12th COGNITIVE DAY Proceedings 10 MAY 2024, LJUBLJANA, SLOVENIA 12th COGNITIVE DAY Proceedings Published by: Centre for Cognitive impairments, Department of neurology, University Medical Centre ljubljana Edited by: Milica Gregorič Kramberger Proceedings was published at 12th Cognitive day meeting on 10 May 2024. Cognitive Day is an annual scientific meeting with international participation organised by Centre for Cognitive Impairments, Department of Neurology, University Medical Centre Ljubljana Kataložni zapis o publikaciji (CIP) pripravili v Narodni in univerzitetni knjižnici v Ljubljani. COBISS.SI-ID 194664963 ISBN 978-961-7080-09-4 (PDF) Contents 4 List of authors/ lecturers 5 Preface 15 Diagnostic performance of novel P-tau biomarkers in clinical practice 6 Program Andreja EMERŠIČ, MPharm, EuSpLM 7 Cardiovascular health and cognition in older 20 Alzheimer‘s disease imaging protocol, adults: Differences across screening strategies implementation, and challenges and European countries in the MOPEAD project Srečko DOBRECOVIĆ, MD Andreja ŠPEH, MA, Psychology, PhD candidate 10 Genetics and epigenetics of Alzheimer’s disease 22 ARIA-E, ARIA-H, and iatrogenic CAA-related Alja VIDETIČ PASKA ,PhD, Professor inflammation. Time for reconsiderations? Fabrizio PIAZZA, PhD 12 Late-life depression: diagnostic and treatment strategies 23 Alzheimer Disease – therapies with focus Polona RUS PRELOG, MD, PhD on future Bengt WINBLAD, MD, PhD, Professor 14 Blood biomarkers for clinical diagnosis and anti-amyloid therapy monitoring: 24 Lecanemab – from a mutation to a treatment Important factors to consider for Alzheimer’s disease Thomas K. KARIKARI, PhD Lars LANNFELT,MD, PhD, Professor List of authors/ lecturers Andreja ŠPEH, MA, Psychology, PhD candidate Department of Neurology, University Medical Centre Ljubljana, Slovenia Alja VIDETIČ PASKA ,PhD, Professor Andreja EMERŠIČ, MPharm, EuSpLM Centre for Functional Genomics and Bio-Chips, Laboratory for CSF diagnostics, Department of Neurology, Institute of Biochemistry and Molecular Genetics, University Medical Centre Ljubljana, Faculty of Medicine, University of Ljubljana, Slovenia Slovenia Thomas K. KARIKARI, PhD University of Pittsburgh, Department of Psychiatry, Polona RUS PRELOG, MD, PhD Pittsburgh, USA University Psychiatric Clinic Ljubljana, Slovenia Bengt WINBLAD, MD, PhD, Professor, Karolinska Institutet, Dept NVS, Center for Alzheimer Research, Division of Neurogeriatrics, Srečko DOBRECOVIĆ, MD Stockholm, Sweden Institute of Radiology,University Medical Centre Ljubljana, Slovenia Lars LANNFELT,MD, PhD, Professor Uppsala University, Fabrizio PIAZZA, PhD Dept of Public health and Caring Sciences; Molecular Geriatrics, University of Milano Bicocca, Rudbeck laboratory, Monza, Italy Uppsala, Sweden Preface Milica G. KRAMBERGER, MD, PhD Dear esteemed colleagues, It is with genuine enthusiasm that I extend to you a collection of scholarly articles and abstracts curated for the upcoming 12th Cognitive Day international meeting. Alzheimer’s disease (AD) stands as a formidable challenge in the realm of neurodegenerative disorders, its pathogenesis woven from a globe – psychiatry, geriatrics, neurology, psychology, and tapestry of intricate factors. Marked by the accumulation of Aβ neuroradiology, among others. Central to our mission is the provision plaques and tau neurofibrillary tangles (NFTs), AD heralds neuronal of dynamic education, empowering all stakeholders involved in the loss and cognitive decline. The insidious nature of AD manifests care of patients with neurodegenerative conditions. Through through years of silent aggregation before clinical symptoms emerge, collaborative efforts, we strive to fortify the endeavors of underscoring the urgent need for proactive interventions. Over the multidisciplinary teams dedicated to addressing the needs of years, the landscape of AD research has witnessed remarkable individuals navigating cognitive challenges. strides towards early detection through in-vivo biomarkers and the Through this compendium and the collective wisdom it encapsulates, pursuit of multimodal therapeutic approaches. Promising avenues, we aim to illuminate the latest breakthroughs in our shared field of including therapies targeting amyloid accumulation and tau inquiry. This anthology, designed to serve as both an enriching pathology, offer hope in the global effort to combat this relentless resource and a testament to higher education, promises to captivate disease. medical students, trainee specialists, and seasoned practitioners alike. Its insights will undoubtedly enrich the practice of every The significance of Cognitive Day international meetings transcends member of the multidisciplinary team, fostering enhanced care for mere academic discourse; they serve as crucibles for ongoing those entrusted to our collective stewardship. education and refinement of clinical practices in managing patients grappling with cognitive impairments. We are honored by the Our heartfelt appreciation extends to all the esteemed lecturers and enduring support extended to us, enabling the congregation of contributors whose unwavering dedication has enriched this esteemed experts hailing from diverse disciplines and corners of the endeavor beyond measure. Program 08:30 - 09:00 Registration 11:30 - 11:45 Coffee Break 09:00 Welcome and introduction FLUID BIOMARKERS Milica G. KRAMBERGER, Ljubljana, Slovenia 11:45 Diagnostic performance of novel p tau RISK FACTORS biomarkers in clinical practice Andreja EMERŠIČ, Ljubljana, Slovenia 09:05 Cardiovascular risk factors in older adults Andreja ŠPEH, Ljubljana, Slovenia 12:15 Blood biomarkers for clinical diagnosis and anti-amyloid therapy monitoring: important 09:25 Genetics and epigenetics of Alzheimer’s disease factors to consider Alja VIDETIČ PASKA, Ljubljana, Slovenia Thomas K. KARIKARI, Pittsburgh, USA 09:45 Late life depression - diagnostic and treatment 12:45 Discussion strategies Polona RUS PRELOG, Ljubljana, Slovenia 13:00 - 14:00 LUNCH 10:05 Discussion THERAPY 14:00 STRUCTURAL IMAGING BIOMARKERS Alzheimer disease – future treatment strategies & challenges 10:15 Alzheimer’s disease - imaging protocol, Bengt WINBLAD, Stockholm, Sweden implementation and challenges 14:30 Srečko DOBRECOVIĆ, Ljubljana, Slovenia Lecanemab - from mutation to a treatment for Alzheimer’s disease 10:45 ARIA-E, ARIA-H, and iatrogenic CAA-related Lars LANNFELT, Uppsala, Sweden inflammation. Time for reconsiderations? 15:00 Fabrizio PIAZZA, Milan, Italy Discussion 15:15 11:15 Discussion Closing remarks Cardiovascular health and cognition in countries [5]. Our aim was to examine differences in cardiovascular factors and cognitive function among five European countries and older adults: Differences across screen-four screening strategies using MOPEAD data. ing strategies and European countries in RESULTS the MOPEAD project We analysed data from 414 individuals aged 65-85 (M = 71.9, SD = 5.0) years with a positive screening result indicating high risk of prodromal or mild AD. Four different screening strategies were used: a web-based screening tool, an open house initiative (OHI), a primary Andreja Špeh care-based protocol for early detection of cognitive decline, and a tertiary care-based screening at diabetologist clinics. Participants from Germany, Spain, the Netherlands, Sweden, and Slovenia were included. Our findings revealed significant differences in cardiovascular health and cognition among five European countries BACKGROUND and four screening strategies using data from the MOPEAD project. The number of people with dementia is expected to increase in the future, yet the projected increases vary across different geographical Cross-country differences regions. The smallest percentage changes in projected dementia cases are expected in high income Asia Pacific and western Europe, Significant differences were observed between included countries in and the largest in north Africa and Middle East [1]. These regional physical activity, high blood pressure, dyslipidaemia, and all cognitive variations stem from many factors including cultural disparities, outcomes. Participants from Sweden exhibited the highest levels of policy variations, and economic disparities, all of which impact an physical activity and the lowest prevalence of dyslipidaemia, whereas individual’s health and cognitive status, thus affecting dementia individuals from Spain demonstrated the opposite trend. While prevalence. Swedish participants have been previously documented as highly active [6], individuals