Basic Science and Pathogenesis.

Background: The amyloid cascade hypothesis posits a sequence of events proceeding from amyloid-β (Aβ) deposition to entorhinal cortical (EC) tau to neocortical (meta-temporal) tau. This study examined how genetics may modify relationships between these variables on the AD pathway.

Methods: We used causal path analyses to model effects of sex, APOE-ε4 (0,1,2 alleles), and genetic risk for neuroinflammation on Aβ, EC tau and meta temporal tau. We modelled main effects and pairwise interactions between genetic profiles and earlier pathology on downstream pathologies, accounting for the full mediation path from Aβ→ EC tau → meta-temporal tau (Figure 1.). Participants were 628 individuals from ADNI and A4 with whole genome sequencing, Aβ-PET (Centiloids, CL) and [18F]flortaucipir (FTP)-PET SUVR. Neuroinflammation gene burden (1/0) was defined as one or more rare polymorphisms on the coding region of the TREM2 gene that have been previously associated with AD (Table 1.).

Results: We observed interactions between Aβ and APOE-ε4(2-alleles) (β = 0.002, P = 0.002), and Aβ and sex(F) (β = 0.0008, p = 0.032) on EC tau: higher Aβ was associated with more EC tau in APOE-ε4 homozygotes and females (Figure 2ab.). Next, we observed interactions between EC tau and APOE-ε4(2-alleles) (β = 0.364, P<0.001), and EC tau and TREM2(1) (β = 0.309, P<0.001) on the spread of tau to meta-temporal regions: both APOE-ε4 homozygotes and individuals with a TREM2 risk allele had greater downstream meta-temporal tau burden for a given level of EC tau (Figure 2cd). A significant interaction between APOE-ε4 and TREM2 (β = 0.0186, p = 0.0168) indicated highest risk in those with a TREM2 risk allele and 1 or 2 ε4 alleles (Figure 2e.).

Conclusion: Genetic factors affect tau pathological burden above and beyond the effects of Aβ. Both females and APOE-ε4 homozygotes express tau deposition in the EC at lower Aβ CL than males and non-homozygotes. Neocortical tau deposition is related to EC tau and is greater in APOE-ε4 homozygotes and individuals with a genetic risk for impaired neuroinflammatory responses. These findings may explain variable effects of anti-amyloid treatments and provide insights into the potential biological drivers of tau spread.