Years to Parental Symptom Onset Predicts Amyloid Burden in ...€¦ · • We sought to assess...
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spEYO 0 -10 -20 -30 CSF Amyloid 1500 1250 1000 750 500 Prevent-AD (CSF, n = 101) Cross-sectional data Main effect APOE interaction Gender interaction p = 0.04 spEYO 10 0 -10 -20 -30 CSF Amyloid 1500 1250 1000 750 500 p < 0.01 spEYO 10 0 -10 -20 -30 CSF Amyloid 1500 1250 1000 750 500 p = 0.03 ACS (CSF, n = 112) ACS (PIB-PET, n = 107) spEYO 20 10 0 -10 -20 -30 -40 CSF Amyloid 1750 1500 1250 1000 750 500 250 p = 0.31 spEYO 20 10 0 -10 -20 -30 -40 CSF Amyloid 1500 1250 1000 750 500 250 p = 0.03 spEYO 20 10 0 -10 -20 -30 -40 CSF Amyloid 1500 1250 1000 750 500 250 p = 0.69 PET Amyloid 1.50 1.25 1.00 .75 .50 .25 .00 p = 0.04 PET Amyloid 1.50 1.25 1.00 .75 .50 .25 .00 p < 0.05 spEYO 20 10 0 -10 -20 -30 -40 PET Amyloid 1.50 1.25 1.00 .75 .50 .25 .00 p = 0.52 ACS (PIB-PET, n = 58) spEYO 10 0 -10 -20 -30 -40 PET Amyloid Rate of change .20 .15 .10 .05 .00 -.05 p = 0.52 spEYO 20 10 0 -10 -20 -30 -40 PET Amyloid Rate of change .20 .15 .10 .05 .00 -.05 p = 0.07 spEYO 20 10 0 -10 -20 -30 -40 PET Amyloid Rate of change .20 .15 .10 .05 .00 -.05 p = 0.09 Main effect APOE interaction non APOE e4 APOE e4 Gender interaction men women Villeneuve S, 1 Vogel JW, 1 Gonneaud J, 1 Pichet Binette A, 1 Rosa-Neto P, 1 Gauthier S, 1 Bateman RJ, 2 Fagan AM, 2 Morris JC, 2 Benzinger TL, 2 Johnson SC, 3 Breitner JC, 1 Poirier J, 1 Prevent-AD group. 1 McGill University; 2 Washington University; 3 University of Wisconsin Years to Parental Symptom Onset Predicts Amyloid Burden in Healthy Elderly with a Parental History of Sporadic Alzheimer’s Disease. Background and objectives • In the autosomal dominant genetic forms of Alzheimer’s disease (AD), symptom onset is predictable across generations. It is possible to estimate the number of years until symptom onset (EYO) in individuals that have a genetic mutation causing AD by subtracting their parent’s symptom onset age from their current age. 1 • Whether the age of the parent’s symptom onset can help predict biomarker abnormalities in sporadic AD is not known. • We sought to assess whether amyloid-beta (Aβ) burden, a pathological hallmark of AD, appears in a similarly predictable manner among cognitively normal persons with a parental history of sporadic AD. • Because apolipoprotein E (APOE) ε4 and female gender increase the risk of sporadic AD, we further assessed whether the relationship between spEYO and AD biomarkers are influenced by these risk factors. Method: spEYO calculation The “Sporadic Parental Estimated Years from Symptom Onset” (spEYO) score was calculated as follows: age of the participant at assessment – age of the parent at symptom onset Method: Participants • Analyses were performed on cognitively normal older adults from the Pre-symptomatic Evaluation of Novel or Experimental Treatments for Alzheimer's Disease (PREVENT-AD) cohort, McGill University, Montreal, Canada. 2 • The main analyses were repeated in two independent cohorts [the Knight Alzheimer’s Disease Research Center Adult Children Study (ACS) 3 and the Wisconsin Registry for Alzheimer's Prevention (WRAP) 4 ] using cerebrospinal fluid (CSF) and Pittsburgh compound B positron emission tomography (PIB-PET) Aβ biomarkers. Method: Aβ assessment • CSF Aβ 1-42 levels from the PREVENT-AD and the ACS cohort were determined by INNOTEST ELISA. CSF Aβ 1-42 levels from the WRAP were quantified by electrochemiluminescence using an Aβ triplex assay. • PIB-PET was not available for the PREVENT-AD cohort; PIB-PET from the ACS cohort [60-minute, cerebellar ref. region]; PIB-PET from the WRAP cohort [70-minute, cerebellar ref. region]. • PIB-PET annual rate of change was calculated as follows: [Aβ scores at follow-up – Aβ scores at baseline] ÷ interval (in years) between the two scans Proximity to parental symptom onset and amyloid burden in the PREVENT-AD cohort. • As individuals get closer to their parent’s symptom age of onset they show decreased concentrations of CSF Aβ 1-42 (indicating increased brain Aβ deposition). • These relationships are stronger in women (pink, second row) and in APOE4 carriers (green, third row). • Analyses were