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Background: Alzheimer’s disease (AD) and cerebrovascular pathology are the two most common causes of dementia, frequently co-occurring in older people. Community-based neuropathology studies indicate that vascular disease accounts for approximately one-third of the population-attributable risk of dementia, controlling for other pathologies (including AD). The proportion with vascular disease as co-pathology is likely to be higher (50–70%). The most common vascular substrate is cerebral small vessel disease, which includes small artery fibrosis (arteriolosclerosis), vascular amyloid deposits (cerebral amyloid angiopathy), and monogenic forms of small vessel disease, the commonest being Cerebral Autosomal Dominant Arteriopathy with Subcortical Infarcts and Leukoencephalopathy (CADASIL). Post-stroke cognitive impairment following both ischemic stroke and intracerebral hemorrhage also contributes. Aims and Methods: In this World Stroke Organization (WSO) scientific statement, we assembled a multi-disciplinary international group of experts to review the vascular contribution to dementia, encompassing both vascular and neurodegenerative dementia. This statement has been reviewed and approved by the WSO executive. Results: We summarize the epidemiology, neuropathology, cognitive profile, clinical impact and management of vascular disease in dementia and discuss the recent VasCog-2-WSO diagnostic criteria. We consider the substantial overlap with clinical stroke and with AD dementia. We catalog transcriptomic and proteomic studies that have revealed novel candidate molecules ( COL4A1/4A2, HTRA1, TRIM47, FOXF2 ) as possible treatment targets. We appraise imaging-based biomarkers relevant to vascular disease and potential biochemical markers (vascular endothelial growth factor-A, placental growth factor, interleukin-6, matrix metalloproteinase-9, cathepsin-B). We highlight the potential for vascular interventions to treat not only vascular dementia but also the vascular component of neurodegenerative dementia. We review recent clinical trials targeting multiple pathways, including nitric oxide signaling, high blood pressure, the GABAergic system, angiogenic activity, microglial inhibition, PDE3 and PDE5 inhibition, as well as dietary supplementation with omega-3 fatty acids, s-equol and vitamin E. Finally, we consider upcoming opportunities and challenges relevant to vascular disease in dementia. Conclusion: The vascular contribution to dementia is i) substantial, ii) increasingly understood at molecular and mechanistic levels, iii) a source of potential treatment opportunities. Data Access Statement: no original data are presented in this document.

Abstract Genetic studies have significantly advanced our understanding of tauopathies, yet the genetic aetiology of Pick’s disease, a rare 3-Repeat tauopathy, remains unclear. The MAPT p.A152T variant has been identified as a risk factor for Alzheimer’s disease and progressive supranuclear palsy, but its role in Pick’s disease is unknown. In this study, we examined the prevalence of MAPT p.A152T in the largest series of neuropathologically confirmed Pick’s disease cases to date (n = 401). Through genotyping, we identified a single mutation carrier in the Pick’s disease cohort (minor allele frequency = 0.12%). We previously reported MAPT p.A152T at a 0.20% frequency in healthy controls (n = 2456), suggesting that it does not associate with 3-Repeat tauopathy risk. To further investigate the effect of the variant on MAPT transcript expression, we used bulk RNA sequencing in Alzheimer’s disease and progressive supranuclear palsy A152T mutation carriers. We did not detect significant differences in 4-Repeat tau levels, though preliminary trends may indicate more nuanced effects that need to be examined with long-read sequencing in a larger series. Overall, our study suggests that MAPT p.A152T does not increase Pick’s disease risk and may instead be linked to 4-Repeat or mixed tau pathologies, warranting further functional investigation.

