Citations

Abstract Patients with atypical variants of Alzheimer's disease (AD) often present at a younger age with predominantly non‐amnestic impairments and a more aggressive disease course. Historically, individuals with atypical presentations have not been included in large‐scale clinical trials, which typically focus on late‐onset, sporadic amnestic‐predominant AD. Consequently, treatment options and research efforts specific to atypical AD remain limited. The emergence of amyloid‐targeting therapies that slow disease progression underscores these challenges, as evidence supporting their efficacy in early‐onset amnestic and non‐amnestic AD variants is scarce. This perspective article argues that atypical AD represents an excellent disease model for clinical trials and proposes strategies to address critical gaps in clinical trial design for this population. Key considerations include optimizing participant selection approaches, establishing syndrome‐specific or surrogate biological and clinical endpoints, and fostering advocacy to enhance early and accurate diagnosis, equitable representation, and outcomes for these populations.

Abstract Alzheimer's disease (AD) is neuropathologically defined by amyloid‐beta (Aβ) plaques and tau neurofibrillary tangles. However, co‐pathologies and other pathobiological processes are involved in the pathogenesis of AD, contributing to neurodegeneration and clinical symptoms. The most common co‐pathologies in people with AD are alpha‐synucleinopathy, vascular brain injury and transactive response DNA‐binding protein of 43 kDa‐related pathology. Neuroinflammation, iron accumulation, cholinergic dysfunction and cellular senescence are recognized pathobiological processes beyond Aβ‐ and tau‐related pathology. However, the exact mechanisms by which these co‐pathologies and pathobiological processes contribute to the neurodegeneration and clinical symptoms in people with AD remain unclear. The individual combination of these co‐pathologies and pathobiological processes increases phenotypical heterogeneity in people with AD. This highlights the unmet need to advance their current understanding, and the field strives to develop accurate biomarkers for personalized assessment and investigation. Elucidating this biologic‐clinical complexity and heterogeneity is crucial for increasing our current understanding of AD, with implications for diagnosis, prognosis and therapeutics.

AbstractBackgroundPatterns of regional atrophy and hypometabolism have been observed in dementia with Lewy bodies (DLB). However, determinants of regional vulnerability to structural and functional neurodegeneration remain largely unexplored. First, we investigated the association between regional gene expression and grey matter volumes in probable DLB patients. Since hypometabolism presumably precedes overt brain atrophy, we additionally investigate the association between regional gene expression and hypometabolism in DLB.MethodTo investigate the association between gene expression and regional volumes, 165 DLB patients along with 165 age‐ and sex‐matched healthy controls from three European centres and the Mayo Clinic (USA) were included. Regional volumes were quantified from MRI using SPM12 in 112 cortical, subcortical, and cerebellar brain regions, and compared between groups, using w‐scores. Regional expression data of seven genes involved in the formation and degradation of pathological protein aggregates (APOE, APP, BIN1, GBA, MAPT, SNCA, TMEM175) was extracted from six healthy donors from the Allen Human Brain Atlas and correlated with regional volumetric w‐scores. To assess the predictive value of regional gene expression on regional volumes we used Gaussian stepwise backwards linear regression including all seven genes as predictors. To investigate the association between gene expression and hypometabolism, we are currently applying the same analysis pipeline to FDG‐PET data of 139 DLB patients from 8 European centres.ResultMost brain regions showed lower volumes in DLB patients compared to healthy controls, with differences being most pronounced in occipital and parietal lobes. Regional expression of APOE correlated positively with regional volumes in DLB. Conversely, regional expression of MAPT correlated negatively with regional volumes. Both APOE and MAPT gene expression were significant predictors of regional volumes in the regression analysis. None of the other gene expression values was significantly associated with regional volumes in DLB.ConclusionOur findings show that regional expression of genes associated with the abnormal accumulation of amyloid and tau, common co‐pathologies in DLB, partially account for the brain atrophy pattern observed in DLB patients. Analyses are ongoing for the hypometabolism pattern. Our finding emphasises the relevance of co‐pathologies in predicting atrophy progression and identifying potential targets for future disease‐modifying treatments.

