APOE effects on regional tau in preclinical Alzheimer’s disease

Molecular Neurodegeneration

Research Article

Keith A. Johnson¹  Reisa A. Sperling¹  Elizabeth C. Mormino²  Christina B. Young²  Gabriel Kennedy²  Michael D. Greicius²  Emily Johns²  Michael E. Belloy²  Kathleen L. Poston²  Philip S. Insel³ 

[1] Brigham and Women’s Hospital, Boston, MA, USA;Massachusetts General Hospital, Boston, MA, USA;Stanford University School of Medicine, 453 Quarry Rd., Palo Alto, 94304, Stanford, CA, USA;University of California San Francisco, San Francisco, CA, USA;

关键词: APOE;    e2;    e4;    Amyloid;    Tau;    PET;    Preclinical Alzheimer’s disease;    Clinically unimpaired;   

DOI  :  10.1186/s13024-022-00590-4

 received in 2022-10-12, accepted in 2022-12-14,  发布年份 2022

来源: Springer

【 摘 要 】

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.

【 授权许可】

CC BY   
© The Author(s) 2022

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