Referral Sources Across Racial and Ethnic Groups at Alzheimer's Disease Research Centers.

Background: Despite the need to increase engagement of underrepresented groups (URG) in Alzheimer's disease and related dementias (ADRD) studies, enrollment remains low. Objective: Compare referral sources across racial and ethnic groups among participants enrolled in ADRC studies. Methods: Data for this cross-sectional secondary analysis were extracted from the National Alzheimer's Coordinating Center Uniform Data Set. We performed mixed effects logistic regression models using generalized estimating equations for professional referral versus non-professional referral by racial and ethnic group, adjusted for age, gender, education, visit year, and Clinical Dementia Rating scale (CDR) with a random effect for study site. Results: Included in the analysis were 48,330 participants across 46 ADRCs (mean [SD] age, 71.3 [10.5] years; 20,767 female [57%]; 4,138 Hispanic [8.6%]; 1,392 non-Hispanic Asian [2.9%]; 6,766 non-Hispanic Black [14%] individuals; and 676 individuals [1.4%] of other races. Non-Hispanic Black and Asian participants had lower odds of being referred by a professional contact compared to non-Hispanic White participants (Black: adjusted OR = 0.61, 95% CI = 0.44-0.86, p = 0.005; Asian: adjusted OR = 0.65, 95% CI, p = 0.004). In participants who had completed an MRI, there was no significant difference in referral source across ethnic and racial groups. Conclusions: Further studies are needed to better understand the systemic and structural factors that contribute to differences in referral sources and disparities in recruitment of URG into ADRD studies.

Integrating amyloid imaging and genetics for early risk stratification of Alzheimer's disease.

INTRODUCTION: Alzheimer's disease (AD) initiates years prior to symptoms, underscoring the importance of early detection. While amyloid accumulation starts early, individuals with substantial amyloid burden may remain cognitively normal, implying that amyloid alone is not sufficient for early risk assessment. METHODS: Given the genetic susceptibility of AD, a multi-factorial pseudotime approach was proposed to integrate amyloid imaging and genotype data for estimating a risk score. Validation involved association with cognitive decline and survival analysis across risk-stratified groups, focusing on patients with mild cognitive impairment (MCI). RESULTS: Our risk score outperformed amyloid composite standardized uptake value ratio in correlation with cognitive scores. MCI subjects with lower pseudotime risk score showed substantial delayed onset of AD and slower cognitive decline. Moreover, pseudotime risk score demonstrated strong capability in risk stratification within traditionally defined subgroups such as early MCI, apolipoprotein E (APOE) ε4+ MCI, APOE ε4- MCI, and amyloid+ MCI. DISCUSSION: Our risk score holds great potential to improve the precision of early risk assessment. HIGHLIGHTS: Accurate early risk assessment is critical for the success of clinical trials. A new risk score was built from integrating amyloid imaging and genetic data. Our risk score demonstrated improved capability in early risk stratification.

The plasma miRNAome in ADNI: Signatures to aid the detection of at-risk individuals.

INTRODUCTION: MicroRNAs are short non-coding RNAs that control proteostasis at the systems level and are emerging as potential prognostic and diagnostic biomarkers for Alzheimer's disease (AD). METHODS: We performed small RNA sequencing on plasma samples from 847 Alzheimer's Disease Neuroimaging Initiative (ADNI) participants. RESULTS: We identified microRNA signatures that correlate with AD diagnoses and help predict the conversion from mild cognitive impairment (MCI) to AD. DISCUSSION: Our data demonstrate that plasma microRNA signatures can be used to not only diagnose MCI, but also, critically, predict the conversion from MCI to AD. Moreover, combined with neuropsychological testing, plasma microRNAome evaluation helps predict MCI to AD conversion. These findings are of considerable public interest because they provide a path toward reducing indiscriminate utilization of costly and invasive testing by defining the at-risk segment of the aging population. HIGHLIGHTS: We provide the first analysis of the plasma microRNAome for the ADNI study. The levels of several microRNAs can be used as biomarkers for the prediction of conversion from MCI to AD. Adding the evaluation of plasma microRNA levels to neuropsychological testing in a clinical setting increases the accuracy of MCI to AD conversion prediction.

Plasma miRNAs across the Alzheimer's disease continuum: Relationship to central biomarkers.