Abstract INTRODUCTION Sex influences neurodegeneration, but it has been poorly investigated in dementia with Lewy bodies (DLB). We investigated sex differences in brain atrophy in DLB using magnetic resonance imaging (MRI). METHODS We included 436 patients from the European‐DLB consortium and the Mayo Clinic. Sex differences and sex‐by‐age interactions were assessed through visual atrophy rating scales ( n = 327; 73 ± 8 years, 62% males) and automated estimations of regional gray matter volume and cortical thickness ( n = 165; 69 ± 9 years, 72% males). RESULTS We found a higher likelihood of frontal atrophy and smaller volumes in six cortical regions in males and thinner olfactory cortices in females. There were significant sex‐by‐age interactions in volume (six regions) and cortical thickness (seven regions) across the entire cortex. DISCUSSION We demonstrate that males have more widespread cortical atrophy at younger ages, but differences tend to disappear with increasing age, with males and females converging around the age of 75. Highlights Male DLB patients had higher odds for frontal atrophy on radiological visual rating scales. Male DLB patients displayed a widespread pattern of cortical gray matter alterations on automated methods. Sex differences in gray matter measures in DLB tended to disappear with increasing age.

Abstract Background Subjective cognitive decline (SCD) has gained recent interest as a potential harbinger of neurodegenerative diseases such as Alzheimer’s disease (AD) and cerebrovascular disease (CVD). In addition, SCD can be related to depressive symptomatology. However, the association between AD and CVD biomarkers, depressive symptomatology, and SCD is still unclear. We investigated the association of AD and CVD biomarkers and depressive symptomatology with SCD in individuals with subjective memory complaints (SCD-memory group) and individuals with subjective concentration complaints (SCD-concentration group). Methods We recruited a population-based cohort of 217 individuals (all aged 70 years, 53% female participants, 119 SCD-memory individuals, 23 SCD-concentration individuals, and 89 controls). AD and CVD were assessed through cerebrospinal fluid levels of the Aβ42/40 ratio and phosphorylated tau, and white matter signal abnormalities on magnetic resonance imaging, respectively. Associations between biomarkers, depressive symptomatology, and SCD were tested via logistic regression and correlation analyses. Results We found a significant association between depressive symptomatology with SCD-memory and SCD-concentration. Depressive symptomatology was not associated with AD and CVD biomarkers. Both the phosphorylated tau biomarker and depressive symptomatology predicted SCD-memory, and the Aβ42/40 ratio and depressive symptomatology predicted SCD-concentration. Conclusions The role of depressive symptomatology in SCD may differ depending on the stage within the spectrum of preclinical AD (as determined by amyloid-beta and tau positivity), and does not seem to reflect AD pathology. Our findings contribute to the emerging field of subclinical depressive symptomatology in SCD and clarify the association of different types of subjective complaints with distinct syndromic and biomarker profiles.

AbstractBackgroundDementia with Lewy bodies (DLB) is the second most common neurodegenerative dementia, after Alzheimer’s disease (AD). While alpha‐synuclein pathology is the hallmark of DLB, AD and cerebrovascular pathologies are common in DLB patients. However, the contribution of these pathologies towards neurodegeneration in DLB is largely unknown. We investigated associations of amyloid‐beta, tau, and cerebrovascular biomarkers with regional gray matter (GM) volume in DLB patients and cognitively unimpaired (CU) controls.MethodWe included 30 DLB patients (69.3±10.2 years old, 87% men) and 100 CU individuals balanced on age and sex (Table 1). We used 11C‐Pittsburgh Compound‐B (PiB) and 18F‐Flortaucipir positron emission tomography (PET) to assess amyloid‐beta and tau in‐vivo. We used structural MRI to assess white matter hyperintensity (WMH) volume, a marker of cerebrovascular lesion load, and regional GM volume (a marker of neurodegeneration). We used correlations and ANCOVA in the whole dataset and structural equation modelling in the DLB patients to investigate associations of WMH volume and regional amyloid‐beta and tau PET standardized uptake value ratios (SUVRs) with regional GM volume.ResultDLB patients showed lower GM volume across all cortical and subcortical regions except for cuneus, putamen, and pallidum (Fig.1). Greater WMH volume was associated with lower volume in the medial and orbital frontal cortices, insula, fusiform cortex, and thalamus in DLB patients (Fig.2). Greater PiB SUVR was associated with lower volume in the inferior temporal cortex, while Flortaucipir SUVR did not correlate with GM volume (Fig.2). Structural equation modelling showed that higher age and positivity for the APOE e4 genotype were significant predictors of greater WMH, and WMH in turn was a significant predictor of GM volume in medial and orbital frontal cortices, insula, and inferior temporal cortex (Fig.3). In contrast, we observed two distinct paths for the fusiform cortex, with age having an effect through PiB and Flortaucipir SUVRs on the one path, and through WMH on the other path (Fig.3).ConclusionDLB patients have widespread cortical atrophy, most of which likely is influenced by alpha‐synuclein pathology. Although amyloid‐beta, tau, and cerebrovascular pathologies often coexist in DLB, their contributions to neurodegeneration seem to be region specific.

