Apolipoprotein E and Alzheimer's disease pathology in African American older adults.

The apolipoprotein-E4 (APOE*4) and apolipoprotein-E2 (APOE*2) alleles are more common in African American versus non-Hispanic white populations, but relationships of both alleles with Alzheimer's disease (AD) pathology among African American individuals are unclear. We measured APOE allele and ß-amyloid (Aß) and tau using blood samples and positron emission tomography (PET) images, respectively. Individual regression models tested associations of each APOE allele with Aß or tau PET overall, stratified by racialized group, and with a racialized group interaction. We included 358 older adults (42% African American) with Aß PET, 134 (29% African American) of whom had tau PET. APOE*4 was associated with higher Aß in non-Hispanic white (P < 0.0001), but not African American (P = 0.64) participants; racialized group modified the association between APOE*4 and Aß (P < 0.0001). There were no other racialized group differences. These results suggest that the association of APOE*4 and Aß differs between African American and non-Hispanic white populations. Other drivers of AD pathology in African American populations should be identified as potential therapeutic targets.

Unhealthy white matter connectivity, cognition, and racialization in older adults.

INTRODUCTION: White matter hyperintensities (WMH) may promote clinical Alzheimer's disease (AD) disparities between Black American (BA) and non-Hispanic White (nHW) populations. Using a novel measurement, unhealthy white matter connectivity (UWMC), we interrogated racialized group differences in associations between WMH in AD pathology-affected regions and cognition. METHODS: UWMC is the proportion of white matter fibers that pass through WMH for every pair of brain regions. Individual regression models tested associations of UWMC in beta-amyloid (Aß) or tau pathology-affected regions with cognition overall, stratified by racialized group, and with a racialized group interaction. RESULTS: In 201 older adults ranging from cognitively unimpaired to AD, BA participants exhibited greater UWMC and worse cognition than nHW participants. UWMC was negatively associated with cognition in 17 and 5 Aß- and tau-affected regions, respectively. Racialization did not modify these relationships. DISCUSSION: Differential UWMC burden, not differential UWMC-and-cognition associations, may drive clinical AD disparities between racialized groups. HIGHLIGHTS: Unhealthy white matter connectivity (UWMC) in Alzheimer's disease (AD) pathology-affected brain regions is associated with cognition. Relationships between UWMC and cognition are similar between Black American (BA) and non-Hispanic White (nHW) individuals. More UWMC may partially drive higher clinical AD burden in BA versus nHW populations. UWMC risk factors, particularly social and environmental, should be identified.

Multi-ancestry genome-wide meta-analysis of 56,241 individuals identifies LRRC4C, LHX5-AS1 and nominates ancestry-specific loci PTPRK , GRB14 , and KIAA0825 as novel risk loci for Alzheimer's disease: the Alzheimer's Disease Genetics Consortium.

Limited ancestral diversity has impaired our ability to detect risk variants more prevalent in non-European ancestry groups in genome-wide association studies (GWAS). We constructed and analyzed a multi-ancestry GWAS dataset in the Alzheimer's Disease (AD) Genetics Consortium (ADGC) to test for novel shared and ancestry-specific AD susceptibility loci and evaluate underlying genetic architecture in 37,382 non-Hispanic White (NHW), 6,728 African American, 8,899 Hispanic (HIS), and 3,232 East Asian individuals, performing within-ancestry fixed-effects meta-analysis followed by a cross-ancestry random-effects meta-analysis. We identified 13 loci with cross-ancestry associations including known loci at/near CR1 , BIN1 , TREM2 , CD2AP , PTK2B , CLU , SHARPIN , MS4A6A , PICALM , ABCA7 , APOE and two novel loci not previously reported at 11p12 ( LRRC4C ) and 12q24.13 ( LHX5-AS1 ). Reflecting the power of diverse ancestry in GWAS, we observed the SHARPIN locus using 7.1% the sample size of the original discovering single-ancestry GWAS (n=788,989). We additionally identified three GWS ancestry-specific loci at/near ( PTPRK ( P =2.4×10 -8 ) and GRB14 ( P =1.7×10 -8 ) in HIS), and KIAA0825 ( P =2.9×10 -8 in NHW). Pathway analysis implicated multiple amyloid regulation pathways (strongest with P adjusted =1.6×10 -4 ) and the classical complement pathway ( P adjusted =1.3×10 -3 ). Genes at/near our novel loci have known roles in neuronal development ( LRRC4C, LHX5-AS1 , and PTPRK ) and insulin receptor activity regulation ( GRB14 ). These findings provide compelling support for using traditionally-underrepresented populations for gene discovery, even with smaller sample sizes.

