Individuals with Down syndrome (DS) have an increased genetic risk of developing Alzheimer’s disease (AD), with most adults developing AD neuropathology in their 40s. Despite having a low frequency of systemic vascular risk factors such as hypertension and atherosclerosis, adults with DS display cerebrovascular pathology, including microbleeds, microinfarcts, and cerebral amyloid angiopathy. This suggests that blood-brain barrier (BBB) integrity may be compromised allowing the extravasation of blood proteins in the brain parenchyma. The blood coagulation factor fibrin promotes immune-mediated neurodegeneration and is a marker of BBB disruption in a wide range of neurological diseases. This study investigated the severity of fibrin deposition as a measure of BBB integrity in the brains of adults with DS and AD pathology (DSAD). We hypothesized that fibrin deposition is increased in DSAD in comparison to neurotypical controls without DS or AD. Fibrin immunoreactivity was assessed by free-floating immunohistochemistry in 30µm tissue sections from the occipital cortex from neurotypical controls (n = 12; 41-65 years old) and DSAD (n = 12; 46-66 years old). Using whole slide imaging, brain sections were digitized, and the severity of fibrin deposition was scored using Aperio Imagescope. Individuals with DSAD display significantly higher fibrin deposition in the white and grey matter of the occipital cortex in comparison to the age-matched neurotypical controls (p<0.0001). Neurotypical controls display minimal fibrin deposition in the brain parenchyma and perivascular space. However, compared to neurotypical controls, adults with DS at advanced stages of AD neuropathology display significant fibrin deposition in the occipital cortex, suggesting that the BBB may be compromised in this population. Funding : NIH U19AG068054, RF1AG079519, P30AG066519 and 23AARFD-1022715.

Small vessel cerebrovascular disease (CVD), visualized as white matter hyperintensities (WMH) on magnetic resonance imaging (MRI), is associated with risk and progression of Alzheimer’s disease (AD) in clinical, community, and genetic studies of AD. However, it is unclear whether these observations indicate a role of CVD in AD pathogenesis. One approach towards understanding whether there is a mechanistic or fundamental function of CVD in AD pathogenesis is by examining whether genetic risk factors for AD are also associated with WMH. Here, we examined whether polygenic hazard scores (PHS) and cumulative incidence rates (CIR) scores are associated with WMH volume in older adults without dementia. We used data from the Alzheimer’s Disease Neuroimaging Initiative, including available WMH, PHS, and CIR scores from individuals without dementia. Polygenic hazard scores reflect the contribution of APOE and 31 other genetic variants to future risk for AD, calculated from over 54,000 AD cases and controls by Desikan and colleagues. The CIR scores combined the PHS and US population-based incidence rates to reflect an age-specific instantaneous risk for developing AD in each participant. Linear models were used to evaluate the relationship of PHS and CIR scores with log transformed WMH volumes. To confirm our findings among people with pathophysiological evidence of AD, we restricted the analysis to a subset of participants with amyloid positivity on amyloid PET scans. Six hundred two participants were included (mean±SD age=72.6±7.12, 46% women). Polygenic hazard scores for AD were not associated with WMH volume (R=-0.04, 95% CI:[-0.12-0.04], p=0.33), but higher CIR scores were associated with greater WMH volume (R=0.29, 95% CI:[0.21-0.36], p<0.0001). The association between WMH and CIR remained after restricting the analyses to the amyloid positive subgroup (n=271, age=73.8±6.83, 51% women; R=0.20, 95% CI:[0.09-0.31], p=0.0007). Higher cumulative incidence rate derived from polygenic risk scores for AD is related to WMH volume in individuals without dementia, suggesting that age-anchored genetic risk for development of AD also increases small vessel CVD. The findings implicate WMH in the genetic pathway towards AD pathogenesis.