from Spain displayed notably higher rates of In dementia research, recruitment procedures for individuals with negative health outcomes, including hypertension (67.2 %), cognitive impairment vary, leading to study samples with different hyperlipidaemia (65.7 %), physical inactivity (61.9 %), and smoking (5.2 characteristics. Population-based sampling tend to include subjects %). Despite the Mediterranean region’s reputation for healthy living, who are older, less educated, and exhibit poorer cognitive perfor-Spanish adults appear comparatively less active than their European mance, along with a less frequent family history of Alzheimer’s counterparts [7] [8]. Additionally, studies focusing on diet report than disease (AD) [2, 3], while convenience samples show more the adherence to the Mediterranean diet among Spanish older pronounced rates of hippocampal volume decline [3]. individuals has declined [9–11], reflecting a shift towards more westernized eating habits characterised by increased consumption of Modifiable risk factors, such as hypertension, obesity, and physical commercial pastries, sweetened beverages, and red or processed inactivity account for 40 % of dementias, which could theoretically be meats. prevented or delayed [4], emphasizing the potential for preventive interventions. Additionally, in the future of disease-modifying treat-In terms of cognition, similar trends emerged among participants. ments for AD, early and efficient diagnostics gain importance, requir-Individuals from Germany and the Netherlands achieved the highest ing an understanding of individual and environmental characteristics. scores on cognition, whereas Spanish participants had the lowest The European Union Innovative Medicines Initiative project, Models scores across most of cognitive domains. The cognitive performance of Patient Engagement for Alzheimer’s Disease (MOPEAD), aimed to of Spanish participants could be explained with their poorer identify the most effective and cost-efficient screening method for cardiovascular health. Interestingly, previous studies on European detecting prodromal AD and mild AD dementia in different European participants have often highlighted Scandinavians as exhibiting the highest cognitive performance [12, 13]. However, Formanek et al. broader community engagement, enabling clinicians to reach individuals reported that Scandinavians experienced an annual cognitive decline from various backgrounds and demographics who may not typically seek at approximately twice the rate compared to other European regions, clinical evaluation. a phenomenon attributed to their high cognitive reserve [13]. It is plausible that this process of cognitive decline has already compensated for their earlier cognitive performance, potentially CONCLUSIONS explaining why Scandinavians may not stand out as prominently in our comparisons. Our study unveils significant disparities in cardiovascular health and cognition among five European countries participating in the MOPEAD project, as well as across four distinct screening strategies. Emphasizing the Screening differences importance of recruitment methods, the OHI shows promise in capturing a more representative sample. Future research should focus on formulating Participants recruited via diabetologist clinics had worse tailored recommendations for reducing risk factors considering the specific cardiovascular health, poorer performance on cognitive tests, and characteristics of different populations. the highest proportion of individuals diagnosed with MCI and dementia. Considering the frequently present concurrent risk factors in diabetes, this finding did not come as a surprise. However, it represents a significant weakness in relation to (early) diagnosis of cognitive disorders. Individuals enrolled via web-based testing demonstrated the most favourable outcomes, with the highest levels of physical activity, lowest incidence of diabetes and heart disease, and best cognitive performance on the domains of global cognition, immediate memory, visuo-spatial/constructional abilities, attention, and delayed memory. Virtually recruited samples tend to be slightly younger and more geographically diverse [17]. Diverse recruitment methods yield study samples with different characteristics. While memory clinic settings provide the most cost-effective context to study the phenomenology of subjective cognitive decline (SCD) to AD and eventually recruit patients for secondary prevention trials, population-based samples seem to be less biased and probably more suitable for the study of memory complaints [20]. Our findings underscore the importance of considering diverse recruitment methods in assessing and managing cardiovascular health and cognitive function. The high proportion of under detected dementia cases in community and residential settings [21] further supports the importance of implementing effective screening programs to identify individuals at risk and provide timely interventions. Recognizing potential problems early in their course offers many advantages, prompting a demand for quick and effective identification methods. We believe that the OHI emerges as a promising strategy for capturing a diverse range of participants, which could be especially relevant for early diagnostics in the context of future disease-modifying treatments. This approach facilitates REFERENCES 12. Weber D, Skirbekk V, Freund I, Herlitz A. The changing face of cognitive gender differences in Europe. Proc Natl Acad Sci U S A. 1. Nichols E, Steinmetz JD, Vollset SE, Fukutaki K, Chalek J, Abd-Allah F, et al. 2014;111:11673–8. Estimation of the global prevalence of dementia in 2019 and forecasted prevalence in 2050: an analysis for the Global Burden of Disease Study 2019. 13. Formanek T, Kagstrom A, Winkler P, Cermakova P. Differences in Lancet Public Heal. 2022;7:e105–25. cognitive performance and cognitive decline across European regions: a population-based prospective cohort study. Eur Psychiatry. 2019;58:80–6. 2. Brodaty H, Mothakunnel A, de Vel-Palumbo M, Ames D, Ellis KA, Repper-mund S, et al. Influence of population versus convenience sampling on 14. Papunen S, Mustakallio-Könönen A, Auvinen J, Timonen M, sample characteristics in studies of cognitive aging. Ann Epidemiol. Keinänen-Kiukaanniemi S, Sebert S. The association between diabetes and 2014;24:63–71. cognitive changes during aging. Scand J Prim Health Care. 2020;38:281–90. 3. Whitwell JL, Wiste HJ, Weigand SD, Rocca WA, Knopman DS, Roberts RO, et 15. Tomlin A, Sinclair A. The influence of cognition on self-management of al. Comparison of imaging biomarkers in the Alzheimer Disease Neuroimag-type 2 diabetes in older people. Psychol Res Behav Manag. 2016;9:7–20. ing Initiative and the Mayo Clinic Study of Aging. Arch Neurol. 2012;69:614–22. 16. Marseglia A, Fratiglioni L, Kalpouzos G, Wang R, Bäckman L, Xu W. Prediabetes and diabetes accelerate cognitive decline and predict 4. Livingston G, Huntley J, Sommerlad A, Ames D, Ballard C, Banerjee S, et al. microvascular lesions: A population-based cohort study. Alzheimer’s Dementia prevention, intervention, and care: 2020 report of the Lancet Dement. 2019;15:25–33. Commission. Lancet. 2020;396:413–46. 17. Moseson H, Kumar S, Juusola JL. Comparison of study samples recruited 5. Rodríguez-Gómez O, Rodrigo A, Iradier F, Santos-Santos MA, Hundemer H, with virtual versus traditional recruitment methods. Contemp Clin Trials Ciudin A, et al. The MOPEAD project: Advancing patient engagement for the Commun. 2020;19:100590. detection of “hidden” undiagnosed cases of Alzheimer’s disease in the community. Alzheimer’s Dement. 2019;15:828–39. 18. Abdelnour C, Rodríguez-Gómez O, Alegret M, Valero S, Moreno-Grau S, Sanabria Á, et al. Impact of Recruitment Methods in Subjective Cognitive 6. Vilhelmson B, Thulin E, Elldér E. Time change in the distribution of physical Decline. J Alzheimers Dis. 2017;57:625–32. activity and its correlates among retired older Swedish adults: a repeated cross-sectional study from a national survey. BMC Public Health. 19. Farias ST, Mungas D, Reed BR, Harvey D, DeCarli C. Progression of mild 2022;22:1–10. cognitive impairment to dementia in clinic- vs community-based cohorts. Arch Neurol. 2009;66:1151–7. 7. Loyen A, Hecke L Van, Verloigne M, Hendriksen I, Lakerveld J, Steene-jo-hannessen J, et al. Variation in population levels of physical activity in Euro-20. Rodríguez-Gómez O, Abdelnour C, Jessen F, Valero S, Boada M. Influence pean adults according to cross-European studies : a systematic literature of Sampling and Recruitment Methods in Studies of Subjective Cognitive review within DEDIPAC. Int J Behav Nutr Phys Act. 2016. Decline. J Alzheimer’s Dis. 2015;48:S99–107. 