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

• Published in: Nature medicine Vol. 28; no. 11; pp. 2381 - 2387
• Main Authors: Ossenkoppele, Rik, Pichet Binette, Alexa, Groot, Colin, Smith, Ruben, Strandberg, Olof, Palmqvist, Sebastian, Stomrud, Erik, Tideman, Pontus, Ohlsson, Tomas, Jögi, Jonas, Johnson, Keith, Sperling, Reisa, Dore, Vincent, Masters, Colin L., Rowe, Christopher, Visser, Denise, van Berckel, Bart N. M., van der Flier, Wiesje M., Baker, Suzanne, Jagust, William J., Wiste, Heather J., Petersen, Ronald C., Jack, Clifford R., Hansson, Oskar
• Format: Journal Article
• Language: English
• Published: New York Nature Publishing Group US 01.11.2022; Nature Publishing Group
• Subjects: 692/53/2422; 692/617/375/132/1283; Alzheimer Disease - pathology; Alzheimer's disease; Amyloid - metabolism; Amyloid beta-Peptides - metabolism; Amyloidosis; Basic Medicine; Biomarkers; Biomedical and Life Sciences; Biomedicine; Brain - metabolism; Cancer Research; Cerebral cortex; Clinical Medicine; Cognition; Cognitive ability; Cognitive Dysfunction - diagnostic imaging; Dementia; Dementia disorders; Emission analysis; Humans; Impairment; Infectious Diseases; Klinisk medicin; Medical and Health Sciences; Medicin och hälsovetenskap; Medicinska och farmaceutiska grundvetenskaper; Metabolic Diseases; Molecular Medicine; Neocortex; Neurodegenerative diseases; Neurofibrillary tangles; Neurologi; Neurology; Neurosciences; Neurovetenskaper; Plaque, Amyloid; Positron emission; Positron emission tomography; Positron-Emission Tomography - methods; Risk; Senile plaques; Tau protein; tau Proteins - metabolism; Temporal lobe; β-Amyloid
• ISSN: 1078-8956; 1546-170X; 1546-170X
• DOI: 10.1038/s41591-022-02049-x

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 + T MTL + ) and/or in the temporal neocortex (A + T NEO-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 + T NEO-T + (hazard ratio (HR) = 19.2, 95% confidence interval (CI) = 10.9–33.7), A + T MTL + (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 + T MTL + (HR = 6.0, 95% CI = 3.4–10.6) and A + T NEO-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 + T NEO-T + ( β  = −0.056 ± 0.005, T  = −11.55, P  < 0.001), A + T MTL + ( 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 + T NEO-T + ( P  < 0.001) and A + T MTL + ( 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. Abnormal amyloid and tau PET in cognitively unimpaired individuals is strongly associated with short-term cognitive decline and subsequent development of dementia.