White matter hyperintensities (WMHs) are areas of increased signal on T2-weighted MRI scans. They vary in size, location, and intensity, suggesting different underlying conditions like small vessel disease and inflammation. This variation potentially links WMH to outcomes ranging from normal aging to severe neurological disorders. We used a texture analytic approach, Gray-Level Co-occurrence Matrix (GLCM), to characterize the intensity heterogeneity of WMHs. This method classifies WMHs into distinct zones based on homogeneity scores that represent uniformity in signal intensity. We explored associations among white matter microstructure, cerebral blood flow, and WMH volume within these zones. One hundred sixty-one participants from the Washington Heights-Inwood Columbia Aging Project (WHICAP) were included. White matter hyperintensities were labeled using in-house software, which also created normalized homogeneity maps through GLCM. These maps were used to define three WMH zones based on their degree of homogeneity (i.e., homogeneous, intermediate, and heterogeneous) (Figure 1). We examined the relationship among fractional anisotropy (FA), cerebral blood flow (CBF), and WMH volume within these WMH zones and compared CBF and FA values across the zones. In homogeneous and intermediate WMH zones, there was no association between FA and CBF (r homo. =0.022, p homo. =0.787; r inter. =-0.12, p inter. =0.132). However, both FA and CBF negatively correlated with WMH volume in these zones (r FA-homo. =-0.348, p FA-homo. < 0.0001; r FA-inter. =-0.538, p FA-inter. < 0.0001; r CBF-homo. =-0.36, p CBF-homo. < 0.0001; r CBF-inter. =-0.40, p CBF-inter. < 0.0001). In the heterogeneous zone (Figure 2), FA and CBF were negatively correlated (r hetero. =-0.422, p hetero. < 0.0001). CBF, but not FA, was associated with WMH volume (r CBF-hetero. =-0.471, p CBF-hetero. < 0.0001; r FA-hetero. =0.085, p FA-hetero. =0.300) In homogenous WMH regions, both [FA Ratio (0.776±0.009) and CBF Ratio (0.96±0.014)] values were lower than in intermediate [FA Ratio (0.84±0.009) and CBF Ratio (0.97±0.014)] and heterogeneous zones [FA Ratio : (1.029±0.009), CBF Ratio : (1.002±0.014)].(Figure 3) Distinct correlation patterns exist between CBF and FA in WMH clusters defined by intensity heterogeneity. Homogeneous zones, likely reflect older lesions, show low microstructural integrity and minimal relationship with CBF, suggesting high gliosis. Heterogeneous zones, possibly reflecting recent white matter damage, show associations between CBF and microstructure, potentially indicating active inflammatory processes contributing to vascular injury.

By age 40 years, adults with Down syndrome (DS) develop Alzheimer’s disease (AD) pathology and progress to dementia in their 60s. Despite minimal systemic vascular risk factors, individuals with DS have MRI evidence of cerebrovascular injury that progresses with AD severity, suggesting an intrinsic vascular component to DS-AD that may interact with neuroinflammatory processes to promote tau pathology and cognitive decline. In the current study we examined whether cerebrovascular disease (CVD) burden and inflammation/astrocytosis independently and interactively were associated with incident diagnosis among adults with DS. This study included 149 participants from the Alzheimer Biomarkers Consortium – Down Syndrome (baseline mean age[SD]=44.6[9] years) with available baseline MRI, plasma biomarker data, and at least two time-points of clinical consensus diagnosis data (i.e., cognitively stable, mild cognitive impairment [MCI], and clinical AD) who were classified as cognitively stable or MCI at baseline. Logistic regression models assessed if baseline small vessel CVD, operationalized as white matter hyperintensity (WMH) volume, and plasma glial fibrillary acidic protein (GFAP), Aβ42/Aβ40, p-tau217, and neurofilament light (NfL) concentrations are associated with conversion from a milder diagnosis to a more severe clinical diagnosis. Mediation models examined relationships between biomarkers and diagnostic conversion. All models adjusted for study site, sex/gender, latency between visit dates, and age group (below or above/equal to the median age of the sample). Diagnostic conversion occurred in 26% of the sample. Higher baseline WMH volume (OR 1.08 [1.01, 1.81]), GFAP (OR 1.006 [1.003, 1.01]), and p-tau217 (OR 20.56 [5.01, 112.43]), but not NfL nor Aβ42/Aβ40 concentrations were associated with higher odds of conversion to more severe cognitive impairment. GFAP concentration mediated the relationship between WMH and diagnostic conversion (ACME 0.05 [0.01, 0.1], p=0.006). P-tau217 concentration mediated the relationship between GFAP and diagnostic conversion (ACME 0.13 [0.05, 0.23], p=0.004). Our findings suggest that among individuals with DS, CVD promotes AD-related clinical progression by increasing astrocytosis which, in turn, promotes tau pathophysiology and downstream MCI and AD incidence. The results implicate CVD and its interface with inflammation as a core feature of AD in DS.

