PS1 mutation position influences regional PiB‐uptake and white matter lesion volume

Abstract

AbstractBackgroundMutations in the Presenilin‐1 (PS1) gene account for 80% of dominantly inherited Alzheimer disease (DIAD). Previous findings suggest PS1 mutation position relative to codon 200 may impact the distribution and amount of cerebral β‐amyloid pathology (Mann et al., 2001; Ryan et al., 2015). We investigated the effect of mutation position on imaging markers of β‐amyloidosis and small vessel disease with a focus on regional variability and disease progression.MethodIndividuals with PS1 mutations before (Pre‐200MC, n=76) or after codon‐200 (Post‐200MC, n=126) and non‐carriers of these mutations (n=129) from the same families were assessed with the Clinical Dementia Rating (CDR) scale and underwent neuroimaging including PiB‐PET to assess β‐amyloid burden and T2‐FLAIR MRI to assess white matter lesions. A subset (52 non‐carriers, 63 Pre‐200MC, 73 Post‐200MC) had longitudinal data available. Accounting for estimated year to symptom onset (EYO) and APOE‐ɛ4 status, cross‐sectional and longitudinal linear mixed‐effects models evaluated the effect of mutation positions on PiB‐uptake (SUVR) in 40 FreeSurfer regions, white matter hyperintensity (WMH) volumes in periventricular and deep areas, and their associations with dementia.ResultPre‐200MC had earlier age of symptom onset versus Post‐200MC (43.34±8.97 versus 46.81±7.55 years, p<0.0001). Pre‐200MC presented with higher amyloid burden (mean cortical SUVR of 2.28±1.27 versus 1.91±1.0, p<0.02). Differences were observed mostly in frontal, temporal, and subcortical regions. Stronger associations between PiB‐uptake and EYO were observed in Pre‐200MC versus Post‐200MC in nearly all regions (precuneus: F(1,192)=9.37, p<0.01; caudate: F(1,192)=17.65, p<0.001; Figure 1A). In contrast, Post‐200MC presented with stronger associations of periventricular WMH with EYO (F(1,25)=5.02, p<0.05) and deep WMH with dementia as measured by CDR‐SB (F(1,25)=14.01, p=0.01). Longitudinal analyses showed higher rates of change in PiB uptake in Pre‐200MC versus Post‐200MC in several frontal, temporal, and striatal regions (inferior temporal: F(1,171)=13.71, p<0.0005; caudate: F(1,171)=8.22, p<0.005; Figure 1B). Mutation position did not influence rates of change in WMH volumes nor cognitive decline.ConclusionThese findings confirm that mutation position within the PS1 gene influences disease presentation in DIAD. Improved characterization of heterogeneity in disease progression may inform further clinical trials in this population. Further investigation into biological mechanisms responsible for these differences is necessary. Funding: AARFD‐20‐681815;U19AG032438.