Scheltens, Philip

Abstract In response to a Cochrane review (published in April 2026) on the clinical trials of monoclonal antibodies targeting beta amyloid, this perspective outlines a number of critiques. The scientists, methodologists, subject‐matter experts, and clinicians on this perspective strongly recommend that the Cochrane editorial board consider a call for editorial response, correction of press materials, or commissioned reply to this review for four overarching reasons: (1) decision to pool antibodies that do and do not clear beta amyloid, (2) decision to include studies from a time when biomarkers of Alzheimer's disease were not available, (3) analytical and methodological limitations of the approach used, (4) conflating the distinct roles and methodological processes of systematic review and guideline methodologies, (5) contextualizing the present critique within the existing evidence‐synthesis literature, and (6) mechanistic inference beyond the scope of the presented analyses. Conclusions that may not accurately reflect treatment‐specific effects could cause significant downstream clinical and psychosocial harm to those currently undergoing treatment and their family members as well as individuals considering participation in Alzheimer's clinical trials.

Abstract Background The last several decades have seen intense research into Alzheimer’s disease (AD) resulting in several current and emerging disease modifying treatments that target hallmarks of the AD pathology. Previous evidence has indicated that neurologists and primary care physicians (PCPs) frequently lack knowledge of the most recent findings pertaining to the use of biomarkers and antibody‐based therapies in AD. An online CME program was developed to educate neurologists and PCPs on biomarker and therapeutic data in AD from a 2024 dementia conference. Method The online CME activity consisted of a chapterized 30‐minute video presentation featuring dementia specialists who reviewed data from a 2024 dementia conference on biomarkers or therapeutics. Educational effect was assessed by comparing a matched sample of responses to four identical questions presented before and directly after exposure to the intervention. A paired samples t‐test assessed the number of correct responses and for confidence rating; McNemar’s test was used to identify significant differences between pre‐ and post‐assessment question responses. Cohen’s d was used to calculate the effect size of the online education. Data were collected between August 2024 and October 2024. Result A moderate educational effect was observed for both neurologist ( n =88; d =.77, p <0.001) and PCP ( n =141; d =.75, p <.001) learners. Both physician groups demonstrated significant (P <.05) pre‐ vs post‐educational improvements on the following: clinical data on AD diagnostic accuracy comparing blood‐based biomarker testing to a clinical diagnosis made by a physician and risk factors for amyloid‐relating imaging abnormalities associated with an approved anti‐amyloid therapy (AAT). PCPs, but not neurologists, demonstrated a pre‐post educational improvement on a question about outcomes from an open‐label extension study of an approved ATT. Participation in the activity resulted in 44% of neurologists and 48% of PCPs reporting an increase in confidence regarding their ability to apply the latest clinical data on approved AATs in clinical practice. Conclusion The results indicated that a CME‐certified 30‐minute video program was effective at improving knowledge among a diversity of physician learners regarding emerging data from a recent medical conference. Future CME should continue to highlight impactful new data released at medical conferences.

Background The association between lifestyle factors and Alzheimer's disease (AD) pathophysiology remains incompletely understood. Objective The aim of this study was to assess the association of alcohol consumption, smoking behavior, sleep quality and physical, cognitive, and social activity with cerebral amyloid pathology. Methods For this cross-sectional study, we selected participants from the Amyloid Biomarker Study data pooling initiative. We used generalized estimating equations to assess associations of dichotomized lifestyle measures with amyloid pathology. Results We included 9171 participants with normal cognition (NC) and 2555 participants with mild cognitive impairment (MCI) from the Amyloid Biomarker Study. Of participants with NC, 58% were women, 34% were APOE ε4 carrier, and 27% had amyloid pathology. Of participants with MCI, 48% were women, 47% were APOE ε4 carrier, and 57% had amyloid pathology. In NC, cognitively active participants were less likely to have amyloid pathology (OR = 0.77, 95%CI 0.66–0.89, p < 0.001). In MCI, participants who had ever smoked or had sleep problems were less likely to have amyloid pathology (OR = 0.85, 95%CI 0.73–0.99, p = 0.029; OR = 0.62, 95%CI 0.45–0.86, p = 0.004). Conclusions In NC, cognitive activity was associated with a lower frequency of amyloid pathology. In MCI, favorable lifestyle behaviors were not associated with a lower frequency of amyloid pathology. The results of the current study contribute to the broader evidence base on lifestyle and AD by further characterizing the role of lifestyle behaviors in AD pathology across different clinical stages.

