Presenilin-1 mutation position influences amyloidosis, small vessel disease, and dementia with disease stage

Abstract

Introduction: Amyloidosis, including cerebral amyloid angiopathy, and markers of small vessel disease (SVD) vary across dominantly inherited Alzheimer's disease (DIAD) presenilin-1 (PSEN1) mutation carriers. We investigated how mutation position relative to codon 200 (pre-/postcodon 200) influences these pathologic features and dementia at different stages.

Methods: Individuals from families with known PSEN1 mutations (n = 393) underwent neuroimaging and clinical assessments. We cross-sectionally evaluated regional Pittsburgh compound B-positron emission tomography uptake, magnetic resonance imaging markers of SVD (diffusion tensor imaging-based white matter injury, white matter hyperintensity volumes, and microhemorrhages), and cognition.

Results: Postcodon 200 carriers had lower amyloid burden in all regions but worse markers of SVD and worse Clinical Dementia Rating^® scores compared to precodon 200 carriers as a function of estimated years to symptom onset. Markers of SVD partially mediated the mutation position effects on clinical measures.

Discussion: We demonstrated the genotypic variability behind spatiotemporal amyloidosis, SVD, and clinical presentation in DIAD, which may inform patient prognosis and clinical trials.

Highlights: Mutation position influences Aβ burden, SVD, and dementia. PSEN1 pre-200 group had stronger associations between Aβ burden and disease stage. PSEN1 post-200 group had stronger associations between SVD markers and disease stage. PSEN1 post-200 group had worse dementia score than pre-200 in late disease stage. Diffusion tensor imaging-based SVD markers mediated mutation position effects on dementia in the late stage.

Keywords: PSEN1; PiB‐PET; autosomal dominant Alzheimer's disease (ADAD); cerebral amyloid angiopathy (CAA); codon 200; dominantly inherited Alzheimer's disease (DIAD); microbleeds; microhemorrhages; peak width of skeletonized mean diffusivity (PSMD); presenilin‐1; small vessel disease (SVD); white matter hyperintensity (WMH).

FIGURE 1

Cross‐sectional regional PiB uptake as a function of EYO. (A and B) Brain maps displaying significant different slope estimates between PiB SUVR and EYO for 34 cortical (A) and subcortical (B) FreeSurfer regions in pre‐200 carriers versus non‐carriers (top row), post‐200 carriers versus non‐carriers (middle row), and pre‐200 versus post‐200 (bottom row). The rostral anterior cingulate (green outline) and caudate showed the strongest divergence between pre‐ and post‐200. (C and D) Plots of cross‐sectional PiB uptake as a function of EYO for pre‐200 carriers (blue triangle), post‐200 carriers (red square), and non‐carriers (black circle) in rostral anterior cingulate (C) and in caudate (D). Color bar = estimates from LME model of PiB SUVR per EYO. EYO, estimated years to symptom onset; LME, linear mixed effect; NC, non‐carriers; MC, mutation carrier; PiB, Pittsburgh compound B; SUVR, standardized uptake value ratio.

FIGURE 2

Topographical and temporal progression profiles of regional Aβ burden accumulation in pre‐ and post‐200 MC groups per 5‐year range of EYO. Brain maps displaying regional PiB uptake estimates for pre‐ and post‐200 MC groups compared to non‐carriers and pre‐ compared to post‐200 group (third row), split by EYO ranges of 5 years. Colored regions are significantly different in corresponding 5‐year range, and regions in gray are not significantly different after multiple comparisons. The post‐200 MC group starts to show abnormal accumulation in the occipital cortex between −20 and −15 EYO, while pre‐200 shows abnormal burden in occipital and frontal areas around −15 to −10 EYO but display higher values past −5 EYO and beyond. Color bar = estimates of regional mean PiB SUVR. EYO, estimated years to symptom onset; NC, non‐carriers; PiB, Pittsburgh compound B; SUVR, standardized uptake value ratio.