Prospective Longitudinal Perfusion in Probable Alzheimer's Disease Correlated with Atrophy in Temporal Lobe.

Reduced cerebral blood flow (CBF) in the temporoparietal region and gray matter volumes (GMVs) in the temporal lobe were previously reported in patients with mild cognitive impairment (MCI) and Alzheimer's disease (AD). However, the temporal relationship between reductions in CBF and GMVs requires further investigation. This study sought to determine if reduced CBF is associated with reduced GMVs, or vice versa. Data came from 148 volunteers of the Cardiovascular Health Study Cognition Study (CHS-CS), including 58 normal controls (NC), 50 MCI, and 40 AD who had perfusion and structural MRIs during 2002-2003 (Time 2). Sixty-three of the 148 volunteers had follow-up perfusion and structural MRIs (Time 3). Forty out of the 63 volunteers received prior structural MRIs during 1997-1999 (Time 1). The relationships between GMVs and subsequent CBF changes, and between CBF and subsequent GMV changes were investigated. At Time 2, we observed smaller GMVs (p<0.05) in the temporal pole region in AD compared to NC and MCI. We also found associations between: (1) temporal pole GMVs at Time 2 and subsequent declines in CBF in this region (p=0.0014) and in the temporoparietal region (p=0.0032); (2) hippocampal GMVs at Time 2 and subsequent declines in CBF in the temporoparietal region (p=0.012); and (3) temporal pole CBF at Time 2 and subsequent changes in GMV in this region (p = 0.011). Therefore, hypoperfusion in the temporal pole may be an early event driving its atrophy. Perfusion declines in the temporoparietal and temporal pole follow atrophy in this temporal pole region.

An Emerging Screening Method for Interrogating Human Brain Function: Tutorial.

Cognitive decline can be observed due to a myriad of causes. Clinicians would benefit from a noninvasive quantitative tool to screen and monitor brain function based on direct measures of neural features. In this study, we used neuroimaging data from magnetoencephalography (with a whole-head Elekta Neuromag 306 sensor system) to derive a set of features that strongly correlate with brain function. We propose that simple signal characteristics related to peak variability, timing, and abundance can be used by clinicians as a screening tool to investigate cognitive function in at-risk individuals. Using a minimalistic set of features, we were able to perfectly distinguish between participants with normative and nonnormative brain function, and we were also able to successfully predict participants' Mini-Mental Test score (r=0.99; P<.001; mean absolute error=0.413). This set of features can be easily visualized in an analog fashion, providing clinicians with several graded measurements (in comparison to a single binary diagnostic tool) that can be used for screening and monitoring cognitive decline.

MEG Oscillatory Slowing in Cognitive Impairment is Associated with the Presence of Subjective Cognitive Decline.

The mechanisms behind Alzheimer's disease are not yet fully described, and changes in the electrophysiology of patients across the continuum of the disease could help to understand them. In this work, we study the power spectral distribution of a set of 129 individuals from the Connectomics of Brian Aging and Dementia project.From this sample, we acquired task-free data, with eyes closed, and estimated the power spectral distribution in source space. We compared the spectral profiles of three groups of individuals: 70 healthy controls, 27 patients with amnestic MCI, and 32 individuals showing cognitive impairment without subjective complaints (IWOC).The results showed a slowing of the brain activity in the aMCI patients, when compared to both the healthy controls and the IWOC individuals. These differences appeared both as a decrease in power for high frequency oscillations and an increase in power in alpha oscillations. The slowing of the spectrum was significant mainly in parietal and medial frontal areas.We were able to validate the slowing of the brain activity in individuals with aMCI, appearing in our sample in areas related to the default mode network. However, this pattern did not appear in the IWOC individuals, suggesting that their condition is not part of the AD continuum. This work raises interesting questions about this group of individuals, and the underlying brain mechanisms behind their cognitive impairment.

Dynamic impairment classification through arrayed comparisons.

