Clinical implications of APOE genotyping for late-onset Alzheimer's disease (LOAD) risk estimation: a review of the literature.

Alzheimer's disease is a genetically complex neurodegenerative disorder representing the leading cause of dementia. Advances in personal genomics are increasing the public uptake of genetic susceptibility testing for complex diseases such as late-onset Alzheimer's disease (LOAD). For LOAD, the discovery of the major risk ε4 allele of the APOE gene has prompted a debate on the ethics and utility of presymptomatic (i.e., predictive) testing. Although the mechanistic contribution of APOE to disease onset remains uncertain, presymptomatic genetic testing provides a relative risk of developing LOAD. Presymptomatic testing for complex disorders, such as LOAD is much less conclusive than early-onset Alzheimer's disease (EOAD) which follows a Mendelian inheritance pattern. Given the lack of preventive strategies available for EOAD or LOAD, APOE genotyping offers limited clinical utility, thus, raising ethical and practical questions. We conducted a systematic search of five electronic databases or primary studies published during January 2008-January 2018 which investigated practical and ethical issues of presymptomatic APOE genotyping for LOAD risk estimation. We identified 31 articles which suggested that APOE genotyping for LOAD susceptibility provides potential benefits to at-risk patients and can guide changes in positive health-related behaviors. However, other individuals may experience test-related anxiety, depression and psychological distress. Future research should focus on developing an integrated risk assessment tool to enhance the utility of APOE genotyping. Furthermore, empirical research is required to understand actual psychological and social implications associated with testing.

Cholinergic Surveillance over Hippocampal RNA Metabolism and Alzheimer's-Like Pathology.

The relationship between long-term cholinergic dysfunction and risk of developing dementia is poorly understood. Here we used mice with deletion of the vesicular acetylcholine transporter (VAChT) in the forebrain to model cholinergic abnormalities observed in dementia. Whole-genome RNA sequencing of hippocampal samples revealed that cholinergic failure causes changes in RNA metabolism. Remarkably, key transcripts related to Alzheimer's disease are affected. BACE1, for instance, shows abnormal splicing caused by decreased expression of the splicing regulator hnRNPA2/B1. Resulting BACE1 overexpression leads to increased APP processing and accumulation of soluble Aß1-42. This is accompanied by age-related increases in GSK3 activation, tau hyperphosphorylation, caspase-3 activation, decreased synaptic markers, increased neuronal death, and deteriorating cognition. Pharmacological inhibition of GSK3 hyperactivation reversed deficits in synaptic markers and tau hyperphosphorylation induced by cholinergic dysfunction, indicating a key role for GSK3 in some of these pathological changes. Interestingly, in human brains there was a high correlation between decreased levels of VAChT and hnRNPA2/B1 levels with increased tau hyperphosphorylation. These results suggest that changes in RNA processing caused by cholinergic loss can facilitate Alzheimer's-like pathology in mice, providing a mechanism by which decreased cholinergic tone may increase risk of dementia.

Family physician access to and wait times for cancer diagnostic investigations: Regional differences among 3 provinces.

OBJECTIVE: To examine provincial and regional differences in FPs' direct access to cancer diagnostic investigations and advice from other specialists regarding investigations and referrals, and to explore FPs' perceptions about wait times for diagnostic investigations and receipt of results. DESIGN: A cross-sectional, online survey. SETTING: British Columbia, Manitoba, and Ontario. PARTICIPANTS: A sample of FPs from participating provinces. MAIN OUTCOME MEASURES: Direct FP access to various diagnostic investigations and advice from other specialists regarding investigations and referrals; FPs' perceptions about wait times for diagnostic investigations ordered directly; and FPs' perceptions about wait times for results. RESULTS: A total of 1054 surveys were completed by FPs from British Columbia (n = 229), Manitoba (n = 228), and Ontario (n = 597). Distance from a cancer centre was not significantly associated with direct access to or wait times for diagnostic investigations for most of the investigations studied; however, provincial differences were observed. Family physicians in Manitoba and British Columbia were 30% to 45% less likely to report having direct access to endoscopy and some imaging investigations compared with FPs in Ontario. Family physicians in Manitoba and British Columbia were also at increased odds of waiting longer than 12 weeks for endoscopy investigations and longer than 4 weeks for imaging investigations compared with FPs in Ontario. Most FPs reported wait times of less than 2 weeks for imaging results; however, the proportion of FPs who waited longer than 2 weeks for colonoscopy results ranged from 15% in Ontario to 96% in British Columbia. CONCLUSION: Given the disparities observed among provinces, there is an opportunity for provinces to learn from one another to improve direct access to and shorten wait times for diagnostic investigations. This in turn has the potential to shorten the primary care interval for cancer diagnostic assessment.