Abstract Histopathological assessment has served as the gold standard for diagnosing Alzheimer’s disease (AD). Emerging technological advancements, including the development of amyloid positron emission tomography (PET), have enabled early detection of amyloid pathology, one of the neuropathological hallmarks of AD. Genome-wide association study (GWAS) across cohorts of aging and AD, leveraging different measurements of amyloid burden, may facilitate the identification of novel genetic variants that drive the earliest neuropathological changes in AD. This study presents the largest GWAS of brain amyloidosis to date, leveraging amyloid β (Aβ) measured by in vivo amyloid PET and postmortem histopathology from 13,555 individuals of European ancestry. Amyloid positivity was defined as moderate or frequent neuritic plaques according to the Consortium to Establish a Registry for Alzheimer’s Disease (CERAD) staging scores for each postmortem cohort. A Gaussian mixture model (GMM) was applied to each amyloid PET cohort to identify the cohort and tracer-specific cut-offs that differentiate amyloid positive and negative populations. In silico and ex vivo analyses further characterized implicated loci, including interrogating the association between bulk and single-nucleus gene expression profiles and AD-related traits. Genetic covariance analysis assessed the extent amyloid PET and postmortem measures reflect the shared genetic architecture of brain amyloidosis. Our combined amyloidosis GWAS identified three established AD risk loci: BIN1 (rs6733839, OR = 1.20, 95% CI 1.14-1.26, P = 1.32 × 10−11), CR1 (rs4844610, OR = 1.24, 95% CI = 1.16-1.32, P = 4.21 × 10−10), APOE (rs429358, OR = 4.01, 95% CI = 3.66-4.38, P = 4.54 × 10−201), and a newly identified brain amyloidosis-associated variant on chromosome 17 (rs35635959, OR = 1.18, 95% CI = 1.12-1.25, P = 1.47 × 10−8). SuSiE fine-mapping identified a single credible set of 15 putative causal variants with rs35635959 as the lead variant. Subsequent eQTL and SuSiE-based colocalization analyses prioritized rs35635959 as a strong eQTL for TUBG2, encoding tubulin gamma 2, which is involved in microtubule organization and synaptic plasticity. Further cell-type-specific characterization of this gene in neurons from dorsolateral prefrontal cortex tissue indicated that decreased TUBG2 expression was associated with increased Aβ burden and AD case status (PFDR < 0.045). Furthermore, our study is the first to report a modest genetic covariance (covariance=0.17, P < 6.54 × 10−8) between the genetic architecture of amyloid burden captured by different modalities. While APOE showed a strong association with both amyloid endophenotypes, the observed genetic covariance was not substantially attenuated after excluding variants within the APOE region (covariance=0.16, P < 1.32 × 10−7). Our results highlight the benefits of leveraging compatible, harmonized AD endophenotypes to increase power to uncover new molecular insights into the etiology of AD neuropathology. Wang et al. present the largest GWAS of brain amyloidosis to date, analysing 13,555 individuals using amyloid PET and postmortem Aβ measures. They identify a novel amyloidosis-associated variant on chromosome 17, demonstrate genetic covariance between modalities, and highlight complex traits sharing genetic architecture with Aβ burden.

Abstract Since 2016, the Alzheimer's Association and the Fondation Alzheimer have hosted Global Alzheimer's Leadership Series (GoALS) global think tanks, with world‐leading experts for innovative discussions to advance Alzheimer's disease (AD) research and care. The second GoALS think tank, held in June 2024 in Paris, focused on the relationship between biological changes and clinical manifestations of AD in the context of the evolving therapeutic landscape. Discussions spanned real‐world experiences of providers, patients, and their families, theoretical considerations, and health system challenges. The lived experience perspective was central to these discussions. The importance of shared decision‐making, clear and transparent communication, and the need for real‐world data to holistically support patients during their experiences were highlighted. This manuscript shares key insights from both the think tank meeting in Paris and a featured research session at the 2024 Alzheimer's Association International Conference that expanded the discussion themes for broader dissemination with the community.

Abstract INTRODUCTION The vascular endothelial growth factor (VEGF) signaling family plays a role in neurodegenerative diseases, including Alzheimer's disease (AD). Previous work has shown widespread effects of the members FLT1 , FLT4 , and VEGFB on AD outcomes. However, these analyses have focused within the non‐Hispanic White (NHW) population. METHODS The goal of this study was to analyze the effects of the VEGF family in underrepresented populations, leveraging large and diverse bulk RNA sequencing and tandem mass tag–mass spectrometry (TMT‐MS) proteomic data. Outcomes included measures of AD pathology and diagnosis. RESULTS Within underrepresented populations, we replicated previously reported effects of FLT1 and FLT4 , whereby higher protein abundance was observed in the AD brain and was associated with higher neuropathology burden. In stratified analyses, these associations were largely consistent across race and ethnicity. DISCUSSION This multi‐omic study on the role of the VEGF family in AD emphasizes the need for more representative studies focused on therapeutic targets for AD. Highlights Vascular endothelial growth factor (VEGF) genes and proteins were quantified in four different brain regions. Samples included participants from four different populations. Previously observed effects were replicated in diverse populations. This study is the largest multi‐omic study of the vascular endothelial growth factor (VEGF) genes among Alzheimer's disease (AD) participants from diverse populations.