By age 40 years, over 90% of adults with Down syndrome have Alzheimer's disease pathology and most progress to dementia. Despite having few systemic vascular risk factors, individuals with Down syndrome have elevated cerebrovascular disease markers that track with the clinical progression of Alzheimer's disease, suggesting a role of cerebrovascular disease that is hypothesized to be mediated by inflammatory factors. This study examined the pathways through which small vessel cerebrovascular disease contributes to Alzheimer's disease-related pathophysiology and neurodegeneration in adults with Down syndrome. One hundred eighty-five participants from the Alzheimer's Biomarkers Consortium-Down Syndrome [mean (SD) age = 45.2 (9.3) years] with available MRI and plasma biomarker data were included in this study. White matter hyperintensity (WMH) volumes were derived from T2-weighted fluid-attenuated inversion recovery MRI scans, and plasma biomarker concentrations of amyloid beta 42/40, phosphorylated tau 217, astrocytosis (glial fibrillary acidic protein) and neurodegeneration (neurofilament light chain) were measured with ultrasensitive immunoassays. We examined the bivariate relationships of WMH, amyloid beta 42/40, phosphorylated tau 217 and glial fibrillary acidic protein with age-residualized neurofilament light chain across Alzheimer's disease diagnostic groups. A series of mediation and path analyses examined statistical pathways linking WMH and Alzheimer's disease pathophysiology to promote neurodegeneration in the total sample and groups stratified by clinical diagnosis. There was a direct and indirect bidirectional effect through the glial fibrillary acidic protein of WMH on phosphorylated tau 217 concentration, which was associated with neurofilament light chain concentration in the entire sample. Amongst cognitively stable participants, WMH was directly and indirectly, through glial fibrillary acidic protein, associated with phosphorylated tau 217 concentration, and in those with mild cognitive impairment, there was a direct effect of WMH on phosphorylated tau 217 and neurofilament light chain concentrations. There were no associations of WMH with biomarker concentrations among those diagnosed with dementia. The findings from this cross-sectional study suggest that among individuals with Down syndrome, cerebrovascular disease promotes neurodegeneration by increasing astrocytosis and tau pathophysiology in the presymptomatic phases of Alzheimer's disease, but future studies will need to confirm these associations with longitudinal data. This work joins an emerging literature that implicates cerebrovascular disease and its interface with neuroinflammation as a core pathological feature of Alzheimer's disease in adults with Down syndrome. Edwards et al. report an association of an MRI marker of cerebrovascular disease with plasma markers of phosphorylated tau protein and neurodegeneration that appears to be mediated by astrocytosis in the presymptomatic phases of Alzheimer's disease among adults with Down syndrome. Graphical abstract

Background Secondary prevention clinical trials for Alzheimer’s disease (AD) target amyloid accumulation in asymptomatic, amyloid-positive individuals, but it is unclear to what extent other pathophysiological processes, such as small vessel cerebrovascular disease, account for participant performance on the primary cognitive outcomes in those trials. White matter hyperintensities are areas of increased signal on T2-weighted magnetic resonance imaging (MRI) that reflect small vessel cerebrovascular disease. They are associated with cognitive functioning in older adults and with clinical presentation and course of AD, particularly when distributed in posterior brain regions. The purpose of this study was to examine to what degree regional WMH volume is associated with performance on the primary cognitive outcome measure in the Anti-Amyloid Treatment in Asymptomatic Alzheimer’s Disease (A4) study, a secondary prevention trial. Methods Data from 1791 participants (59.5% women, mean age (SD) 71.6 (4.74)) in the A4 study and the Longitudinal Evaluation of Amyloid Risk and Neurodegeneration (LEARN) companion study at the screening visit were used to quantify WMH volumes on T2-weighted fluid-attenuated inversion recovery (FLAIR) MR images. Cognition was assessed with the preclinical Alzheimer cognitive composite (PACC). We tested the association of total and regional WMH volumes with PACC performance, adjusting for age, education, and amyloid positivity status, with general linear models. We also considered interactions between WMH and amyloid positivity status. Results Increased frontal and parietal lobe WMH volume was associated with poorer performance on the PACC. While amyloid positivity was also associated with lower cognitive test scores, WMH volumes did not interact with amyloid positivity status. Conclusion These results highlight the potential of small vessel cerebrovascular disease to drive AD-related cognitive profiles. Measures of small vessel cerebrovascular disease should be considered when evaluating outcome in trials, both as potential effect modifiers and as a possible target for intervention or prevention.

