APOE effects on regional tau in preclinical Alzheimer’s disease

Abstract

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.

Brain morphology mediating the effect of genetic risk variants on Alzheimer’s disease

“…We showed that APOE ε4 increased the risk of LOAD by altering the morphology of brain regions reported to be affected at an early stage in the pathological process of LOAD (12, 13, 50, 51). Our results correspond with previous research on the association of APOE ε4 with the middle temporal lobe, more specifically the entorhinal cortex, amygdala and hippocampus (26, 52). APOE ε4 has also been linked to enlargement of the choroid plexus, a hallmark of LOAD (53).…”

ApoE4 and Connectivity-Mediated Spreading of Tau Pathology at Lower Amyloid Levels

“…Second, we tested whether ApoE4 not only accelerates tau accumulation via increased amyloid (ie, mediation effect), but whether ApoE4 and amyloid have synergistic effects on accelerating tau accumulation as suggested by previous cross-sectional studies . Supporting this, we found significant centiloid–by–ApoE4 status interactions on annual tau accumulation rates for Braak ROIs III-V in ADNI and for Braak III and V in Avid-A05 (Figure 3).…”