevo JL, Blennow K, DeKosky ST, Gauthier S, Selkoe D, Bateman R. Advancing research diagnostic criteria for Alzheimer’s disease: the IWG-2 criteria. Lancet Neurol. 2014;13, 614–629.
Zetterberg H, Mattsson N. Understanding the cause of sporadic Alzheimer’s disease. Expert Rev. Neurother. 2014;14, 621–630.
Awada A. Early and late-onset Alzheimer’s disease: What are the differences? J. Neurosci. Rural Pract. 2015;6, 455.
Ryman DC, Acosta-Baena N, Aisen PS, Bird T, Danek A, Fox NC, Goate A, Frommelt P, Ghetti B, Langbaum JBS, Lopera F, Martins R, Masters CL, Mayeux RP, McDade E, Moreno S, Reiman EM, Ringman JM, Salloway S, Schofield PR, Sperling R, Tariot PN, Xiong C, Morris JC, Bateman RJ. Symptom onset in autosomal dominant Alzheimer disease. Neurology 2014;83, 253–260.
Tang Y-P, Gershon ES. Genetic studies in Alzheimer’s disease. Dialogues Clin. Neurosci. 2003;5, 17.
Sun L, Zhou R, Yang G, Shi Y. Analysis of 138 pathogenic mutations in presenilin-1 on the in vitro production of Aß42 and Aß40 peptides by γ-secretase. Proc. Natl. Acad. Sci. 2017;114, E476–E485.
Cornejo W, Lopera F, Uribe C, Salinas M. Descripción de una familia con demencia presenil tipo Alzheimer. Acta Médica Colomb. 1987;12,.
Lopera F, Arcos M, Madrigal L, Kosik K, Cornejo W, Ossa J. Demencia tipo Alzheimer con agregación familiar enAntioquia, Colombia. Acta Neurol Colomb 1994;10,.
Acosta-Baena N, Sepulveda-Falla D, Lopera-Gómez CM, Jaramillo-Elorza MC, Moreno S, Aguirre-Acevedo DC, Saldarriaga A, Lopera F. Pre-dementia clinical stages in presenilin 1 E280A familial early-onset Alzheimer’s disease: a retrospective cohort study. Lancet Neurol. 2011;10, 213–220.
Reiman EM, Langbaum J, Fleisher AS, Caselli RJ, Chen K, Ayutyanont N, Quiroz YT, Kosik KS, Lopera F, Tariot PN. Alzheimer’s Prevention Initiative: a plan to accelerate the evaluation of presymptomatic treatments. J. Alzheimers Dis. 2011; 26, 321–329.
Tariot PN, Lopera F, Langbaum JB, Thomas RG, Hendrix S, Schneider LS, Rios-Romenets S, Giraldo M, Acosta N, Tobon C, Ramos C, Espinosa A, Cho W, Ward M, Clayton D, Friesenhahn M, Mackey H, Honigberg L, Sanabria Bohorquez S, Chen K, Walsh T, Langlois C, Reiman EM. The Alzheimer’s Prevention Initiative Autosomal-Dominant Alzheimer’s Disease Trial: A study of crenezumab versus placebo in preclinical PSEN1 E280A mutation carriers to evaluate efficacy and safety in the treatment of autosomaldominant Alzheimer’s disease, including a placebo-treated noncarrier cohort. Alzheimers Dement. Transl. Res. Clin. Interv. 2018;4, 150–160.
Lopera F, Ardilla A, Martínez A, Madrigal L, Arango-Viana JC, Lemere CA, Arango-Lasprilla JC, Hincapié L, Arcos-Burgos M, Ossa JE. Clinical features of early-onset Alzheimer disease in a large kindred with an E280A presenilin-1 mutation. Jama 1997;277, 793–799.
Aguirre-Acevedo DC, Lopera F, Henao E, Tirado V, Muñoz C, Giraldo M, Bangdiwala SI, Reiman EM, Tariot PN, Langbaum JB. Cognitive decline in a Colombian kindred with autosomal dominant Alzheimer disease: a retrospective cohort study. JAMA Neurol. 2016;73, 431–438.
Sepulveda-Falla D, Glatzel M, Lopera F. Phenotypic profile of early-onset familial Alzheimer’s disease caused by presenilin-1 E280A mutation. J. Alzheimers Dis. 2012;32, 1–12.