The multivariate normative comparison (MNC) method has been used for identifying cognitive impairment. When participants' cognitive brain domains are evaluated regularly, the longitudinal MNC (LMNC) has been introduced to correct for the intercorrelation among repeated assessments of multiple cognitive domains in the same participant. However, it may not be practical to wait until the end of study for diagnosis. For example, in participants of the Multicenter AIDS Cohort Study (MACS), cognitive functioning has been evaluated repeatedly for more than 35 years. Therefore, it is optimal to identify cognitive impairment at each assessment, while the family-wise error rate (FWER) is controlled with unknown number of assessments in future. In this work, we propose to use the difference of consecutive LMNC test statistics to construct independent tests. Frequency modeling can help predict how many assessments each participant will have, so Bonferroni-type correction can be easily adapted. A chi-squared test is used under the assumption of multivariate normality, and permutation test is proposed where this assumption is violated. We showed through simulation and the MACS data that our method controlled FWER below a predetermined level.

Developing a digital music program for older adults with changing cognition: A program development report.

This program development report describes the adaptation of a music program for older adults with memory loss from in-person to a digital format. The objective was to develop a music program that was both engaging for the older adults, acceptable for the music instructor, and clearly defined for future research and implementation. This report describes the content of the music program and the systematic process of its development.

Higher Soluble CD163 in Blood Is Associated With Significant Depression Symptoms in Men With HIV.

BACKGROUND: People with HIV (PWH) are more likely to experience depression, a highly morbid disease. More evidence is needed to better understand mechanisms of depression in PWH. We evaluated a panel of blood biomarkers in relation to depression symptoms in the Multicenter AIDS Cohort Study (MACS). SETTING: Four sites in the United States. METHODS: A cross-sectional analysis was performed within the MACS, a prospective study of cisgender men with and without HIV. Depression was assessed with the Center for Epidemiological Studies-Depression Scale, and six blood biomarkers were measured: GlycA, high sensitivity C-reactive protein (CRP), interleukin-6, CCL2, soluble CD14 (sCD14), and soluble CD163 (sCD163). Using univariable and multivariable logistic regression, the biomarkers and other factors were evaluated in relation to significant depression symptoms (SDS) by Center for Epidemiological Studies-Depression score ≥16. RESULTS: 784 men were analyzed; most of whom (63%) were PWH. PWH were more likely to have SDS (32% vs. 21%). In univariable analysis, higher GlycA, CRP, and sCD163 concentrations were associated with SDS. In multivariable analysis, however, only higher sCD163 concentration was associated with SDS (odds ratio = 2.30, 95% CI = 1.11 to 4.76). This relationship was driven by the PWH group (odds ratio = 2.72, 95% CI = 1.12 to 6.58) and remained significant when controlling for antidepressant use. Lack of college education was also associated with SDS. CONCLUSIONS: Higher sCD163, a marker of macrophage activation, was significantly associated with significant depression symptoms in the MACS. Further research on this biomarker and macrophage activation in general is warranted to better understand and treat depression in PWH.

Pattern of Altered Magnetization Transfer Rate in Alzheimer's Disease.

BACKGROUND: Biomarkers for Alzheimer's disease (AD) are crucial for early diagnosis and treatment monitoring once disease modifying therapies become available. OBJECTIVE: This study aims to quantify the forward magnetization transfer rate (kfor) map from brain tissue water to macromolecular protons and use it to identify the brain regions with abnormal kfor in AD and AD progression. METHODS: From the Cardiovascular Health Study (CHS) cognition study, magnetization transfer imaging (MTI) was acquired at baseline from 63 participants, including 20 normal controls (NC), 18 with mild cognitive impairment (MCI), and 25 AD subjects. Of those, 53 participants completed a follow-up MRI scan and were divided into four groups: 15 stable NC, 12 NC-to-MCI, 12 stable MCI, and 14 MCI/AD-to-AD subjects. kfor maps were compared across NC, MCI, and AD groups at baseline for the cross-sectional study and across four longitudinal groups for the longitudinal study. RESULTS: We found a lower kfor in the frontal gray matter (GM), parietal GM, frontal corona radiata (CR) white matter (WM) tracts, frontal and parietal superior longitudinal fasciculus (SLF) WM tracts in AD relative to both NC and MCI. Further, we observed progressive decreases of kfor in the frontal GM, parietal GM, frontal and parietal CR WM tracts, and parietal SLF WM tracts in stable MCI. In the parietal GM, parietal CR WM tracts, and parietal SLF WM tracts, we found trend differences between MCI/AD-to-AD and stable NC. CONCLUSION: Forward magnetization transfer rate is a promising biomarker for AD diagnosis and progression.