AbstractBackgroundPure Alzheimer’s disease (AD), characterized by combined amyloid and tau pathology, is not the most prevalent form of the disease as non‐AD pathologies (e.g., alpha‐synuclein and TDP‐43) are commonly observed postmortem. The role of AD and non‐AD pathologies is unclear in relation to disease heterogeneity. Therefore, we investigated whether antemortem MRI‐based atrophy subtypes of AD differ in postmortem neuropathological features and comorbid non‐AD pathologies.MethodsWe selected individuals from the ADNI with antemortem MRI evaluating brain atrophy within 2 years before death; antemortem diagnosis of AD dementia/mild cognitive impairment; and a postmortem‐confirmed AD neuropathologic change. Antemortem atrophy subtypes were modeled as continuous phenomena using a recent conceptual framework: typicality (spanning limbic predominant AD to hippocampal sparing AD) and severity (spanning typical AD to minimal atrophy AD). Postmortem neuropathological evaluation included AD hallmarks (amyloid‐beta, tau), non‐AD pathologies (alpha‐synuclein, TDP‐43) and concomitant pathological burden. Partial correlations assessed the associations between antemortem atrophy subtype dimensions and postmortem neuropathological outcomes.ResultsIn 31 individuals (mean age = 80y, 26% females), antemortem typicality was significantly associated with neuropathological features: amyloid‐beta (rho = ‐0.39 overall), tau (rho = ‐0.38 regionally), neuritic plaque density (rho = ‐0.4 overall), alpha‐synuclein (rho = ‐0.39 regionally), TDP‐43 (rho = ‐0.49 overall), and concomitance pathological burden (rho = ‐0.59 regionally). This suggests that limbic predominant AD was associated with higher burden of these pathologies compared to hippocampal sparing AD. Antemortem severity was significantly associated with concomitant pathological burden (rho = ‐0.43 regionally), such that typical AD showed higher burden than minimal atrophy AD.ConclusionsBased on our direct antemortem‐to‐postmortem validation, we hypothesize that: (a) typicality and severity in atrophy reflect differential aspects of susceptibility of the brain to AD and non‐AD pathologies; (b) limbic predominant AD and typical AD subtypes may share similar biological pathways, making them more vulnerable to the investigated AD and non‐AD pathologies compared to hippocampal sparing AD, which may follow a different biological pathway. Our findings provide a deeper understanding of associations of atrophy subtypes in AD with different pathologies, enhancing prevailing knowledge of biological heterogeneity in AD.

AbstractBackgroundSubjective cognitive decline (SCD) is topic of mayor interest when identifying individuals at risk for future cognitive impairment and dementia. The degeneration of the cholinergic system is linked to the onset of cognitive symptoms in mild cognitive impairment (MCI) and dementia. Yet, it is uncertain whether the neurodegeneration of the cholinergic system is already present in SCD individuals. This review is the first to synthetize the available data on the association of SCD with multiple markers of degeneration in the cholinergic system.MethodFollowing the PRISMA guidelines, original articles focused on the association of SCD and the cholinergic system were extracted from three databases: Pubmed, WOS and Scopus, in November 2021. Two researchers reviewed the studies independently in a 2‐stepwise approach. The quality of the studies and risk of bias were assessed using FLC 3.0, that allows to systematically evaluate the studies and summarize them easily.ResultAmong 119 studies found in our systematic search, 11 were included in the current review. Seven were cross‐sectional and 4 had a longitudinal design. Most of the studies operationalized SCD based on amnestic cognitive complaints (n = 9, 82%). The cholinergic system measures were based on neuroimaging markers for volume of the basal forebrain and/or functional connectivity, transcranial magnetic stimulation, or biofluid markers (i.e. cerebrospinal fluid (CSF) and plasma). The studies focused on association of SCD with basal brain atrophy, 75% reported reduce volumes in SCD; From those focused on functional connectivity of the cholinergic system, 33% reported poorer connectivity in SCD.ConclusionBased on scientific evidence, neurodegeneration of the cholinergic system is already evident during SCD. Using multiple cholinergic biomarkers, degeneration of cholinergic system in SCD seems to occur with significant structural and functional degeneration of cholinergic nuclei in the basal forebrain and their connections with other brain areas. These findings have implications on identifying individuals with increased vulnerability to cognitive impairment and for targeting individuals that might benefit from cholinergic‐target treatments. Further research is needed to elucidate potential contributors to the cholinergic degeneration in SCD and its impact on cognition and clinical progression.

