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Importance: Vascular disease is a treatable contributor to dementia risk, but the role of specific markers remains unclear, making prevention strategies uncertain., Objective: To investigate the causal association between white matter hyperintensity (WMH) burden, clinical stroke, blood pressure (BP), and dementia risk, while accounting for potential epidemiologic biases., Design, Setting, and Participants: This study first examined the association of genetically determined WMH burden, stroke, and BP levels with Alzheimer disease (AD) in a 2-sample mendelian randomization (2SMR) framework. Second, using population-based studies (1979-2018) with prospective dementia surveillance, the genetic association of WMH, stroke, and BP with incident all-cause dementia was examined. Data analysis was performed from July 26, 2020, through July 24, 2022., Exposures: Genetically determined WMH burden and BP levels, as well as genetic liability to stroke derived from genome-wide association studies (GWASs) in European ancestry populations., Main Outcomes and Measures: The association of genetic instruments for WMH, stroke, and BP with dementia was studied using GWASs of AD (defined clinically and additionally meta-analyzed including both clinically diagnosed AD and AD defined based on parental history [AD-meta]) for 2SMR and incident all-cause dementia for longitudinal analyses., Results: In 2SMR (summary statistics-based) analyses using AD GWASs with up to 75 024 AD cases (mean [SD] age at AD onset, 75.5 [4.4] years; 56.9% women), larger WMH burden showed evidence for a causal association with increased risk of AD (odds ratio [OR], 1.43; 95% CI, 1.10-1.86; P = .007, per unit increase in WMH risk alleles) and AD-meta (OR, 1.19; 95% CI, 1.06-1.34; P = .008), after accounting for pulse pressure for the former. Blood pressure traits showed evidence for a protective association with AD, with evidence for confounding by shared genetic instruments. In the longitudinal (individual-level data) analyses involving 10 699 incident all-cause dementia cases (mean [SD] age at dementia diagnosis, 74.4 [9.1] years; 55.4% women), no significant association was observed between larger WMH burden and incident all-cause dementia (hazard ratio [HR], 1.02; 95% CI, 1.00-1.04; P = .07). Although all exposures were associated with mortality, with the strongest association observed for systolic BP (HR, 1.04; 95% CI, 1.03-1.06; P = 1.9 × 10-14), there was no evidence for selective survival bias during follow-up using illness-death models. In secondary analyses using polygenic scores, the association of genetic liability to stroke, but not genetically determined WMH, with dementia outcomes was attenuated after adjusting for interim stroke., Conclusions: These findings suggest that WMH is a primary vascular factor associated with dementia risk, emphasizing its significance in preventive strategies for dementia. Future studies are warranted to examine whether this finding can be generalized to non-European populations.

Introduction: Volumetric and morphological changes in subcortical brain structures are present in persons with dementia, but it is unknown if these changes occur prior to diagnosis., Methods: Between 2005 and 2016, 5522 Rotterdam Study participants (mean age: 64.4) underwent cerebral magnetic resonance imaging (MRI) and were followed for development of dementia until 2018. Volume and shape measures were obtained for seven subcortical structures., Results: During 12 years of follow-up, 272 dementia cases occurred. Mean volumes of thalamus (hazard ratio [HR] per standard deviation [SD] decrease 1.94, 95% confidence interval [CI]: 1.55-2.43), amygdala (HR 1.66, 95% CI: 1.44-1.92), and hippocampus (HR 1.64, 95% CI: 1.43-1.88) were strongly associated with dementia risk. Associations for accumbens, pallidum, and caudate volumes were less pronounced. Shape analyses identified regional surface changes in the amygdala, limbic thalamus, and caudate., Discussion: Structure of the amygdala, thalamus, hippocampus, and caudate is associated with risk of dementia in a large population-based cohort of older adults., (© 2022 The Authors. Alzheimer's & Dementia published by Wiley Periodicals LLC on behalf of Alzheimer's Association.)