8. Omes MAG, Igueiredo DAF, Eixeira LAT, Oveda VEP, Aúl COP. Physical 21. Lang L, Clifford A, Wei L, Zhang D, Leung D, Augustine G, et al. Prevalence inactivity among older adults across Europe based on the SHARE database. and determinants of undetected dementia in the community: A systematic 2014;430:71–7. literature review and a meta-analysis. BMJ Open. 2017;7:1–8. 9. Navarro-mart R, Mafla-españa MA, Cauli O. Mediterranean Diet Adherence in Community-Dwelling Older Adults in Spain : Social Determinants Related to the Family. 2022;:1–12. 10. Leo LM, Guallar-castillo P, Mesas AE, Aguilera MT, Banegas R, Rodrı F. Adherence to the Mediterranean Diet Pattern Has Declined in Spanish Adults 1 – 3. 2012;:1843–50. 11. Conde-pip J, Bouzas C, Zurita-ortega F, Olea-serrano F, Tur JA, Mari-scal-arcas M. Adherence to a Mediterranean Diet Pattern , Physical Activity , and Physical Self-Concept in Spanish Older Adults. 2022;:1–11. Genetics and epigenetics of Alzheimer’s The aim of our study was to identify the frequency of ApoE alleles in the Slovene memory clinic population of patients with cognitive disease impairment. The cohort included almost 700 patients with dementia and healthy volunteer controls for which classical AD biomarker tests like amyloid- and tau protein and also ApoE genotypes were determined. Genotyping revealed that ApoE ε 3/ ε 3 is the most common genotype in Slovenian population. The ApoE ε 4/ ε 4 Alja Videtič Paska genotype that was not identified in controls and showed gradual increase in frequency from controls, through subjective cognitive decline and mild cognitive impairment to AD patients, supporting ApoE as significant clinical biomarker also in Slovenian population. We can conclude that genotyping for ApoE alleles could be used also in clinical setting when the genotype information is crucial in decisions regarding administration of novel drugs, such as Alzheimer’s disease (AD) is a complex and multifactorial disorder that lacenemab. is influenced by the interplay of genetic background and environmental factors. Development of AD has long prodromal phase in which The AD pathology is complex and is, beside genetics, the AD initiation, early prevention strategies could importantly contribute to slower age of onset, and disease progression, driven also by lifestyle and progression of the disease. Currently, the significant biomarkers of environmental factors [3]. The interplay of these factors could be AD are senile extracellular plaques of amyloid- and intracellular explained by epigenetics – the mechanisms that do not change the neurofibrillary tangles of hyperphosphorylated tau protein in the DNA sequence, but affect the gene expression. Among the most brain, but these are determined when the characteristic symptoms of studied and understood epigenetic mechanisms is DNA methylation. the disease already appear [1]. For better prognosis and timely It affects cognitive functions through maintenance of basic cellular treatment interventions additional biomarkers of AD would be neces-processes and synaptic plasticity in the central nervous system. sary. Recent advances in sequencing technologies and bioinformatics analysis enabled DNA methylation studies in larger scale. Several More than 95% of AD cases are sporadic or late-onset AD (LOAD) and candidate genes, like APOE, brain-derived neurotrophic factor (BDNF), the etiology is heavily influenced by interconnected genetic and ankyrin 1 (ANK1), and others were studied, but so far no clear environmental risk factors [2,3]. The search for genetic biomarkers, conclusion can be drawn. Namely, studies reported both increased including extensive genome-wide association studies, revealed more and decreased levels of DNA methylation, which could be partially than 20 genes that could affect the risk of developing AD. The stron-explained by different tissue samples used [5]. In our study DNA gest association with AD showed the apolipoprotein E (ApoE) gene. methylation status of BDNF and catechol-o-methyltransferase (COMT) The most common alleles are Apo E4, E3 and E2 in heterozygous or were interrogated. BDNF is an important nervous growth factor that homozygous states. The strongest genetic risk factor for AD is the promotes neuronal survival, development and function. It plays an allele ApoE E4 that causes earlier disease onset and accelerates important role in modulating cognition, learning and memory. COMT symptoms. The ApoE has been implicated in atherosclerosis, as well is involved in catecholamine metabolism through dopamine as hypertension, and it is of much interest due to its relation to the degradation, and its COMT genetic variants have been shown to amyloid- pathology [3]. influence cognitive functions. Our results revealed higher expression levels of BDNF in mild cognitive impairment (MCI) subjects compared The AD-related genetic variants of ApoE are composed of two single to individuals diagnosed with AD. Analysis of DNA methylation nucleotide polymorphisms (SNPs): rs429358 and rs7412. With the showed difference in DNA methylation between AD and MCI subjects. combination of these SNPs the distinct allelic variants ApoE-ε2, The results of this study suggest BDNF as potential biomarker that ApoE-ε3, and ApoE-ε4 are formed. The most common variant is could help distinguish between MCI and AD patients. On the other ApoE-ε3, while ApoE-ε4 is the AD susceptibility variant. The ApoE-ε4 hand, no difference in the COMT gene expression or DNA homozygotes have a 25-fold increased risk for developing AD com-methylation was detected between two groups of subjects [6]. pared to ApoE-ε3 homozygotes [4]. REFERENCES 1. Zhang XX, Tian Y, Wang ZT, Ma YH, Tan L, Yu JT. The Epidemiology of Alzheimer's Disease Modifiable Risk Factors and Prevention. The journal of prevention of Alzheimer's disease. 2021;8(3):313-21. [PMID] [10.14283/- jpad.2021.15] 2. Raulin AC, Doss SV, Trottier ZA, Ikezu TC, Bu G, Liu CC. ApoE in Alzheimer's disease: pathophysiology and therapeutic strategies. Mol Neurodegener. 2022;17(1):72. [PMID] [10.1186/s13024-022-00574-4] 3. Robinson M, Lee BY, Hane FT. Recent Progress in Alzheimer's Disease Research, Part 2: Genetics and Epidemiology. J Alzheimers Dis. 2017;57(2):317-30. [PMID] [10.3233/jad-161149] 4. Bertram L, McQueen MB, Mullin K, Blacker D, Tanzi RE. Systematic meta-analyses of Alzheimer disease genetic association studies: the AlzGene database. Nature Genetics. 2007;39(1):17-23. [PMID] [10.1038/ng1934] 5. Nikolac Perkovic M, Videtic Paska A, Konjevod M, Kouter K, Svob Strac D, Nedic Erjavec G, et al. Epigenetics of Alzheimer's Disease. Biomolecules. 2021;11(2). [PMID] [10.3390/biom11020195] 6. Kouter K, Nikolac Perkovic M, Nedic Erjavec G, Milos T, Tudor L, Uzun S, et al. Difference in Methylation and Expression of Brain-Derived Neurotrophic Factor in Alzheimer's Disease and Mild Cognitive Impairment. Biomedicines. 2023;11(2). [PMID] [10.3390/biomedicines11020235] Late-life depression: diagnostic and treat-Research suggests that depression, while treatable, presents a significant risk factor for dementia, and its elimination could ment strategies potentially decrease the incidence of dementia on a population level by 4%, surpassing even the impact of reducing other risk factors such as hypertension, diabetes, obesity, and physical inactivity (2). The interconnection between depression, cognitive decline, and dementia is complex and remains not fully elucidated. Research evidence Polona Rus Prelog shows that depression is a potential causal factor for dementia, especially Alzheimer’s disease (AD), with studies indicating a two-fold increase in the risk of dementia associated with depression. Additionally, the severity of depressive symptoms and the frequency of depressive episodes have been linked to a higher risk of all-cause dementia, suggesting that depression might also present a prodromal phase of dementia (3). The association was found for various dementia types, including AD and vascular dementia. Late-life depression (LLD) is an umbrella term for major depressive Furthermore, depression has been recognized as an accelerating disorder in the elderly, irrespective of when the initial depressive factor in cognitive decline. Irrespective of the viewpoint, the potential episode occurred. It includes both early-onset cases, often linked to of depression as a modifiable