controlled for age, gender and education. • In the PREVENT-AD cohort, CSF Aβ 1-42 values changed with proximity to parental symptom onset, such that individuals approaching their parent’s symptom onset age showed lower Aβ levels. Interaction analyses showed that this effect is stronger in both APOE4 carriers and women. • In the ACS cohort, the main effect was replicated using PIB-PET data and the gender interaction was replicated using both CSF and PIB-PET data. • In the WRAP cohort, the results were not replicated using cross-sectional data, but the main effect and the APOE interaction were replicated using PIB-PET longitudinal data, suggesting that APOE4 carriers accumulate brain Aβ at a faster rate as they approach the age of their parent’s symptom onset. • These results suggest that proximity to parental symptom onset can help estimate Aβ biomarker changes in asymptomatic individuals at risk of AD, particularly in women and APOE4 carriers. References: 1 Bateman RJ et al., NEJM 2012; 2 Breitner JC et al., JPAD 2016; 3 Coats M, Morris J Geriatr Psychiatry Neurol 2005; 4 Sager MA, et al., J Geriatr Psychiatry Neurol 2005. Prevent-AD (n = 101) ACS (n = 128) WRAP (n = 135) Group differences Age 61.75 ± 5.11 63.39 ± 5.08 59.88 ± 6.00 a,b,c Male 29.41% 27.68% 31.76% Education 14.99 ± 2.97 15.87 ± 2.33 16.49 ± 2.51 a,b APOE4 38.24% 43.75% 42.35% CDR = 0 100% 100% 70.97% MMSE - 29.02 ± 1.29 29.21 ± 1.16 MOCA 27.87 ± 1.50 - - spEYO -12.52 ± 6.68 -10.21 ± 8.70 -13.87 ± 7.39 a,c a Difference between Prevent-AD and ACS; b Difference between Prevent-AD and WRAP; c Difference between ACS and WRAP, p < 0.05 APOE interaction non APOE e4 APOE e4 2000 1500 1000 500 0 p = 0.87 spEYO 20 10 0 -10 -20 -30 -40 2.2 2.0 1.8 1.6 1.4 1.2 1.0 .8 p = 0.61 spEYO 10 0 -10 -20 -30 2000 1500 1000 500 0 p = 0.17 spEYO 20 10 0 -10 -20 -30 -40 2.2 2.0 1.8 1.6 1.4 1.2 1.0 .8 p < 0.01 spEYO 20 10 0 -10 -20 -30 PET Amyloid Rate of change .10 .05 .00 -.05 -.10 p = 0.61 spEYO 20 10 0 -10 -20 -30 PET Amyloid Rate of change .10 .05 .00 -.05 -.10 p < 0.01 CSF Amyloid 2000 1500 1000 500 0 p = 0.87 spEYO 20 10 0 -10 -20 -30 -40 PET Amyloid 2.2 2.0 1.8 1.6 1.4 1.2 1.0 .8 p = 0.48 WRAP (PIB-PET, n = 91) Longitudinal data spEYO 20 10 0 -10 -20 -30 PET Amyloid Rate of change .10 .05 .00 -.05 -.10 p = 0.02 Summary and Conclusions ACS cohort WRAP cohort • The relationship between spEYO and Aβ burden was replicated in the ACS PIB-PET cohort, with an increase of brain Aβ deposition as individuals approach their parent’s symptom onset. • The interaction between spEYO and sex was also replicated using both CSF Aβ 1-42 level and PIB-PET data. • The spEYO*APOE interaction was not replicated in the ACS cohort. • Longitudinal ACS PIB-PET data further suggests that women tend to accumulate brain Aβ at a faster rate than men as they approach the age of their parent’s onset. • We did not replicate the PREVENT-AD cross-sectional findings. • As individuals approach the age of their parent’s symptom onset they however demonstrate faster rate of brain Aβ accumulation. • The spEYO*APOE interaction further suggests that this last association is stronger in APOE4 carriers than in non-APOE4 carriers.
Transcript of Years to Parental Symptom Onset Predicts Amyloid Burden in ...€¦ · • We sought to assess...
spEYO100- 1 0- 2 0- 3 0
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Villeneuve S,1 Vogel JW,1 Gonneaud J,1 Pichet Binette A,1 Rosa-Neto P,1 Gauthier S,1 Bateman RJ,2 Fagan AM,2 Morris JC,2 Benzinger TL,2 Johnson SC,3 Breitner JC,1 Poirier J,1 Prevent-AD group.1 McGill University; 2 Washington University; 3 University of Wisconsin
Years to Parental Symptom Onset Predicts Amyloid Burden in Healthy Elderly with a Parental History of Sporadic Alzheimer’s Disease.
Backgroundandobjectives• In the autosomal dominant genetic forms of Alzheimer’s disease (AD),
symptom onset is predictable across generations. It is possible toestimate the number of years until symptom onset (EYO) in individualsthat have a genetic mutation causing AD by subtracting their parent’ssymptom onset age from their current age.1
• Whether the age of the parent’s symptom onset can help predictbiomarker abnormalities in sporadic AD is not known.