Objective: To test the hypothesis that the inflammatory marker plasma soluble CD14 (sCD14) associates with incident dementia and related endophenotypes in 2 community-based cohorts., Methods: Our samples included the prospective community-based Framingham Heart Study (FHS) and Cardiovascular Health Study (CHS) cohorts. Plasma sCD14 was measured at baseline and related to the incidence of dementia, domains of cognitive function, and MRI-defined brain volumes. Follow-up for dementia occurred over a mean of 10 years (SD 4) in the FHS and a mean of 6 years (SD 3) in the CHS., Results: We studied 1,588 participants from the FHS (mean age 69 ± 6 years, 47% male, 131 incident events) and 3,129 participants from the CHS (mean age 72 ± 5 years, 41% male, 724 incident events) for the risk of incident dementia. Meta-analysis across the 2 cohorts showed that each SD unit increase in sCD14 was associated with a 12% increase in the risk of incident dementia (95% confidence interval 1.03-1.23; p = 0.01) following adjustments for age, sex, APOE ε4 status, and vascular risk factors. Higher levels of sCD14 were associated with various cognitive and MRI markers of accelerated brain aging in both cohorts and with a greater progression of brain atrophy and a decline in executive function in the FHS., Conclusion: sCD14 is an inflammatory marker related to brain atrophy, cognitive decline, and incident dementia., (© 2019 American Academy of Neurology.)

Brain imaging data are increasingly made publicly accessible, and volumetric imaging measures derived from population-based cohorts may serve as normative data for individual patient diagnostic assessment. Yet, these normative cohorts are usually not a perfect reflection of a patient's base population, nor are imaging parameters such as field strength or scanner type similar. In this proof of principle study, we assessed differences between reference curves of subcortical structure volumes of normal controls derived from two population-based studies and a case-control study. We assessed the impact of any differences on individual assessment of brain structure volumes. Percentile curves were fitted on the three healthy cohorts. Next, percentile values for these subcortical structures for individual patients from these three cohorts, 91 mild cognitive impairment and 95 Alzheimer's disease cases and patients from the Alzheimer Center, were calculated, based on the distributions of each of the three cohorts. Overall, we found that the subcortical volume normative data from these cohorts are highly interchangeable, suggesting more flexibility in clinical implementation., (Copyright © 2019 The Authors. Published by Elsevier Inc. All rights reserved.)

The gap between predicted brain age using magnetic resonance imaging (MRI) and chronological age may serve as a biomarker for early-stage neurodegeneration. However, owing to the lack of large longitudinal studies, it has been challenging to validate this link. We aimed to investigate the utility of such a gap as a risk biomarker for incident dementia using a deep learning approach for predicting brain age based on MRI-derived gray matter (GM). We built a convolutional neural network (CNN) model to predict brain age trained on 3,688 dementia-free participants of the Rotterdam Study (mean age 66 ± 11 y, 55% women). Logistic regressions and Cox proportional hazards were used to assess the association of the age gap with incident dementia, adjusted for age, sex, intracranial volume, GM volume, hippocampal volume, white matter hyperintensities, years of education, and APOE ε4 allele carriership. Additionally, we computed the attention maps, which shows which regions are important for age prediction. Logistic regression and Cox proportional hazard models showed that the age gap was significantly related to incident dementia (odds ratio [OR] = 1.11 and 95% confidence intervals [CI] = 1.05-1.16; hazard ratio [HR] = 1.11, and 95% CI = 1.06-1.15, respectively). Attention maps indicated that GM density around the amygdala and hippocampi primarily drove the age estimation. We showed that the gap between predicted and chronological brain age is a biomarker, complimentary to those that are known, associated with risk of dementia, and could possibly be used for early-stage dementia risk screening., Competing Interests: Competing interest statement: The authors declare no competing interest. W.J.N. is co-founder, scientific lead, and shareholder of Quantib BV. Other authors report no biomedical financial interests.

Background: Total hippocampal volume has been consistently linked to cognitive function and dementia. Yet, given its complex and parcellated internal structure, the role of subregions of the hippocampus in cognition and risk of dementia remains relatively underexplored. We studied subregions of the hippocampus in a large population-based cohort to further understand their role in cognitive impairment and dementia risk., Methods: We studied 5035 dementia- and stroke-free persons from the Rotterdam Study, aged over 45 years. All participants underwent magnetic resonance imaging (1.5 T) between 2005 and 2015. Automatic segmentation of the hippocampus and 12 of its subregions was performed using the FreeSurfer software (version 6.0). A cognitive test battery was performed, and participants were followed up for the development of dementia until 2015. Associations of hippocampal subregion volumes with cognition and incident dementia were examined using linear and Cox regression models, respectively. All analyses were adjusted for age, sex, education, and total hippocampal volume., Results: Mean age was 64.3 years (SD 10.6) with 56% women. Smaller volumes of the hippocampal fimbria, presubiculum and subiculum showed the strongest associations with poor performance on several cognitive domains, including executive function but not memory. During a mean follow-up of 5.5 years, 76 persons developed dementia. Smaller subiculum volume was associated with risk of dementia adjusted for total volume (hazard ratio per SD decrease in volume: 1.75, 95% confidence interval 1.35; 2.26)., Conclusions: In a community-dwelling non-demented population, we describe patterns of association between hippocampal subregions with cognition and risk of dementia. Specifically, the subiculum was associated with both poorer cognition and higher risk of dementia., (Copyright © 2018 The Authors. Published by Elsevier Inc. All rights reserved.)