factor in the development of dementia genetic predispositions and adverse childhood experiences, as well suggests that treatment strategies for depression could delay the as late-onset cases, more frequently associated with life stressors progression of dementia. characteristic of advancing age and physical decline. The risk factors for developing LLD are multidimensional, including biological LLD correlates with an array of detrimental long-term outcomes, elements like subcortical cerebrovascular disease, cognitive impair-including growing disability, functional and cognitive decline, an ment, frailty, sleep disturbances, and other coexisting medical condi-increased risk of dementia, and higher mortality due to medical tions, particularly cardiovascular diseases and chronic illnesses (1). conditions or suicide (4). Despite the well-developed treatment Psychological and psychiatric symptoms, often present in LLD, such protocols, it is estimated that approximately half of the elderly as anxiety, neuroticism (observed through personality assessments), individuals with LLD do not respond sufficiently to first-line dysthymia, loneliness and substance misuse disorders, are significant antidepressant therapies (5). This leads to an increased risk of contributors to the disease burden and presentation. Moreover, the relapse, treatment non-adherence for concurrent physical conditions, social environment, including factors like grief, a role of caregiving, and an increased likelihood of early mortality, which may include other family and relational stressors and diminished social support death by suicide. Barriers to accessing care remain significant, with are critical in the manifestation of LLD. LLD differs from depression in less than half of the elderly with mental health and substance use younger individuals in various aspects, including risk and protective issues receiving appropriate care. factors, clinical presentation, cognitive impairment, and co-occurring physical symptoms. Current treatments for LLD, comprising pharmacotherapy, neuromodulation, psychotherapy, and a suite of LLD is increasingly recognized as both a mood and cognitive disorder non-pharmacological interventions, demonstrate efficacy (6). due to the intricate link between affective symptoms and cognitive Psychotherapeutic interventions for LLD have been examined decline, traditionally presenting as a triad of executive dysfunctions through several systematic reviews and network meta-analyses, (e.g., planning, sequencing, multitasking), attentional deficits, and a comparing the effectiveness and acceptability of various therapies general slowing in cognitive processing. However, recent studies including cognitive-behavioral therapy, life review therapy, and indicate that memory impairment should also be considered in the mindfulness, among others (7). The evidence suggests no significant assessment of LLD, as a factor complicating the cognitive profile differences in effectiveness among these therapies, with life review associated with depression in the elderly. The efficacy of antidepres-therapy ranking high in terms of effectiveness and acceptability. sants in potentially ameliorating cognitive deficits as part of the Despite limitations in the quality of evidence, psychotherapy treatment for LLD has yet to be clearly established. approaches appear effective for LLD. REFERENCES 1. Patrick RE, Dickinson RA, Gentry MT, Kim JU, Oberlin LE, Park S, Principe JL, Teixeira AL, Weisenbach SL. Treatment resistant late-life depression: A narrative review of psychosocial risk factors, non-pharmacological interventions, and the role of clinical phenotyping. Journal of Affective Disorders. 2024 Apr 7. 2. Livingston G, Huntley J, Sommerlad A, Ames D, Ballard C, Banerjee S, Brayne C, Burns A, Cohen-Mansfield J, Cooper C, Costafreda SG. Dementia prevention, intervention, and care: 2020 report of the Lancet Commission. The Lancet. 2020 Aug 8;396(10248):413-46. 3. Dafsari FS, Jessen F. Depression—an underrecognized target for prevention of dementia in Alzheimer’s disease. Translational Psychiatry. 2020 May 20;10(1):160. 4. Gao M, Wong NM, Lin C, Huang CM, Liu HL, Toh CH, Wu C, Tsai YF, Lee SH, Lee TM. Multimodal brain connectome-based prediction of suicide risk in people with late-life depression. Nature mental health. 2023 Feb;1(2):100-13. 5. Steffens DC. Treatment-Resistant Depression in Older Adults. New England Journal of Medicine. 2024 Feb 15;390(7):630-9. 6. Dafsari FS, Bewernick B, Böhringer S, Domschke K, Elsaesser M, Löbner M, Luppa M, Schmitt S, Wingenfeld K, Wolf E, Zehender N. Perceived Physical Health and Cognitive Behavioral Therapy vs Supportive Psychotherapy Outcomes in Adults With Late-Life Depression: A Secondary Analysis of a Randomized Clinical Trial. JAMA Network Open. 2024 Apr 1;7(4):e245841-. 7. Ji M, Sun Y, Zhou J, Li X, Wei H, Wang Z. Comparative effectiveness and acceptability of psychotherapies for late-life depression: A systematic review and network meta-analysis. Journal of Affective Disorders. 2023 Feb 15;323:409-16. 8. Ainsworth NJ, Marawi T, Maslej MM, Blumberger DM, McAndrews MP, Perivolaris A, Pollock BG, Rajji TK, Mulsant BH. Cognitive outcomes after antidepressant pharmacotherapy for late-life depression: a systematic review and meta-analysis. American Journal of Psychiatry. 2024 Feb 7:ap-pi-jp. Alzheimer‘s disease imaging protocol, or volumetric. Purpose: white matter signal abnormalities such as small vessel ischemia resulting in multi-infarct dementia and implementation, and challenges abnormal sulcal signal in leptomeningeal processes (e.g. leptomeningeal carcinomatosis). DWI/ADC Purpose: cortical or deep grey matter restricted diffusion in Creutzfeldt Jakob disease (CJD) and restriction in demyelination of infarction (e.g. cerebral vasculitis). SWI sequence (if not option T2*): SWI including phase and magnitude Srečko Dobrecović images. Purpose: microhemorrhages (e.g. cerebral amyloid angiopathy (CAA), hypertensive encephalopathy). Mineral deposition in the cortex (e.g. AD, amyotrophic lateral sclerosis (ALS)). Loss of low signal in substantia nigra (Parkinson disease). Additionally, functional imaging techniques such as positron emission tomography (PET) can provide valuable information on brain metabolism and amyloid deposition in Alzheimer's disease. Alzheimer's disease (AD) is a progressive neurodegenerative disorder The implementation of imaging protocols in Alzheimer's disease that affects millions of individuals worldwide. Imaging techniques involves standardized procedures for image acquisition, processing, play a crucial role in the diagnostic pathway, diagnosis and monitor-and interpretation. These protocols aim to ensure consistency and ing of AD progression. There are several objectives that imaging aims reproducibility in imaging studies, allowing for accurate diagnosis and to asses. Detecting disease in preclinical stage when symptoms are monitoring of disease progression. Collaboration between diminutive, as mild cognitive impairment or in the early stages of AD. radiologists, neurologists, and other healthcare professionals is More than half of cases of AD remain undetected in the early stages. essential for the successful implementation of imaging protocols in Imaging techniques play a crucial role in the diagnosis and manage-AD. ment of AD. Magnetic resonance imaging (MRI) is commonly used to assess abnormalities in specific brain regions associated with AD, Despite the advancements in imaging technology, several challenges such as the hippocampus and entorhinal cortex. MRI provides remain in the imaging of AD. These challenges include the variability detailed structural information of the brain, allowing for the detection in imaging findings among patients, the interpretation of imaging of atrophy and changes in brain volume associated with the disease. results in the context of clinical symptoms, and the need for Structural MRI is sensitive to presymptomatic disease and can be longitudinal imaging studies to track disease progression over time. used as a biomarker. Therefore, standardized methods that produce Additionally, the cost and availability of imaging techniques can pose stable results across scanners and over time are required. MRI proto-barriers to widespread implementation in clinical practice. In col should approach a wide variety of disorders, typically slowly conclusion, imaging plays a crucial role in the diagnosis and progressive, with variable gradual neurologic dysfunction. As is the management of AD. Standardized imaging protocols, collaboration case with most MRI protocols, there is no such thing as a universally among healthcare professionals, and addressing challenges in agreed upon MRI protocol to image an individual with a suspected imaging interpretation are essential for improving the accuracy and neurodegenerative condition. What is essential is that good quality utility of imaging in AD. three plane imaging (sagittal, coronal and axial) is obtained which includes T1, T2, FLAIR, DWI and SWI sequences. A standard protocol should include: T1 sequence, volumetric gradi-ent-echo e.g. MPRAGE, preferably isometric e.g. 0.9 mm reformatted in three planes. Anatomical, best for assessing regional volume loss and may be used for automated brain morphometry. T2 sequence: fast spin echo, whole-brain, e.g. 3 mm. Purpose: signal intensity of basal ganglia, and posterior fossa structures (often less well seen on FLAIR due to flow artefact) FLAIR sequence: whole-brain axial or REFERENCES 1. Lang, L. et al. Prevalence and determinants of undetected dementia in the community: a systemic literature review and meta-analysis. BMJ Open 7, e011146 (2017). 