Eider M Arenaza-Urquijo1, Gemma Salvadó2, Gregory Operto2, Carolina Minguillón2, Gonzalo Sánchez-Benavides2, Marta Crous-Bou2, Oriol Grau-Rivera2, Aleix Sala-Vila2, Carles Falcón2, Marc Suárez-Calvet2, Henrik Zetterberg2, Kaj Blennow2, Juan Domingo Gispert2, José Luis Molinuevo2. 1. From the Barcelonaβeta Brain Research Center (E.M.A.-U., G.S., G.O., C.M., G.S.-B., M.C.-B., O.G.-R., A.S.-V, C.F., M.S.-C., J.D.G., J.L.M.), Pasqual Maragall Foundation; IMIM (Hospital del Mar Medical Research Institute) (E.M.A.-U., G.S., G.O., C.M., G.S.-B., M.C.-B., O.G.-R., A.S.-V, C.F., M.S.-C., J.D.G., J.L.M.), Barcelona; Centro de Investigación Biomédica en Red de Fragilidad y Envejecimiento Saludable (E.M.A.-U., G.S., G.O., C.M., G.S.-B., M.C.-B., O.G.-R., M.S.-C., J.L.M.), Madrid, Spain; Department of Epidemiology (M.C.-B.), Harvard TH Chan School of Public Health, Boston, MA; Servei de Neurologia (O.G.-R., M.S.-C.), Hospital del Mar, Barcelona; Investigación Biomédica en Red Bioingeniería, Biomateriales y Nanomedicina (C.F., J.D.G.), Madrid, Spain; Clinical Neurochemistry Laboratory (H.Z., K.B.), Sahlgrenska University Hospital, Mölndal; Department of Psychiatry and Neurochemistry (H.Z., K.B.), Institute of Neuroscience and Physiology, The Sahlgrenska Academy at the University of Gothenburg, Mölndal, Sweden; Department of Neurodegenerative Disease (H.Z.), UCL Institute of Neurology, Queen Square; UK Dementia Research Institute at UCL (H.Z.), London; and Universitat Pompeu Fabra (J.D.G., J.L.M.), Barcelona, Spain. earenaza@barcelonabeta.org. 2. From the Barcelonaβeta Brain Research Center (E.M.A.-U., G.S., G.O., C.M., G.S.-B., M.C.-B., O.G.-R., A.S.-V, C.F., M.S.-C., J.D.G., J.L.M.), Pasqual Maragall Foundation; IMIM (Hospital del Mar Medical Research Institute) (E.M.A.-U., G.S., G.O., C.M., G.S.-B., M.C.-B., O.G.-R., A.S.-V, C.F., M.S.-C., J.D.G., J.L.M.), Barcelona; Centro de Investigación Biomédica en Red de Fragilidad y Envejecimiento Saludable (E.M.A.-U., G.S., G.O., C.M., G.S.-B., M.C.-B., O.G.-R., M.S.-C., J.L.M.), Madrid, Spain; Department of Epidemiology (M.C.-B.), Harvard TH Chan School of Public Health, Boston, MA; Servei de Neurologia (O.G.-R., M.S.-C.), Hospital del Mar, Barcelona; Investigación Biomédica en Red Bioingeniería, Biomateriales y Nanomedicina (C.F., J.D.G.), Madrid, Spain; Clinical Neurochemistry Laboratory (H.Z., K.B.), Sahlgrenska University Hospital, Mölndal; Department of Psychiatry and Neurochemistry (H.Z., K.B.), Institute of Neuroscience and Physiology, The Sahlgrenska Academy at the University of Gothenburg, Mölndal, Sweden; Department of Neurodegenerative Disease (H.Z.), UCL Institute of Neurology, Queen Square; UK Dementia Research Institute at UCL (H.Z.), London; and Universitat Pompeu Fabra (J.D.G., J.L.M.), Barcelona, Spain.
Abstract
OBJECTIVE: To evaluate the hypothesis that proximity to parental age at onset (AAO) in sporadic Alzheimer disease (AD) is associated with greater AD and neural injury biomarker alterations during midlife and to assess the role of nonmodifiable and modifiable factors. METHODS: This observational study included 290 cognitively unimpaired (CU) participants with a family history (FH) of clinically diagnosed sporadic AD (age 49-73 years) from the Alzheimer's and Families (ALFA) study. [18F]flutemetamol-PET standardized uptake value ratios, CSF β-amyloid42/40 ratio, and phosphorylated tau were used as AD biomarkers. Hippocampal volumes and CSF total tau were used as neural injury biomarkers. Mental and vascular health proxies were calculated. In multiple regression models, we assessed the effect of proximity to parental AAO and its interaction with age on AD and neural injury biomarkers. Then, we evaluated the effects of FH load (number of parents affected), sex, APOE ε4, education, and vascular and mental health. RESULTS: Proximity to parental AAO was associated with β-amyloid, but not with neural injury biomarkers, and interacted with sex and age, showing that women and older participants had increased β-amyloid. FH load and APOE ε4 showed independent contributions to β-amyloid load. Education and vascular and mental health proxies were not associated with AD biomarkers. However, lower mental health proxies were associated with decreased hippocampal volumes with age. CONCLUSION: The identification of the earliest biomarker changes and modifiable factors to be targeted in early interventions is crucial for AD prevention. Proximity to parental AAO may offer a timeline for detection of incipient β-amyloid changes in women. In risk-enriched middle-aged cohorts, mental health may be a target for early interventions. CLINICALTRIALSGOV IDENTIFIER: NCT02485730. CLASSIFICATION OF EVIDENCE: This study provides Class II evidence that in CU adults with FH of sporadic AD, proximity to parental AAO was associated with β-amyloid but not with neural injury biomarkers.
