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. 2023 Jan 4;18(1):1.
doi: 10.1186/s13024-022-00590-4.

APOE effects on regional tau in preclinical Alzheimer's disease

Christina B Young  1 , Emily Johns  2 , Gabriel Kennedy  2 , Michael E Belloy  2 , Philip S Insel  3 , Michael D Greicius  2 , Reisa A Sperling  4   5 , Keith A Johnson  4   5 , Kathleen L Poston  2 , Elizabeth C Mormino  2 ; Alzheimer’s Disease Neuroimaging Initiative; A4 Study Team
Affiliations

APOE effects on regional tau in preclinical Alzheimer's disease

Christina B Young et al. Mol Neurodegener. .

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.

Keywords: APOE; Amyloid; Clinically unimpaired; PET; Preclinical Alzheimer’s disease; Tau; e2; e4.

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Conflict of interest statement

KLP received consulting fees from CuraSen Therapeutics Inc. ECM is a paid consultant for Roche, Genentech, and Eli Lilly. All other authors have no disclosures relevant to the manuscript.

Figures

Fig. 1
Fig. 1
APOE interactions with age and sex. The top row shows associations between age and probability of Aβ+ status as a function of APOE carriership. The top left panel depicts reduced effects of age on Aβ+ status in e2 carriers. The top right panel shows increasing associations between age and Aβ+ status across all levels of e4 carriership. The bottom row shows associations between sex and probability of Aβ+ status as a function of APOE carriership. The bottom left panel depicts protective effects of e2 in females. The bottom right panel shows no significant difference between sexes in probability of Aβ+ status across all levels of e4 carriership
Fig. 2
Fig. 2
Association between amyloid and tau burden in (A) Aβ- and Aβ+ participants and in (B) only Aβ+ participants. Plotted tau SUVRs and amyloid centiloids (CLs) are residualized by age and sex
Fig. 3
Fig. 3
Regional tau differences between Aβ+ APOE e2/e3, e3/e3, and e3/e4 groups. Plotted tau SUVRs are residualized by age and sex. Note: * p < 0.05, **p < 0.01, ***p < 0.001
Fig. 4
Fig. 4
Mediating effects of amyloid (centiloids) on APOE and regional tau SUVRs. (A) Stacked bar plots depict the total effect, as well as indirect and direct subcomponents, extracted from mediation models examining the effects of APOE on regional tau among Aβ+ clinically unimpaired (CU) individuals from A4. A comparison of e2 and e4 direct effect sizes are also shown. Error bars reflect standard error. (B) Stacked bar plots depict the total effect, as well as indirect and direct subcomponents, extracted from mediation models examining the effects of APOE e4 on regional tau among Aβ+ CU and mild cognitive impairment (MCI) individuals from ADNI. Note: * p < 0.05, **p < 0.01, ***p < 0.001
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