Ardila A, Lopera F, Rosselli M, Moreno S, Madrigal L, Arango-Lasprilla JC, Arcos M, Murcia C, Arango-Viana JC, Ossa J. Neuropsychological profile of a large kindred with familial Alzheimer’s disease caused by the E280A single presenilin-1 mutation. Arch. Clin. Neuropsychol. 2000;15, 515–528.
Arango-Lasprilla JC, Cuetos F, Valencia C, Uribe C, Lopera F. Cognitive changes in the preclinical phase of familial Alzheimer’s disease. J. Clin. Exp. Neuropsychol. 2007;29, 892–900.
Tirado V, Motta M, Aguirre-Acevedo DC, Pineda D, Lopera F. Analysis of intrusive errors in a memory test as possible pre-clinical marker of familial Alzheimer disease, in E280A presenilin-1 mutation carrier. Rev. Neurol. 2008;47, 290–294.
Rosselli M, Ardila A, Moreno S, Standish V, Arango-Lasprilla JC, Tirado V, Ossa J, Goate AM, Kosik KS, Lopera F. Cognitive decline in patients with familial Alzheimer’s disease associated with E280a presenilin-1 mutation: a longitudinal study. J. Clin. Exp. Neuropsychol. 2000;22, 483–495.
Cuetos F, Arango-Lasprilla J, Uribe C, Valencia C, Lopera F. Linguistic changes in verbal expression: A preclinical marker of Alzheimer’s disease. J. Int. Neuropsychol. Soc. JINS 2007;13, 433–9.
Norton DJ, Amariglio R, Protas H, Chen K, Aguirre-Acevedo DC, Pulsifer B, Castrillon G, Tirado V, Munoz C, Tariot P. Subjective memory complaints in preclinical autosomal dominant Alzheimer disease. Neurology 2017;89, 1464–1470.
Tirado V, Munoz C, Aguirre C, Pineda D, Lopera F. Performance of carriers and non-carriers of the E280A mutation for familial Alzheimer’s disease in a naming test. Rev. Neurol. 2004;39, 322–326.
Lasprilla JCA, Iglesias J, Lopera F. Neuropsychological stydy of familial Alzheimer’s disease caused by mutation E280A in the presenilin 1 gene. Am. J. Alzheimers Dis. Dementiasr 2003;18, 137–146.
Parra MA, Abrahams S, Logie RH, Méndez LG, Lopera F, Della Sala S. Visual short-term memory binding deficits in familial Alzheimer’s disease. Brain 2010;133, 2702–2713.
Parra MA, Della Sala S, Abrahams S, Logie RH, Méndez LG, Lopera F. Specific deficit of colour–colour short-term memory binding in sporadic and familial Alzheimer’s disease. Neuropsychologia 2011;49, 1943–1952.
Parra MA, Saarimäki H, Bastin ME, Londoño AC, Pettit L, Lopera F, Della Sala S, Abrahams S. Memory binding and white matter integrity in familial Alzheimer’s disease. Brain 2015;138, 1355–1369.
Rodriguez R, Lopera F, Alvarez A, Fernandez Y, Galan L, Quiroz Y, Bobes MA. Spectral analysis of EEG in familial Alzheimer’s disease with E280A presenilin-1 mutation gene. Int. J. Alzheimer’s Dis. 2014;2014,.
Quiroz YT, Ally BA, Celone K, McKeever J, Ruiz-Rizzo AL, Lopera F, Stern CE, Budson AE. Event-related potential markers of brain changes in preclinical familial Alzheimer disease. Neurology 2011;77, 469–475.
Suárez-Revelo JX, Ochoa-Gómez JF, Duque-Grajales JE, Tobón-Quintero CA. Biomarkers identification in Alzheimer’s disease using effective connectivity analysis from electroencephalography recordings. Ing. E Investig. 2016;36, 50–57.
Ochoa JF, Alonso JF, Duque JE, Tobón CA, Mañanas MA, Lopera F, Hernández AM. Successful Object Encoding Induces Increased Directed Connectivity in Presymptomatic Early-Onset Alzheimer’s Disease. J. Alzheimers Dis. 2017;55, 1195–1205.
Penny W, Iglesias-Fuster J, Quiroz YT, Lopera FJ, Bobes MA. Dynamic Causal Modeling of Preclinical Autosomal-Dominant Alzheimer’s Disease. J. Alzheimers Dis. 2018;1–15.