Abstract Background The interplay between vascular dysfunction and brain amyloidosis in driving Alzheimer's disease (AD) pathogenesis and cognitive decline is increasingly recognized. The retina, sharing an embryonic origin with the brain, offers an accessible CNS organ for high‐resolution, noninvasive imaging of AD‐related vascular pathology. However, the exact nature of retinal vascular damage in AD—especially in early disease stages—and its relationship with cerebral amyloid angiopathy (CAA) and cognitive impairment remain understudied. Method We examined vascular abnormalities in retinas of MCI and AD via histopathology and in‐vivo imaging studies. Postmortem retinas from 53–62 individuals (CN: 22; MCI/AD: 31–40) underwent immunohistochemistry for pericyte integrity, vascular Aβ42/40, and endothelial TJ proteins, with dysregulated proteins quantified by mass spectrometry in 12 additional AD/CN cases. Retinal curcumin‐amyloid imaging by scanning‐laser ophthalmoscope in 28–34 live participants (CN[MOCA>26]: 8–15; MCI/AD[MOCA≤26]: 13–19) assessed peri‐arteriolar/venular amyloid plaques (APs). Perivascular AP burden was correlated with MRI measures (hippocampal volume, WMH lesions) and cognitive/neuropsychiatric parameters. Result Retinal pericyte loss, reflected by PDGFRβ deficiency and apoptosis, was evident in MCI and AD patients and correlated with vascular Aβ42/40 accumulation and CAA severity (r=0.68–0.84; p <0.01–0.0001). Retinal endothelial ZO‐1 and claudin‐5 levels were significantly reduced, correlating with arteriolar Aβ40 deposition, suggesting impaired retinal Aβ clearance. Retinal capillary claudin‐5 and arteriolar Aβ40 strongly associated with CAA (r=0.75–0.77, p <0.0001), while ZO‐1 moderately correlated with brain amyloidosis/tauopathy, CAA, and cognitive decline (r=0.43–0.57, p <0.01–0.001). Both histological and in‐vivo imaging studies revealed greater Aβ deposition in retinal arterioles, particularly in secondary and tertiary branches, compared to venules or capillaries ( p <0.01–0.0001). Retinal perivascular APs in secondary/tertiary branches imaged in living patients correlated with cognitive impairment (global CDR, MOCA), hippocampal atrophy, and WMH lesions (r=0.51–0.66, p <0.05–0.001). Perivascular APs in the secondary (β=0.397, p = 0.033) and tertiary (β=0.756, p = 0.017) arteriolar branches showed significant interactions with hippocampal volumetry for visual memory. Conclusion Retinal arteriolar Aβ accumulation, pericyte loss, and TJ dysfunction contribute to early AD vascular pathology. If validated in larger cohorts, these findings support retinal vascular biomarkers as tools for predicting cognitive decline, monitoring AD progression, and assessing CAA severity.