INTRODUCTION: MicroRNAs (miRNAs) play important roles in gene expression regulation and Alzheimer's disease (AD) pathogenesis. METHODS: We investigated the association between baseline plasma miRNAs and central AD biomarkers from the Alzheimer's Disease Neuroimaging Initiative (ADNI; N = 803): amyloid, tau, and neurodegeneration (A/T/N). Differentially expressed miRNAs and their targets were identified, followed by pathway enrichment analysis. Machine learning approaches were applied to investigate the role of miRNAs as blood biomarkers. RESULTS: We identified nine, two, and eight miRNAs significantly associated with A/T/N positivity, respectively. We identified 271 genes targeted by amyloid-related miRNAs with estrogen signaling receptor-mediated signaling among the enriched pathways. Additionally, 220 genes targeted by neurodegeneration-related miRNAs showed enrichment in pathways including the insulin growth factor 1 pathway. The classification performance of demographic information for A/T/N positivity was increased up to 9% with the inclusion of miRNAs. DISCUSSION: Plasma miRNAs were associated with central A/T/N biomarkers, highlighting their potential as blood biomarkers. HIGHLIGHTS: We performed association analysis of microRNAs (miRNAs) with amyloid/tau/neurodegeneration (A/T/N) biomarker positivity. We identified dysregulated miRNAs for A/T/N biomarker positivity. We identified Alzheimer's disease biomarker-specific/common pathways related to miRNAs. miRNAs improved the classification for A/T/N positivity by up to 9%. Our study highlights the potential of miRNAs as blood biomarkers.

CYP1B1-RMDN2 Alzheimer's disease endophenotype locus identified for cerebral tau PET.

Determining the genetic architecture of Alzheimer's disease pathologies can enhance mechanistic understanding and inform precision medicine strategies. Here, we perform a genome-wide association study of cortical tau quantified by positron emission tomography in 3046 participants from 12 independent studies. The CYP1B1-RMDN2 locus is associated with tau deposition. The most significant signal is at rs2113389, explaining 4.3% of the variation in cortical tau, while APOE4 rs429358 accounts for 3.6%. rs2113389 is associated with higher tau and faster cognitive decline. Additive effects, but no interactions, are observed between rs2113389 and diagnosis, APOE4, and amyloid beta positivity. CYP1B1 expression is upregulated in AD. rs2113389 is associated with higher CYP1B1 expression and methylation levels. Mouse model studies provide additional functional evidence for a relationship between CYP1B1 and tau deposition but not amyloid beta. These results provide insight into the genetic basis of cerebral tau deposition and support novel pathways for therapeutic development in AD.

Coupled pulsatile vascular and paravascular fluid dynamics in the human brain.

BACKGROUND: Cardiac pulsation propels blood through the cerebrovascular network to maintain cerebral homeostasis. The cerebrovascular network is uniquely surrounded by paravascular cerebrospinal fluid (pCSF), which plays a crucial role in waste removal, and its flow is suspected to be driven by arterial pulsations. Despite its importance, the relationship between vascular and paravascular fluid dynamics throughout the cardiac cycle remains poorly understood in humans. METHODS: In this study, we developed a non-invasive neuroimaging approach to investigate the coupling between pulsatile vascular and pCSF dynamics within the subarachnoid space of the human brain. Resting-state functional MRI (fMRI) and dynamic diffusion-weighted imaging (dynDWI) were retrospectively cardiac-aligned to represent cerebral hemodynamics and pCSF motion, respectively. We measured the time between peaks (∆TTP) in d d ϕ f M R I and dynDWI waveforms and measured their coupling by calculating the waveforms correlation after peak alignment (correlation at aligned peaks). We compared the ∆TTP and correlation at aligned peaks between younger [mean age: 27.9 (3.3) years, n = 9] and older adults [mean age: 70.5 (6.6) years, n = 20], and assessed their reproducibility within subjects and across different imaging protocols. RESULTS: Hemodynamic changes consistently precede pCSF motion. ∆TTP was significantly shorter in younger adults compared to older adults (-0.015 vs. -0.069, p < 0.05). The correlation at aligned peaks were high and did not differ between younger and older adults (0.833 vs. 0.776, p = 0.153). The ∆TTP and correlation at aligned peaks were robust across fMRI protocols (∆TTP: -0.15 vs. -0.053, p = 0.239; correlation at aligned peaks: 0.813 vs. 0.812, p = 0.985) and demonstrated good to excellent within-subject reproducibility (∆TTP: intraclass correlation coefficient = 0.36; correlation at aligned peaks: intraclass correlation coefficient = 0.89). CONCLUSION: This study proposes a non-invasive technique to evaluate vascular and paravascular fluid dynamics. Our findings reveal a consistent and robust cardiac pulsation-driven coupling between cerebral hemodynamics and pCSF dynamics in both younger and older adults.

