Alzheimer's genetic risk factor lowers tau threshold, accelerating disease onset

In Alzheimer's disease, carriage of the apolipoprotein E epsilon 4 (ApoE4) risk allele is linked to faster tau accumulation at lower amyloid-PET levels, thereby accelerating disease progression. However, it remains unclear whether this ApoE4-facilitated transition from amyloidosis to tauopathy is mechanistically promoted by increased secretion of phosphorylated tau (ptau), a key intermediate that drives the amyloid-to-tauopathy transition, or alternatively by increased ptau-driven tau aggregation. Therefore, we investigated where along the amyloid-to-tau axis ApoE4 accelerates tau aggregation and assessed: (i) whether ApoE4 increases ptau secretion; or (ii) whether ApoE4 increases ptau-associated tau aggregation. To this end, we analysed two large-scale APOE-genotyped cohorts covering the full Alzheimer's disease spectrum (Alzheimer's Disease Neuroimaging Initiative; ADNI: n = 201) as well as a preclinical cohort (Anti-Amyloid Treatment in Asymptomatic Alzheimer's and Longitudinal Evaluation of Amyloid Risk and Neurodegeneration study; A4-LEARN: n = 200), integrating baseline amyloid-PET, plasma ptau(217) and CSF ptau181 with longitudinal tau-PET. Using linear regression, we tested whether ApoE4 carriage moderates: (i) amyloid-PET-associated plasma ptau(217) increases; or (ii) ptau(217)-associated tau spreading from local epicentres across patient-tailored tau spreading stages. All analyses were independently validated across both cohorts, including an additional replication in an ADNI subset (n = 115) with available CSF ptau181 measures as an alternative marker of ptau secretion. Finally, we used logistic regression to determine ApoE4 allele count-stratified plasma ptau(217 )thresholds marking early pathological tau-PET increases. We found that ApoE4 did not facilitate amyloid-PET-associated ptau increases, suggesting that amyloid-related ptau secretion is not altered by ApoE4 carriage. Contrastingly, we found that plasma ptau(217) elevations were linked to faster tau-PET spread from local epicentres across connected brain regions in an ApoE4 allele dose-dependent manner, independent of amyloid [ADNI/A4-LEARN: mean standardized beta (beta) = 0.44/0.56, P < 0.001/P < 0.001]. Lastly, we found that a higher ApoE4 allele count was linked to lower ptau(217) thresholds marking transition to tauopathy, i.e. early abnormal tau-PET increases, consistently across both samples (ADNI: 0/1/2 ApoE4 alleles = 0.62/0.34/0.15 pg/ml, representing similar to 45% and similar to 76% reductions from non-carriers; Fujirebio ptau(217) assay; A4-LEARN: 0/1/2 ApoE4 alleles = 0.31/0.23/0.18 pg/ml, representing similar to 26% and similar to 42% reductions; Eli Lilly ptau(217) assay). These findings suggest that ApoE4, i.e. the key genetic risk factor for sporadic Alzheimer's disease, facilitates amyloid-dependent tau aggregation in an allele dose-dependent manner by enhancing the ptau-driven spread of fibrillar tau, leading to an earlier transition from amyloidosis to tauopathy at lower ptau(217) levels. This has implications for plasma ptau-based screening approaches and therapeutic timing of anti-amyloid drugs in ApoE4 carriers. Specifically, ApoE4 carriers may require genotype-adjusted ptau thresholds to detect Alzheimer's disease pathophysiology, as well as anti-amyloid treatment at lower ptau levels to prevent the transition to tauopathy, which ultimately drives neurodegeneration and cognitive decline.