Dataset Information

Regional Aβ-tau interactions promote onset and acceleration of Alzheimer's disease tau spreading.

ABSTRACT: Amyloid-beta and tau are key molecules in the pathogenesis of Alzheimer's disease, but it remains unclear how these proteins interact to promote disease. Here, by combining cross-sectional and longitudinal molecular imaging and network connectivity analyses in living humans, we identified two amyloid-beta/tau interactions associated with the onset and propagation of tau spreading. First, we show that the lateral entorhinal cortex, an early site of tau neurofibrillary tangle formation, is subject to remote, connectivity-mediated amyloid-beta/tau interactions linked to initial tau spreading. Second, we identify the inferior temporal gyrus as the region featuring the greatest local amyloid-beta/tau interactions and a connectivity profile well suited to accelerate tau propagation. Taken together, our data address long-standing questions regarding the topographical dissimilarity between early amyloid-beta and tau deposition.

SUBMITTER: Lee WJ

PROVIDER: S-EPMC9233123 | biostudies-literature | 2022 Jun

REPOSITORIES: biostudies-literature

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Regional Aβ-tau interactions promote onset and acceleration of Alzheimer's disease tau spreading.

Lee Wha Jin WJ Brown Jesse A JA Kim Hye Ryun HR La Joie Renaud R Cho Hanna H Lyoo Chul Hyoung CH Rabinovici Gil D GD Seong Joon-Kyung JK Seeley William W WW

Neuron 20220419 12

Amyloid-beta and tau are key molecules in the pathogenesis of Alzheimer's disease, but it remains unclear how these proteins interact to promote disease. Here, by combining cross-sectional and longitudinal molecular imaging and network connectivity analyses in living humans, we identified two amyloid-beta/tau interactions associated with the onset and propagation of tau spreading. First, we show that the lateral entorhinal cortex, an early site of tau neurofibrillary tangle formation, is subject ...[more]

PMID: 35443153

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Project description:BackgroundAPOE 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.MethodsWe 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).ResultsAPOE2 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.ConclusionsAPOE 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.

Dataset Information

Regional Aβ-tau interactions promote onset and acceleration of Alzheimer's disease tau spreading.

Publications

Regional Aβ-tau interactions promote onset and acceleration of Alzheimer's disease tau spreading.

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