Abnormal tau in amyloid PET negative individuals

Yoon, Bora; Guo, Tengfei; Provost, Karine; Korman, Deniz; Ward, Tyler J.; Landau, Susan; Initiative, Alzheimer’s Disease Neuroimaging

doi:10.1016/j.neurobiolaging.2021.09.019

Cited by 33 publications

(43 citation statements)

References 55 publications

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“…Early-tau deposition likely occurs in the entorhinal and amygdala in the early stage of AD. Consistently, one recent study also observed the most considerable tau deposition in the amygdala in both A-/T + and A+/T + individuals [37], and numerous studies [11,13,[38][39][40] have reported entorhinal being the earliest site of neuro brillary tau tangle formation.…”

Section: Discussionsupporting

confidence: 67%

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

Cai

et al. 2022

Preprint

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Background Clarifying the relative roles of β-amyloid (Aβ) plaques and tau tangles in longitudinal tau replication and propagation inside and outside the medial temporal lobe (MTL) as well as how age, sex, APOE-4, and Klotho-VS heterozygosity (KL-VShet) modulate their relationships in Alzheimer’s disease (AD) may help with designing therapeutic clinical trials for AD and aid in our understanding of the disease’s symptoms. Methods We divided the 325 Aβ PET positive (A+) participants in this study into two groups, A+/T- (143) and A+/T+ (182), based on the threshold (1.25) of the Temporal-metaROI 18F-flortaucipir (FTP) standardized uptake value ratio (SUVR). We compared the baseline and slopes of A+/T- and A+/T + individuals’ Aβ plaques and Temporal-metaROI tau tangles with those of 162 A-/T- cognitively normal individuals without neurodegeneration. We also looked into how baseline Aβ and tau predict longitudinal tau increases and how age, sex, APOE-4, and KL-VShet affect these associations. Results In entorhinal, amygdala, and parahippocampal (early tau-affected regions of Temporal-metaROI), we found baseline Aβ and tau deposition were positively linked with more rapid tau increases in A+/T- participants. However, in A+/T + individuals, the longitudinal tau propagation of the fusiform, inferior temporal, and middle temporal cortices (late tau-affected regions of Temporal-metaROI) was primarily fueled by the presence of tau tangles rather than Aβ plaques. Furthermore, compared to older people (age≥65), younger individuals (age≤65) had faster Aβ-dependent but slower tau-related tau accumulation. Additionally, compared to the KL-VShet− group, KL-VShet+ carriers showed significantly less longitudinal tau accumulation associated with baseline entorhinal tau in the fusiform and inferior temporal regions. Conclusion These findings offer novel perspectives on developing AD treatment plans and aid in understanding tau replication and propagation inside and outside MTL in AD. In particular, decreasing Aβ plaques might be adequate for A+/T- persons but may not be sufficient for A+/T + individuals in preventing tau propagation and subsequent downstream effects connected to tau.

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Section: Discussionsupporting

confidence: 67%

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

Cai

et al. 2022

Preprint

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“…Finally, because we only examined Aβ+ individuals, we are unable to determine whether direct APOE effects on tau only emerge after amyloid positivity has been reached or whether the same direct APOE effects on tau would be present in the absence of amyloid. Although elevated tau PET values are sparse among Aβ- individuals, these elevations have been associated with reduced cognitive performance and greater atrophy [ 80 ]. Thus, it is possible that APOE exerts effects even among Aβ- individuals, warranting future larger studies that can determine whether effects of APOE on tau pathology are dependent on the presence of abnormal amyloid.…”

Section: Discussionmentioning

confidence: 99%

APOE effects on regional tau in preclinical Alzheimer’s disease

Young

Johns

Kennedy

et al. 2023

Mol Neurodegeneration

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Background APOE variants are strongly associated with abnormal amyloid aggregation and additional direct effects of APOE on tau aggregation are reported in animal and human cell models. The degree to which these effects are present in humans when individuals are clinically unimpaired (CU) but have abnormal amyloid (Aβ+) remains unclear. Methods We analyzed data from CU individuals in the Anti-Amyloid Treatment in Asymptomatic AD (A4) and Longitudinal Evaluation of Amyloid Risk and Neurodegeneration (LEARN) studies. Amyloid PET data were available for 4486 participants (3163 Aβ-, 1323 Aβ+) and tau PET data were available for a subset of 447 participants (55 Aβ-, 392 Aβ+). Linear models examined APOE (number of e2 and e4 alleles) associations with global amyloid and regional tau burden in medial temporal lobe (entorhinal, amygdala) and early neocortical regions (inferior temporal, inferior parietal, precuneus). Consistency of APOE4 effects on regional tau were examined in 220 Aβ + CU and mild cognitive impairment (MCI) participants from the Alzheimer’s Disease Neuroimaging Initiative (ADNI). Results APOE2 and APOE4 were associated with lower and higher amyloid positivity rates, respectively. Among Aβ+ CU, e2 and e4 were associated with reduced (−12 centiloids per allele) and greater (+15 centiloids per allele) continuous amyloid burden, respectively. APOE2 was associated with reduced regional tau in all regions (-0.05 to -0.09 SUVR per allele), whereas APOE4 was associated with greater regional tau (+0.02 to +0.07 SUVR per allele). APOE differences were confirmed by contrasting e3/e3 with e2/e3 and e3/e4. Mediation analyses among Aβ+ s showed that direct effects of e2 on regional tau were present in medial temporal lobe and early neocortical regions, beyond an indirect pathway mediated by continuous amyloid burden. For e4, direct effects on regional tau were only significant in medial temporal lobe. The magnitude of protective e2 effects on regional tau was consistent across brain regions, whereas detrimental e4 effects were greatest in medial temporal lobe. APOE4 patterns were confirmed in Aβ+ ADNI participants. Conclusions APOE influences early regional tau PET burden, above and beyond effects related to cross-sectional amyloid PET burden. Therapeutic strategies targeting underlying mechanisms related to APOE may modify tau accumulation among Aβ+ individuals.