Abstract INTRODUCTION New methods estimate amyloid positivity onset age (EAOA) from amyloid positron emission tomography (PET). We explore the genetics of EAOA to identify molecular factors underlying the earliest Alzheimer's disease (AD) changes. METHODS Harmonized amyloid PET data from 4216 participants were used in genome‐wide survival, tissue‐specific gene expression, and genetic covariance analyses of EAOA. RESULTS Variants in apolipoprotein E ( APOE ), ABCA7 , and RASGEF1C associated with earlier EAOA. APOE ε4/ε4 and ε3/ε4 converted 6.3 and 5 years earlier than ε3/ε3, respectively. ε2 was protective against earlier EAOA. rs4147929, an expression quantitative trait locus for ABCA7 , associated with a 4 year earlier EAOA. This variant was associated with lower brain expression of ABCA7 , which was associated with increased amyloid pathology at autopsy. Multiple immune‐related diseases shared genetic covariance with EAOA. DISCUSSION APOE , ABCA7 , and RASGEF1C associated with earlier EAOA, with supporting evidence from tissue‐specific expression analyses, offering insights into intervenable targets at early stages of AD. Highlights Novel methods estimate how long ago a patient converted to amyloid positivity. Estimating this amyloid clock allows us to determine the onset of the earliest Alzheimer's disease changes. We evaluated what genes influence when someone converts to amyloid positivity. Apolipoprotein E ( APOE ) , ABCA7 , and RASGEF1C associated with earlier age of amyloid positivity. Genetic results were supported by tissue‐specific expression analyses.

Abstract INTRODUCTION Few African American (AA) donors have been included in post mortem Alzheimer's disease (AD) studies compared to European‐ancestry (EA) individuals. METHODS We generated transcriptome‐wide bulk pre‐frontal cortex (PFC) gene expression data from 125 AA donors with neuropathologically determined AD and 82 AA controls. RESULTS Transcriptome‐wide significant differential expression was observed with 482 genes. The most significant, ADAMTS2 , showed 1.52 times higher expression in AD cases ( p = 2.96x10 −8 ). Comparison of findings with those from a recent gene expression study of EA brain donors revealed substantial concordance, including ADAMTS2 . Other associations not observed in EA results may be especially relevant to AD risk in the AA population. Examination of AA AD GWAS‐implicated variants identified several expression quantitative trait loci. CONCLUSION This first large‐scale AA brain AD gene expression study identified many differentially expressed genes, including ADAMTS2 , and supports gene expression as a molecular pathway underlying the impact of several AA AD risk variants. Highlights We performed the largest African American brain tissue Alzheimer's disease (AD) gene expression study. Expression differences for 482 genes, notably ADAMTS2 , were study‐wide significant. Many significant differentially expressed genes are involved in energy metabolism. Several previously known AD‐associated variants in African Americans are eQTLs. These results advance knowledge of the genetic basis of AD in the AA population.

Objective To establish a framework for validating candidate biomarkers of cerebral small vessel diseases (SVD) associated with cognitive impairment and characterize individuals enrolled by the MarkVCID2 consortium under this framework. Methods Participants age 60 to 90 years were enrolled across 17 MarkVCID2 sites. Recruitment was targeted to enrich in cognitive symptoms (mild dementia, mild cognitive impairment, subjective cognitive decline), defined risk factors (diabetes mellitus, advanced hypertension), and Black/African American, White, and Hispanic/Latino subgroups. Enrolled participants underwent baseline visits that included cognitive testing, multimodal magnetic resonance imaging (MRI), and biofluid collection. Provisional risk for SVD‐related cognitive decline was estimated primarily by baseline cognitive symptoms plus SVD risk factors. Adjudicated risk status was estimated by cognitive symptoms plus presence of moderate‐to‐severe white matter hyperintensities, microbleeds, or lacunes on baseline MRI. Results MarkVCID2 enrolled 1883 individuals age 73.4 ± 7.5 years, 65.0% female, 24.2% Hispanic, and 27.1% non‐Hispanic Black. Among enrollees, 44.8% were provisionally designated high‐risk. After baseline MRI, 48.5% were categorized as adjudicated high‐risk status, with substantial recategorization both from low‐ to high‐risk (primarily because of MRI lesions without SVD risk factors) and high‐ to low‐risk (primarily suspected cognitive impairment at screening not confirmed by baseline testing). Interpretation MarkVCID2 baseline data indicate successful enrollment of diverse individuals enriched in factors associated with SVD‐related cognitive decline. Changes over 3 years of longitudinal follow‐up will be analyzed to validate the candidate biomarkers for 2 projected contexts of use: subject selection (identifying likelihood of future SVD progression) and study outcome (efficiently measuring SVD progression). ANN NEUROL 2026;99:449–458

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.