Amyloid and Tau PET positive cognitively unimpaired individuals: Destined to decline?

Abstract

A major unanswered question in the dementia field is whether cognitively unimpaired individuals who harbor both Alzheimer disease (AD) neuropathological hallmarks (i.e., amyloid-beta plaques and tau neurofibrillary tangles) can preserve their cognition over time or are destined to decline. In this large multi-center amyloid and tau PET study (n=1325), 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 neocortex (A+TNEO+) and compared them with A+T- and A-T- groups. Cox proportional hazard models showed a substantially increased risk for progression to mild cognitive impairment in the A+TNEO+ (Hazard ratio [HR]=19.2[95% confidence interval: 10.9-33.7]), A+TMTL+ (HR=14.6[8.1-26.4) and A+T- (HR=2.4[1.4-4.3]) groups vs the A-T- (reference) group. Linear mixed effect models indicated that the A+TNEO+ (beta=-0.056+/-0.005, T=-11.55, p<0.001), A+TMTL+ (beta=-0.024+/-0.005, T=-4.72, p<0.001) and A+T- (beta=-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). Evidence of advanced AD pathological changes provided by amyloid and tau PET is strongly associated with short-term (i.e., 3-5 years) cognitive decline in cognitively unimpaired individuals and is therefore of high clinical relevance.

Association of Phosphorylated Tau Biomarkers With Amyloid Positron Emission Tomography vs Tau Positron Emission Tomography

“…8,16 Tau tangle aggregation measured with PET occurs later and is strongly predictive of cognitive decline. 53 In this connection, the much higher association of p-tau biomarkers with amyloidosis than tangle burden in CU individuals suggests that p-tau biomarkers may be less well-positioned to predict future cognitive decline. In contrast, the high association of p-tau biomarkers with both amyloidosis and tangle burden in individuals with cognitive impairment suggest that abnormal p-tau biomarkers have a strong predictive value for AD in diagnostic settings.…”

Onset of Alzheimer disease in apolipoprotein ɛ4 carriers is earlier in butyrylcholinesterase K variant carriers

“…and BCHE-K carriers into AD at an earlier age with less global tau and neurodegenerative pathology (Table 3; Figure 4) (77,78). Such neuroanatomical distinctions are not discernible on CSF indices that summarize pathology changes across the brain.…”

Tau-PET Bildgebung der Demenzerkrankungen

“…Aktuelle Arbeiten in einer Studienkohorte, in denen Personen die in der Amyloid Bildgebung als auch im Tau-PET (18F-AV1451) positiv waren, aber keine klinischen Symptome der Alzheimer Demenz aufgezeigt (präklinische Phase der AD) haben, zeigten eine größere Wahrscheinlichkeit des progressiven kognitiven Leistungsabbau, als Personen die keine klinischen Symptome der AD aufzeigen und in den Biomarkern für Amyloid und Tau negativ sind [23]. Interessanterweise zeigten die Personen, deren Tau-Last über den medialen-temporalen Kortex hinaus ging und bereits Tau-Ablagerungen in neokortikalen Arealen zeigten, den stärksten kognitiven Abbau.…”