The most commonly encountered opening sentence in scientific publications about dementia undoubtedly relates to the overwhelming burden of disease. Finding an effective preventive or therapeutic intervention against dementia has been considered the most important unmet need in contemporary medicine. While efforts on tackling this devastating disease have increased exponentially, it is difficult to imagine that in the 1980s and early-1990s, the disease did not feature prominently on any public health report. Yet, it was already then that epidemiologists recognized the growing societal burden of dementia and rationalized that dementia is not necessarily part of aging. Indeed, the conviction that dementia is pathologically distinct from aging led to various efforts in search of unravelling its risk factors and understanding its pre-clinical phase. Among the early pioneers, the population-based Rotterdam Study was initiated in 1990 clearly aiming on chronic diseases including dementia, and among this Alzheimer's disease, as one of its focus points. Ever since, the Rotterdam Study has been an important cornerstone in increasing our knowledge about dementia from an epidemiological perspective. Here, we summarize the main findings originating from this study, and put these into perspective with previous and current work in the field. With an expanding scope of the Rotterdam Study over the years, we discuss findings on occurrence, modifiable risk factors, imaging, and its genetic underpinnings. Importantly, we conclude with recommendations- or, perhaps better stated, a wish list- for future research which may help us reach our finish line: finding an effective preventive or therapeutic intervention against dementia.

Introduction: Neurodegenerative diseases are a major cause of cognitive impairment and can ultimately lead to dementia. Genome-wide association studies have uncovered many genetic variants conferring risk of neurodegenerative diseases, but their role in cognitive impairment remains unexplored., Methods: In the prospective, population-based Rotterdam Study, 3605 nondemented persons aged ≥55 years were genotyped, screened for mild cognitive impairment (MCI) in 2002 to 2005 and underwent continuous follow-up for dementia until 2012. Weighted polygenic risk scores of genetic variants for Alzheimer's disease (AD), Parkinson's disease (PD), and the frontotemporal lobar degeneration/amyotrophic lateral sclerosis disease spectrum (FTLD/ALS) were constructed and investigated for association with MCI and the subsequent conversion to dementia., Results: In total, 360 (10.0%) persons had MCI, of whom 147 (4.1%) were amnestic and 213 (5.9%) nonamnestic. The AD risk score was associated with both MCI subtypes (odds ratio for all MCI 1.15 [95% CI, 1.03-1.28]), whereas PD and FTLD/ALS risk scores were associated only with nonamnestic MCI (odds ratios 1.15 [1.00-1.32] and 1.19 [1.03-1.37], respectively). The AD risk score, but not PD and FTLD/ALS risk scores, was associated with an increased risk of dementia (hazard ratio 1.55 [1.37-1.77])., Discussion: Genetic evidence supports the view that multiple neurodegenerative pathways lead to MCI and that the subsequent conversion to dementia, primarily of the AD subtype, is mainly due to the AD pathway(s)., (Copyright © 2015 The Alzheimer's Association. Published by Elsevier Inc. All rights reserved.)

Background and Purpose: Dilated Virchow-Robin spaces are an emerging neuroimaging biomarker, but their assessment on MRI needs standardization., Methods: We developed a rating method for dilated Virchow-Robin spaces in 4 brain regions (centrum semiovale, basal ganglia, hippocampus, and mesencephalon) and tested its reliability in a total of 125 MRI scans from 2 population-based studies. Six investigators with varying levels of experience performed the ratings. Intraclass correlation coefficients were calculated to determine intra- and interrater reliability., Results: Intrarater reliability was excellent for all 4 regions (intraclass correlation coefficient, >0.8). Interrater reliability was excellent for the centrum semiovale and hippocampus (intraclass correlation coefficient, >0.8) and good for the basal ganglia and mesencephalon (intraclass correlation coefficient, 0.6-0.8). This did not differ between the cohorts or experience levels., Conclusions: We describe a reliable rating method that can facilitate pathogenic and prognostic research on dilated Virchow-Robin spaces using MRI.

