Central to this aim is the study of deeply phenotyped longitudinal cohorts with a focus on young onset and familial dementias and on presymptomatic disease.

The sub-theme’s focus is on:

• Familial Alzheimer’s disease (FAD)
• Sporadic, young onset and atypical AD
• Frontotemporal dementia (FTD) and familial FTD
• Dementia with Lewy Bodies
• Presymptomatic dementias: Insight46 – the 1946 birth cohort

Major progress has been made:

Cohorts:

• Insight46, the pre-dementia sub-study of the 1946 birth cohort, completed Wave one (assessing 502 subjects) and now assessed >300 for follow-up in Wave 2; major papers published (e.g. Lane et al Lancet Neurol 2019); $7.7M award from the US Alzheimer’s Association will support study expansion and continuation (2019-22)
• Trials underway in familial Alzheimer’s disease (FAD) and cohort extended; UK lead for FAD; UK centre for international Dominantly Inherited Alzheimer Network (DIAN) & DIAN-TU (trials arm): leveraged support £1.7M
• GENFI the international study of familial frontotemporal dementia (FTD), led from UCL, has recruited over 1,000 subjects and secured £0.7M in funding
• A new Lewy body dementia cohort study established and led by a recently appointed PI, who working closely with UCL GenFI, AD and Insight46 PIs to create a coherent cross-disease trials platform.

Therapies:

• We have now built expertise in early phase 1/2 trials in various forms of dementia, including implementation of genetic therapies.
• Identification of drug targets with iPSC: We are currently developing APP-targeting antisense oligonucleotides and drugs enhancing tau proteostasis.
• Demonstration of efficacy of one AD and one FTD disease modifying drug: We were the UK lead site for the aducanumab trial, the first drug to show clinical and biomarker significant effect in AD. We have expanded our trial portfolio to include multiple methodologies.
• Use SILK to support target engagement of tau interventions: SILK clinical protocols, isotope manufacturing pipelines and mass spectrometry analysis pipelines are now in place in preparation for clinical trials, with SILK protocols to measure neurofilament light chain now in development.  
• Expand research into cognitive deficits in systemic disease. We have worked in the fields of both head injury (James, Ann Clin Transl Neurol 2021; Graham, Brain 2020) and air pollution (Delgado-Saborit, Sci Total Environ, 2021).

Collaborations with industry to take forward genetic therapies:

• Phase 1 AAV gene therapy in genetic FTD (progranulin) with Prevail Therapeutics: first AAV therapy in FTD; lead site and agreed 3-year collaborative programme with pharma to develop trial based fluid biomarkers of inflammation using trial participant CSF samples
• UK Lead for first gene silencing therapy in AD – phase I IONIS MAPT-Rx trial: 1^st author presenting baseline results at CTAD 2020 and will present topline results of phase I trial at AAIC June 2021