Association of Alzheimer's disease polygenic risk score with concussion severity and recovery metrics.

Identification of genetic alleles associated with both Alzheimer's disease (AD) and concussion severity/recovery could help explain the association between concussion and elevated dementia risk. However, there has been little investigation into whether AD risk genes associate with concussion severity/recovery, and the limited findings are mixed. We used AD polygenic risk scores (PRS) and APOE genotypes to investigate any such associations in the NCAA-DoD Grand Alliance CARE Consortium (CARE) dataset. We assessed six outcomes in 931 total participants. The outcomes were two concussion recovery measures (number of days to asymptomatic status, number of days to return to play (RTP)) and four concussion severity measures (scores on SAC and BESS, SCAT symptom severity, and total number of symptoms). We calculated PRS using a published score [1] and performed multiple linear regression (MLR) to assess the relationship of PRS with the outcomes. We also used t-tests and chi-square tests to examine outcomes by APOE genotype, and MLR to analyze outcomes in European and African genetic ancestry subgroups. Higher PRS was associated with longer injury to RTP in the normal RTP (<24 days) subgroup ( p = 0.024), and one standard deviation increase in PRS resulted in a 9.89 hour increase to the RTP interval. There were no other consistently significant effects, suggesting that high AD genetic risk is not strongly associated with more severe concussions or poor recovery in young adults. Future studies should attempt to replicate these findings in larger samples with longer follow-up using PRS calculated from diverse populations.

Sex, racial, and APOE-ε4 allele differences in longitudinal white matter microstructure in multiple cohorts of aging and Alzheimer's disease.

INTRODUCTION: The effects of sex, race, and Apolipoprotein E (APOE) - Alzheimer's disease (AD) risk factors - on white matter integrity are not well characterized. METHODS: Diffusion MRI data from nine well-established longitudinal cohorts of aging were free-water (FW)-corrected and harmonized. This dataset included 4,702 participants (age=73.06 ± 9.75) with 9,671 imaging sessions over time. FW and FW-corrected fractional anisotropy (FAFWcorr) were used to assess differences in white matter microstructure by sex, race, and APOE-ε4 carrier status. RESULTS: Sex differences in FAFWcorr in association and projection tracts, racial differences in FAFWcorr in projection tracts, and APOE-ε4 differences in FW limbic and occipital transcallosal tracts were most pronounced. DISCUSSION: There are prominent differences in white matter microstructure by sex, race, and APOE-ε4 carrier status. This work adds to our understanding of disparities in AD. Additional work to understand the etiology of these differences is warranted.

Identifying Shared Neuroanatomic Architecture between Cognitive Traits through Multiscale Morphometric Correlation Analysis.

We introduce an informative metric, called morphometric correlation, as a measure of shared neuroanatomic similarity between two cognitive traits. Traditional estimates of trait correlations can be confounded by factors beyond brain morphology. To exclude these confounding factors, we adopt a Gaussian kernel to measure the morphological similarity between individuals and compare pure neuroanatomic correlations among cognitive traits. In our empirical study, we employ a multiscale strategy. Given a set of cognitive traits, we first perform morphometric correlation analysis for each pair of traits to reveal their shared neuroanatomic correlation at the whole brain (or global) level. After that, we extend our whole brain concept to regional morphometric correlation and estimate shared neuroanatomic similarity between two cognitive traits at the regional (or local) level. Our results demonstrate that morphometric correlation can provide insights into shared neuroanatomic architecture between cognitive traits. Furthermore, we also estimate the morphometricity of each cognitive trait at both global and local levels, which can be used to better understand how neuroanatomic changes influence individuals' cognitive status.

Spatial transcriptomic patterns underlying amyloid-ß and tau pathology are associated with cognitive dysfunction in Alzheimer's disease.

Amyloid-ß (Aß) and tau proteins accumulate within distinct neuronal systems in Alzheimer's disease (AD). Although it is not clear why certain brain regions are more vulnerable to Aß and tau pathologies than others, gene expression may play a role. We study the association between brain-wide gene expression profiles and regional vulnerability to Aß (gene-to-Aß associations) and tau (gene-to-tau associations) pathologies by leveraging two large independent AD cohorts. We identify AD susceptibility genes and gene modules in a gene co-expression network with expression profiles specifically related to regional vulnerability to Aß and tau pathologies in AD. In addition, we identify distinct biochemical pathways associated with the gene-to-Aß and the gene-to-tau associations. These findings may explain the discordance between regional Aß and tau pathologies. Finally, we propose an analytic framework, linking the identified gene-to-pathology associations to cognitive dysfunction in AD at the individual level, suggesting potential clinical implication of the gene-to-pathology associations.