• We sought to assess whether amyloid-beta (Aβ) burden, a pathologicalhallmark of AD, appears in a similarly predictable manner amongcognitively normal persons with a parental history of sporadic AD.
• Because apolipoprotein E (APOE) ε4 and female gender increase therisk of sporadic AD, we further assessed whether the relationshipbetween spEYO and AD biomarkers are influenced by these riskfactors.
Method:spEYO calculation
The “Sporadic Parental Estimated Years from Symptom Onset”(spEYO) score was calculated as follows:
age of the participant at assessment – age of the parent at symptom onset
Method:Participants
• Analyses were performed on cognitively normal older adults from thePre-symptomatic Evaluation of Novel or Experimental Treatments forAlzheimer's Disease (PREVENT-AD) cohort, McGill University,Montreal, Canada.2
• The main analyses were repeated in two independent cohorts [theKnight Alzheimer’s Disease Research Center Adult Children Study(ACS)3 and the Wisconsin Registry for Alzheimer's Prevention (WRAP)4]using cerebrospinal fluid (CSF) and Pittsburgh compound B positronemission tomography (PIB-PET) Aβ biomarkers.
Method:Aβassessment• CSF Aβ1-42 levels from the PREVENT-AD and the ACS cohort were
determined by INNOTEST ELISA. CSF Aβ1-42 levels from the WRAPwere quantified by electrochemiluminescence using an Aβ triplex assay.
• PIB-PET was not available for the PREVENT-AD cohort; PIB-PET fromthe ACS cohort [60-minute, cerebellar ref. region]; PIB-PET from theWRAP cohort [70-minute, cerebellar ref. region].
• PIB-PET annual rate of change was calculated as follows:[Aβ scores at follow-up – Aβ scores at baseline] ÷ interval (in years)between the two scans
ProximitytoparentalsymptomonsetandamyloidburdeninthePREVENT-ADcohort.
• As individuals get closer to their parent’s symptom age of onset they show decreased concentrations of CSF Aβ1-42 (indicating increased brain Aβ deposition).
• These relationships are stronger in women (pink, second row) and in APOE4 carriers (green, third row).
• Analyses were controlled for age, gender and education.
• In the PREVENT-AD cohort, CSF Aβ1-42 values changed with proximity to parental symptom onset, such that individuals approaching their parent’s symptom onset age showed lower Aβ levels. Interaction analyses showed that this effect is stronger in both APOE4 carriers and women.
• In the ACS cohort, the main effect was replicated using PIB-PET data and the gender interaction was replicated using both CSF and PIB-PET data.
• In the WRAP cohort, the results were not replicated using cross-sectional data, but the main effect and the APOE interaction were replicated using PIB-PET longitudinal data, suggesting that APOE4 carriers accumulate brain Aβ at a faster rate as they approach the age of their parent’s symptom onset.
• These results suggest that proximity to parental symptom onset can help estimate Aβ biomarker changes in asymptomatic individuals at risk of AD, particularly in women and APOE4 carriers.References:1 Bateman RJ et al., NEJM 2012; 2 Breitner JC et al., JPAD 2016; 3 Coats M, Morris J Geriatr Psychiatry Neurol 2005; 4 Sager MA, et al., J Geriatr Psychiatry Neurol 2005.
Prevent-AD(n = 101)
ACS (n = 128)
WRAP (n = 135)
Group differences
Age 61.75 ± 5.11 63.39 ± 5.08 59.88 ± 6.00 a,b,cMale 29.41% 27.68% 31.76%Education 14.99 ± 2.97 15.87 ± 2.33 16.49 ± 2.51 a,bAPOE4 38.24% 43.75% 42.35%CDR = 0 100% 100% 70.97%MMSE - 29.02 ± 1.29 29.21 ± 1.16MOCA 27.87 ± 1.50 - -spEYO -12.52 ± 6.68 -10.21 ± 8.70 -13.87 ± 7.39 a,c
a Difference between Prevent-AD and ACS; b Difference between Prevent-AD and WRAP; c Difference between ACS and WRAP, p < 0.05
APOE interactionnon APOE e4 APOE e4
Gender interactionmen women
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SummaryandConclusions
ACScohort WRAPcohort
• The relationship between spEYO and Aβ burden was replicated in the ACS PIB-PET cohort, with an increase of brain Aβ deposition as individuals approach their parent’s symptom onset.
• The interaction between spEYO and sex was also replicated using both CSF Aβ1-42 level and PIB-PET data.
• The spEYO*APOE interaction was not replicated in the ACS cohort.
• Longitudinal ACS PIB-PET data further suggests that women tend to accumulate brain Aβ at a faster rate than men as they approach the age of their parent’s onset.
• We did not replicate the PREVENT-AD cross-sectional findings.
• As individuals approach the age of their parent’s symptom onset they however demonstrate faster rate of brain Aβ accumulation.
• The spEYO*APOE interaction further suggests that this last association is stronger in APOE4 carriers than in non-APOE4 carriers.
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