Amyloid and tau PET-positive cognitively unimpaired individuals are at high risk for future cognitive decline

Rik Ossenkoppele; Alexa Pichet Binette; Colin Groot; Ruben Smith; Olof Strandberg; Sebastian Palmqvist; Erik Stomrud; Pontus Tideman; Tomas Ohlsson; Jonas Jögi; Keith Johnson; Reisa Sperling; Vincent Dore; Colin L Masters; Christopher Rowe; Denise Visser; Bart N M van Berckel; Wiesje M van der Flier; Suzanne Baker; William J Jagust; Heather J Wiste; Ronald C Petersen; Clifford R Jack; Oskar Hansson

doi:10.1038/s41591-022-02049-x

Amyloid and tau PET-positive cognitively unimpaired individuals are at high risk for future cognitive decline

Rik Ossenkoppele, Alexa Pichet Binette, Colin Groot, Ruben Smith, Olof Strandberg, Sebastian Palmqvist, Erik Stomrud, Pontus Tideman, Tomas Ohlsson, Jonas Jögi, Keith Johnson, Reisa Sperling, Vincent Dore, Colin L Masters, Christopher Rowe, Denise Visser, Bart N M van Berckel, Wiesje M van der Flier, Suzanne Baker, William J JagustHeather J Wiste, Ronald C Petersen, Clifford R Jack, Oskar Hansson

Research output: Contribution to journal › Article › peer-review

Abstract

A major unanswered question in the dementia field is whether cognitively unimpaired individuals who harbor both Alzheimer's disease neuropathological hallmarks (that is, amyloid-β plaques and tau neurofibrillary tangles) can preserve their cognition over time or are destined to decline. In this large multicenter amyloid and tau positron emission tomography (PET) study (n = 1,325), we examined the risk for future progression to mild cognitive impairment and the rate of cognitive decline over time among cognitively unimpaired individuals who were amyloid PET-positive (A+) and tau PET-positive (T+) in the medial temporal lobe (A+TMTL+) and/or in the temporal neocortex (A+TNEO-T+) and compared them with A+T- and A-T- groups. Cox proportional-hazards models showed a substantially increased risk for progression to mild cognitive impairment in the A+TNEO-T+ (hazard ratio (HR) = 19.2, 95% confidence interval (CI) = 10.9-33.7), A+TMTL+ (HR = 14.6, 95% CI = 8.1-26.4) and A+T- (HR = 2.4, 95% CI = 1.4-4.3) groups versus the A-T- (reference) group. Both A+TMTL+ (HR = 6.0, 95% CI = 3.4-10.6) and A+TNEO-T+ (HR = 7.9, 95% CI = 4.7-13.5) groups also showed faster clinical progression to mild cognitive impairment than the A+T- group. Linear mixed-effect models indicated that the A+TNEO-T+ (β = -0.056 ± 0.005, T = -11.55, P < 0.001), A+TMTL+ (β = -0.024 ± 0.005, T = -4.72, P < 0.001) and A+T- (β = -0.008 ± 0.002, T = -3.46, P < 0.001) groups showed significantly faster longitudinal global cognitive decline compared to the A-T- (reference) group (all P < 0.001). Both A+TNEO-T+ (P < 0.001) and A+TMTL+ (P = 0.002) groups also progressed faster than the A+T- group. In summary, evidence of advanced Alzheimer's disease pathological changes provided by a combination of abnormal amyloid and tau PET examinations is strongly associated with short-term (that is, 3-5 years) cognitive decline in cognitively unimpaired individuals and is therefore of high clinical relevance.

Original language	English
Pages (from-to)	2381-2387
Number of pages	7
Journal	Nature Medicine
Volume	28
Issue number	11
DOIs	https://doi.org/10.1038/s41591-022-02049-x
Publication status	Published - 2022 Nov

Subject classification (UKÄ)

Neurology
Neurosciences

Free keywords

Humans
Alzheimer Disease/pathology
tau Proteins/metabolism
Brain/metabolism
Cognitive Dysfunction/diagnostic imaging
Positron-Emission Tomography/methods
Amyloid/metabolism
Amyloid beta-Peptides/metabolism
Amyloidosis
Plaque, Amyloid
Biomarkers

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Ossenkoppele, R., Pichet Binette, A., Groot, C., Smith, R., Strandberg, O., Palmqvist, S., Stomrud, E., Tideman, P., Ohlsson, T., Jögi, J., Johnson, K., Sperling, R., Dore, V., Masters, C. L., Rowe, C., Visser, D., van Berckel, B. N. M., van der Flier, W. M., Baker, S., ... Hansson, O. (2022). Amyloid and tau PET-positive cognitively unimpaired individuals are at high risk for future cognitive decline. Nature Medicine, 28(11), 2381-2387. https://doi.org/10.1038/s41591-022-02049-x