Cognitively defined Alzheimer's dementia subgroups have distinct atrophy patterns.

INTRODUCTION: We sought to determine structural magnetic resonance imaging (MRI) characteristics across subgroups defined based on relative cognitive domain impairments using data from the Alzheimer's Disease Neuroimaging Initiative (ADNI) and to compare cognitively defined to imaging-defined subgroups. METHODS: We used data from 584 people with Alzheimer's disease (AD) (461 amyloid positive, 123 unknown amyloid status) and 118 amyloid-negative controls. We used voxel-based morphometry to compare gray matter volume (GMV) for each group compared to controls and to AD-Memory. RESULTS: There was pronounced bilateral lower medial temporal lobe atrophy with relative cortical sparing for AD-Memory, lower left hemisphere GMV for AD-Language, anterior lower GMV for AD-Executive, and posterior lower GMV for AD-Visuospatial. Formal asymmetry comparisons showed substantially more asymmetry in the AD-Language group than any other group (p = 1.15 × 10-10 ). For overlap between imaging-defined and cognitively defined subgroups, AD-Memory matched up with an imaging-defined limbic predominant group. DISCUSSION: MRI findings differ across cognitively defined AD subgroups.

Paravascular fluid dynamics reveal arterial stiffness assessed using dynamic diffusion-weighted imaging.

Paravascular cerebrospinal fluid (pCSF) surrounding the cerebral arteries within the glymphatic system is pulsatile and moves in synchrony with the pressure waves of the vessel wall. Whether such pulsatile pCSF can infer pulse wave propagation-a property tightly related to arterial stiffness-is unknown and has never been explored. Our recently developed imaging technique, dynamic diffusion-weighted imaging (dynDWI), captures the pulsatile pCSF dynamics in vivo and can explore this question. In this work, we evaluated the time shifts between pCSF waves and finger pulse waves, where pCSF waves were measured by dynDWI and finger pulse waves were measured by the scanner's built-in finger pulse oximeter. We hypothesized that the time shifts reflect brain-finger pulse wave travel time and are sensitive to arterial stiffness. We applied the framework to 36 participants aged 18-82 years to study the age effect of travel time, as well as its associations with cognitive function within the older participants (N = 15, age > 60 years). Our results revealed a strong and consistent correlation between pCSF pulse and finger pulse (mean CorrCoeff = 0.66), supporting arterial pulsation as a major driver for pCSF dynamics. The time delay between pCSF and finger pulses (TimeDelay) was significantly lower (i.e., faster pulse propagation) with advanced age (Pearson's r = -0.44, p = 0.007). Shorter TimeDelay was further associated with worse cognitive function in the older participants. Overall, our study demonstrated pCSF as a viable pathway for measuring intracranial pulses and encouraged future studies to investigate its relevance with cerebrovascular functions.

Associations Between Social Network Characteristics and Brain Structure Among Older Adults.

INTRODUCTION: Social connectedness is associated with slower cognitive decline among older adults. Recent research suggests that distinct aspects of social networks may have differential effects on cognitive resilience, but few studies analyze brain structure. METHODS: This study includes 117 cognitively impaired and 59 unimpaired older adults. The effects of social network characteristics (bridging/bonding) on brain regions of interests were analyzed using linear regressions and voxel-wise multiple linear regressions of gray matter density. RESULTS: Increased social bridging was associated with greater bilateral amygdala volume and insular thickness, and left frontal lobe thickness, putamen, and thalamic volumes. Increased social bonding was associated with greater bilateral medial orbitofrontal and caudal anterior cingulate thickness, as well as right frontal lobe thickness, putamen, and amygdala volumes. DISCUSSION: The associations between social connectedness and brain structure vary depending on the types of social enrichment accessible through social networks, suggesting that psychosocial interventions could mitigate neurodegeneration. HIGHLIGHTS: Distinct forms of social capital are uniquely linked to gray matter density (GMD). Bridging is associated with preserved GMD in limbic system structures. Bonding is associated with preserved GMD in frontal lobe regions. Bridging is associated with increased brain reserve in sensory processing regions. Bonding is associated with increased brain reserve in regions of stress modulation.

