Divergent Cortical Tau Positron Emission Tomography Patterns Among Patients With Preclinical Alzheimer Disease

Abstract

IMPORTANCE Characterization of early tau deposition in individuals with preclinical Alzheimer disease (AD) is critical for prevention trials that aim to select individuals at risk for AD and halt the progression of disease.OBJECTIVE To evaluate the prevalence of cortical tau positron emission tomography (PET) heterogeneity in a large cohort of clinically unimpaired older adults with elevated β-amyloid (A+). DESIGN, SETTING, AND PARTICIPANTSThis cross-sectional study examined prerandomized tau PET, amyloid PET, structural magnetic resonance imaging, demographic, and cognitive data from the Anti-Amyloid Treatment in Asymptomatic AD (A4) Study from April 2014 to December 2017. Follow-up analyses used observational tau PET data from the Alzheimer's Disease Neuroimaging Initiative (ADNI), the Harvard Aging Brain Study (HABS), and the Wisconsin Registry for Alzheimer's Prevention and the Wisconsin Alzheimer's Disease Research Center (together hereinafter referred to as Wisconsin) to evaluate consistency. Participants were clinically unimpaired at the study visit closest to the tau PET scan and had available amyloid and tau PET data (A4 Study, n = 447; ADNI, n = 433; HABS, n = 190; and Wisconsin, n = 328). No participants who met eligibility criteria were excluded.

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

“…However, several recent studies also highlighted the heterogeneity of tau spreading patterns [21,[50][51][52]. Consent for publication: Not applicable.…”

“…Examining the factors in uencing tau tangle replication and propagation inside and outside of MTL in various A/T pro les may offer novel perspectives on comprehending the characteristics of tau pathology and formulating anti-AD clinical trial designs. Additionally, it has been suggested that 28], Klotho-VS heterozygosity(KL-VS het )[29], sex [26,27], and age [19,21,23,25,26] may all be involved to tau increases. Further investigation is needed to determine how they interact with baseline Aβ plaques and tau levels to predict longitudinal tau accumulation in early Braak stages.…”

“…Examining the factors in uencing tau tangle replication and propagation inside and outside of MTL in various A/T pro les may offer novel perspectives on comprehending the characteristics of tau pathology and formulating anti-AD clinical trial designs. Additionally, it has been suggested that 28], Klotho-VS heterozygosity(KL-VS het )[29], sex [26,27], and age [19,21,23,25,26] may all be involved to tau increases. Further investigation is needed to determine how they interact with baseline Aβ plaques and tau levels to predict longitudinal tau accumulation in early Braak stages.In this study, we examined participants from the Alzheimer's Disease Neuroimaging Initiative (ADNI) cohort to investigate how baseline Aβ and tau levels affect longitudinal tau replication and propagation over time in MTL, inferior temporal, and middle temporal cortices, as well as how age, sex, APOE-ε4, and KL-VS het modulate these relations.…”

“…Importantly, aberrant neocortical tau aggregations rather than Aβ plaques are more strongly associated with neurodegeneration and cognitive decline in AD [5,6,12].Previous post-mortem[13] and neuroimaging [14,15] studies have shown that the medial temporal lobe (MTL) (Braak stages I-III) is the site of cortical neuro brillary tau tangle progression in the brain, followed by the temporal neocortex (Braak stages III-IV), and nally the parietal, occipital, and frontal lobes (Braak stages V) [16,17]. The initial tau aggregations can be seen in the entorhinal region of Aβ-negative people [11,18], but they seldom spread outside of the neocortex without a signi cant amount of neocortical Aβ plaques [11,[19][20][21][22]. Tau tangles [11,[23][24][25] and baseline Aβ plaques [8][9][10][11] can both indicate a faster tau accumulation in AD.…”

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

“…In contrast, the more recently introduced technique tau-PET measures more advanced pathological changes as it captures insoluble tau aggregates. 9 Although tau-PET positivity in the neocortex is relatively rare among cognitively unimpaired individuals (~5-10% [10][11][12] ), its presence is strongly associated with worse cross-sectional and longitudinal cognitive outcomes. 13,14 However, large-scale longitudinal studies with amyloid-PET and tau-PET as predictors of clinical progression among cognitively unimpaired individuals are lacking.…”