Adults with Down syndrome are less likely to have hypertension than neurotypical adults. However, whether blood pressure measures are associated with brain health and clinical outcomes in this population has not been studied in detail. Here, we assessed whether pulse pressure is associated with markers of cerebrovascular disease and is linked to a diagnosis of dementia in adults with Down syndrome via structural imaging markers of cerebrovascular disease and atrophy. The study included participants with Down syndrome from the Alzheimer's Disease - Down Syndrome study (n = 195, age = 50.6 +/- 7.2 years, 44% women, 18% diagnosed with dementia). Higher pulse pressure was associated with greater global, parietal and occipital white matter hyperintensity volume but not with enlarged perivascular spaces, microbleeds or infarcts. Using a structural equation model, we found that pulse pressure was associated with greater white matter hyperintensity volume, which in turn was related to increased neurodegeneration, and subsequent dementia diagnosis. Pulse pressure is an important determinant of brain health and clinical outcomes in individuals with Down syndrome despite the low likelihood of frank hypertension. Rizvi et al. found that increased pulse pressure is associated with small vessel cerebrovascular disease in adults with Down syndrome. They also found that pulse pressure was indirectly related to dementia through intermediate markers of white matter hyperintensities and neurodegeneration. Graphical Abstract

Abstract Adults with Down syndrome have a genetic form of Alzheimer’s disease (AD) and evidence of cerebrovascular disease across the AD continuum, despite few systemic vascular risk factors. The onset and progression of AD in Down syndrome is highly age-dependent, but it is unknown at what age cerebrovascular disease emerges and what factors influence its severity. In the Alzheimer’s Biomarker Consortium-Down Syndrome study (ABC-DS; n = 242; age = 25–72), we estimated the age inflection point at which MRI-based white matter hyperintensities (WMH), enlarged perivascular spaces (PVS), microbleeds, and infarcts emerge in relation to demographic data, risk factors, amyloid and tau, and AD diagnosis. Enlarged PVS and infarcts appear to develop in the early 30s, while microbleeds, WMH, amyloid, and tau emerge in the mid to late 30s. Age-residualized WMH were higher in women, in individuals with dementia, and with lower body mass index. Participants with hypertension and APOE-ε4 had higher age-residualized PVS and microbleeds, respectively. Lifespan trajectories demonstrate a dramatic cerebrovascular profile in adults with Down syndrome that appears to evolve developmentally in parallel with AD pathophysiology approximately two decades prior to dementia symptoms.

Clinically normal females exhibit higher 18F-flortaucipir (FTP)-PET signal than males across the cortex. However, these sex differences may be explained by neuroimaging idiosyncrasies such as off-target extracerebral tracer retention or partial volume effects (PVEs). 343 clinically normal participants (female = 58%; mean[SD]=73.8[8.5] years) and 55 patients with mild cognitive impairment (female = 38%; mean[SD] = 76.9[7.3] years) underwent cross-sectional FTP-PET. We parcellated extracerebral FreeSurfer areas based on proximity to cortical ROIs. Sex differences in cortical tau were then estimated after accounting for local extracerebral retention. We simulated PVE by convolving group-level standardized uptake value ratio means in each ROI with 6 mm Gaussian kernels and compared the sexes across ROIs post-smoothing. Widespread sex differences in extracerebral retention were observed. Although attenuating sex differences in cortical tau-PET signal, covarying for extracerebral retention did not impact the largest sex differences in tau-PET signal. Differences in PVE were observed in both female and male directions with no clear sex-specific bias. Our findings suggest that sex differences in FTP are not solely attributed to off-target extracerebral retention or PVE, consistent with the notion that sex differences in medial temporal and neocortical tau are biologically driven. Future work should investigate sex differences in regional cerebral blood flow kinetics and longitudinal tau-PET.

