Association of Elevated Amyloid and Tau Positron Emission Tomography Signal With Near-Term Development of Alzheimer Disease Symptoms in Older Adults Without Cognitive Impairment

Abstract

ImportanceNational Institute on Aging–Alzheimer’s Association (NIA-AA) workgroups have proposed biological research criteria intended to identify individuals with preclinical Alzheimer disease (AD).ObjectiveTo assess the clinical value of these biological criteria to identify older individuals without cognitive impairment who are at near-term risk of developing symptomatic AD.Design, Setting, and ParticipantsThis longitudinal cohort study used data from 4 independent population-based cohorts (PREVENT-AD, HABS, AIBL, and Knight ADRC) collected between 2003 and 2021. Participants were older adults without cognitive impairment with 1 year or more of clinical observation after amyloid β and tau positron emission tomography (PET). Median clinical follow-up after PET ranged from 1.94 to 3.66 years.ExposuresBased on binary assessment of global amyloid burden (A) and a composite temporal region of tau PET uptake (T), participants were stratified into 4 groups (A+T+, A+T−, A−T+, A−T−). Presence (+) or absence (−) of neurodegeneration (N) was assessed using temporal cortical thickness.Main Outcomes and MeasuresEach cohort was analyzed separately. Primary outcome was clinical progression to mild cognitive impairment (MCI), identified by a Clinical Dementia Rating score of 0.5 or greater in Knight ADRC and by consensus committee review in the other cohorts. Clinical raters were blind to imaging, genetic, and fluid biomarker data. A secondary outcome was cognitive decline, based on a slope greater than 1.5 SD below the mean of an independent subsample of individuals without cognitive impairment. Outcomes were compared across the biomarker groups.ResultsAmong 580 participants (PREVENT-AD, 128; HABS, 153; AIBL, 48; Knight ADRC, 251), mean (SD) age ranged from 67 (5) to 76 (6) years across cohorts, with between 55% (137/251) and 74% (95/128) female participants. Across cohorts, 33% to 83% of A+T+ participants progressed to MCI during follow-up (mean progression time, 2-2.72 years), compared with less than 20% of participants in other biomarker groups. Progression further increased to 43% to 100% when restricted to A+T+(N+) individuals. Cox proportional hazard ratios for progression to MCI in the A+T+ group vs other biomarker groups were all 5 or greater. Many A+T+ nonprogressors also showed longitudinal cognitive decline, while cognitive trajectories in other groups remained predominantly stable.Conclusions and RelevanceThe clinical prognostic value of NIA-AA research criteria was confirmed in 4 independent cohorts, with most A+T+(N+) older individuals without cognitive impairment developing AD symptoms within 2 to 3 years.

APOE effects on regional tau in preclinical Alzheimer’s disease

“…It is likely that other non-amyloid factors have a similar impact on disease progression, accelerating progression in some Aβ+ individuals but allowing for resilience to downstream changes in other Aβ+ individuals [56]. Given the link between elevated tau burden and risk of clinical progression from CU to MCI [14], the identification of factors that influence tau burden among Aβ+s will improve individual level prediction and shed insight into mechanisms of disease risk and resilience.…”

“…Tau abnormalities are a stronger predictor of concurrent cognitive ability and future cognitive impairment than Aβ status alone [12][13][14]. Although both amyloid and tau abnormalities are strongly related such that elevated tau is very uncommon among Aβ-individuals, there is substantial variability in the magnitude of tau PET uptake within Aβ+ individuals [12,[15][16][17][18][19][20], highlighting that additional factors beyond amyloid contribute to downstream tau accumulation.…”

Initial levels of β-amyloid and tau deposition have distinct effects on longitudinal tau accumulation in Alzheimer’s disease

“…The amount of Aβ plaques and regional tau tangles were modeled separately to distinguish their respective contributions in the downstream tau accumulation. Furthermore, many studies reported that abnormal tau tangles outside the entorhinal cortex were rarely observed in the absence of substantial cortical Aβ burden [9,20,21,25,42], and larger Aβ burden was strongly related to more rapid tau accumulation over time [5,10,11,20]. Altogether, it might be possible that the existing tau tangles contribute more to longitudinal tau accumulations in late tau-deposited ROIs of temporal meta-ROI than cortical Aβ plaques when Aβ plaques and tau tangles are already widespread in neocortex and temporal meta-ROI.…”

Medial temporal tau predicts memory decline in cognitively unimpaired elderly

“…10 Given this information, the ability to measure tau burden in living persons is crucial in establishing an accurate diagnosis of Alzheimer’s disease and predicting one’s risk towards clinical progression. 25 …”