Modifiable Factors Associated with the Longitudinal Increase and Spatial Extent of Tau Pathology in Alzheimer Disease

There are 14 modifiable factors that are associated with a significantly lower risk of dementia. We tested the interactive effect of modifiable factors, genetic determinants, and initial pathologic burden on the spatial progression and local amplification of tau pathology. <b>Methods:</b> In total, 162 amyloid-positive individuals were included, for whom longitudinal [¹⁸F]AV-1451 PET scans, baseline information on global amyloid burden, ApoE4 status, body mass index (BMI), hypertension, education, neuropsychiatric symptom severity, and demographic information were available in the Alzheimer Disease Neuroimaging Initiative. All [¹⁸F]AV-1451 scans were intensity-standardized (reference: inferior cerebellum), <i>z</i>-transformed (control sample: 147 amyloid-negative subjects), thresholded (<i>z</i> score, >1.96), and converted to volume maps. Longitudinal tau changes were then assessed in terms of tau spatial extent (i.e., newly affected volume at follow-up) and tau level rise (i.e., tau increase in previously affected volume). These 2 measures were entered as dependent variables in linear mixed-effects models, including baseline modifiable risk factors (BMI, education, hypertension, neuropsychiatric symptom severity), global amyloid, tau volume or tau burden, ApoE4 status, clinical stage, sex, and age as predictors. Next, we tested the interactive effects between baseline amyloid or tau burden with the 4 modifiable factors on tau extent or tau level rise, respectively. <b>Results:</b> Greater tau extent was linked to higher BMI (β = 0.002; 95% CI, 0.0003-0.003), ApoE4 status (β = 0.024; 95% CI, 0.001-0.046), and baseline tau volume (β = 0.207; 95% CI, 0.107-0.308) across groups. In terms of tau level rise, we observed that absence of hypertension (β = 0.295; 95% CI, -0.477 to -0.114), dementia group (β = 0.305; 95% CI, 0.088-0.522), and BMI (β = 0.011; 95% CI, 0.00004-0.022) were linked to increased tau burden. A load-dependent effect of baseline amyloid and tau volume/burden was found for both tau extent (β = -0.005; 95% CI, -0.008 to -0.002) and tau level rise (β = -0.003; 95% CI, -0.005 to -0.001). Higher amyloid and BMI (β = 0.001; 95% CI, 0.0004-0.001) and lower education and higher tau burden (β = -0.035; 95% CI, -0.064 to -0.006) were linked to greater tau level rise. <b>Conclusion:</b> Education, BMI, and hypertension differentially influence tau's spatial extent and increase by its interaction with initial pathologic burden. Timely modification of these factors may overall slow tau progression.