Bobes MA, García YF, Lopera F, Quiroz YT, Galán L, Vega M, Trujillo N, Valdes-Sosa M, Valdes-Sosa P. ERP generator anomalies in presymptomatic carriers of the Alzheimer’s disease E280A PS-1 mutation. Hum. Brain Mapp. 2010;31, 247–265.
Klimesch W. EEG alpha and theta oscillations reflect cognitive and memory performance: a review and analysis. Brain Res. Rev. 1999;29, 169–195.
Wróbel A. Beta activity: a carrier for visual attention. Acta Neurobiol. Exp. (Warsz.) 2000;60, 247–260.
Duque-Grajales JE, Tobon C, Aponte-Restrepo CP, Ochoa-Gómez JF, MUÑOZ-ZAPATA C, Valdivieso H, Quiroz-Zapata YT, Lopera F. Quantitative EEG analysis disease during resting and memory task in carriers and non-carriers of PS-1 E280A mutation of familial Alzheimer’s. CES Med. 2014;28, 165–176.
Fleisher AS, Chen K, Quiroz YT, Jakimovich LJ, Gomez MG, Langois CM, Langbaum JB, Ayutyanont N, Roontiva A, Thiyyagura P. Florbetapir PET analysis of amyloid-ß deposition in the presenilin 1 E280A autosomal dominant Alzheimer’s disease kindred: a cross-sectional study. Lancet Neurol. 2012;11, 1057–1065.
Quiroz YT, Sperling RA, Norton DJ, Baena A, Arboleda-Velasquez JF, Cosio D, Schultz A, Lapoint M, Guzman-Velez E, Miller JB. Association between amyloid and tau accumulation in young adults with autosomal dominant Alzheimer disease. JAMA Neurol, 2018.
Lopera F, Tobon N, Arcos-Burgos M, Vargas S, Gutiérrez J, Rosselli M, Adrilla A. Caracterización imagenológica de la enfermedad de Alzheimerasociada a la mutación E280A-PS1. Estudio caso-control:hallazgos en la resonancia magnética. Rev. Neurol. 1999; 29, 6–12.
Reiman EM, Quiroz YT, Fleisher AS, Chen K, Velez-Pardo C, Jimenez-Del-Rio M, Fagan AM, Shah AR, Alvarez S, Arbelaez A. Brain imaging and fluid biomarker analysis in young adults at genetic risk for autosomal dominant Alzheimer’s disease in the presenilin 1 E280A kindred: a case-control study. Lancet Neurol. 2012;11, 1048–1056.
Quiroz Y, Reiman E, Brickhouse M, Chen K, Fleisher A, Munoz C, Langbaum J, Alvarez S, Tariot P, Lopera F. Trajectory of the Alzheimer’s-signature MRI biomarker in familial Alzheimer’s disease, for the Alzheimer’s Prevention Initiative. Alzheimers Dement. J. Alzheimers Assoc. 2012;8, P36.
Quiroz YT, Stern CE, Reiman EM, Brickhouse M, Ruiz A, Sperling RA, Lopera F, Dickerson BC. Cortical atrophy in presymptomatic Alzheimer’s disease presenilin 1 mutation carriers. J Neurol Neurosurg Psychiatry 2013;84, 556–561.
Quiroz YT, Schultz AP, Chen K, Protas HD, Brickhouse M, Fleisher AS, Langbaum JB, Thiyyagura P, Fagan AM, Shah AR. Brain imaging and blood biomarker abnormalities in children with autosomal dominant Alzheimer disease: a cross-sectional study. JAMA Neurol. 2015;72, 912–919.
Dean D, Jerskey B, Chen K, Protas H, Thiyyagura P, Roontiva A, O’muircheartaigh J, Dirks H, Waskiewicz N, Lehman K, Siniard A. Brain differences in infants at differential genetic risk for late-onset Alzheimer disease: a cross-sectional imaging study. JAMA Neurol. 2014;71, 11–22.
Wright RO, Hu H, Silverman EK, Tsaih SW, Schwartz J, Bellinger D, Palazuelos E, Weiss ST, Hernandez-Avila M. Apolipoprotein E genotype predicts 24-month bayley scales infant development score. Pediatr. Res. 2003;54, 819–825.
Ihle A, Bunce D, Kliegel M. APOE e4 and cognitive function in early life: a meta-analysis. Neuropsychology 2012;26, 267–277.
