Longitudinal cognitive and biomarker changes in dominantly inherited Alzheimer disease

Dominantly Inherited Alzheimer Network

Research output: Contribution to journalArticle

9 Citations (Scopus)

Abstract

OBJECTIVE: To assess the onset, sequence, and rate of progression of comprehensive biomarker and clinical measures across the spectrum of Alzheimer disease (AD) using the Dominantly Inherited Alzheimer Network (DIAN) study and compare these to cross-sectional estimates.

METHODS: We conducted longitudinal clinical, cognitive, CSF, and neuroimaging assessments (mean of 2.7 [±1.1] visits) in 217 DIAN participants. Linear mixed effects models were used to assess changes in each measure relative to individuals' estimated years to symptom onset and to compare mutation carriers and noncarriers.

RESULTS: Longitudinal β-amyloid measures changed first (starting 25 years before estimated symptom onset), followed by declines in measures of cortical metabolism (approximately 7-10 years later), then cognition and hippocampal atrophy (approximately 20 years later). There were significant differences in the estimates of CSF p-tau181 and tau, with elevations from cross-sectional estimates preceding longitudinal estimates by over 10 years; further, longitudinal estimates identified a significant decline in CSF p-tau181 near symptom onset as opposed to continued elevations.

CONCLUSION: These longitudinal estimates clarify the sequence and temporal dynamics of presymptomatic pathologic changes in autosomal dominant AD, information critical to a better understanding of the disease. The pattern of biomarker changes identified here also suggests that once β-amyloidosis begins, additional pathologies may begin to develop less than 10 years later, but more than 15 years before symptom onset, an important consideration for interventions meant to alter the disease course.

Original languageEnglish (US)
Pages (from-to)e1295-e1306
JournalNeurology
Volume91
Issue number14
DOIs
StatePublished - Oct 2 2018

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Alzheimer Disease
Biomarkers
Amyloidosis
Amyloid
Neuroimaging
Cognition
Atrophy
Pathology
Mutation

ASJC Scopus subject areas

  • Clinical Neurology

Cite this

Longitudinal cognitive and biomarker changes in dominantly inherited Alzheimer disease. / Dominantly Inherited Alzheimer Network.

In: Neurology, Vol. 91, No. 14, 02.10.2018, p. e1295-e1306.

Research output: Contribution to journalArticle

Dominantly Inherited Alzheimer Network. / Longitudinal cognitive and biomarker changes in dominantly inherited Alzheimer disease. In: Neurology. 2018 ; Vol. 91, No. 14. pp. e1295-e1306.
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abstract = "OBJECTIVE: To assess the onset, sequence, and rate of progression of comprehensive biomarker and clinical measures across the spectrum of Alzheimer disease (AD) using the Dominantly Inherited Alzheimer Network (DIAN) study and compare these to cross-sectional estimates.METHODS: We conducted longitudinal clinical, cognitive, CSF, and neuroimaging assessments (mean of 2.7 [±1.1] visits) in 217 DIAN participants. Linear mixed effects models were used to assess changes in each measure relative to individuals' estimated years to symptom onset and to compare mutation carriers and noncarriers.RESULTS: Longitudinal β-amyloid measures changed first (starting 25 years before estimated symptom onset), followed by declines in measures of cortical metabolism (approximately 7-10 years later), then cognition and hippocampal atrophy (approximately 20 years later). There were significant differences in the estimates of CSF p-tau181 and tau, with elevations from cross-sectional estimates preceding longitudinal estimates by over 10 years; further, longitudinal estimates identified a significant decline in CSF p-tau181 near symptom onset as opposed to continued elevations.CONCLUSION: These longitudinal estimates clarify the sequence and temporal dynamics of presymptomatic pathologic changes in autosomal dominant AD, information critical to a better understanding of the disease. The pattern of biomarker changes identified here also suggests that once β-amyloidosis begins, additional pathologies may begin to develop less than 10 years later, but more than 15 years before symptom onset, an important consideration for interventions meant to alter the disease course.",
author = "{Dominantly Inherited Alzheimer Network} and Eric McDade and Guoqiao Wang and Gordon, {Brian A.} and Jason Hassenstab and Benzinger, {Tammie L.S.} and Virginia Buckles and Fagan, {Anne M.} and Holtzman, {David M.} and Cairns, {Nigel J.} and Goate, {Alison M.} and Marcus, {Daniel S.} and Morris, {John C.} and Katrina Paumier and Chengjie Xiong and Ricardo Allegri and Berman, {Sarah B.} and William Klunk and James Noble and John Ringman and Bernardino Ghetti and Martin Farlow and Sperling, {Reisa A.} and Jasmeer Chhatwal and Stephen Salloway and Graff-Radford, {Neill R.} and Schofield, {Peter R.} and Colin Masters and Rossor, {Martin N.} and Fox, {Nick C.} and Johannes Levin and Mathias Jucker and Bateman, {Randall J.}",
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T1 - Longitudinal cognitive and biomarker changes in dominantly inherited Alzheimer disease

AU - Dominantly Inherited Alzheimer Network

AU - McDade, Eric

AU - Wang, Guoqiao

AU - Gordon, Brian A.

AU - Hassenstab, Jason

AU - Benzinger, Tammie L.S.

AU - Buckles, Virginia

AU - Fagan, Anne M.

AU - Holtzman, David M.

AU - Cairns, Nigel J.

AU - Goate, Alison M.

AU - Marcus, Daniel S.

AU - Morris, John C.

AU - Paumier, Katrina

AU - Xiong, Chengjie

AU - Allegri, Ricardo

AU - Berman, Sarah B.

AU - Klunk, William

AU - Noble, James

AU - Ringman, John

AU - Ghetti, Bernardino

AU - Farlow, Martin

AU - Sperling, Reisa A.

AU - Chhatwal, Jasmeer

AU - Salloway, Stephen

AU - Graff-Radford, Neill R.

AU - Schofield, Peter R.

AU - Masters, Colin

AU - Rossor, Martin N.

AU - Fox, Nick C.

AU - Levin, Johannes

AU - Jucker, Mathias

AU - Bateman, Randall J.

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N2 - OBJECTIVE: To assess the onset, sequence, and rate of progression of comprehensive biomarker and clinical measures across the spectrum of Alzheimer disease (AD) using the Dominantly Inherited Alzheimer Network (DIAN) study and compare these to cross-sectional estimates.METHODS: We conducted longitudinal clinical, cognitive, CSF, and neuroimaging assessments (mean of 2.7 [±1.1] visits) in 217 DIAN participants. Linear mixed effects models were used to assess changes in each measure relative to individuals' estimated years to symptom onset and to compare mutation carriers and noncarriers.RESULTS: Longitudinal β-amyloid measures changed first (starting 25 years before estimated symptom onset), followed by declines in measures of cortical metabolism (approximately 7-10 years later), then cognition and hippocampal atrophy (approximately 20 years later). There were significant differences in the estimates of CSF p-tau181 and tau, with elevations from cross-sectional estimates preceding longitudinal estimates by over 10 years; further, longitudinal estimates identified a significant decline in CSF p-tau181 near symptom onset as opposed to continued elevations.CONCLUSION: These longitudinal estimates clarify the sequence and temporal dynamics of presymptomatic pathologic changes in autosomal dominant AD, information critical to a better understanding of the disease. The pattern of biomarker changes identified here also suggests that once β-amyloidosis begins, additional pathologies may begin to develop less than 10 years later, but more than 15 years before symptom onset, an important consideration for interventions meant to alter the disease course.

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