Dementia research in 2020: moving forward despite the COVID-19 pandemic
Authors: Miia Kivipelto, Francesca Mangialasche
Journal: The Lancet Neurology (2020)

2020 has been the year of the COVID-19 pandemic, which has substantially affected our lives and interfered with clinical and research activities. However, there have been several major research findings and initiatives moving the dementia field forward. Important progress has been achieved in blood-based biomarkers, which are minimally invasive and more accessible compared with CSF-based and PET-based investigations. Blood-based biomarkers could, therefore, be applied to large populations for early and accurate detection of Alzheimer's disease across the clinical spectrum, from at-risk individuals with no cognitive symptoms to patients with dementia. An ultrasensitive plasma immunoassay for tau phosphorylated at Thr181 (p-tau181), a highly specific biomarker of Alzheimer's disease pathology, has been developed and tested in four clinic-based prospective cohorts,1Karikari TK Pascoal TA Ashton NJ et al.Blood phosphorylated tau 181 as a biomarker for Alzheimer's disease: a diagnostic performance and prediction modelling study using data from four prospective cohorts.Lancet Neurol. 2020; 19: 422-433Summary Full Text Full Text PDF PubMed Scopus (606) Google Scholar which overall consisted of 1131 individuals, including elderly patients at different stages of the Alzheimer's disease clinical continuum, age-matched controls, patients with other neurodegenerative disorders or vascular dementia, and healthy young adults. The study findings suggested that blood-based p-tau181 can predict tau and amyloid β neuropathology, differentiate Alzheimer's disease from other neurodegenerative disorders, and identify Alzheimer's disease across the clinical continuum.1Karikari TK Pascoal TA Ashton NJ et al.Blood phosphorylated tau 181 as a biomarker for Alzheimer's disease: a diagnostic performance and prediction modelling study using data from four prospective cohorts.Lancet Neurol. 2020; 19: 422-433Summary Full Text Full Text PDF PubMed Scopus (606) Google Scholar Encouraging findings have also been reported for a blood-based assay measuring tau phosphorylated at Thr217 (p-tau217), which has been tested in three cross-sectional cohorts consisting of 1402 individuals,2Palmqvist S Janelidze S Quiroz YT et al.Discriminative accuracy of plasma phospho-tau217 for Alzheimer disease vs other neurodegenerative disorders.JAMA. 2020; 324: 772-781Crossref PubMed Scopus (560) Google Scholar including elderly patients at different stages of the Alzheimer's disease clinical continuum, age-matched controls, and patients with other neurodegenerative disorders. The study also included an autosomal-dominant Alzheimer's disease kindred of carriers (and age-matched non-carriers) of the PSEN1 Glu280Ala mutation. The p-tau217 assay showed good ability to differentiate clinically diagnosed Alzheimer's disease from other neurodegenerative conditions, and it differentiated individuals with Alzheimer's disease neuropathology from those without diagnostic levels of Alzheimer's disease neuropathology, either by post-mortem analysis or by neuroimaging and CSF analysis. In the same study, the diagnostic accuracy of p-tau217 was superior to that of other Alzheimer's disease biomarkers, including plasma p-tau181, plasma neurofilament light chain, and structural neuroimaging (MRI). Plasma p-tau217 levels were notably increased in PSEN1 mutation carriers at a young age (age ≥25 years).2Palmqvist S Janelidze S Quiroz YT et al.Discriminative accuracy of plasma phospho-tau217 for Alzheimer disease vs other neurodegenerative disorders.JAMA. 2020; 324: 772-781Crossref PubMed Scopus (560) Google Scholar The blood-based assay p-tau217 needs further validation, and clinical standardisation is required for both p-tau181 and p-tau217. These blood-based assays represent promising methods that can aid early identification of Alzheimer's disease underlying pathology. Another promising study of blood-based biomarkers aimed to map the complexity of Alzheimer's disease pathophysiology by describing changes in omics profiles.3Huynh K Lim WLF Giles C et al.Concordant peripheral lipidome signatures in two large clinical studies of Alzheimer's disease.Nat Commun. 2020; 115698Crossref PubMed Scopus (65) Google Scholar A lipidomic analysis was done that included individuals from two longitudinal cohorts with normal cognition, mild cognitive impairment, or dementia due to Alzheimer's disease. Lipid signatures were associated with prevalent and incident Alzheimer's disease.3Huynh K Lim WLF Giles C et al.Concordant peripheral lipidome signatures in two large clinical studies of Alzheimer's disease.Nat Commun. 2020; 115698Crossref PubMed Scopus (65) Google Scholar Replicability of these findings will be crucial to validate such an approach. Nonetheless, advances in identifying and validating blood-based biomarkers for early detection of pathology are important to identify people at risk of dementia, who can be enrolled in trials aimed at preventing or delaying dementia onset. The challenges in identifying effective disease-modifying treatments are still present. On Nov 6, 2020, a US Food and Drug Administration (FDA) advisory committee decided not to give regulatory approval for aducanumab because evidence of safety and efficacy was insufficient.4BiogenUpdate on FDA advisory committee's meeting on aducanumab in Alzheimer's disease.https://investors.biogen.com/news-releases/news-release-details/update-fda-advisory-committees-meeting-aducanumab-alzheimersDate: Nov 6, 