by Benedetta Bodini & Salvatore Mazzeo
This very interesting Special Session in cooperation with the European Psychiatric Association covered recent progress made in Alzheimer’s disease and frontotemporal dementia, including evolving disease definitions, treatment, and prevention. It started with a lecture by Prof. Bruno Dubois, who discussed the definition, natural history and diagnostic criteria of preclinical Alzheimer’s disease. He started his lecture indicating that at present the definition of Alzheimer’s disease is clinico-biological, as it includes both clinical and biological elements. Changes in biomarkers, which reflect underlying pathology, can precede the occurrence of clinical symptoms by years. All stages of disease evolution (the preclinical stage, the prodromal stage and the dementia stage) are associated with changes in biomarkers but the critical challenge for the clinician is that the presence of amyloid plaques and tau protein is necessary but definitely not sufficient to determine the occurrence of clinical symptoms. Dubois underlined that there is no certainty that presymptomatic patients will actually develop the disease, considering the available evidence of a low predictive accuracy of amyloid and tau depositions on further development of cognitive decline in healthy individuals. Indeed, other factors such as compensatory mechanisms and brain resilience have been identified as key variables in determining whether presymptomatic patients will develop clinical symptoms or not. Research is now moving towards the definition of a personalised risk profile of developing Alzheimer’s disease in asymptomatic people with positive biomarkers, which will be able to identify people with an absolute risk of developing Alzheimer’s disease (carriers of autosomal dominant mutations for the disease); people with a high risk of developing the disease; and people with a low risk of evolving towards Alzheimer’s disease. Dubois concluded his lecture highlighting that the risk of Alzheimer’s disease in asymptomatic individuals results from the conjunction of Alzheimer’s disease biomarker status, personal risk and preventive factors. We need to develop novel biomarkers able to accurately identify patients at high risk of developing Alzheimer’s disease to allow an early and effective treatment to prevent clinical manifestations of the disease.
In the. second lecture of the session, Prof. Yolande Pijnenburg discussed the clinical and biological characteristics of frontotemporal dementia subtypes. She started her lecture defining the four clinical variants of frontotemporal dementia: the behavioral variant, the semantic variant of primary progressive aphasia, the non-fluent variant of primary progressive aphasia, and the right temporal variant of frontotemporal dementia. When we compare post-mortem brains of patients with Alzheimer’s disease with those of patients with frontotemporal dementia, we note that while Alzheimer’s disease affects the brain diffusively, frontotemporal dementia selectively affects the frontal part of the brain. When we investigate specifically each subtype of the disease, we can see that in the behavioral variant the atrophy is localised in the frontal area, in the semantic variant it affects the anterior left temporal lobe, in the non-fluent variant it is localised around the insula and in the right temporal variant of the disease it affects the right temporal lobe (mirroring the localisation of the semantic variant). Research studies have identified the proteins associated with frontotemporal dementia, which include TDP, TAU and FUS. However, it is currently impossible for a clinician to know which protein is responsible for the symptoms of a given patient with frontotemporal dementia considering the high neuropathological variability of each subtype of disease, with the exception of the semantic variant which is very frequently associated with TDP. There have been several attempts to define some clinico-pathological associations and two useful studies in this perspective have been performed by Scarioni et al (2020, 2022). Pijnenburg then underlined the urgent need to identify specific biomarkers for frontotemporal dementia, which is a complex disease that can be easily confused with other pathologies. For example, the behavioral variant of frontotemporal dementia can be very challenging to distinguish from a purely psychiatric syndrome. There are currently some biomarkers that can be helpful in the differential diagnosis (for example neurofilaments) but they remain nonspecific.
Prof. Alina Solomon’s talk focused on prevention of dementia, starting from a question: what is the dementia prevention potential? To what degree could we reduce the risk of progression to dementia? A recent study by Livingston et al (Lancet 2020) estimated a prevention potential of about 40% including many risk factors which could be targeted during life. Prevention potential also varies between countries and continents, with the highest prevention potential in low-income countries. Therefore, to maximise the prevention potential, clinical intervention should be tailored to each patient, targeting many risk factors at the same time, in a personalised approach.
The Finnish Geriatric Intervention Study to Prevent Cognitive Impairment and Disability (FINGER) is a lifestyle intervention trial on 1,260 patients recruited from the general population and randomised into two groups: 1) a group of patients who underwent nutrition management, physical exercises, cognitive training, social activities and vascular risk monitoring; and 2) a group of individuals who only received regular health advice. The follow-up of the study has been extended up to eleven years and showed that individuals in the first groups had an improvement in global cognition, executive function, processing speed and memory, while the control groups had a 30% increase of cognitive decline. The effect of lifestyle intervention seems to be modulated by APOE genotype, maybe through a mechanism involving 27-hydroxycholesterol. Furthermore, lifestyle intervention also had other benefits beyond cognition. FINGER is now expanding thanks to collaboration with centres from 45 other countries (the ww-Finger network), through the collaboration with the Alzheimer Disease Data Initiative (ADDI), including drugs (such as metformin) and new technology (e-health and m-health tools, machine learning). In conclusion, according to Solomon, AD Dementia could be prevented by a multimodal approach.
Finally Prof. Robert Perneczky presented the new therapeutic strategies against AD. He stated that multidomain interventions are promising but clinical trials are inconclusive so far, as meta-analysis of studies did not show an effect on dementia incidence and only a small effect on cognitive score.
Regarding a pharmacological approach, nowadays 82 agents are in phase 2, most of which are disease modifying drugs. Amyloid plaques and intermediate products of the amyloid cascade is the main therapeutic focus, but other agents of the AD pathological substrate are being targeted, such as tau protein and inflammation. Two independent randomised clinical trials (EMERGE and ENGAGE) on the efficacy and safety of Aducanumab, a monoclonal antibody that selectively targets aggregated forms of Aβ, were halted based on futility analysis. Nevertheless, subsequent analyses on biomarker substudies confirmed target engagement and dose-dependent reduction in markers of Alzheimer’s disease pathophysiology. Based on this evidence, Adacanumab has been approved in the US, but its use and its efficacy are still controversial, in part because the side effects of Aducanumab (in particular ARIA) are clinically relevant. Regarding anti-tau immunisation, clinical trials (e.g. Semorinemab) showed no effect on cognitive function and on biomarkers. In conclusion, other anti-amyloid trials are expected soon and other mechanisms of Alzheimer’s Disease (e.g. the role of microglia) have to be explored as therapeutic targets.