Adults with Down syndrome (DS) overproduce amyloid precursor protein, develop amyloid plaques at an early age, and are diagnosed with Alzheimer’s disease (AD) dementia at a high frequency. There is emerging evidence that cerebrovascular disease is elevated across the AD continuum in older adults with DS, independent of age and vascular risk, around the same time as amyloid and tau, but the regional rates of accumulation within individuals are unknown. Adults with DS from the multisite Alzheimer’s Biomarker Consortium-Down Syndrome study (ABC-DS; n=78; age=50±6; 40% women) have two timepoints of T2 FLAIR MRI (1.2±0.6 years apart) quantified as white matter hyperintensity volume (WMH), which represents ischemic small vessel disease. Participants underwent consensus diagnosis at both timepoints (59% Cognitively-Stable at both timepoints, 9% Cognitively-Stable to MCI-DS, 8% MCI-DS at both timepoints, 14% MCI-DS to AD, 10% AD at both timepoints). The annual rate of change in frontal, temporal, parietal, and occipital WMH volume was assessed, adjusting for baseline WMH volume. The annual rate of change in frontal WMH was not significantly different by diagnosis. The annual rate of change in temporal (0.7 [0.4, 1.1], p<0.001) and in occipital WMH (1.6 [0.7, 2.5], p=0.0008) was faster in the group that remained AD at both timepoints compared to the group that remained Cognitively-Stable at both timepoints. The annual rate of change in parietal WMH was greater in the group that progressed from MCI-DS to AD (0.6 [0.1, 1.0], p=0.02) and in the group that remained AD at both timepoints (1.1 [0.6, 1.7], p=0.0002) compared to the group that remained Cognitively-Stable at both timepoints. In adults with DS, parietal WMH accumulates fastest in those that progress to or have a diagnosis of AD, while temporal and occipital WMH accumulate fastest in those with a diagnosis of AD. Posteriorly distributed WMH may have specificity for AD progression in adults with DS with implications for anti-amyloid therapeutics that have cerebrovascular side effects.

Cerebrovascular disease contributes to clinical onset and course of Alzheimer’s disease (AD) but it is unclear if it is related directly to AD pathogenesis. In late onset AD, MRI markers of small vessel cerebrovascular disease relate to AD diagnosis, genetic risk for AD, and severity of AD symptoms, but it is not possible to determine whether these associations reflect comorbidity due to risk factor exposure or whether they represent a core feature of AD. We have been studying cerebrovascular features of Alzheimer’s disease in adults with Down syndrome, who are at genetic risk for developing AD but have very low prevalence of classical vascular risk factors. In the context of the Alzheimer’s Biomarker Consortium – Down Syndrome (ABC-DS), a US-based multisite observational study of the clinical, biomarker, and pathological features of AD in adults with Down syndrome, our laboratory has analyzed high-resolution, harmonized MRI scans for markers of cerebrovascular disease, including white matter hyperintensities (WMH), enlarged perivascular spaces, microbleeds, and infarcts, in adults with Down syndrome across the adult lifespan. We tested the association of these markers with age, AD-related clinical diagnoses, proteomic profiles of vascular function and inflammation, and AD-related biofluidic biomarker concentrations. Our studies show that MRI-derived markers of cerebrovascular disease are prevalent in adults with Down syndrome and increase in severity across AD-associated clinical diagnoses. Age analyses suggest that there is an inflection of these markers at around age 40, when other pathological features also begin to emerge. Proteomic correlates of these cerebrovascular disease markers suggest an association with inflammatory processes in presymptomatic and neurodegenerative processes in symptomatic adults with Down syndrome. Finally, markers of cerebrovascular disease are particularly associated with plasma phosphorylated tau concentrations in adults with Down syndrome. Our work shows that MRI-derived markers of cerebrovascular disease are prevalent, related to AD symptoms, temporally track with AD pathology, relate to inflammation and neurodegeneration markers, and associate with markers of tau pathology. Without the confound of exposure to peripheral vascular risk factors, these observations suggest that cerebrovascular disease represents a “core feature” of AD that contributes both to symptoms and to disease pathogenesis.

