TY - JOUR
T1 - The bivariate distribution of amyloid-β and tau
T2 - Relationship with established neurocognitive clinical syndromes
AU - Jack, Clifford R.
AU - Wiste, Heather J.
AU - Botha, Hugo
AU - Weigand, Stephen D.
AU - Therneau, Terry M.
AU - Knopman, David S.
AU - Graff-Radford, Jonathan
AU - Jones, David T.
AU - Ferman, Tanis J.
AU - Boeve, Bradley F.
AU - Kantarci, Kejal
AU - Lowe, Val J.
AU - Vemuri, Prashanthi
AU - Mielke, Michelle M.
AU - Fields, Julie A.
AU - Machulda, Mary M.
AU - Schwarz, Christopher G.
AU - Senjem, Matthew L.
AU - Gunter, Jeffrey L.
AU - Petersen, Ronald C.
N1 - Funding Information:
Study funding was provided by the National Institutes of Health, R37 AG011378, RO1 AG041851, R01 AG056366, R01 NS097495, U01 AG06786, R01 AG034676, P50 AG016574; Alexander Family Professorship of Alzheimer's Disease Research; Alzheimer's Association; The GHR Foundation. The funding organizations/sponsors had no role in design and conduct of the study; collection, management, analysis, and interpretation of the data; preparation, review, or approval of the manuscript; and decision to submit the manuscript for publication.
Funding Information:
Study funding was provided by the National Institutes of Health, R37 AG011378, RO1 AG041851, R01 AG056366, R01 NS097495, U01 AG06786, R01 AG034676, P50 AG016574; Alexander Family Professorship of Alzheimer’s Disease Research; Alzheimer’s Association; The GHR Foundation. The funding organizations/sponsors had no role in design and conduct of the study; collection, management, analysis, and interpretation of the data; preparation, review, or approval of the manuscript; and decision to submit the manuscript for publication.
Publisher Copyright:
© The Author(s) (2019). Published by Oxford University Press on behalf of the Guarantors of Brain. This is an Open Access article distributed under the terms of the Creative Commons Attribution Non-Commercial License
PY - 2019/10/1
Y1 - 2019/10/1
N2 - Large phenotypically diverse research cohorts with both amyloid and tau PET have only recently come into existence. Our objective was to determine relationships between the bivariate distribution of amyloid-b and tau on PET and established clinical syndromes that are relevant to cognitive ageing and dementia. All individuals in this study were enrolled in the Mayo Clinic Study of Aging, a longitudinal population-based study of cognitive ageing, or the Mayo Alzheimer Disease Research Center, a longitudinal study of individuals recruited from clinical practice. We studied 1343 participants who had amyloid PET and tau PET from 2 April 2015 to 3 May 2019, and met criteria for membership in one of five clinical diagnostic groups: cognitively unimpaired, mild cognitive impairment, frontotemporal dementia, probable dementia with Lewy bodies, and Alzheimer clinical syndrome. We examined these clinical groups in relation to the bivariate distribution of amyloid and tau PET values. Individuals were grouped into amyloid (A)/tau (T) quadrants based on previously established abnormality cut points of standardized uptake value ratio 1.48 (A) and 1.33 (T). Individual participants largely fell into one of three amyloid/tau quadrants: low amyloid and low tau (A-T-), high amyloid and low tau (A + T-), or high amyloid and high tau (A + T +). Seventy per cent of cognitively unimpaired and 74% of FTD participants fell into the A-T- quadrant. Participants with mild cognitive impairment spanned the A-T- (42%), A + T- (28%), and A + T + (27%) quadrants. Probable dementia with Lewy body participants spanned the A-T- (38%) and A + T- (44%) quadrants. Most (89%) participants with Alzheimer clinical syndrome fell into the A + T + quadrant. These data support several conclusions. First, among 1343 participants, abnormal tau PET rarely occurred in the absence of abnormal amyloid PET, but the reverse was common. Thus, with rare exceptions, amyloidosis appears to be required for high levels of 3R/4R tau deposition. Second, abnormal amyloid PET is compatible with normal cognition but highly abnormal tau PET is not. These two conclusions support a dynamic biomarker model in which Alzheimer's disease is characterized first by the appearance of amyloidosis and later by tauopathy, with tauopathy being the proteinopathy associated with clinical symptoms. Third, bivariate amyloid and tau PET relationships differed across clinical groups and thus have a role for clarifying the aetiologies underlying neurocognitive clinical syndromes.
AB - Large phenotypically diverse research cohorts with both amyloid and tau PET have only recently come into existence. Our objective was to determine relationships between the bivariate distribution of amyloid-b and tau on PET and established clinical syndromes that are relevant to cognitive ageing and dementia. All individuals in this study were enrolled in the Mayo Clinic Study of Aging, a longitudinal population-based study of cognitive ageing, or the Mayo Alzheimer Disease Research Center, a longitudinal study of individuals recruited from clinical practice. We studied 1343 participants who had amyloid PET and tau PET from 2 April 2015 to 3 May 2019, and met criteria for membership in one of five clinical diagnostic groups: cognitively unimpaired, mild cognitive impairment, frontotemporal dementia, probable dementia with Lewy bodies, and Alzheimer clinical syndrome. We examined these clinical groups in relation to the bivariate distribution of amyloid and tau PET values. Individuals were grouped into amyloid (A)/tau (T) quadrants based on previously established abnormality cut points of standardized uptake value ratio 1.48 (A) and 1.33 (T). Individual participants largely fell into one of three amyloid/tau quadrants: low amyloid and low tau (A-T-), high amyloid and low tau (A + T-), or high amyloid and high tau (A + T +). Seventy per cent of cognitively unimpaired and 74% of FTD participants fell into the A-T- quadrant. Participants with mild cognitive impairment spanned the A-T- (42%), A + T- (28%), and A + T + (27%) quadrants. Probable dementia with Lewy body participants spanned the A-T- (38%) and A + T- (44%) quadrants. Most (89%) participants with Alzheimer clinical syndrome fell into the A + T + quadrant. These data support several conclusions. First, among 1343 participants, abnormal tau PET rarely occurred in the absence of abnormal amyloid PET, but the reverse was common. Thus, with rare exceptions, amyloidosis appears to be required for high levels of 3R/4R tau deposition. Second, abnormal amyloid PET is compatible with normal cognition but highly abnormal tau PET is not. These two conclusions support a dynamic biomarker model in which Alzheimer's disease is characterized first by the appearance of amyloidosis and later by tauopathy, with tauopathy being the proteinopathy associated with clinical symptoms. Third, bivariate amyloid and tau PET relationships differed across clinical groups and thus have a role for clarifying the aetiologies underlying neurocognitive clinical syndromes.
KW - Alzheimer's disease
KW - Amyloid PET
KW - Dementia with Lewy bodies
KW - Frontotemporal dementia
KW - Tau PET
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U2 - 10.1093/brain/awz268
DO - 10.1093/brain/awz268
M3 - Article
C2 - 31501889
AN - SCOPUS:85072717828
SN - 0006-8950
VL - 142
SP - 3230
EP - 3242
JO - Brain
JF - Brain
IS - 10
ER -