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.

Personalized virtual brains of Alzheimer’s Disease link dynamical biomarkers of fMRI with increased local excitability

“…In addition, our findings confirm the importance of the limbic regions in the development of AD pathology and the potential impact of protein burden on brain function. In line with the recent evidence that cement the importance of Aβ and pTau in the limbic regions as AD biomarkers (Ossenkoppele et al, 2022), our approach provides a mechanistic link to the observed dynamical alterations. Additionally, as a validation step we adapt a mechanistic causal inference framework for the accurate estimation of pathological trajectory by training the deep neural density estimators on model simulations, and the low-dimensional empirical evidence.…”

“…2016, Pontecorvo et al,. 2017, Ossenkoppele et al, 2022). The extent of AD-related pathology in the brain can be assessed using positron emission tomography (PET) scans and cerebrospinal fluid (CSF) assays, along degeneration at the structural level and functional changes detected with functional magnetic resonance imaging (fMRI) and non-invasive electromagnetic recording techniques such as electroencephalography (EEG) and magnetoencephalography (MEG).…”

Early β-amyloid accumulation in the brain is associated with peripheral T cell alterations

“…Accumulation and aggregation of misfolded β-amyloid peptide (Aβ) in the brain represents a primary pathological event of AD (Jack et al, 2018) that occurs over decades before symptom onset in a silent, preclinical phase of the disease (Villemagne et al, 2013) . Cognitively healthy control subjects (HCS) with elevated brain β-amyloid are individuals at such an early, preclinical stage of the AD continuum, with higher risk for disease progression towards ‘mild cognitive impairment’ (MCI) and established AD dementia stage (Donohue et al, 2017) (Ossenkoppele et al, 2022) . Therefore, preclinical AD is currently considered an ideal window of opportunity for disease-modifying therapeutic strategies (Bateman et al, 2019) .…”

The past and present of therapeutic strategy for Alzheimer’s diseases: potential for stem cell therapy

“…Aβ peptides form SPs in the early preclinical stage in patients with AD and individuals with normal cognition before the onset of clinical symptoms [15,17]. Aβ peptides are proteolytic fragments that are derived from APP.…”

“…Intracellular hyperphosphorylated tau protein causes the formation of neurofibrillary tangles (NFTs) in neural cells [12,13] Both SPs and NFTs are typical neuropathological hallmarks of patients with AD [14]. Abnormal amyloid and tau have been reported as risk factors for future cognitive decline in individuals with normal cognition [15].…”