AbstractBackgroundThe relation between cerebrospinal fluid (CSF) biomarkers of Alzheimer’s disease (AD) and neurodegeneration and brain regions of relevance for very early pathological processes in AD is poorly understood. This study aims to investigate cross‐sectional associations between the CSF biomarkers amyloid‐β1‐42 (Aβ42), total‐tau (T‐tau), phosphorylated‐tau (P‐tau), neurogranin (Ng) and neurofilament light (NfL) protein and normalized intracranial volumes of the hippocampus, amygdala, entorhinal cortex and basal forebrain observed on structural magnetic resonance imaging (MRI) in cognitively healthy 70‐year olds from the general population.MethodThe analyses included 226 cognitively normal individuals (clinical dementia rating of zero), examined during 2014‐2016 as part of the population‐based Gothenburg H70 Birth Cohort Studies in Sweden. The study participants had undergone lumbar puncture examination to extract CSF samples for biomarker measurements (pg/mL), MRI scan (volumes in mm³), and apolipoprotein E (APOE) genotyping. Linear regressions, adjusted for sex, were used to examine potential associations.ResultElevated CSF T‐tau, P‐tau, and Ng concentrations were associated with smaller volumes of the hippocampus, amygdala, and entorhinal cortex among individuals with amyloid pathology (p = 8×10−8 – 0.04) and among APOE ε4 carriers (p = 8×10−5 – 0.04). In addition, elevated CSF T‐tau, P‐tau, and Ng concentrations were associated with larger basal forebrain among individuals without pathological Aβ42 (p = 0.001 – 0.01) and among APOE ε4 non‐carriers (p = 0.004 – 0.02).ConclusionThe results of our study suggest that among cognitively normal adults who have amyloid pathology or genetic susceptibility to AD, there are associations between axonal degeneration, tangle pathology, and synapse loss and decreased volumes of AD vulnerable brain regions. The associations between elevated CSF biomarkers and larger basal forebrain in cognitively normal individuals were unexpected, but could possibly be explained by compensatory mechanisms or an inflammatory response (generating neuronal or glial swelling) as a very early reaction to the presence of increased levels of tau and Ng. Our findings highlight the clinical pathophysiological relevance of CSF biomarkers of AD and neurodegeneration and how they relate to AD specific brain regions seen on structural MRI in 70‐year‐olds that may be at risk to develop dementia.

Abstract Objectives Sex differences permeate many aspects of dementia with Lewy bodies (DLB), including epidemiology, pathogenesis, disease progression, and symptom manifestation. However, less is known about potential sex differences in patterns of neurodegeneration in DLB. Here, we test whether grey matter networks also differ between female and male DLB patients. To assess the specificity of these sex differences to DLB, we additionally investigate sex differences in healthy controls (HCs). Methods A total of 119 (68.7 ± 8.4 years) male and 45 female (69.9 ± 9.1 years) DLB patients from three European centres and the Mayo Clinic were included in this study. Additionally, we included 119 male and 45 female age-matched HCs from the Mayo Clinic. Grey matter volumes of 58 cortical, subcortical, cerebellar, and pontine brain regions derived from structural magnetic resonance images were corrected for age, intracranial volume, and centre. Sex-specific grey matter networks for DLB patients and HCs were constructed by correlating each pair of brain regions. Network properties of the correlation matrices were compared between sexes and groups. Additional analyses were conducted on W-scored data to identify DLB-specific findings. Results Networks of male HCs and male DLB patients were characterised by a lower nodal strength compared to their respective female counterparts. In comparison to female HCs, the grey matter networks of male HCs showed a higher global efficiency, modularity, and a lower number of modules. None of the global and nodal network measures showed significant sex differences in DLB. Conclusions The disappearance of sex differences in the structural grey matter networks of DLB patients compared to HCs may indicate a sex-dependent network vulnerability to the alpha-synuclein pathology in DLB. Future studies might investigate whether the differences in structural network measures are associated with differences in cognitive scores and clinical symptoms between the sexes.