FIGURE 3

PSMD maps in NCs and pre‐ and post‐200 carriers per 10‐year range of EYO. Axial sections representing averaged mean diffusivity maps for each group per ranges of 10 years. High mean diffusivity in yellow reflects more injury in white matter. Late stages EYO ≥ 0 show higher mean diffusivity in carrier groups. The corresponding average PSMD values per group are indicated in reference (units in square millimeters per second [mm²/s]). EYO, estimated years to symptom onset; NC, non‐carrier; PSMD, peak width of skeletonized mean diffusivity; SUVR, standardized uptake value ratio. Color bar = mean diffusivity. Image orientations: L, left; A, anterior.

FIGURE 4

Cross‐sectional progression of global imaging markers of SVD in NC and pre‐ and post‐200 MC groups. (A) Scatterplot of raw PSMD values as a function of EYO (left panel) and plots of LME mean estimates of PSMD for pre‐200 carriers (blue triangle), post‐200 carriers (red square), and non‐carriers (black circle) per 10‐year range of EYO (right panel). Post‐200 carriers have significantly higher injury with advanced EYO compared to NCs and pre‐200 MC. (B) Scatterplot of log‐transformed total WMH volume values as a function of EYO (left panel) and plots of LME mean estimates of log‐transformed total WMH volume per 10‐year range of EYO (right panel). Both pre‐ and post‐200 MC show larger volumes compared to NC at EYO≥0. (C) Scatterplot of log‐transformed total mH count (dark red horizontal line denotes 5 mH) as a function of EYO (left panel), and plots of negative binomial mixed effect models mean estimates of total count of mHs broken down by EYO −15, −10, −5, and 0. Post‐200 MC have more mHs compared to pre‐200 MC at EYO = −10 and EYO = −5 years. EYO, estimated years to symptom onset; LME, linear mixed effect; mH, microhemorrhage; MC, mutation carrier; NC, non‐carrier; PSMD, peak width of skeletonized mean diffusivity; PVWMH, periventricular white matter hyperintensity; SVD, small vessel disease; WMH, white matter hyperintensity. Significance levels: *p < 0.05; **p  < 0.005, ***p < 0.0005 in blue for pre‐200 versus NC, in red for post‐200 versus NC, and in black for pre‐200 versus post‐200 carriers.

FIGURE 5

Cross‐sectional progression of regional imaging markers of SVD in non‐carrier, pre‐ and post‐200 MC groups. (A) Scatterplot of regional WMH volumes as a function of EYO (left panel) and plots of LME mean estimates (middle panel) of deep, total periventricular, anterior, and posterior periventricular (top to bottom) WMH for pre‐200 carriers (blue triangle), post‐200 carriers (red square), and NCs (black circle) by per 10‐year range of EYO. Deep WMH is presented as log (1 + x) to facilitate visualization. (B) Scatterplot of regional mH count as a function of EYO (right panel) for frontal, parietal, temporal, and occipital (top to bottom). Counts are presented as log (1 + x) to facilitate visualization and dark red horizontal lines denote five mHs. EYO, estimated years to symptom onset; mH, microhemorrhage; NC, non‐carrier; MC, mutation carrier; PVWMH, periventricular white matter hyperintensity; SVD, small vessel disease; WMH, white matter hyperintensity. Significance levels: *p < 0.05, **p < 0.005, ***p < 0.0005 in blue for pre‐200 versus NC, in red for post‐200 versus NC, and in black for pre‐200 versus post‐200 carriers.

FIGURE 6

Cross‐sectional progression of clinical and cognitive measures in pre‐ and post‐200 MC groups per 5‐year range of EYO. Scatterplot of raw values as a function of EYO (left panel) and plots of LME mean estimates (right panel) of CDR‐SB (top), MMSE (middle), and cognitive composite (bottom) for pre‐200 (blue triangle), post‐200 carriers (red square), and NCs (black circle) by EYO ranges. Post‐200 had worse measures of CDR‐SB and MMSE in EYO +5 years compared to pre‐200 carriers. EYO, estimated years to symptom onset; LME, linear mixed effect; MC, mutation carrier; NC, non‐carrier; CDR‐SB, Clinical Dementia Rating Sum of Boxes; MMSE, Mini‐Mental State Examination. Significance levels: *p < 0.05, **p < 0.005, ***p < 0.0005 in blue for pre‐200 versus NC, in red for post‐200 versus NC, and in black for pre‐200 versus post‐200 carriers.