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title = "Amyloid and tau PET-positive cognitively unimpaired individuals are at high risk for future cognitive decline",

abstract = "A major unanswered question in the dementia field is whether cognitively unimpaired individuals who harbor both Alzheimer's disease neuropathological hallmarks (that is, amyloid-β plaques and tau neurofibrillary tangles) can preserve their cognition over time or are destined to decline. In this large multicenter amyloid and tau positron emission tomography (PET) study (n = 1,325), we examined the risk for future progression to mild cognitive impairment and the rate of cognitive decline over time among cognitively unimpaired individuals who were amyloid PET-positive (A+) and tau PET-positive (T+) in the medial temporal lobe (A+TMTL+) and/or in the temporal neocortex (A+TNEO-T+) and compared them with A+T- and A-T- groups. Cox proportional-hazards models showed a substantially increased risk for progression to mild cognitive impairment in the A+TNEO-T+ (hazard ratio (HR) = 19.2, 95\% confidence interval (CI) = 10.9-33.7), A+TMTL+ (HR = 14.6, 95\% CI = 8.1-26.4) and A+T- (HR = 2.4, 95\% CI = 1.4-4.3) groups versus the A-T- (reference) group. Both A+TMTL+ (HR = 6.0, 95\% CI = 3.4-10.6) and A+TNEO-T+ (HR = 7.9, 95\% CI = 4.7-13.5) groups also showed faster clinical progression to mild cognitive impairment than the A+T- group. Linear mixed-effect models indicated that the A+TNEO-T+ (β = -0.056 ± 0.005, T = -11.55, P < 0.001), A+TMTL+ (β = -0.024 ± 0.005, T = -4.72, P < 0.001) and A+T- (β = -0.008 ± 0.002, T = -3.46, P < 0.001) groups showed significantly faster longitudinal global cognitive decline compared to the A-T- (reference) group (all P < 0.001). Both A+TNEO-T+ (P < 0.001) and A+TMTL+ (P = 0.002) groups also progressed faster than the A+T- group. In summary, evidence of advanced Alzheimer's disease pathological changes provided by a combination of abnormal amyloid and tau PET examinations is strongly associated with short-term (that is, 3-5 years) cognitive decline in cognitively unimpaired individuals and is therefore of high clinical relevance.",

keywords = "Humans, Alzheimer Disease/pathology, tau Proteins/metabolism, Brain/metabolism, Cognitive Dysfunction/diagnostic imaging, Positron-Emission Tomography/methods, Amyloid/metabolism, Amyloid beta-Peptides/metabolism, Amyloidosis, Plaque, Amyloid, Biomarkers",

author = "Rik Ossenkoppele and \{Pichet Binette\}, Alexa and Colin Groot and Ruben Smith and Olof Strandberg and Sebastian Palmqvist and Erik Stomrud and Pontus Tideman and Tomas Ohlsson and Jonas J{\"o}gi and Keith Johnson and Reisa Sperling and Vincent Dore and Masters, \{Colin L\} and Christopher Rowe and Denise Visser and \{van Berckel\}, \{Bart N M\} and \{van der Flier\}, \{Wiesje M\} and Suzanne Baker and Jagust, \{William J\} and Wiste, \{Heather J\} and Petersen, \{Ronald C\} and Jack, \{Clifford R\} and Oskar Hansson",

year = "2022",

month = nov,

doi = "10.1038/s41591-022-02049-x",

language = "English",

volume = "28",

pages = "2381--2387",

journal = "Nature Medicine",

issn = "1546-170X",

publisher = "Nature Publishing Group",

number = "11",

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Ossenkoppele, R , Pichet Binette, A , Groot, C , Smith, R , Strandberg, O , Palmqvist, S , Stomrud, E , Tideman, P, Ohlsson, T, Jögi, J, Johnson, K, Sperling, R, Dore, V, Masters, CL, Rowe, C, Visser, D, van Berckel, BNM, van der Flier, WM, Baker, S, Jagust, WJ, Wiste, HJ, Petersen, RC, Jack, CR & Hansson, O 2022, 'Amyloid and tau PET-positive cognitively unimpaired individuals are at high risk for future cognitive decline', Nature Medicine, vol. 28, no. 11, pp. 2381-2387. https://doi.org/10.1038/s41591-022-02049-x

TY - JOUR

T1 - Amyloid and tau PET-positive cognitively unimpaired individuals are at high risk for future cognitive decline