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“…One challenge for this framework in PET studies is choice of anatomical region from which to define tau positivity 23 . While the entorhinal cortex (EC) is often the site of earliest tau deposition in AD 24 , tau in this region is not necessarily specific to AD and may also occur with increasing age, independent of Aβ 25,26 . Accordingly, a temporal meta-ROI, comprising both medial and neocortical temporal regions, has been proposed as an alternative to the EC ROI for detecting AD-specific early tau deposition 19 .…”

Section: Discussionmentioning

confidence: 99%

AT(N) predicts near-term development of Alzheimer’s disease symptoms in unimpaired older adults

Strikwerda‐Brown

Gonneaud

Hobbs

et al. 2022

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ImportanceNational Institute on Aging-Alzheimer’s Association (NIA-AA) workgroups have proposed biological research criteria intended to identify individuals with preclinical Alzheimer’s disease (AD).ObjectiveAssess the clinical value of these biological criteria for prediction of near-term cognitive impairment in cognitively unimpaired older individuals.Design, Setting, and ParticipantsWe studied 580 cognitively unimpaired older adults from four independent cohorts (PREVENT-AD: 128; HABS: 153; AIBL: 48; Knight ADRC: 251) having ≥1 year of clinical observation following Aβ and tau PET (median follow-up: PREVENT-AD = 3.16 yrs [1.51-4.50]; HABS = 1.94yrs [1.13-5.42]; AIBL = 3.66yrs [1.72-5.98]); Knight ADRC = 3.01 yrs [1.04-6.20]).ExposuresBased on binary assessment of global amyloid burden (A) and of a composite temporal region of tau PET uptake (T), we stratified participants into four groups (A+T+, A+T-, A-T+, A-T-). Presence (+) or absence (-) of neurodegeneration (N) was assessed using temporal cortical thickness.Main Outcomes and MeasuresWe analyzed each cohort separately. Primary outcome was clinical progression to mild cognitive impairment (MCI). A secondary outcome was cognitive decline. We compared MCI progression and cognitive decline across the four biomarker groups. MCI was identified by consensus committee review in PREVENT-AD, HABS, and AIBL, and by a CDR ≥ 0.5 in Knight ADRC. Clinical raters were blinded to imaging, genetic, and fluid biomarker data. Using a composite measure, cognitive decline was identified by a slope >1 SD below that of A-T- ‘non-progressors’.ResultsAcross cohorts, 32 - 83% of A+T+ participants progressed to MCI during follow-up (mean progression time 2.0 - 2.72 years), as compared with <12% of participants in other biomarker groups. In two cohorts, progression increased to 100% when A+T+ individuals were also (N+). Cox proportional hazard ratios for progression to MCI in the A+T+ group vs. other biomarker groups were >5. Many A+T+ ‘non-progressors’ nonetheless showed longitudinal cognitive decline, while cognitive trajectories in other groups remained predominantly stable.Conclusions and RelevanceClinical prognostic value of the NIA-AA research criteria was confirmed in four independent cohorts, with nearly all A+T+(N+) cognitively unimpaired older individuals developing AD symptoms within ∼2-3 years.Key PointsQuestionWhat is the clinical relevance of the AT(N) biological classification of Alzheimer’s disease (AD) in unimpaired older adults?FindingsIn this prospective study of 580 cognitively unimpaired participants from four independent cohorts, between 31.58 and 100% of A+T+(N+) participants progressed to mild cognitive impairment (MCI) within 2-3 years after PET. The majority of A+T+ non-progressors also showed cognitive decline.MeaningCognitively unimpaired older adults with biological AD are at imminent risk of developing MCI. These individuals may be ideal candidates for disease modifying therapies.

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Abnormal tau in amyloid PET negative individuals

Cited by 33 publications

References 55 publications

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

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

APOE effects on regional tau in preclinical Alzheimer’s disease

AT(N) predicts near-term development of Alzheimer’s disease symptoms in unimpaired older adults

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