Citations

ObjectivePrevious studies suggest that the brain‐derived neurotrophic factor (BDNF) Val66Met (rs6265) polymorphism may influence symptom onset in Alzheimer's disease (AD). Our recent cross‐sectional findings suggest that Met66 may influence clinical expression in dominantly inherited AD (DIAD) through its effects on tau. However, it remains unclear whether carriage of Met66 in DIAD results in faster increases in cerebrospinal fluid (CSF) tau and ptau181, and whether these increases are associated with accelerated brain volume loss and memory decline.MethodsA total of 211 subjects (101 mutation noncarriers, 110 mutation carriers), who were cognitively normal, as defined by a Clinical Dementia Rating global score of 0, completed assessments of cognitive function, neuroimaging, and CSF sampling over 3.5 years as part of the Dominantly Inherited Alzheimer's Network.ResultsIn mutation carriers, Met66 carriers showed faster memory decline (4×), hippocampal volume loss (16×), and CSF tau and ptau181increases (6×) than Val66 homozygotes.BDNFdid not influence rates of cortical β‐amyloid accumulation or change in CSF Aβ42levels in mutation carriers. In mutation noncarriers,BDNFgenotype had no effect on change in cognition, brain volume, cortical β‐amyloid accumulation, or change in any CSF measures of tau, ptau181, and CSF Aβ42.InterpretationAs in sporadic AD, the deleterious effects of β‐amyloid on cognitive function, brain volume loss, and CSF tau in DIAD mutation carriers are less in Val66 homozygotes. TheBDNFVal66Met polymorphism should be considered as a potential moderator of clinical trial outcomes in current treatment and prevention trials in DIAD and sporadic AD. Ann Neurol 2018;84:424–435

Abstract Background: There have been varying reports on risk of different cancers, other than pancreatic cancer (PC), among first-degree relatives (FDRs) of PC patients. Because the pattern and scope of aggregation of PC with other malignancies in families of PC patients are not entirely clear, we investigated risk of 15 common malignancies among FDRs of unselected PC probands. Methods: The study included 17,181 FDRs with more than 336,000 person-years at risk. The FDRs were identified through sequentially enrolled PC probands (n=2,305) in the Mayo Clinic prospective pancreatic cancer patient registry from 2000-2016. Data on family history of cancer were provided by the probands at the time of enrollment in structured risk factor questionnaires. Standardized incidence ratios (SIRs) and 95% confidence intervals (CIs) were calculated by comparing cases of each cancer type observed among the FDRs with those expected using data from the Surveillance Epidemiology and End Results Program (SEER). Stratified analyses were performed among siblings of the probands based on whether the related proband tested positive for a mutation in ATM, BARD1, BRCA1, BRCA2, CDKN2A, CHEK2, MUTYH, NBN, PALB2, or PMS2; or tested negative for mutation in a total of 25 sequenced cancer susceptibility genes. Results: Compared to the SEER reference population, risk of PC was two-fold higher than expected among the FDRs (SIR=2.04, 95% CI: 1.78-2.31) and 12-fold higher than expected among FDRs with history of PC in at least two blood relatives (SIR=11.99, 95% CI: 10.48-13.64). Siblings of mutation-positive probands had higher risk of PC (SIR=13.57, 95% CI: 6.19-25.76) than siblings of mutation-negative probands (SIR=8.91, 95% CI=6.73-11.57). For other cancer types, primary liver cancer was elevated among female FDRs (SIR=2.10, 95% CI: 1.34-3.12), whereas breast (SIR=3.16, 95% CI: 1.63-5.52) and ovarian (SIR =6.61, 95% CI: 1.33-19.31) cancers were elevated only among siblings of the mutation-positive probands. There also were suggestions of lower than expected risk of other malignancies, such as bladder, colorectal and prostate cancers, among the FDRs as compared with the SEER population. Conclusions: These findings confirm familial aggregation of PC with breast and ovarian cancers, and further suggest a potential aggregation of PC and primary liver cancer among female FDRs of PC probands. The elevated risks of breast cancer and ovarian cancer among siblings of the mutation-positive probands suggests a strong influence of genetic susceptibility shared with the related proband, possibly due to an inherited mutation in BRCA1, BRCA2, or PALB2. These findings lend support to genetic counseling and targeted screening of certain cancers in high-risk families. Citation Format: Samuel O. Antwi, Sarah E. Fagan, Kari G. Chaffee, William R. Bamlet, McWilliams R. Robert, Ann L. Oberg, Gloria M. Petersen. Risk of different cancers among first-degree relatives of pancreatic cancer patients and impact of probands’ germline mutation on sibling cancer risk [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 4269. doi:10.1158/1538-7445.AM2017-4269

AbstractIntroductionThe objective of this study was to evaluate the relationship between self‐reported exercise levels and Alzheimer's disease (AD) biomarkers, in a cohort of autosomal dominant AD mutation carriers.MethodsIn 139 presymptomatic mutation carriers from the Dominantly Inherited Alzheimer Network, the relationship between self‐reported exercise levels and brain amyloid load, cerebrospinal fluid (CSF) Aβ42, and CSF tau levels was evaluated using linear regression.ResultsNo differences in brain amyloid load, CSF Aβ42, or CSF tau were observed between low and high exercise groups. Nevertheless, when examining only those already accumulating AD pathology (i.e., amyloid positive), low exercisers had higher mean levels of brain amyloid than high exercisers. Furthermore, the interaction between exercise and estimated years from expected symptom onset was a significant predictor of brain amyloid levels.DiscussionOur findings indicate a relationship exists between self‐reported exercise levels and brain amyloid in autosomal dominant AD mutation carriers.