Quiroz YT, Budson AE, Celone K, Ruiz A, Newmark R, Castrillón G, Lopera F, Stern CE. Hippocampal hyperactivation in presymptomatic familial Alzheimer’s disease. Ann. Neurol. 2010;68, 865–875.
Quiroz YT, Willment KC, Castrillon G, Muniz M, Lopera F, Budson A, Stern CE. Successful scene encoding in presymptomatic early-onset Alzheimer’s disease. J. Alzheimers Dis. JAD 2015;47, 955–964.
Johnson KA, Lopera F, Jones K, Becker A, Sperling R, Hilson J, Londono J, Siegert I, Arcos M, Moreno S. Presenilin-1–associated abnormalities in regional cerebral perfusion. Neurology 2001;56, 1545–1551.
Fleisher A, Chen K, Quiroz Y, Jakimovich L, Gutierrez M, Langbaum J, Roontiva A, Thiyyagura P, Luo J, Liu X. Pre-symptomatic functional brain changes in PS1 E280A mutation carriers compared with other biomarkers: Pilot data from the Alzheimer’s Prevention Initiative Biomarker project. Alzheimers Dement. J. Alzheimers Assoc. 2013;9, P729.
Mosconi L, Pupi A, De Leon MJ. Brain Glucose Hypometabolism and Oxidative Stress in Preclinical Alzheimer’s Disease. Ann. N. Y. Acad. Sci. 2008;1147, 180–195.
Fleisher AS, Chen K, Quiroz YT, Jakimovich LJ, Gomez MG, Langois CM, Langbaum JB, Roontiva A, Thiyyagura P, Lee W. Associations between biomarkers and age in the presenilin 1 E280A autosomal dominant Alzheimer disease kindred: a cross-sectional study. JAMA Neurol. 2015;72, 316–324.
Quiroz YT, Protas H, Chen K, Roontiva A, Thiyyagura P, Fagan AM, Shah A, Gutierrez M, Londono M, Giraldo M. Relationships between baseline biomarkers and subsequent cognitive decline in cognitively unimpaired PSEN1 E280A mutation carriers from the colombian kindred with autosomal dominant Alzheimer’s disease. Alzheimers Dement. J. Alzheimers Assoc. 2015;11, P888.
Morcom AM, Henson RN. Increased prefrontal activity with aging reflects nonspecific neural responses rather than compensation. Journal of Neuroscience. 2018;15;38(33): 7303–13.
McDade E, Wang G, Gordon BA, Hassenstab J, Benzinger TLS, Buckles V, Fagan AM, Holtzman DM, Cairns NJ, Goate AM, Marcus DS, Morris JC, Paumier K, Xiong C, Allegri R, Berman SB, Klunk W, Noble J, Ringman J, Ghetti B, Farlow M, Sperling RA, Chhatwal J, Salloway S, Graff-Radford NR, Schofield PR, Masters C, Rossor MN, Fox NC, Levin J, Jucker M, Bateman RJ, for the Dominantly Inherited Alzheimer Network. Longitudinal cognitive and biomarker changes in dominantly inherited Alzheimer disease. Neurology 2018;91, e1295–e1306.
Jack Jr CR, Knopman DS, Jagust WJ, Petersen RC, Weiner MW, Aisen PS, Shaw LM, Vemuri P, Wiste HJ, Weigand SD. Tracking pathophysiological processes in Alzheimer’s disease: an updated hypothetical model of dynamic biomarkers. Lancet Neurol. 2013;12, 207–216.
Sperling RA, Aisen PS, Beckett LA, Bennett DA, Craft S, Fagan AM, Iwatsubo T, Jack CR, Kaye J, Montine TJ. 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. J. Alzheimers Assoc. 2011;7, 280–292.
Vradenburg G. A pivotal moment in Alzheimer’s disease and dementia: how global unity of purpose and action can beat the disease by 2025. Expert Rev. Neurother. 2015;15, 73–82.
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Fuller, J.T., Cronin-Golomb, A., Gatchel, J.R. et al. Biological and Cognitive Markers of Presenilin1 E280A Autosomal Dominant Alzheimer’s Disease: A Comprehensive Review of the Colombian Kindred. J Prev Alzheimers Dis 6, 112–120 (2019). https://doi.org/10.14283/jpad.2019.6
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DOI: https://doi.org/10.14283/jpad.2019.6