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 journalArticlepeer-review


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 AT 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 AT (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 AT (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 languageEnglish (US)
Pages (from-to)2381-2387
Number of pages7
JournalNature Medicine
Issue number11
StatePublished - Nov 2022

ASJC Scopus subject areas

  • General Biochemistry, Genetics and Molecular Biology


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