2. Eicher T. et al. Rates of formal diagnosis in people screend positive for dementia in primary care: results of the DepHi-Trial. J. Alzheimers Dis. $2, 451-458 (2014). 3. Fox NC, Warrington EK, Freeborough PA, et al. Presymptomatic hippocampal atrophy in Alzheimer's disease. A longitudinal MRI study. Brain. 1996;119:2001–2007. 4. Dickerson BC, Salat D, Bates JF, et al. Medial temporal lobe function and structure in mild cognitive impairment. Ann Neurol. 2004;56:27–35. 5. Fox NC, Warrington EK, Freeborough PA, et al. Presymptomatic hippocampal atrophy in Alzheimer's disease. A longitudinal MRI study. Brain. 1996;119:2001–2007. 6. Jack CR, Jr, Petersen RC, Xu Y, et al. Prediction of AD with MRI- based hippocampal volume in mild cognitive impairment. Neurology. 1999;52:1397–1403. 7. radiopaedia.org/articles/neurodegenerative-protocol-mri ARIA-E, ARIA-H, and iatrogenic CAA-re-REFERENCES lated inflammation. Time for reconsiderations? 1. Kelly L. et al. Clearance of interstitial fluid (ISF) and CSF (CLIC) group-part of Vascular Professional Interest Area (PIA), updates in 2022-2023. Cerebrovascular disease and the failure of elimination of Amyloid-β from the brain and retina with age and Alzheimer's disease: Opportunities for Fabrizio Piazza therapy. Alzheimer's and Dementia, 2023. DOI 10.1002/alz.13512 2. Piazza F et al. Association of Microglial Activation With Spontaneous ARIA-E and CSF Levels of Anti-Aβ Autoantibodies. Neurology, 2022. DOI 10.1212/WNL.0000000000200892 ARIA-E/H (amyloid-related imaging abnormalities-edema/hemorrhage) is an umbrella term coined to define the radiographic appear-3. Zedde ML et al. CAA-ri and ARIA: Two Faces of the Same Coin? American ance of MRI images abnormality during treatments with Aβ-lowering Journal of Neuroradiology, 2023. DOI 10.3174/ajnr.A7759 monoclonal antibodies (mAbs) for Alzheimer's disease immunothera-4. Piazza, F. et al. Anti-amyloid β autoantibodies in cerebral amyloid py. angiopathy-related inflammation: Implications for amyloid-modifying therapies Annals of Neurology, 2013, 73(4), pp. 449–458. DOI Today, it is well recognized that ARIA-E events can also occur sponta-10.1002/ana.23857 neously in patients with cerebral amyloid angiopathy-related inflammation (CAA-ri), a rare autoimmune encephalopathy associated with 5. Antolini, L. et al. Spontaneous ARIA-like events in cerebral amyloid raised cerebrospinal fluid (CSF) concentrations of spontaneous angiopathy–related inflammation a multicenter prospective longitudinal auto-antibodies against Aβ (aAbs). cohort study. Neurology, 2021, 97(18), pp. E1809–E1822. DOI 10.1212/WNL.0000000000012778 In this framework, the last years of research and experience of the Funding Sponsor iCAB international Network generated an increased consensus that Award Grant Number: 23AARG‐1030214. Program: Alzheimer's Association therapy-induced ARIA is the iatrogenic manifestation of CAA-ri. Research Grant (AARG). Project Title: UncoveriNg Immune MechanIsms and Indeed, the natural history of CAA-ri, the response-to-corticosteroid Biomarkers of ARIA (UNIMIB‐ARIA Toolkit). therapy outcomes, the regional and temporal co-localization of radiographic ARIA-E with microglial activation (both on neuropathology and in vivo with TSPO-PET), and the downstream negative effects on the Aβ-clearance pathways and related risks on the subsequent occurrence of an ARIA-H event, all provide remarkable supportive evidence that ARIA-E associated with mAbs therapy is iatrogenic CAA-ri. In this talk, we will present and critically discuss the emerging new data supporting the potential of the assay for anti-Aβ (auto)antibody CSF testing as a companion diagnostic and early biomarker for CAA-ri and ARIA in real-world clinical practice and immunotherapy trials. In this framework, we will also present the recently launched "ARIAis-CAAri" Biomarkers Research study; an international, prospective, longitudinal cohort Registry and Biobank of patients with ARIA and CAA-ri from the real-world clinical practice aimed at fostering a preci-sion medicine approach and improving research collaborations between the AD and CAA community. Diagnostic performance of novel P-tau which diversly affect protein function.6,7 Furthermore, the so-called big tau isoform is abundant in peripheral nervous system neurons biomarkers in clinical practice and contributes up to 80% to the tau protein measured in plasma.8,9 The role of tau in microtubule assembly and stability is regulated primarily by the phosphorylation of amino acid residues in the microtubule-binding region, effectively modulating the binding affinity of tau for tubulin.10 Frequent cycles of phosphorylation and Andreja Emeršič dephosphorylation (detachment from and binding of tau to microtubules) are fundamental to maintaining normal axonal transport, however, hyperphosphorylation can lead to tau misfolding and aggregation.7,10 Neurofibrillary tangles from AD brain have been shown to contain tau phosphorylated at more than 40 residues out of 85 potential phosphorylation sites (serine (S), threonine (T), and tyrosine residues), whereas only about 20 phosphorylated sites have been identified in tau extracted from healthy brains.7,11 Introduction Interestingly, tau is transiently hyperphosphorylated during brain development, hypothermia, and hibernation in hibernating Alzheimer’s disease (AD) is characterized by extracellular amyloid mammals, so the process itself is not detrimental as long as it is plaques made of aggregated amyloid-β (Aβ) peptides and neurofibril-reversible.12,13 lary tangles of hyperphosphorylated tau (p-tau) protein that accumu-late within neurons. Although underlying pathology can only be Despite the overlaps between sites that have been found to undergo confirmed by postmortem examination, cerebrospinal fluid (CSF) and phosphorylation in AD and healthy brains,13 several p-tau neuroimaging biomarkers are considered valid indicators of neuro-biomarkers have proven useful for AD diagnosis. Antibody against tau pathological hallmarks and have greatly improved the diagnostic phosphorylated at S202/T205 is commonly used in accuracy for AD during life.1,2 However, the long-awaited approval of immunohistochemistry to reveal neurofibrillary tangles at disease-modifying therapies might challenge clinical pathways in the postmortem examination14 while in CSF, p-tau181 is an established future, as identifying potential candidates for treatment early in the biomarker currently being used in clinical practice.3,15 Additionally, disease course and monitoring drug activity with easily accessible and new assays targeting p-tau181, 217, 212, 231, and 235 have been cost-effective tools will become crucial.2,3 Because established CSF shown to differentiate AD from non-AD neurodegenerative disorders, and PET biomarkers require specialized facilities and costly or rela-including other tauopathies, which are also associated with tively invasive diagnostic procedures, they are less convenient for pathological aggregates of hyperphosphorylated tau protein.16–24 widespread application or frequent assessments of therapeutic The finding that CSF (plasma) p-tau is not consistently increased in response. Recent progress in the field of blood-based biomarkers of primary tauopathies could indicate different rates of p-tau secretion AD is well-timed and offers the possibility of broader communi-into the extracellular