Edge time series components of functional connectivity and cognitive function in Alzheimer's disease.

Understanding the interrelationships of brain function as measured by resting-state magnetic resonance imaging and neuropsychological/behavioral measures in Alzheimer's disease is key for advancement of neuroimaging analysis methods in clinical research. The edge time-series framework recently developed in the field of network neuroscience, in combination with other network science methods, allows for investigations of brain-behavior relationships that are not possible with conventional functional connectivity methods. Data from the Indiana Alzheimer's Disease Research Center sample (53 cognitively normal control, 47 subjective cognitive decline, 32 mild cognitive impairment, and 20 Alzheimer's disease participants) were used to investigate relationships between functional connectivity components, each derived from a subset of time points based on co-fluctuation of regional signals, and measures of domain-specific neuropsychological functions. Multiple relationships were identified with the component approach that were not found with conventional functional connectivity. These involved attentional, limbic, frontoparietal, and default mode systems and their interactions, which were shown to couple with cognitive, executive, language, and attention neuropsychological domains. Additionally, overlapping results were obtained with two different statistical strategies (network contingency correlation analysis and network-based statistics correlation). Results demonstrate that connectivity components derived from edge time-series based on co-fluctuation reveal disease-relevant relationships not observed with conventional static functional connectivity.

Traumatic brain injury and Alzheimer's Disease biomarkers: A systematic review of findings from amyloid and tau positron emission tomography (PET).

Traumatic brain injury (TBI) has been discussed as a risk factor for Alzheimer's disease (AD) due to its association with dementia risk and earlier cognitive symptom onset. However, the mechanisms behind this relationship are unclear. Some studies have suggested TBI may increase pathological protein deposition in an AD-like pattern; others have failed to find such associations. This review covers literature that uses positron emission tomography (PET) of amyloid-ß and/or tau to examine subjects with history of TBI who are at risk for AD due to advanced age. A comprehensive literature search was conducted on January 9, 2023, and 24 resulting citations met inclusion criteria. Common methodological concerns included small samples, limited clinical detail about subjects' TBI, recall bias due to reliance on self-reported TBI, and an inability to establish causation. For both amyloid and tau, results were widespread but inconsistent. The regions which showed the most compelling evidence for increased amyloid deposition were the cingulate gyrus, cuneus/precuneus, and parietal lobe. Evidence for increased tau was strongest in the medial temporal lobe, entorhinal cortex, precuneus, and frontal, temporal, parietal, and occipital lobes. However, conflicting findings across most regions of interest in both amyloid- and tau-PET studies indicate the critical need for future work in expanded samples and with greater clinical detail to offer a clearer picture of the relationship between TBI and protein deposition in older subjects at risk for AD.

BrainAGE Estimation: Influence of Field Strength, Voxel Size, Race, and Ethnicity.

The BrainAGE method is used to estimate biological brain age using structural neuroimaging. However, the stability of the model across different scan parameters and races/ethnicities has not been thoroughly investigated. Estimated brain age was compared within- and across- MRI field strength and across voxel sizes. Estimated brain age gap (BAG) was compared across demographically matched groups of different self-reported races and ethnicities in ADNI and IMAS cohorts. Longitudinal ComBat was used to correct for potential scanner effects. The brain age method was stable within field strength, but less stable across different field strengths. The method was stable across voxel sizes. There was a significant difference in BAG between races, but not ethnicities. Correction procedures are suggested to eliminate variation across scanner field strength while maintaining accurate brain age estimation. Further studies are warranted to determine the factors contributing to racial differences in BAG.

White matter integrity is associated with cognition and amyloid burden in older adult Koreans along the Alzheimer's disease continuum.

BACKGROUND: White matter (WM) microstructural changes in the hippocampal cingulum bundle (CBH) in Alzheimer's disease (AD) have been described in cohorts of largely European ancestry but are lacking in other populations. METHODS: We assessed the relationship between CBH WM integrity and cognition or amyloid burden in 505 Korean older adults aged ≥ 55 years, including 276 cognitively normal older adults (CN), 142 with mild cognitive impairment (MCI), and 87 AD patients, recruited as part of the Korean Brain Aging Study for the Early Diagnosis and Prediction of Alzheimer's disease (KBASE) at Seoul National University. RESULTS: Compared to CN, AD and MCI subjects showed significantly higher RD, MD, and AxD values (all p-values < 0.001) and significantly lower FA values (left p ≤ 0.002, right p ≤ 0.015) after Bonferroni adjustment for multiple comparisons. Most tests of cognition and mood (p < 0.001) as well as higher medial temporal amyloid burden (p < 0.001) were associated with poorer WM integrity in the CBH after Bonferroni adjustment. CONCLUSION: These findings are consistent with patterns of WM microstructural damage previously reported in non-Hispanic White (NHW) MCI/AD cohorts, reinforcing existing evidence from predominantly NHW cohort studies.