Legacy effect on neuropsychological function in HIV-infected men on combination antiretroviral therapy.

OBJECTIVE: To determine whether combination antiretroviral therapy (cART) initiation alters the trajectory of cognitive performance in HIV+ men, and whether cognition prior to cART predicts postcART function. DESIGN: Longitudinal cohort study. Multicenter AIDS Cohort Study. METHODS: From an initial set of 3701 men with complete neuropsychological data, men with HIV infection were initially matched with men without infection on cognitive status, race, age, and timeline (T0 defined as cART initiation). Propensity score matching was then used to match pairs on depressive symptoms at T0, education, T0 cognitive scores, and recruitment cohort. There were 506 matched pairs of infected and uninfected men in the final analysis. Mixed effect models were constructed to analyze the trajectories of cognitive functions and to test the effect of cART and HIV on cognitive functions over time. RESULTS: Performance in each cognitive domain did not change following the initiation of cART among HIV-infected men with prior impairment and was comparable to the performance of their matched uninfected men. However, among the infected men who were unimpaired prior to cART, motor function declined significantly faster than it did for uninfected controls. CONCLUSIONS: Cognitive dysfunction is persistent in HIV-infected men and cART does not alter the trajectory of cognitive decline in men who were impaired prior to effective therapy. This suggests that current cognitive impairment in HIV+ men results from a legacy effect, and from factors other than the HIV itself. Furthermore, motor skills may be uniquely vulnerable to the virus, cART, or age-related co-morbidities.

Sex Differences in Magnetoencephalography-Identified Functional Connectivity in the Human Connectome Project Connectomics of Brain Aging and Dementia Cohort.

Introduction: The human brain shows modest traits of sexual dimorphism, with the female brain, on average, 10% smaller than the male brain. These differences do not imply a lowered cognitive performance, but suggest a more optimal brain organization in women. Here we evaluate the patterns of functional connectivity (FC) in women and men from the Connectomics of Brain Aging and Dementia sample. Methods: We used phase locking values to calculate FC from the magnetoencephalography time series in a sample of 138 old adults (87 females and 51 males). We compared the FC patterns between sexes, with the intention of detecting regions with different levels of connectivity. Results: We found a frontal cluster, involving anterior cingulate and the medial frontal lobe, where women showed higher FC values than men. Involved connections included the following: (1) medial parietal areas, such as posterior cingulate cortices and precunei; (2) right insula; and (3) medium cingulate and paracingulate cortices. Moreover, these differences persisted when considering only cognitively intact individuals, but not when considering only cognitively impaired individuals. Discussion: Increased anteroposterior FC has been identified as a biomarker for increased risk of developing cognitive impairment or dementia. In our study, cognitively intact women showed higher levels of FC than their male counterparts. This result suggests that neurodegenerative processes could be taking place in these women, but the changes are undetected by current diagnosis tools. FC, as measured here, might be valuable for early identification of this neurodegeneration.

Connectomics in Brain Aging and Dementia - The Background and Design of a Study of a Connectome Related to Human Disease.

The natural history of Alzheimer's Disease (AD) includes significant alterations in the human connectome, and this disconnection results in the dementia of AD. The organizing principle of our research project is the idea that the expression of cognitive dysfunction in the elderly is the result of two independent processes - the neuropathology associated with AD, and second the neuropathological changes of cerebrovascular disease. Synaptic loss, senile plaques, and neurofibrillary tangles are the functional and diagnostic hallmarks of AD, but it is the structural changes as a consequence of vascular disease that reduce brain reserve and compensation, resulting in an earlier expression of the clinical dementia syndrome. This work is being completed under the auspices of the Human Connectome Project (HCP). We have achieved an equal representation of Black individuals (vs. White individuals) and enrolled 60% Women. Each of the participants contributes demographic, behavioral and laboratory data. We acquire data relative to vascular risk, and the participants also undergo in vivo amyloid imaging, and magnetoencephalography (MEG). All of the data are publicly available under the HCP guidelines using the Connectome Coordinating Facility and the NIMH Data Archive. Locally, we use these data to address specific questions related to structure, function, AD, aging and vascular disease in multi-modality studies leveraging the differential advantages of magnetic resonance imaging (MRI), functional magnetic resonance imaging (fMRI), MEG, and in vivo beta amyloid imaging.

Cerebral Blood Flow Predicts Conversion of Mild Cognitive Impairment into Alzheimer's Disease and Cognitive Decline: An Arterial Spin Labeling Follow-up Study.