space, site-specific phosphorylation, or ty-based screening that is not limited to specialist care hospitals.3,4 alternative proteolytic processing of tau in these diseases, resulting in Particularly promising are plasma p-tau biomarkers, demonstrating protein concentrations or epitopes that are not detected by present similar performances to detect AD pathology as their CSF counter-immunoassays.25,26 Indeed, elevated CSF tau can arise from the parts.3–5 passive release of tau from dying neurons, thereby reflecting the intensity of neurodegeneration or acute brain injury (total tau), but growing evidence suggests that tau is also actively secreted from Tau phosphorylation and truncation AD-affected neurons.3,6,27 Because truncated C-terminal fragments are retained in the neurofibrillary tangles in the brain, CSF tau was Tau is a more complex and heterogeneous biomarker than first shown to consist of mid-region and N-terminal tau fragments. The thought. Aside from six tau isoforms, resulting from alternative pool of soluble tau forms released into the blood is likely further splicing of the mRNA in the adult brain, tau can undergo several reduced to contain mostly N-terminal tau species.27 A better posttranslational modifications and proteolytic cleavage (truncation), understanding of tau processing has led to the development of several blood p-tau biomarkers, with the best performance achieved Diagnostic performances of plasma p-tau biomarkers by assays that quantify N-terminal p-tau.3,27 The diagnostic potential of plasma p-tau181, 217, and 231 has been extensively studied and validated compared to the established CSF and PET Novel p-tau biomarkers in the cerebrospinal fluid biomarkers and against the postmortem examination.3,4,20,23,36–38 Plasma p-tau181 and p-tau217 were found to increase already in Biomarkers of Aβ pathology are considered the earliest detectable presymptomatic stages in both sporadic and familial AD, up to 20 years change in AD as reduced CSF Aβ42 (Aβ42/40 ratio) is observed 10-20 before the estimated onset of MCI among the PSEN1 mutation carriers.22,39 years before the onset of dementia.1,28–30 The established CSF Blood p-tau concentrations correlate with cognitive assessments and predict p-tau181 targeting mid-region parts of the protein becomes future decline and progression to AD MCI or dementia.16,22,24,40,41 Same abnormal later, during mild cognitive impairment (MCI) or dementia as the corresponding CSF biomarkers, plasma p-tau231, and p-tau217 have stage, with the evolution of the following cognitive symptoms largely demonstrated earlier and stronger associations with Aβ and tau pathologies depending on the presence of other comorbidities, AD risk factors, than the p-tau181.20,23 Due to the observed associations with disease and individual differences in cognitive reserve.1,28,30,31 severity and increases along the AD continuum plasma p-tau biomarkers Nevertheless, some p-tau forms seem to increase earlier in the could become accessible tools to detect underlying AD pathology and disease course, in parallel with subtle changes in Aβ provide insights into disease progression in different clinical and research deposition.18,32,33 CSF mid-region p-tau231, N-terminal p-tau181, settings.3,4 For example, pre-screening with plasma p-tau181 in the and N-terminal p-tau217 have been shown to increase before the Alzheimer’s disease neuroimaging initiative would presumably save almost mid-region p-tau181 in cognitively unimpaired individuals in 60% of the costs compared with the Aβ-PET screening alone.3 A two-step preclinical stage of the AD continuum.18 Accordingly, these approach based on plasma p-tau217 has been proposed to risk stratify MCI biomarkers differentiated better between Aβ positive and Aβ patients for Aβ positivity, which could reduce the number of confirmatory negative individuals (determined by CSF Aβ42/40 < 0.071, Aβ-PET CSF Aβ42/40 tests by >80% and thereby offer a cost-effective strategy to positive visual read or Aβ-PET centiloid >12) than the established detect AD in memory clinic settings.42 In the clinical trial with donanemab p-tau181.18 We obtained similar results when comparing the pre-screening with plasma p-tau181 enriched the study population for Aβ diagnostic performance of N-terminal p-tau217 and p-tau181 with and tau-PET positivity, which was confirmed in 63% of candidates who mid-region p-tau181 in two memory clinic cohorts; both N-terminal screened positive for p-tau181 compared to 37% of positive PET scans p-tau biomarkers distinguished early AD MCI from non-AD MCI more among those without pre-screening.4 Similarly, plasma p-tau181 was in accurately than the standard p-tau181.33 In line with the previous agreement with CSF Aβ positivity in 51% of cases within our Precision mass spectrometry study34, p-tau217 displayed the highest fold Medicine Interventions in Alzheimer’s Disease (PMI-AD) project.43 Applying changes in our AD patients, indicating greater dynamic ranges p-tau217 to pre-screen individuals in this community-based cohort would compared to p-tau181 biomarkers.33 In participants across the AD increase recommended confirmatory CSF testing by 18%; among the continuum who had undergone Aβ and tau PET,32 increases in CSF participants who actually underwent lumbar puncture, 62% of those with p-tau231 were found to be associated with regional Aβ deposition in plasma p-tau217 above the screening threshold had decreased CSF Aβ42/40 the medial orbitofrontal, precuneus, and posterior cingulate cortices ratio (unpublished data). even before global Aβ-PET positivity was reached.32 Compared to p-tau181, N-terminal p-tau231 also had a greater capacity to detect concomitant AD in our autopsy-verified Creutzfeldt-Jakob disease Outstanding challenges cases.35 Furthermore, novel p-tau235 has been suggested as a potential staging biomarker, since increased CSF concentrations were At present, methods that quantify novel p-tau biomarkers are observed mostly in AD patients with preceding tau phosphorylation research-grade assays, developed in independent academic or at threonine-231.21 Collectively, CSF studies have demonstrated pharmaceutical research laboratories and validated mostly in several p-tau biomarkers can separate AD dementia from Aβ negative well-characterized cohorts. Although commercial assays have become individuals with high accuracy, however, p-tau231 and p-tau217 show available, further standardization efforts are needed before they can be superior performances in preclinical AD and early MCI. classified as in vitro diagnostic medical devices (IVD) to be used for clinical purposes.3,4 Few head-to-head comparison studies published so far have reported high accuracy for AD diagnosis for most of the investigated p-tau biomarkers, however, significantly lower performances and only REFERENCES modest correlations with CSF measurements have been found for some of the existing plasma p-tau assays.3,5 Real-world data on p-tau 1. Jack CR, Bennett DA, Blennow K, et al. NIA-AA Research Framework: performance in memory clinic cohorts with greater heterogeneity and Toward a biological definition of Alzheimer’s disease. Alzheimer’s Dement. diverse clinical presentations is still scarce but will importantly guide 2018;14(4):535-562. doi:10.1016/j.jalz.2018.02.018 decisions on the appropriate use of plasma p-tau biomarkers in daily practice.3,44 Finally, to ensure the correct interpretation of the 2. Zetterberg H, Bendlin BB. Biomarkers for Alzheimer’s disease—preparing results, it will be essential to understand and address various factors for a new era of disease-modifying therapies. Mol Psychiatry. 2021;26(1):296-308. doi:10.1038/s41380-020-0721-9 that may influence p-tau measurements in the blood.3,45 3. Karikari TK, Ashton NJ, Brinkmalm G, et al. Blood phospho-tau in Alzheimer disease: analysis, interpretation, and clinical utility. Nat Rev Conclusions Neurol. 2022;18(7):400-418. doi:10.1038/s41582-022-00665-2 We have witnessed tremendous progress in the field of blood-based 4. Gonzalez-Ortiz F, Kac PR, Brum WS, Zetterberg H, Blennow K, Karikari TK. biomarkers of AD. Recent studies have demonstrated plasma p-tau is Plasma phospho-tau in Alzheimer’s disease: towards diagnostic and a promising biomarker of underlying AD pathology with imminent therapeutic trial applications. Mol Neurodegener. 