Adults with Down syndrome (DS) overproduce amyloid precursor protein, develop amyloid plaques at an early age, and are diagnosed with Alzheimer’s disease (AD) dementia at a high frequency. There is emerging evidence that cerebrovascular disease is elevated across the AD continuum in older adults with DS, independent of age and vascular risk, but it is unknown when cerebrovascular disease emerges across the lifespan. Adults with DS from the multisite Alzheimer’s Biomarker Consortium-Down Syndrome study (ABC-DS; n = 241; age = 25-72, 44±10; 45% women; 77/11/12% Cognitively-Stable/MCI-DS/AD dementia) underwent harmonized MRI and received a cognitive diagnosis at a consensus conference. Cross-sectional white matter hyperintensity volume (WMH; ischemic small vessel disease), enlarged perivascular space score (PVS; impaired toxin clearance), chronic infarcts (large vessel disease), and microbleeds (hemorrhagic small vessel disease/cerebral amyloid angiopathy) were fit against piece-wise, left null regression models with age to estimate the age inflection point at which these cerebrovascular markers emerged. The residuals for each biomarker (i.e., more than expected for their age) were then regressed on diagnosis. Total WMH volume (0.01-31.7, 4±4.6 cm 3 ), enlarged PVS score (0-26, 8±5), infarcts (15% have at least one), and microbleeds (12% have at least one) were present in this lifespan sample of adults with DS. There was a significant inflection point in the fourth decade of life for total WMH (37±6, p = 7E-3), enlarged PVS (31±6, p = 3E-6), and infarcts (31±9, p = 2E-3), but not microbleeds (36±21, p = 0.7). Regionally, there were significant inflection points for frontal (36±6, p = 3E-3), parietal (36±7, p = 0.02), and occipital (42±6, p = 0.02), but not temporal WMH (33±14, p = 0.3). AD dementia was associated with higher residuals in parietal (0.5±0.2, p = 0.02) and occipital WMH (0.6±0.3, p = 0.02). In adults with DS, there is cerebrovascular pathology on MRI that emerges around the same age as what has been reported for amyloid PET positivity and tau PET accumulation in this population. More posterior small vessel disease for a given age may arise with a diagnosis of AD, suggesting a cerebrovascular process in AD pathogenesis. Longitudinal assessment in relation to AD biomarkers, including amyloid and tau PET, will provide additional insight.

Clinically normal females exhibit greater [18]F-flortaucipir (FTP) PET signal than males in both temporal and neocortices. It remains unclear whether sex differences in neocortical regions are primarily explained by technical variability issues. We aimed to investigate the contribution of signal spillover/off-target skull binding to sex differences in FTP-PET. Next, we explored partial volume effects (PVE) by simulating sex differences in smoothed FTP-PET signal. Discerning sex differences in tau signal versus noise is pivotal to understanding sex differences in the pathology of Alzheimer’s disease and associated tauopathies. 343 clinically normal (female=58%; mean[SD]=73.8[8.5] years) (female=38%; mean[SD]=76.9[7.3] years) participants from the Harvard Aging Brain Study and the Alzheimer’s Disease Neuroimaging Initiative underwent cross-sectional FTP-PET (standardized uptake value ratios [SUVrs]). For skull analyses, we created skull ROIs based on signal 12mm from the outer perimeter of voxels in FreeSurfer-defined tau ROIs. Linear regression models estimated the main effects of sex across cortical tau ROIs while correcting for local skull binding. We simulated PVE by convolving group-level SUVr means in each ROI with 6mm Gaussian kernels, and then compared the sexes with linear regression models post-smoothing. Widespread sex differences in skull binding were observed (Table 1). Covarying for skull binding ameliorated weaker sex differences in cortical FTP signal but did not impact the largest effects. Sex differences in PVE were observed in both female and male directions; no clear sex-related biases in PVE were found to impact cortical tau sex differences except for the rostral middle frontal region (Figure 1). Our findings suggest that sex differences in FTP-PET are not solely attributed to skull ‘clouding’ or PVE, but rather support hypotheses of female-related tau vulnerability. Nevertheless, as only two potential confounds were investigated, and gross morphology/volumetric issues remain a key concern, further investigation is needed to fully elucidate this phenomenon. Investigations of sex differences in longitudinal tau accumulation (a few preliminary reports already suggest faster rates in females) will add further support to the argument that noise properties inherent in FTP-PET do not significantly contribute to sex differences in cortical tau signal.