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Risk for late-onset Alzheimer's disease (LOAD), the most prevalent dementia, is partially driven by genetics. To identify LOAD risk loci, we performed a large genome-wide association meta-analysis of clinically diagnosed LOAD (94,437 individuals). We confirm 20 previous LOAD risk loci and identify five new genome-wide loci (IQCK, ACE, ADAM10, ADAMTS1, and WWOX), two of which (ADAM10, ACE) were identified in a recent genome-wide association (GWAS)-by-familial-proxy of Alzheimer's or dementia. Fine-mapping of the human leukocyte antigen (HLA) region confirms the neurological and immune-mediated disease haplotype HLA-DR15 as a risk factor for LOAD. Pathway analysis implicates immunity, lipid metabolism, tau binding proteins, and amyloid precursor protein (APP) metabolism, showing that genetic variants affecting APP and Aβ processing are associated not only with early-onset autosomal dominant Alzheimer's disease but also with LOAD. Analyses of risk genes and pathways show enrichment for rare variants (P = 1.32 × 10-7), indicating that additional rare variants remain to be identified. We also identify important genetic correlations between LOAD and traits such as family history of dementia and education.

We identified rare coding variants associated with Alzheimer's disease in a three-stage case-control study of 85,133 subjects. In stage 1, we genotyped 34,174 samples using a whole-exome microarray. In stage 2, we tested associated variants (P < 1 × 10-4) in 35,962 independent samples using de novo genotyping and imputed genotypes. In stage 3, we used an additional 14,997 samples to test the most significant stage 2 associations (P < 5 × 10-8) using imputed genotypes. We observed three new genome-wide significant nonsynonymous variants associated with Alzheimer's disease: a protective variant in PLCG2 (rs72824905: p.Pro522Arg, P = 5.38 × 10-10, odds ratio (OR) = 0.68, minor allele frequency (MAF)cases = 0.0059, MAFcontrols = 0.0093), a risk variant in ABI3 (rs616338: p.Ser209Phe, P = 4.56 × 10-10, OR = 1.43, MAFcases = 0.011, MAFcontrols = 0.008), and a new genome-wide significant variant in TREM2 (rs143332484: p.Arg62His, P = 1.55 × 10-14, OR = 1.67, MAFcases = 0.0143, MAFcontrols = 0.0089), a known susceptibility gene for Alzheimer's disease. These protein-altering changes are in genes highly expressed in microglia and highlight an immune-related protein-protein interaction network enriched for previously identified risk genes in Alzheimer's disease. These genetic findings provide additional evidence that the microglia-mediated innate immune response contributes directly to the development of Alzheimer's disease.

BackgroundThe burden of cerebral white matter hyperintensities (WMH) is associated with an increased risk of stroke, dementia, and death. WMH are highly heritable, but their genetic underpinnings are incompletely characterized. To identify novel genetic variants influencing WMH burden, we conducted a meta-analysis of multiethnic genome-wide association studies.Methods and resultsWe included 21 079 middle-aged to elderly individuals from 29 population-based cohorts, who were free of dementia and stroke and were of European (n=17 936), African (n=1943), Hispanic (n=795), and Asian (n=405) descent. WMH burden was quantified on MRI either by a validated automated segmentation method or a validated visual grading scale. Genotype data in each study were imputed to the 1000 Genomes reference. Within each ethnic group, we investigated the relationship between each single-nucleotide polymorphism and WMH burden using a linear regression model adjusted for age, sex, intracranial volume, and principal components of ancestry. A meta-analysis was conducted for each ethnicity separately and for the combined sample. In the European descent samples, we confirmed a previously known locus on chr17q25 (P=2.7×10(-19)) and identified novel loci on chr10q24 (P=1.6×10(-9)) and chr2p21 (P=4.4×10(-8)). In the multiethnic meta-analysis, we identified 2 additional loci, on chr1q22 (P=2.0×10(-8)) and chr2p16 (P=1.5×10(-8)). The novel loci contained genes that have been implicated in Alzheimer disease (chr2p21 and chr10q24), intracerebral hemorrhage (chr1q22), neuroinflammatory diseases (chr2p21), and glioma (chr10q24 and chr2p16).ConclusionsWe identified 4 novel genetic loci that implicate inflammatory and glial proliferative pathways in the development of WMH in addition to previously proposed ischemic mechanisms.