AU - Ossenkoppele, Rik

AU - Pichet Binette, Alexa

AU - Groot, Colin

AU - Smith, Ruben

AU - Strandberg, Olof

AU - Palmqvist, Sebastian

AU - Stomrud, Erik

AU - Tideman, Pontus

AU - Ohlsson, Tomas

AU - Jögi, Jonas

AU - Johnson, Keith

AU - Sperling, Reisa

AU - Dore, Vincent

AU - Masters, Colin L

AU - Rowe, Christopher

AU - Visser, Denise

AU - van Berckel, Bart N M

AU - van der Flier, Wiesje M

AU - Baker, Suzanne

AU - Jagust, William J

AU - Wiste, Heather J

AU - Petersen, Ronald C

AU - Jack, Clifford R

AU - Hansson, Oskar

PY - 2022/11

Y1 - 2022/11

N2 - A major unanswered question in the dementia field is whether cognitively unimpaired individuals who harbor both Alzheimer's disease neuropathological hallmarks (that is, amyloid-β plaques and tau neurofibrillary tangles) can preserve their cognition over time or are destined to decline. In this large multicenter amyloid and tau positron emission tomography (PET) study (n = 1,325), we examined the risk for future progression to mild cognitive impairment and the rate of cognitive decline over time among cognitively unimpaired individuals who were amyloid PET-positive (A+) and tau PET-positive (T+) in the medial temporal lobe (A+TMTL+) and/or in the temporal neocortex (A+TNEO-T+) and compared them with A+T- and A-T- groups. Cox proportional-hazards models showed a substantially increased risk for progression to mild cognitive impairment in the A+TNEO-T+ (hazard ratio (HR) = 19.2, 95% confidence interval (CI) = 10.9-33.7), A+TMTL+ (HR = 14.6, 95% CI = 8.1-26.4) and A+T- (HR = 2.4, 95% CI = 1.4-4.3) groups versus the A-T- (reference) group. Both A+TMTL+ (HR = 6.0, 95% CI = 3.4-10.6) and A+TNEO-T+ (HR = 7.9, 95% CI = 4.7-13.5) groups also showed faster clinical progression to mild cognitive impairment than the A+T- group. Linear mixed-effect models indicated that the A+TNEO-T+ (β = -0.056 ± 0.005, T = -11.55, P < 0.001), A+TMTL+ (β = -0.024 ± 0.005, T = -4.72, P < 0.001) and A+T- (β = -0.008 ± 0.002, T = -3.46, P < 0.001) groups showed significantly faster longitudinal global cognitive decline compared to the A-T- (reference) group (all P < 0.001). Both A+TNEO-T+ (P < 0.001) and A+TMTL+ (P = 0.002) groups also progressed faster than the A+T- group. In summary, evidence of advanced Alzheimer's disease pathological changes provided by a combination of abnormal amyloid and tau PET examinations is strongly associated with short-term (that is, 3-5 years) cognitive decline in cognitively unimpaired individuals and is therefore of high clinical relevance.

AB - A major unanswered question in the dementia field is whether cognitively unimpaired individuals who harbor both Alzheimer's disease neuropathological hallmarks (that is, amyloid-β plaques and tau neurofibrillary tangles) can preserve their cognition over time or are destined to decline. In this large multicenter amyloid and tau positron emission tomography (PET) study (n = 1,325), we examined the risk for future progression to mild cognitive impairment and the rate of cognitive decline over time among cognitively unimpaired individuals who were amyloid PET-positive (A+) and tau PET-positive (T+) in the medial temporal lobe (A+TMTL+) and/or in the temporal neocortex (A+TNEO-T+) and compared them with A+T- and A-T- groups. Cox proportional-hazards models showed a substantially increased risk for progression to mild cognitive impairment in the A+TNEO-T+ (hazard ratio (HR) = 19.2, 95% confidence interval (CI) = 10.9-33.7), A+TMTL+ (HR = 14.6, 95% CI = 8.1-26.4) and A+T- (HR = 2.4, 95% CI = 1.4-4.3) groups versus the A-T- (reference) group. Both A+TMTL+ (HR = 6.0, 95% CI = 3.4-10.6) and A+TNEO-T+ (HR = 7.9, 95% CI = 4.7-13.5) groups also showed faster clinical progression to mild cognitive impairment than the A+T- group. Linear mixed-effect models indicated that the A+TNEO-T+ (β = -0.056 ± 0.005, T = -11.55, P < 0.001), A+TMTL+ (β = -0.024 ± 0.005, T = -4.72, P < 0.001) and A+T- (β = -0.008 ± 0.002, T = -3.46, P < 0.001) groups showed significantly faster longitudinal global cognitive decline compared to the A-T- (reference) group (all P < 0.001). Both A+TNEO-T+ (P < 0.001) and A+TMTL+ (P = 0.002) groups also progressed faster than the A+T- group. In summary, evidence of advanced Alzheimer's disease pathological changes provided by a combination of abnormal amyloid and tau PET examinations is strongly associated with short-term (that is, 3-5 years) cognitive decline in cognitively unimpaired individuals and is therefore of high clinical relevance.

KW - Humans

KW - Alzheimer Disease/pathology

KW - tau Proteins/metabolism

KW - Brain/metabolism

KW - Cognitive Dysfunction/diagnostic imaging

KW - Positron-Emission Tomography/methods

KW - Amyloid/metabolism

KW - Amyloid beta-Peptides/metabolism

KW - Amyloidosis

KW - Plaque, Amyloid

KW - Biomarkers

UR - https://www.scopus.com/pages/publications/85141678180

U2 - 10.1038/s41591-022-02049-x

DO - 10.1038/s41591-022-02049-x

M3 - Article

C2 - 36357681

SN - 1546-170X

VL - 28

SP - 2381

EP - 2387

JO - Nature Medicine

JF - Nature Medicine

IS - 11

ER -

Amyloid and tau PET-positive cognitively unimpaired individuals are at high risk for future cognitive decline

Abstract

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