Genome-Wide Association Analysis across Endophenotypes in Alzheimer's Disease: Main Effects and Disease Stage-Specific Interactions.

The underlying genetic susceptibility for Alzheimer's disease (AD) is not yet fully understood. The heterogeneous nature of the disease challenges genetic association studies. Endophenotype approaches can help to address this challenge by more direct interrogation of biological traits related to the disease. AD endophenotypes based on amyloid-ß, tau, and neurodegeneration (A/T/N) biomarkers and cognitive performance were selected from the Alzheimer's Disease Neuroimaging Initiative (ADNI) cohort (N = 1565). A genome-wide association study (GWAS) of quantitative phenotypes was performed using an SNP main effect and an SNP by Diagnosis interaction (SNP × DX) model to identify disease stage-specific genetic effects. Nine loci were identified as study-wide significant with one or more A/T/N endophenotypes in the main effect model, as well as additional findings significantly associated with cognitive measures. These nine loci include SNPs in or near the genes APOE, SRSF10, HLA-DQB1, XKR3, and KIAA1671. The SNP × DX model identified three study-wide significant genetic loci (BACH2, EP300, and PACRG-AS1) with a neuroprotective effect in later AD stage endophenotypes. An endophenotype approach identified novel genetic associations and provided insight into the molecular mechanisms underlying the genetic associations that may otherwise be missed using conventional case-control study designs.

Edge Time Series Components of Functional Connectivity and Cognitive Function in Alzheimer's Disease.

Understanding the interrelationships of brain function as measured by resting-state magnetic resonance imaging and neuropsychological/behavioral measures in Alzheimer's disease is key for advancement of neuroimaging analysis methods in clinical research. The edge time-series framework recently developed in the field of network neuroscience, in combination with other network science methods, allows for investigations of brain-behavior relationships that are not possible with conventional functional connectivity methods. Data from the Indiana Alzheimer's Disease Research Center sample (53 cognitively normal control, 47 subjective cognitive decline, 32 mild cognitive impairment, and 20 Alzheimer's disease participants) were used to investigate relationships between functional connectivity components, each derived from a subset of time points based on co-fluctuation of regional signals, and measures of domain-specific neuropsychological functions. Multiple relationships were identified with the component approach that were not found with conventional functional connectivity. These involved attentional, limbic, frontoparietal, and default mode systems and their interactions, which were shown to couple with cognitive, executive, language, and attention neuropsychological domains. Additionally, overlapping results were obtained with two different statistical strategies (network contingency correlation analysis and network-based statistics correlation). Results demonstrate that connectivity components derived from edge time-series based on co-fluctuation reveal disease-relevant relationships not observed with conventional static functional connectivity.

Leveraging longitudinal diffusion MRI data to quantify differences in white matter microstructural decline in normal and abnormal aging.

Introduction: It is unclear how rates of white matter microstructural decline differ between normal aging and abnormal aging. Methods: Diffusion MRI data from several well-established longitudinal cohorts of aging (Alzheimer's Disease Neuroimaging Initiative [ADNI], Baltimore Longitudinal Study of Aging [BLSA], Vanderbilt Memory & Aging Project [VMAP]) were free-water corrected and harmonized. This dataset included 1723 participants (age at baseline: 72.8 ± 8.87 years, 49.5% male) and 4605 imaging sessions (follow-up time: 2.97 ± 2.09 years, follow-up range: 1-13 years, mean number of visits: 4.42 ± 1.98). Differences in white matter microstructural decline in normal and abnormal agers was assessed. Results: While we found a global decline in white matter in normal/abnormal aging, we found that several white matter tracts (e.g., cingulum bundle) were vulnerable to abnormal aging. Conclusions: There is a prevalent role of white matter microstructural decline in aging, and future large-scale studies in this area may further refine our understanding of the underlying neurodegenerative processes. HIGHLIGHTS: Longitudinal data were free-water corrected and harmonized.Global effects of white matter decline were seen in normal and abnormal aging.The free-water metric was most vulnerable to abnormal aging.Cingulum free-water was the most vulnerable to abnormal aging.