Abstract INTRODUCTION Risk factors associated with sporadic non‐amnestic and early‐onset Alzheimer's disease (AD) remain underexamined. METHODS We investigated a large, clinically heterogeneous, AD cohort for frequencies of established risk factors (hypertension, hypercholesterolemia, diabetes mellitus) alongside novel factors (non–right‐handedness, learning disability, seizures, autoimmune disease). RESULTS Early‐onset AD possessed lower frequencies of established risk factors (hypertension, hypercholesterolemia, diabetes mellitus, all p < 0.001) and higher frequencies of novel factors (non–right‐handedness, learning disability, active seizure, all p < 0.001; remote seizure, p = 0.002; and autoimmune disease, p = 0.007). An age at onset < 70 maximally distinguished novel from typical factors. Principal component analysis loaded novel factors into two components, non–right‐handedness and learning disability versus seizure and autoimmune disease, which combined, resulted in an exponential decrease in age at onset from one factor alone. DISCUSSION Identifying novel factors enriched in early‐onset and non‐amnestic AD introduces new theories of AD susceptibility and phenotypic heterogeneity, with significant implications for disease prediction and treatment. Highlights We identified a suite of novel factors overrepresented in early‐onset and non‐amnestic AD. These factors can be broadly conceptualized as neurodevelopmental (non–right‐handedness and learning disability) and neural environmental (seizure and autoimmunity). The combination of these factors produced exponential decreases in AD age at onset, compared to each alone, supporting a new theoretical framework for understanding AD risk with implications for disease prediction, prevention, and therapeutic intervention.

Abstract Limbic predominant age‐related TDP‐43 encephalopathy neuropathologic change (LATE‐NC) is highly prevalent in late life and a common co‐pathology with Alzheimer's disease neuropathologic change (ADNC). LATE‐NC is a slowly progressive, amnestic clinical syndrome. Alternatively, when present with ADNC, LATE‐NC is associated with a more rapid course. With the emergence of anti‐amyloid therapeutics, discrimination of LATE‐NC from ADNC is critical and will lead to greater clinical recognition of amnestic patients without ADNC. Furthermore, co‐pathology with LATE‐NC may influence outcomes of these therapeutics. Thus there is a need to identify patients during life with likely LATE‐NC. We propose criteria for clinical diagnosis of LATE as an initial framework for further validation. In the context of progressive memory loss and substantial hippocampal atrophy, criteria are laid out for probable (amyloid negative) or possible LATE (amyloid biomarkers are unavailable or when amyloid is present, but hippocampal neurodegeneration is out of proportion to expected pure ADNC). Highlights Limbic‐predominant age‐related TDP‐43 encephalopathy (LATE) is a highly prevalent driver of neuropathologic memory loss in late life. LATE neuropathologic change (LATE‐NC) is a common co‐pathology with Alzheimer's disease neuropathologic change (ADNC) and may influence outcomes with emerging disease‐modifying medicines. We provide initial clinical criteria for diagnosing LATE during life either when LATE‐NC is the likely primary driver of symptoms or when observed in conjunction with AD. Definitions of possible and probable LATE are provided.

Abstract The grey matter of the brain develops and declines in coordinated patterns during the lifespan. Such covariation patterns of grey matter structure can be quantified as grey matter networks, which can be measured with magnetic resonance imaging. In Alzheimer’s disease, the global organization of grey matter networks becomes more random, which is captured by a decline in the small-world coefficient. Such decline in the small-world value has been robustly associated with cognitive decline across clinical stages of Alzheimer’s disease. The biological mechanisms causing this decline in small-world values remain unknown. Cerebrospinal fluid (CSF) protein biomarkers are available for studying diverse pathological mechanisms in humans and can provide insight into decline. We investigated the relationships between 10 CSF proteins and small-world coefficient in mutation carriers (N = 219) and non-carriers (N = 136) of the Dominantly Inherited Alzheimer Network Observational study. Abnormalities in Amyloid beta, Tau, synaptic (Synaptosome associated protein-25, Neurogranin) and neuronal calcium-sensor protein (Visinin-like protein-1) preceded loss of small-world coefficient by several years, while increased levels in CSF markers for inflammation (Chitinase-3-like protein 1) and axonal injury (Neurofilament light) co-occurred with decreasing small-world values. This suggests that axonal loss and inflammation play a role in structural grey matter network changes.

Abstract INTRODUCTION Although frontotemporal dementia (FTD) with right anterior temporal lobe (RATL) predominance has been recognized, a uniform description of the syndrome is still missing. This multicenter study aims to establish a cohesive clinical phenotype. METHODS Retrospective clinical data from 18 centers across 12 countries yielded 360 FTD patients with predominant RATL atrophy through initial neuroimaging assessments. RESULTS Common symptoms included mental rigidity/preoccupations (78%), disinhibition/socially inappropriate behavior (74%), naming/word‐finding difficulties (70%), memory deficits (67%), apathy (65%), loss of empathy (65%), and face‐recognition deficits (60%). Real‐life examples unveiled impairments regarding landmarks, smells, sounds, tastes, and bodily sensations (74%). Cognitive test scores indicated deficits in emotion, people, social interactions, and visual semantics however, lacked objective assessments for mental rigidity and preoccupations. DISCUSSION This study cumulates the largest RATL cohort unveiling unique RATL symptoms subdued in prior diagnostic guidelines. Our novel approach, combining real‐life examples with cognitive tests, offers clinicians a comprehensive toolkit for managing these patients. Highlights This project is the first international collaboration and largest reported cohort. Further efforts are warranted for precise nomenclature reflecting neural mechanisms. Our results will serve as a clinical guideline for early and accurate diagnoses.

