Clinical experience with polygenic risk score in subjects with early cognitive concerns.

BACKGROUND: There is mounting evidence that lifestyle interventions and behavioural changes play a significant role in maintaining cognition and function, as well as preventing dementia. Consequently, it is important that clinicians confronted with subjects with early cognitive concerns, have appropriate tools available to assist in diagnosis and to facilitate risks management appropriately. The application of polygenic risk score (PRS) tests has the potential to contribute towards management planning and to reduce the burden of testing in subjects with low overall risk. METHODS: This retrospective analysis considered the application of genoSCORETM in a small cohort of patients seen over a six month period in a London Memory Clinic. The test was offered to selected patients in the clinic with MCI not clinically attributable to dementia, or cognitively normal individuals concerned about their risks of dementia. The impact upon clinical management and lifestyle modification was reviewed. genoSCORE, a polygenic risk score algorithm, was developed by Cytox to assess genetic risk for the future development of Late-Onset Alzheimer's disease (LOAD). RESULTS: Patients receiving the genoSCORE test included those with early MCI, subjective memory complaints and a small number concerned about their risk of dementia. In each case, a medical history was taken and individuals assessed using the Addenbrooke's Cognitive Examination, conducted either in clinic or remotely. genoSCORE polygenic risk score was easy to conduct and well received. The results stimulated individuals at risk of developing LOAD to make lifestyle adjustments and thereby potentially modifying their dementia risk. CONCLUSIONS: In this study, the genoSCORE PRS test provided a valuable assessment of genetic risk of individuals most likely to decline cognitively decline towards AD and as such, contributed significantly to clinical management decisions. The ease and effectiveness of home sampling of saliva as source DNA for the PRS test was a major factor and well aligned with the continuing need for remote consultations in the light of COVID-19 concerns. Further larger-scale studies to determine the full clinical and associated economic impact of the genoSCORE PRS test are required.

Age-dependent effect of APOE and polygenic component on Alzheimer's disease.

Alzheimer's disease (AD) is a devastating neurodegenerative condition with significant genetic heritability. Several genes have been implicated in the onset of AD with the apolipoprotein E (APOE) gene being the strongest single genetic risk loci. Evidence suggests that the effect of APOE alters with age during disease progression. Here, we aim to investigate the impact of APOE and other variants outside the APOE region on AD risk in younger and older participants. Using data from both the Alzheimer's Disease Neuroimaging Initiative and the UK Biobank, we computed the polygenic risk score of each individual informed by the latest genetic study from the International Genomics of Alzheimer's Project. Our analysis showed that the effect of APOE on the disease risk is greater in younger participants and reduces as participants' age increases. Our findings indicate the increased impact of polygenic risk score as participants' age increases. Therefore, AD in older individuals can potentially be triggered by the cumulative effect of genes which are outside the APOE region.

The discovery of AZD5597, a potent imidazole pyrimidine amide CDK inhibitor suitable for intravenous dosing.

The development of a novel series of imidazole pyrimidine amides as cyclin-dependent kinase (CDK) inhibitors is described. Optimisation of inhibitory potency against multiple CDK's (1, 2 and 9) resulted in imidazole pyrimidine amides with potent in vitro anti-proliferative effects against a range of cancer cell lines. Excellent physiochemical properties and large margins against inhibition of CYP isoforms and the hERG ion channel were achieved by modification of lipophilicity and amine basicity. A candidate with disease model activity in human cancer cell line xenografts and with suitable physiochemical and pharmacokinetic profiles for intravenous (i.v.) dosing was selected for further development as AZD5597.