White matter injury mediates the effects of PS1 mutation position on clinical measures in late disease stage
Authors: Joseph‐Mathurin Nelly , Lu Ruijin , Shirzadi Zahra , Strain Jeremy F. , Clair Junie Saint , Feldman Rebecca L. , McKay Nicole S. , Keefe Sarah J. , Massoumzadeh Parinaz , Chen Gengsheng , Gordon Brian A. , McCullough Austin A. , Chen Charles D. , Schultz Stephanie A. , Llibre‐Guerra Jorge J , Cruchaga Carlos , Morris John C , Bateman Randall J. , McDade Eric , Chhatwal Jasmeer P. , Xiong Chengjie , Benzinger Tammie L.S. 
Published: December 2023

Background

Clinical presentation of dominantly inherited Alzheimer disease (DIAD) varies across individuals with Presenilin‐1 (PS1) pathogenic mutations. Previous findings suggest that individuals with a PS1 mutation after codon 200 have more small vessel disease (SVD) pathology (Mann et al., 2001; Ryan et al., 2015). We investigated the effect of mutation position on clinical measures, including indirect effects via SVD as estimated by imaging markers of white matter injury.

Method

We evaluated 393 individuals with DIAD family history of PS1 mutations who underwent clinical and imaging assessments from the DIAN study. Among them, 245 carried a mutation before (Pre‐200MC, n = 83) or after codon‐200 (Post‐200MC, n = 162) and the remaining were non‐carriers (NC, n = 148). We assessed clinical disease stage with the Clinical Dementia Rating® Sum of Boxes (CDR®‐SB) scale and the estimated years to symptoms onset (EYO). White matter injury metrics included periventricular white matter hyperintensity (PVWMH) volumes from T2‐FLAIR and the peak width of skeletonized mean diffusivity (PSMD) from DTI (Shirzadi et al., 2022). Accounting for age of onset, sex, education, and APOE‐ɛ4 status, linear mixed‐effects models evaluated mutation position by EYO effect on SVD and on dementia in all participants. Further mediation analysis evaluated these effects within the carrier groups. Missing values were imputed using random forest algorithm.

Result

Post‐200MC had more white matter injury with advanced EYO compared to Pre‐200MC (estimatesPVWMH = 65.3±31.8, P‐value<.05, estimatesPSMD = 0.01±0.003, P‐value<.0005) and to non‐carriers (estimatesPVWMH = 61.5±27.4, P‐value<.05, estimatesPSMD = 0.01±0.003, P‐value<.0005; Figure 1A). Post‐200MC presented higher CDR‐SB scores with advanced EYO compared to Pre‐200MC (estimatesCDR‐SB = 0.08±0.03, P‐value<.005) and to non‐carriers (estimatesCDR‐SB = 0.19±0.02, P‐value<.0001; Figure 1B). When EYO>0, the effects of mutation position on CDR‐SB were significantly mediated by PVWMH (e.g., average causal mediation effect at EYO = 0.5: estimatesCDR‐SB = 0.06[0.;0.14], P‐value<.05) or PSMD (e.g., average causal mediation effect at EYO = 0.5: estimatesCDR‐SB = 0.2[0.05;0.37], P‐value<.05; Table1).

Conclusion

These findings give further insights on how mutation position within the PS1 gene influences clinical disease presentation in DIAD. This characterization may inform future clinical trials in this population as the presence of small vessel disease contributes to a more severe disease course, which may influence treatment outcome and decisions. Funding: AARFD‐20‐681815; U19AG032438.