BACKGROUND: This is the first longitudinal study to assess regional cerebral blood flow (rCBF) changes during the progression from normal control (NC) through mild cognitive impairment (MCI) and Alzheimer's disease (AD). OBJECTIVE: We aim to determine if perfusion MRI biomarkers, derived from our prior cross-sectional study, can predict the onset and cognitive decline of AD. METHODS: Perfusion MRIs using arterial spin labeling (ASL) were acquired in 15 stable-NC, 14 NC-to-MCI, 16 stable-MCI, and 18 MCI/AD-to-AD participants from the Cardiovascular Health Study (CHS) cognition study. Group comparisons, predictions of AD conversion and time to conversion, and Modified Mini-Mental State Examination (3MSE) from rCBF were performed. RESULTS: Compared to the stable-NC group: 1) the stable-MCI group exhibited rCBF decreases in the right temporoparietal (p = 0.00010) and right inferior frontal and insula (p = 0.0094) regions; and 2) the MCI/AD-to-AD group exhibited rCBF decreases in the bilateral temporoparietal regions (p = 0.00062 and 0.0035). Compared to the NC-to-MCI group, the stable-MCI group exhibited a rCBF decrease in the right hippocampus region (p = 0.0053). The baseline rCBF values in the posterior cingulate cortex (PCC) (p = 0.0043), bilateral superior medial frontal regions (BSMF) (p = 0.012), and left inferior frontal (p = 0.010) regions predicted the 3MSE scores for all the participants at follow-up. The baseline rCBF in the PCC and BSMF regions predicted the conversion and time to conversion from MCI to AD (p < 0.05; not significant after multiple corrections). CONCLUSION: We demonstrated the feasibility of ASL in detecting rCBF changes in the typical AD-affected regions and the predictive value of baseline rCBF on AD conversion and cognitive decline.

Cardiac-induced cerebral pulsatility, brain structure, and cognition in middle and older-aged adults.

Changes of cardiac-induced regional pulsatility can be associated with specific regions of brain volumetric changes, and these are related with cognitive alterations. Thus, mapping of cardiac pulsatility over the entire brain can be helpful to assess these relationships. A total of 108 subjects (age: 66.5 ± 8.4 years, 68 females, 52 healthy controls, 11 subjective cognitive decline, 17 impaired without complaints, 19 MCI and 9 AD) participated. The pulsatility map was obtained directly from resting-state functional MRI time-series data at 3T. Regional brain volumes were segmented from anatomical MRI. Multidomain neuropsychological battery was performed to test memory, language, attention and visuospatial construction. The Montreal Cognitive Assessment (MoCA) was also administered. The sparse partial least square (SPLS) method, which is desirable for better interpreting high-dimensional variables, was applied for the relationship between the entire brain voxels of pulsatility and 45 segmented brain volumes. A multiple holdout SPLS framework was used to optimize sparsity for assessing the pulsatility-volume relationship model and to test the reliability by fitting the models to 9 different splits of the data. We found statistically significant associations between subsets of pulsatility voxels and subsets of segmented brain volumes by rejecting the omnibus null hypothesis (any of 9 splits has p < 0.0056 (=0.05/9) with the Bonferroni correction). The pulsatility was positively associated with the lateral ventricle, choroid plexus, inferior lateral ventricle, and 3rd ventricle and negatively associated with hippocampus, ventral DC, and thalamus volumes for the first pulsatility-volume relationship. The pulsatility had an additional negative relationship with the amygdala and brain stem volumes for the second pulsatility-volume relationship. The spatial distribution of correlated pulsatility was observed in major feeding arteries to the brain regions, ventricles, and sagittal sinus. The indirect mediating pathways through the volumetric changes were statistically significant between the pulsatility and multiple cognitive measures (p < 0.01). Thus, the cerebral pulsatility, along with volumetric measurements, could be a potential marker for better understanding of pathophysiology and monitoring disease progression in age-related neurodegenerative disorders.

Longitudinal 5-year prediction of cognitive impairment among men with HIV disease.