Introduction: Volumetric and morphological changes in subcortical brain structures are present in persons with dementia, but it is unknown if these changes occur prior to diagnosis. Methods: Between 2005 and 2016, 5522 Rotterdam Study participants (mean age: 64.4) underwent cerebral magnetic resonance imaging (MRI) and were followed for development of dementia until 2018. Volume and shape measures were obtained for seven subcortical structures. Results: During 12 years of follow‐up, 272 dementia cases occurred. Mean volumes of thalamus (hazard ratio [HR] per standard deviation [SD] decrease 1.94, 95% confidence interval [CI]: 1.55–2.43), amygdala (HR 1.66, 95% CI: 1.44–1.92), and hippocampus (HR 1.64, 95% CI: 1.43–1.88) were strongly associated with dementia risk. Associations for accumbens, pallidum, and caudate volumes were less pronounced. Shape analyses identified regional surface changes in the amygdala, limbic thalamus, and caudate. Discussion: Structure of the amygdala, thalamus, hippocampus, and caudate is associated with risk of dementia in a large population‐based cohort of older adults. [ABSTRACT FROM AUTHOR]

Background: Vascular dementia is a common disorder resulting in considerable morbidity and mortality. Determining the extent to which genes play a role in disease susceptibility and their pathophysiological mechanisms could improve our understanding of vascular dementia, leading to a potential translation of this knowledge to clinical practice.Discussion: In this review, we discuss what is currently known about the genetics of vascular dementia. The identification of causal genes remains limited to monogenic forms of the disease, with findings for sporadic vascular dementia being less robust. However, progress in genetic research on associated phenotypes, such as cerebral small vessel disease, Alzheimer's disease, and stroke, have the potential to inform on the genetics of vascular dementia. We conclude by providing an overview of future developments in the field and how such work could impact patients and clinicians.Conclusion: The genetic background of vascular dementia is well established for monogenic disorders, but remains relatively obscure for the sporadic form. More work is needed for providing robust findings that might eventually lead to clinical translation. [ABSTRACT FROM AUTHOR]

The neural substrate of genetic risk variants for Alzheimer's disease (AD) remains unknown. We studied their effect on healthy brain morphology to provide insight into disease etiology in the preclinical phase. We included 4071 nondemented, elderly participants of the population-based Rotterdam Study who underwent brain magnetic resonance imaging and genotyping. We performed voxel-based morphometry (VBM) on all gray-matter voxels for 19 previously identified, common AD risk variants. Whole-brain expression data from the Allen Human Brain Atlas was used to examine spatial overlap between VBM association results and expression of genes in AD risk loci regions. Brain regions most significantly associated with AD risk variants were the left postcentral gyrus with ABCA7 (rs4147929, p = 4.45 × 10 −6 ), right superior frontal gyrus by ZCWPW1 (rs1476679, p = 5.12 × 10 −6 ), and right postcentral gyrus by APOE ( p = 6.91 × 10 −6 ). Although no individual voxel passed multiple-testing correction, we found significant spatial overlap between the effects of AD risk loci on VBM and the expression of genes ( MEF2C , CLU , and SLC24A4 ) in the Allen Brain Atlas. Results are available online on www.imagene.nl/ADSNPs/ . In this single largest imaging genetics data set worldwide, we found that AD risk loci affect cortical gray matter in several brain regions known to be involved in AD, as well as regions that have not been implicated before. [ABSTRACT FROM AUTHOR]

The article discusses a research which examines the genetic variants influencing the burden of cerebral white matter hyperintensities (WMH) on magnetic resonance imaging (MRI) in individuals from population-based cohorts, who were free of stroke and dementia. The study uses a linear regression model to investigate the relationship between each single-nucleotide polymorphism and WMH burden. It reveals the association of WMH burden with an increased risk of dementia, stroke and death.

The most commonly encountered opening sentence in scientific publications about dementia undoubtedly relates to the overwhelming burden of disease. Finding an effective preventive or therapeutic intervention against dementia has been considered the most important unmet need in contemporary medicine. While efforts on tackling this devastating disease have increased exponentially, it is difficult to imagine that in the 1980s and early-1990s, the disease did not feature prominently on any public health report. Yet, it was already then that epidemiologists recognized the growing societal burden of dementia and rationalized that dementia is not necessarily part of aging. Indeed, the conviction that dementia is pathologically distinct from aging led to various efforts in search of unravelling its risk factors and understanding its pre-clinical phase. Among the early pioneers, the population-based Rotterdam Study was initiated in 1990 clearly aiming on chronic diseases including dementia, and among this Alzheimer's disease, as one of its focus points. Ever since, the Rotterdam Study has been an important cornerstone in increasing our knowledge about dementia from an epidemiological perspective. Here, we summarize the main findings originating from this study, and put these into perspective with previous and current work in the field. With an expanding scope of the Rotterdam Study over the years, we discuss findings on occurrence, modifiable risk factors, imaging, and its genetic underpinnings. Importantly, we conclude with recommendations- or, perhaps better stated, a wish list- for future research which may help us reach our finish line: finding an effective preventive or therapeutic intervention against dementia. [ABSTRACT FROM AUTHOR]