2020Date accessed: November 23, 2020Google Scholar This decision is a reminder of how amelioration of Alzheimer's disease pathology might not necessarily translate into unambiguous clinical findings. Aducanumab is a human monoclonal antibody that selectively binds to amyloid β fibrils and soluble oligomers and can remove amyloid β from the brain. Results of a phase 1b trial in 165 patients with prodromal or mild Alzheimer's disease (NCT01677572) showed striking reduction of amyloid plaques with dose-dependent and time-dependent effects. These results led to the initiation of two large phase 3 efficacy trials in patients with mild cognitive impairment due to Alzheimer's disease or mild Alzheimer's disease (NCT02484547, NCT02477800). The trials were prematurely discontinued, but statements on different waves of the trials' data analysis have changed over time, and regulatory approval has been requested from both the FDA and the European Medicines Agency. Although the final decision of regulatory authorities might still change, the aducanumab case is a learning opportunity to improve methodological aspects of Alzheimer's disease drug development. With respect to dementia prevention through non-pharmacological interventions, encouraging news has come from the LipiDiDiet trial,5Soininen H Solomon A Jelle Visser P et al.36-month LipiDiDiet multinutrient clinical trial in prodromal Alzheimer's disease.Alzheimers Dement. 2020; (published online Sept 13.)https://doi.org/10.1002/alz.12172Crossref Scopus (80) Google Scholar in which a nutritional intervention was tested in 311 individuals with prodromal Alzheimer's disease. Results of 36-months' follow-up showed amelioration of global cognition and function and a slower rate of both whole-brain and hippocampal atrophy. LipiDiDiet is a trial model suggesting that early and long-term interventions could be effective in improving cognitive trajectories in individuals with Alzheimer's disease pathology. The trial findings also show the role of adequate nutrition in individuals at risk of dementia, a population in whom it can be difficult to achieve sufficient intake of nutrients. In the context of dementia prevention, the 2020 Lancet Commission on Dementia prevention, intervention, and care6Livingston G Huntley J Sommerlad A et al.Dementia prevention, intervention, and care: 2020 report of the Lancet Commission.Lancet. 2020; 396: 413-446Summary Full Text Full Text PDF PubMed Scopus (4350) Google Scholar identified 12 modifiable factors that can be targeted to reduce risk. These factors include diabetes, mid-life hypertension and obesity, physical inactivity, smoking, low education, hearing loss, traumatic brain injury, excessive alcohol consumption, social isolation, depression, and air pollution. Compared with the findings reported in the 2017 Lancet Commission,7Livingston G Sommerlad A Orgeta V et al.Dementia prevention, intervention, and care.Lancet. 2017; 390: 2673-2734Summary Full Text Full Text PDF PubMed Scopus (3841) Google Scholar three additional factors have been added, and the estimated proportion of preventable cases has increased from 35% to 40%, indicating that we can be more optimistic on prevention opportunities. The role of some the factors needs to be further validated, and other modifiable factors are likely to be added. Underlying mechanisms are also still not fully elucidated. Nevertheless, preventive approaches are being tested and larger collaborative efforts are in place. One such initiative is the World-Wide FINGERS (WW-FINGERS) network of multidomain trials for dementia risk reduction and prevention, which includes more than 30 countries. The network builds on the successful experience of the Finnish Geriatric Intervention Study to Prevent Cognitive Impairment and Disability (FINGER) trial (NCT01041989), a randomised controlled trial that showed the feasibility and efficacy of a multimodal lifestyle intervention consisting of nutritional guidance, exercise, cognitive training, and control of vascular and metabolic risk factors. The WW-FINGERS network aims to test and adapt the FINGER trial model in different settings and populations, to define effective and feasible preventive strategies for people with different risk profiles.8Kivipelto M Mangialasche F Snyder HM et al.World-Wide FINGERS Network: a global approach to risk reduction and prevention of dementia.Alzheimers Dement. 2020; 16: 1078-1094Crossref PubMed Scopus (248) Google Scholar WW-FINGERS has gathered research teams from all continents, granting opportunities to collaborate and involve populations less represented in the dementia prevention field. This collaborative framework has added value in the context of the COVID-19 pandemic, because dementia affects individuals who are also more vulnerable to COVID-19 and related morbidity. WW-FINGERS activities are part of the WHO global action plan on the public health response to dementia 2017–2025 and the Global Forum of Neurology and Covid-19 (launched in June, 2020) which aims to investigate the long-term neurological sequelae of COVID-19. Individuals who survive COVID-19 are at increased risk of psychiatric sequelae, including dementia,9Taquet M Luciano S Geddes JR Harrison PJ Bidirectional associations between COVID-19 and psychiatric disorder: retrospective cohort studies of 62 354 COVID-19 cases in the USA.Lancet Psychiatry. 2020; (published online Nov 9.)https://doi.org/10.1016/S2215-0366(20)30462-4Summary Full Text Full Text PDF PubMed Scopus (909) Google Scholar further emphasising the urgency to have dementia prevention in focus. We declare no competing interests.