OBJECTIVE: To evaluate the hypothesis that proximity to parental age at onset (AAO) in sporadic Alzheimer disease (AD) is associated with greater AD and neural injury biomarker alterations during midlife and to assess the role of nonmodifiable and modifiable factors. METHODS: This observational study included 290 cognitively unimpaired (CU) participants with a family history (FH) of clinically diagnosed sporadic AD (age 49-73 years) from the Alzheimer's and Families (ALFA) study. [18F]flutemetamol-PET standardized uptake value ratios, CSF β-amyloid42/40 ratio, and phosphorylated tau were used as AD biomarkers. Hippocampal volumes and CSF total tau were used as neural injury biomarkers. Mental and vascular health proxies were calculated. In multiple regression models, we assessed the effect of proximity to parental AAO and its interaction with age on AD and neural injury biomarkers. Then, we evaluated the effects of FH load (number of parents affected), sex, APOE ε4, education, and vascular and mental health. RESULTS: Proximity to parental AAO was associated with β-amyloid, but not with neural injury biomarkers, and interacted with sex and age, showing that women and older participants had increased β-amyloid. FH load and APOE ε4 showed independent contributions to β-amyloid load. Education and vascular and mental health proxies were not associated with AD biomarkers. However, lower mental health proxies were associated with decreased hippocampal volumes with age. CONCLUSION: The identification of the earliest biomarker changes and modifiable factors to be targeted in early interventions is crucial for AD prevention. Proximity to parental AAO may offer a timeline for detection of incipient β-amyloid changes in women. In risk-enriched middle-aged cohorts, mental health may be a target for early interventions. CLINICALTRIALSGOV IDENTIFIER: NCT02485730. CLASSIFICATION OF EVIDENCE: This study provides Class II evidence that in CU adults with FH of sporadic AD, proximity to parental AAO was associated with β-amyloid but not with neural injury biomarkers.
Authors: Clifford R Jack; Heather J Wiste; Timothy G Lesnick; Stephen D Weigand; David S Knopman; Prashanthi Vemuri; Vernon S Pankratz; Matthew L Senjem; Jeffrey L Gunter; Michelle M Mielke; Val J Lowe; Bradley F Boeve; Ronald C Petersen Journal: Neurology Date: 2013-02-27 Impact factor: 9.910
Authors: Eider M Arenaza-Urquijo; Alexandre Bejanin; Julie Gonneaud; Miranka Wirth; Renaud La Joie; Justine Mutlu; Malo Gaubert; Brigitte Landeau; Vincent de la Sayette; Francis Eustache; Gaël Chételat Journal: Neurobiol Aging Date: 2017-06-24 Impact factor: 4.673
Authors: Randall J Bateman; Chengjie Xiong; Tammie L S Benzinger; Anne M Fagan; Alison Goate; Nick C Fox; Daniel S Marcus; Nigel J Cairns; Xianyun Xie; Tyler M Blazey; David M Holtzman; Anna Santacruz; Virginia Buckles; Angela Oliver; Krista Moulder; Paul S Aisen; Bernardino Ghetti; William E Klunk; Eric McDade; Ralph N Martins; Colin L Masters; Richard Mayeux; John M Ringman; Martin N Rossor; Peter R Schofield; Reisa A Sperling; Stephen Salloway; John C Morris Journal: N Engl J Med Date: 2012-07-11 Impact factor: 91.245
Authors: Clifford R Jack; Heather J Wiste; Stephen D Weigand; David S Knopman; Michelle M Mielke; Prashanthi Vemuri; Val Lowe; Matthew L Senjem; Jeffrey L Gunter; Denise Reyes; Mary M Machulda; Rosebud Roberts; Ronald C Petersen Journal: Brain Date: 2015-09-30 Impact factor: 13.501
Authors: Michelle J Walters; Joanna Sterling; Crystal Quinn; Christine Ganzer; Ricardo S Osorio; Randolph D Andrews; Dawn C Matthews; Shankar Vallabhajosula; Mony J de Leon; Richard S Isaacson; Lisa Mosconi Journal: BMJ Open Date: 2018-11-25 Impact factor: 2.692
Authors: Prashanthi Vemuri; Timothy G Lesnick; David S Knopman; Scott A Przybelski; Robert I Reid; Michelle M Mielke; Jonathan Graff-Radford; Val J Lowe; Mary M Machulda; Ronald C Petersen; Clifford R Jack Journal: Ann Neurol Date: 2019-10-17 Impact factor: 10.422