Abstract The National Institute on Aging and the Alzheimer's Association convened three separate work groups in 2011 and single work groups in 2012 and 2018 to create recommendations for the diagnosis and characterization of Alzheimer's disease (AD). The present document updates the 2018 research framework in response to several recent developments. Defining diseases biologically, rather than based on syndromic presentation, has long been standard in many areas of medicine (e.g., oncology), and is becoming a unifying concept common to all neurodegenerative diseases, not just AD. The present document is consistent with this principle. Our intent is to present objective criteria for diagnosis and staging AD, incorporating recent advances in biomarkers, to serve as a bridge between research and clinical care. These criteria are not intended to provide step‐by‐step clinical practice guidelines for clinical workflow or specific treatment protocols, but rather serve as general principles to inform diagnosis and staging of AD that reflect current science. Highlights We define Alzheimer's disease (AD) to be a biological process that begins with the appearance of AD neuropathologic change (ADNPC) while people are asymptomatic. Progression of the neuropathologic burden leads to the later appearance and progression of clinical symptoms. Early‐changing Core 1 biomarkers (amyloid positron emission tomography [PET], approved cerebrospinal fluid biomarkers, and accurate plasma biomarkers [especially phosphorylated tau 217]) map onto either the amyloid beta or AD tauopathy pathway; however, these reflect the presence of ADNPC more generally (i.e., both neuritic plaques and tangles). An abnormal Core 1 biomarker result is sufficient to establish a diagnosis of AD and to inform clinical decision making throughout the disease continuum. Later‐changing Core 2 biomarkers (biofluid and tau PET) can provide prognostic information, and when abnormal, will increase confidence that AD is contributing to symptoms. An integrated biological and clinical staging scheme is described that accommodates the fact that common copathologies, cognitive reserve, and resistance may modify relationships between clinical and biological AD stages.

Across multiancestry groups, we analyzed Human Leukocyte Antigen (HLA) associations in over 176,000 individuals with Parkinson’s disease (PD) and Alzheimer’s disease (AD) versus controls. We demonstrate that the two diseases share the same protective association at the HLA locus. HLA-specific fine-mapping showed that hierarchical protective effects of HLA-DRB1 *04 subtypes best accounted for the association, strongest with HLA-DRB1 *04:04 and HLA-DRB1 *04:07, and intermediary with HLA-DRB1 *04:01 and HLA-DRB1 *04:03. The same signal was associated with decreased neurofibrillary tangles in postmortem brains and was associated with reduced tau levels in cerebrospinal fluid and to a lower extent with increased Aβ42. Protective HLA-DRB1 *04 subtypes strongly bound the aggregation-prone tau PHF6 sequence, however only when acetylated at a lysine (K311), a common posttranslational modification central to tau aggregation. An HLA-DRB1 *04-mediated adaptive immune response decreases PD and AD risks, potentially by acting against tau, offering the possibility of therapeutic avenues.

AbstractBackgroundGrey matter covariance networks become disrupted early in Alzheimer’s disease (AD), when amyloid starts aggregating, and before the onset of irreversible atrophy. However, the precise relationship of grey matter network breakdown and the AD pathophysiological process remains unclear. Here, we studied to what extent shared familial (genes and family environment) or environmental factors unique to a twin contribute to these relationships in a sample of older monozygotic twins with intact cognition.MethodFrom the EMIF‐AD PreclinAD study we included monozygotic twins who had at least an MRI scan (n=197) and CSF available (n=124). We assessed the upper limit of genetic contribution to grey matter network measures (size, degree, connectivity density, clustering, path length, small‐world measures) with within‐twin pair correlations. Associations between CSF AD markers (Aβ42/40, t‐tau, p‐tau) and other markers related to AD pathophysiology (neurogranin, Aβ38, Aβ40, BACE1) with grey matter network disruptions were assessed with linear mixed models. Twin analyses (cross‐twin cross‐trait, twin difference analyses) were used to assess the contribution of shared familial and/or unique environmental factors to these associations.ResultTwenty individuals (16%) had abnormal CSF Aβ42/40 levels. Grey matter network measures were highly correlated within twin pairs (r=0.54‐0.97; all p<0.001, Fig.1), suggesting a moderate to strong genetic background. Across the whole sample, more abnormal Aβ42/40 ratios were moderately related to lower connectivity density (β±SE = 0.176±0.09, p=0.055, Fig.2). The strongest associations with grey matter network measures were observed for t‐tau and p‐tau levels (range β=‐0.344‐0.182), followed by Aβ production markers (Aβ38, Aβ40, BACE1) (range β=‐0.202‐0.165). We observed no relationships between neurogranin and grey matter network measures. Cross‐twin cross‐trait analyses showed that levels for t‐tau, p‐tau and Aβ38 in one twin were associated with grey matter network measures in their co‐twin (r=‐0.27 to ‐0.21; p range=0.02 to 0.07, Fig.3). Within‐pair differences in BACE1 were related to within‐pair differences in normalized path length values (r=0.35; p=0.01; Fig.4).ConclusionOur results suggest a shared familial background for the relationship of grey matter network disruptions and AD‐related processes as measured in CSF. In addition, unique environmental factors influencing BACE1 may also affect grey matter network disruptions.