Progressive white matter injury in autosomal dominant Alzheimer’s disease is strongly associated with cerebral microbleeds and neurodegeneration
Authors: Shirzadi Zahra , Schultz Stephanie A. , Yau Wai‐Ying Wendy , Joseph‐Mathurin Nelly , Kantarci Kejal , Preboske Gregory M. , Jack Clifford R. , Farlow Martin R. , Fagan Anne M. , Hassenstab Jason J. , Jucker Mathias , Morris John C. , Xiong Chengjie , Karch Celeste M. , Fitzpatrick Colleen D , Levey Allan I. , Gordon Brian A. , Schofield Peter W. , Salloway Stephen P. , Perrin Richard J. , McDade Eric , Levin Johannes , Cruchaga Carlos , Allegri Ricardo Francisco , Fox Nick C , Goate Alison , Graff‐Radford Neill R. , Koeppe Robert , Noble James M , Chui Helena C , Berman Sarah , Mori Hiroshi , Sanchez‐Valle Raquel , Lee Jae‐Hong , Rosa‐Neto Pedro , Benzinger Tammie L.S. , Sohrabi Hamid R , Martins Ralph N , Schultz Aaron P. , Bateman Randall J. , Johnson Keith A. , Sperling Reisa A. , Greenberg Steven M , Chhatwal Jasmeer P. ,   DIAN Investigators
Published: December 2022

Background

White matter (WM) injury visible on MRI is a common finding in Alzheimer’s disease (AD) and is often attributed to small vessel ischemic changes secondary to increased systemic vascular risk. Increased WM injury has been associated with the progression of Autosomal Dominant AD (ADAD), though ADAD pathogenic variant carriers are relatively young and may not have elevated vascular risk factors. We hypothesized that WM injury in ADAD may reflect worsening of cerebral amyloid angiopathy (CAA) and neurodegeneration. Here we examine this hypothesis using cross‐sectional and longitudinal data from the Dominantly Inherited Alzheimer Network observational study (DIAN).

Method

MRI data from ADAD pathogenic variant carriers (n=223) and non‐carriers (n=136) were used in the present study (Table 1). We extracted FreeSurfer‐based WM lesion (WML) volume from T1‐weighted images (hypointensities). Cortical microbleed (CMB) burden was assessed visually on susceptibility weighted/T2*‐weighted gradient echo images by experienced radiologists (blineded to the mutation status) at the Mayo Clinic in Rochester. Linear regression models compared WML volume at baseline in people with and without CMB. Linear mixed effect models assessed the relationships between longitudinal WML and both CMBs and FreeSurfer‐based total gray matter (GM) volume. Models were corrected for age and estimated years to symptom onset (EYO).

Result

Greater baseline WML volume was seen in ADAD carriers vs. non‐carriers, particularly close to the age of estimated symptom onset. Baseline WML volume was greater in carriers with CMBs compared to those without (t=2.9, p=0.003, Figure 1). Longitudinal increase in WML amongst ADAD pathogenic variant carriers with CMBs was estimated to be 214 mm3/year greater than that amongst carriers without CMBs (t=4.1, p<0.001, Figure 2). Independent of this CMB effect, decreasing GM volume was strongly associated with increasing longitudinal WML volume (t=‐6.2, p<0.001, Figure 3). Similar analyses in the non‐carrier group yielded no significant findings.

Conclusion

Consistent with prior reports, WML volume was increased in ADAD pathogenic variant carriers. However, the results here suggest WML in ADAD may not solely be due to small vessel ischemic changes, but rather may be a result of worsening CAA and more rapid neurodegeneration.