2023;18(1):1-12. diagnostic application. While some clinical trials have already adopted doi:10.1186/s13024-023-00605-8 plasma p-tau to pre-screen eligible participants, outstanding 5. Ashton NJ, Puig-Pijoan A, Milà-Alomà M, et al. Plasma and CSF biomarkers challenges remain before we can implement these blood biomarkers in a memory clinic: Head-to-head comparison of phosphorylated tau into clinical practice. immunoassays. Alzheimer’s Dement. 2023;19(5):1913-1924. doi:10.1002/alz.12841 6. Zetterberg H. Tauomics and Kinetics in Human Neurons and Biological Fluids. Neuron. 2018;97(6):1202-1205. doi:10.1016/j.neuron.2018.02.030 7. Alquezar C, Arya S, Kao AW. Tau Post-translational Modifications: Dynamic Transformers of Tau Function, Degradation, and Aggregation. Front Neurol. 2021;11(January):1-24. doi:10.3389/fneur.2020.595532 8. Gonzalez-Ortiz F, Turton M, Kac PR, et al. Brain-derived tau: a novel blood-based biomarker for Alzheimer’s disease-type neurodegeneration. Brain. 2023;146(3):1152-1165. doi:10.1093/brain/awac407 9. Fischer I. Big Tau: What We Know, and We Need to Know. eNeuro. 2023;10(5):4-8. doi:10.1523/ENEURO.0052-23.2023 10. Ballatore C, Lee VMY, Trojanowski JQ. Tau-mediated neurodegeneration in Alzheimer’s disease and related disorders. Nat Rev Neurosci. 2007;8(9):663-672. doi:10.1038/nrn2194 11. Samimi N, Sharma G, Kimura T, et al. Distinct phosphorylation profiles of tau in brains of patients with different tauopathies. Neurobiol Aging. 2021;108:72-79. doi:10.1016/j.neurobiolaging.2021.08.011 12. Duquette A, Pernègre C, Veilleux Carpentier A, Leclerc N. Similarities and Differences in the Pattern of Tau Hyperphosphorylation in Physiological and Pathological Conditions: Impacts on the Elaboration of Therapies to Prevent Tau Pathology. Front Neurol. 2021;11(January):1-17. doi:10.3389/fneur.2020.607680 13. Xia Y, Prokop S, Giasson BI. “Don’t Phos Over Tau”: recent developments 23. Milà-Alomà M, Ashton NJ, Shekari M, et al. Plasma p-tau231 and p-tau217 in clinical biomarkers and therapies targeting tau phosphorylation in Alzhei-as state markers of amyloid-β pathology in preclinical Alzheimer’s disease. mer’s disease and other tauopathies. Mol Neurodegener. 2021;16(1):1-19. Nat Med. 2022;28(9):1797-1801. doi:10.1038/s41591-022-01925-w doi:10.1186/s13024-021-00460-5 24. Karikari TK, Pascoal TA, Ashton NJ, et al. Blood phosphorylated tau 181 as 14. Moloney CM, Lowe VJ, Murray ME. Visualization of neurofibrillary tangle a biomarker for Alzheimer’s disease: a diagnostic performance and maturity in Alzheimer’s disease: A clinicopathologic perspective for biomark-prediction modelling study using data from four prospective cohorts. Lancet er research. Alzheimer’s Dement. 2021;17(9):1554-1574. Neurol. 2020;19(5):422-433. doi:10.1016/S1474-4422(20)30071-5 doi:10.1002/alz.12321 25. Ashton NJ, Hye A, Rajkumar AP, et al. An update on blood-based 15. Blennow K, Wallin A, Ågren H, Spenger C, Siegfried J, Vanmechelen E. tau biomarkers for non-Alzheimer neurodegenerative disorders. Nat Rev Neurol. protein in cerebrospinal fluid - A biochemical marker for axonal degenera-2020;16(5). doi:10.1038/s41582-020-0348-0 tion in Alzheimer disease? Mol Chem Neuropathol. 1995;26(3). doi:10.1007/BF02815140 26. Barthélemy NR, Horie K, Sato C, Bateman RJ. Blood plasma phosphorylated-tau isoforms track CNS change in Alzheimer’s disease. J Exp 16. Thijssen EH, La Joie R, Strom A, et al. Association of Plasma P-tau217 and Med. 2020;217(11):1-12. doi:10.1084/JEM.20200861 P-tau181 with clinical phenotype, neuropathology, and imaging markers in Alzheimer’s disease and frontotemporal lobar degeneration: a retrospective 27. Sato C, Barthélemy NR, Mawuenyega KG, et al. Tau Kinetics in Neurons diagnostic performance study. Lancet Neurol. 2021;20(9):739-752. and the Human Central Nervous System. Neuron. 2018;97(6):1284-1298.e7. doi:10.1016/S1474-4422(21)00214-3.Association doi:10.1016/j.neuron.2018.02.015 17. Kac PR, González-ortiz F, Emeršič A, et al. Plasma p-tau212 antemortem 28. Buchhave P, Minthon L, Zetterberg H, Wallin ÅK, Blennow K, Hansson O. diagnostic performance and prediction of autopsy verification of Alzheimer’s Cerebrospinal fluid levels of β-amyloid 1-42, but not of tau, are fully changed disease neuropathology. Nat Commun. 2024;15(1):2615. already 5 to 10 years before the onset of Alzheimer dementia. Arch Gen doi:10.1038/s41467-024-46876-7 Psychiatry. 2012;69(1):98-106. doi:10.1001/archgenpsychiatry.2011.155 18. Suárez-Calvet M, Karikari TK, Ashton NJ, et al. Novel tau biomarkers 29. Bateman RJ, Xiong C, Benzinger TLS, et al. Clinical and Biomarker phosphorylated at T181, T217 or T231 rise in the initial stages of the preclini-Changes in Dominantly Inherited Alzheimer’s Disease. N Engl J Med. cal Alzheimer’s continuum when only subtle changes in Aβ pathology are 2012;367(9):795-804. doi:10.1056/NEJMoa1202753.Clinical detected. EMBO Mol Med. 2020;(12:e12921). doi:10.15252/em-mm.202012921 30. Hansson O, Zetterberg H, Buchhave P, Londos E, Blennow K, Minthon L. Association between CSF biomarkers and incipient Alzheimer’s disease in 19. Gonzalez‐Ortiz F, Ferreira PCL, González‐Escalante A, et al. A novel patients with mild cognitive impairment: A follow-up study. Lancet Neurol. ultrasensitive assay for plasma p‐tau217: Performance in individuals with 2006;5(3):228-234. doi:10.1016/S1474-4422(06)70355-6 subjective cognitive decline and early Alzheimer’s disease. Alzheimer’s Dement. November 2023. doi:10.1002/alz.13525 31. Jack CR, Knopman DS, Jagust WJ, et al. Update on hypothetical model of Alzheimer’s disease biomarkers. Lancet Neurol. 2013;12(2):207-216. 20. Ashton NJ, Pascoal TA, Karikari TK, et al. Plasma p-tau231: a new doi:10.1016/S1474-4422(12)70291-0.Update biomarker for incipient Alzheimer’s disease pathology. Acta Neuropathol. 2021. doi:10.1007/s00401-021-02275-6 32. Ashton NJ, Benedet AL, Pascoal TA, et al. Cerebrospinal fluid p-tau231 as an early indicator of emerging pathology in Alzheimer’s disease. 21. Lantero‐Rodriguez J, Snellman A, Benedet AL, et al. P‐tau235: a novel eBioMedicine. 2022;76:1-13. doi:10.1016/j.ebiom.2022.103836 biomarker for staging preclinical Alzheimer’s disease. EMBO Mol Med. 2021;13(12):1-16. doi:10.15252/emmm.202115098 33. Karikari TK, Emeršič A, Vrillon A, et al. Head-to-head comparison of clinical performance of CSF phospho-tau T181 and T217 biomarkers for 22. Palmqvist S, Janelidze S, Quiroz YT, et al. Discriminative Accuracy of Alzheimer’s disease diagnosis. Alzheimer’s Dement. 2021;17(5):755–767. Plasma Phospho-tau217 for Alzheimer Disease vs Other Neurodegenerative doi:10.1002/alz.12236 Disorders. JAMA - J Am Med Assoc. 2020;324(8). doi:10.1001/ja-ma.2020.12134 34. Barthélemy NR, Bateman RJ, Hirtz C, et al. Cerebrospinal fluid phos-44. Hansson O, Edelmayer RM, Boxer AL, et al. The Alzheimer’s Association pho-tau T217 outperforms T181 as a biomarker for the differential diagnosis appropriate use recommendations for blood biomarkers in Alzheimer’s of Alzheimer’s disease and PET amyloid-positive patient identification. disease. Alzheimer’s Dement. 2022;18(12):2669-2686. doi:10.1002/alz.12756 Alzheimer’s Res Ther. 2020;12(1):1-11. doi:10.1186/s13195-020-00596-4 45. Mielke MM, Dage JL, Frank RD, et al. Performance of plasma 35. Emeršič A, Ashton NJ, Vrillon A, et al. Cerebrospinal fluid p-tau181, 217, phosphorylated tau 181 and 217 in the community. Nat Med. and 231 in definite Creutzfeldt-Jakob disease with and without concomitant 2022;28(7):1398-1405. doi:10.1038/s41591-022-01822-2 pathologies. Alzheimer’s Dement. 2024;in press. 36. Kac PR, González-Ortiz F, Emeršič A, et al. Plasma p-tau212 antemortem diagnostic performance and prediction of autopsy verification of Alzheimer’s disease neuropathology. Nat Commun. 2024;15(1):2615. doi:10.1038/s41467-024-46876-7 37. Lantero Rodriguez J, Karikari TK, Suárez-Calvet M, et al. Plasma p-tau181 accurately predicts Alzheimer’s disease pathology at least 8 years prior to post-mortem and improves the clinical characterisation of cognitive decline. Acta Neuropathol. 2020;140(3):267-278. doi:10.1007/s00401-020-02195-x 38. Barthélemy NR, Salvadó G, Schindler SE, et al. Highly accurate blood test for Alzheimer’s disease is similar or superior to clinical cerebrospinal fluid tests. Nat Med. 2024;30(April). doi:10.1038/s41591-024-02869-z 39. O’Connor A, Karikari TK, Poole T, et al. Plasma phospho-tau181 in presymptomatic and symptomatic familial Alzheimer’s disease: a longitudinal cohort study. Mol Psychiatry. 2021;26(10):5967-5976. doi:10.1038/s41380-020-0838-x 40. Moscoso A, Grothe MJ, Ashton NJ, et al. Time course of phosphorylated-tau181 in blood across the Alzheimer’s disease spectrum. Brain. 