BACKGROUND: Although combination antiretroviral therapy reduced the prevalence of HIV-associated dementia, milder syndromes persist. Our goals were to predict cognitive impairment of the Multicenter AIDS Cohort Study (MACS) participants 5 years ahead and from a large pool of factors, select the ones that mostly contributed to our predictions. DESIGN: Longitudinal, natural and treated history of HIV infection among MSM. METHODS: The MACS is a longitudinal study of the natural and treated history of HIV disease in MSM; the neuropsychological substudy aims to characterize cognitive disorders in men with HIV disease. RESULTS: We modeled on an annual basis the risk of cognitive impairment 5 years in the future. We were able to predict cognitive impairment at individual level with high precision and overperform default methods. We found that while a diagnosis of AIDS is a critical risk factor, HIV infection per se does not necessarily convey additional risk. Other infectious processes, most notably hepatitis B and C, are independently associated with increased risk of impairment. The relative importance of an AIDS diagnosis diminished across calendar time. CONCLUSION: Our prediction models are a powerful tool to help clinicians address dementia in early stages for MACS paticipants. The strongest predictors of future cognitive impairment included the presence of clinical AIDS and hepatitis B or C infection. The fact that the pattern of predictive power differs by calendar year suggests a clinically critical change to the face of the epidemic.

Estrogen, brain structure, and cognition in postmenopausal women.

Declining estrogen levels before, during, and after menopause can affect memory and risk for Alzheimer's disease. Undesirable side effects of hormone variations emphasize a role for hormone therapy (HT) where possible benefits include a delay in the onset of dementia-yet findings are inconsistent. Effects of HT may be mediated by estrogen receptors found throughout the brain. Effects may also depend on lifestyle factors, timing of use, and genetic risk. We studied the impact of self-reported HT use on brain volume in 562 elderly women (71-94 years) with mixed cognitive status while adjusting for aforementioned factors. Covariate-adjusted voxelwise linear regression analyses using a model with 16 predictors showed HT use as positively associated with regional brain volumes, regardless of cognitive status. Examinations of other factors related to menopause, oophorectomy and hysterectomy status independently yielded positive effects on brain volume when added to our model. One interaction term, HTxBMI, out of several examined, revealed significant negative association with overall brain volume, suggesting a greater reduction in brain volume than BMI alone. Our main findings relating HT to regional brain volume were as hypothesized, but some exploratory analyses were not in line with existing hypotheses. Studies suggest lower levels of estrogen resulting from oophorectomy and hysterectomy affect brain volume negatively, and the addition of HT modifies the relation between BMI and brain volume positively. Effects of HT may depend on the age range assessed, motivating studies with a wider age range as well as a randomized design.

Tract Specific White Matter Lesion Load Affects White Matter Microstructure and Their Relationships With Functional Connectivity and Cognitive Decline.

White matter hyperintensities (WMHs) are associated with cognitive decline. Assessing the effect of WMH on WM microstructural changes and its relationships with structural and functional connectivity to multiple cognitive domains are helpful to better understand the pathophysiological processes of cognitive impairment. 65 participants (49 normal and 16 MCI subjects, age: 67.4 ± 8.3 years, 44 females) were studied at 3T. The WMHs and fifty fiber tracts were automatically segmented from the T1/T2-weighted images and diffusion-weighted images, respectively. Tract-profiles of WMH were compared with those of apparent fiber density (AFD). The relationship between AFD and tract connectivity (TC) was assessed. Functional connectivity (FC) between tract ends obtained from resting-state functional MRI was examined in relation to TC. Tract-specific relationships of WMH, TC and FC with a multi-domain neuropsychological test battery and Montreal Cognitive Assessment (MoCA) were also separately assessed by lasso linear regression. Indirect pathways of TC and FC between WMH and multiple cognitive measures were tested using the mediation analysis. Higher WMH loads in WM tracts were locally matched with the reduced AFD, which was related to decrease in TC. However, no direct relationship was found between TC and FC. Tract-specific changes on WMH, TC and FC for each cognitive performance may explain that macro- and microstructural and functional changes are associated differently with each cognitive domain in a fiber specific manner. In these identified tracts, the differences between normal and MCI for WMH and TC were increased, and the relationships of WMH, TC and FC with cognitive outcomes were more significant, compared to the results from all tracts. Indirect pathways of two-step (TC-FC) between WMH and all cognitive domains were significant (p < 0.0083 with Bonferroni correction), while the separated indirect pathways through TC and through FC were different depending on cognitive domain. Deterioration in specific cognitive domains may be affected by alterations in a set of different tracts that are differently associated with macrostructural, microstructural, and function changes. Thus, assessments of WMH and its associated changes on specific tracts help for better understanding of the interrelationships of multiple changes in cognitive impairment.