2021;144(1):325-339. doi:10.1093/brain/awaa399 41. Thijssen EH, La Joie R, Wolf A, et al. Diagnostic value of plasma phosphorylated tau181 in Alzheimer’s disease and frontotemporal lobar degeneration. Nat Med. 2020;26(3). doi:10.1038/s41591-020-0762-2 42. Brum WS, Cullen NC, Janelidze S, et al. A two-step workflow based on plasma p-tau217 to screen for amyloid β positivity with further confirmatory testing only in uncertain cases. Nat Aging. 2023;3(9):1079-1090. doi:10.1038/s43587-023-00471-5 43. Emeršič A, Kirsebom BE, Brum W, et al. Towards implementation of plasma phospho-tau 181 as a screening tool for patient recruitment [confer-ence presentation abstract]. CTAD22 (Nov 29– Dec 02). 2022:https://www.ct-ad-alzheimer.com/files/files/Program. Blood biomarkers for clinical diagnosis and anti-amyloid therapy monitoring: Important factors to consider Thomas K. Karikari Plasma biomarkers have shown tremendous potential to support timely and accurate prognosis and diagnosis of Alzheimer’s disease (AD), as well as its differential diagnosis versus other neurodegenerative causes of cognitive impairment. These performances, replicated across cohorts, centers and countries, have led to the inclusion of plasma biomarkers in several clinical and therapeutic trial programs. Furthermore, plasma biomarkers, particularly plasma p-tau217 and p-tau181, have demonstrated utility as potential surrogate markers for brain amyloid-beta (Aβ) plaques since their levels in blood decrease proportionally to the reduction of brain Aβ in anti-amyloid programs in the same individuals. For these reasons, plasma biomarkers are being considered for clinical use. However, several factors need to be considered ahead of time. For instance, which context of use would better suit these markers – primary care or specialist hospitals? Given the different rates of disease prevalence, should we expect the same performance in either context? Other factors include effects of common comorbidities of aging, and the generation and widespread validation of cutpoints to ensure external validity. In this talk, we will discuss these points with lessons learned from recent research findings. Additionally, we will discuss the potential of plasma biomarkers to support patient eligibility determination for approved anti-Aβ therapies, prioritization of patients for these therapies based on who is at increased risk of future clinical decline, and monitoring adverse events in anti-Aβ therapy recipients. Alzheimer Disease – therapies with focus EMA. Donanemab have also applied for EMA approval. Lecanemab is a humanized IgG2 monoclonal antibody that targets amyloid fibrils, on future especially protofibrils. Lecanemab was approved by FDA in January 2023. After a careful positive phase 2 study, the phase 3 study Clarity showed that lecanemab gave 27% slowing of decline on CDR-sb over 18 months. Lecanemab is now in phase 3 for subcutaneous administration. Donanemab has preliminary reported similar results Bengt Winblad as lecanemab. It is very difficult to compare the phase 3 studies with the DMTs lecanemab and donanemab, due to the use of different outcome scales and two different study populations. With the so far observed results and the fact that AD is a multifactorial disorder, we believe that combination therapies will be necessary. One of the challenges with these new immunotherapy trials will certainly be related to a large number of patients requiring The diagnosis of Alzheimer Disease (AD) is now put earlier and earli-diagnosis and treatment. A lack of AD specialists leads to a long er. In addition to the clinical and neuropsychological evaluation, with waiting list for cognitive testing and diagnosis. (Mattke S et al, J Prev the help of biomarkers (in CSF and blood), we can today make a Alzheimer Dis 2023.) definite diagnosis of MCI due to AD. Ongoing discussions indicate that biomarkers should be enough to diagnose even asymptomatic An important discussion will be the costing and reimbursement of the preclinical AD, which to me seem unlikely. Today, lecanemab is drugs. If a treatment is not demonstrated to be cost-effective, approved for treatment of MCI due to AD and mild dementia in the healthcare systems may not be willing to invest in diagnostic services US, Japan and China (van Dyck CH et al, N Engl J Med 2023). Further- (Jönsson L et al, Lancet Reg Health Europe 2023). more, donanemab (Sims JR et al, JAMA 2023) is under evaluation by FDA and EMA (authorities in the US and Europe). This is very promis-We are now approaching a new and optimistic time period with the ing as presently available pharma treatment are regarded as being first approved DMTs on the indication early AD treatment. only symptomatic, while lecanemab and donanemab affecting amyloid-beta aggregation are regarded as being disease-modifying (DMTs). Currently approved anticholinergic drugs and memantine are nowadays generics. A summary of all ongoing trials gives a very optimistic future view as currently 36 DMTs are in in phase 3 development (J Cummings et al, Alzheimer’s Dementia 2023). Most immunotherapy studies have been passive. The most promising therapy against tau is active immunotherapy and the tau vaccination (AADVac1) has passed phase 2 (Novak P et al, Lancet Neurol 2016; Novak P et al, Nature Aging 2021). To summa-rize, the AADVac1 data generated efficacy signals across biomarker and clinical modalities. The therapeutic effect was more pronounced in patients with higher antibody response (Novak et al, Nature Aging 2021). Regarding the passive amyloid-related immunotherapies for AD, aducanumab is now back from Biogen to Neurimmune, and the Swiss company will test a subcutaneous formulation. Lecanemab has been approved in The US, Japan and China and is now under evaluation by Lecanemab – from a mutation to a treat-in Clinical Dementia Rating–Sum of Boxes (CDR-SB) from baseline. The mean change in CDR-SB score was smaller in the lecanemab ment for Alzheimer’s disease group by 27% over 18 months. Positive effects were also seen on secondary clinical endpoints and key biomarkers. However, longer-term follow-up is needed and an open-label extension study is ongoing. Lars Lannfelt This represents a significant advance for patients with AD, although many challenges remain. In particular, it is now more important than ever to identify individuals who are vulnerable to AD, so that treatment can be initiated at an early stage in the disease process. The symptomatic drugs currently on the market for Alzheimer’s disease (AD) have no effect on disease progression, and this creates a large unmet medical need. The type of drug that has developed most rapidly in the last decade is immunotherapy, especially passive vaccination with monoclonal antibodies. Antibodies are attractive drugs as they can be made highly specific for their target. Our detection of an Aβ precursor protein mutation that caused early-onset AD in a Swedish family (the Arctic mutation) by enhancing Aβ protofibril formation sharpened the focus on soluble Aβ aggregates (oligomers and protofibrils) as therapeutic targets. Initial studies tested a mouse monoclonal antibody (mAb158) with specific conformation-dependent binding to these soluble Aβ aggregates. Treatment with mAb158 reduced Aβ protofibrils in the brain and cerebrospinal fluid of a transgenic mouse model of AD. mAb158 had a 1,000-fold higher selectivity for protofibrils as compared with monomers of Aβ and had at least tenfold stronger binding to protofibrils compared to fibrils. A humanized version of mAb158, lecanemab, has been developed in a collaboration between BioArctic and Eisai. We have characterized the binding properties of lecanemab and other Aβ antibodies to different Aβ species with inhibition ELISA, immunodepletion and surface plasmon resonance. Our results show different binding profiles of antibodies which may explain clinical results observed regarding both efficacy and side effects. A phase 3, multicenter, double-blind, randomized, placebo-controlled trial assessed the efficacy and safety of lecanemab in 1795 patients with early AD. The participants received i.v. lecanemab (10 mg/kg every 2 weeks) or placebo. The primary efficacy end point was change The 12th COGNITIVE DAY meeting was made possible by Main sponsor Sponsors Biogen Pharma d.o.o. ABBVIE d. o. o. Organisers ELI LILLY farmacevtska družba d.o.o. Center for Cognitive Impairments, Department of Neurology, University Medical Centre Ljubljana KRKA d. d. LEK farmacevtska družba d.d. MEDIS d. o. o. Slovenian Neurological Association STADA d.o.o. TEVA / PLIVA LJUBLJANA d.o.o.