Interactions among neighborhood conditions, sleep quality, and episodic memory across the adult lifespan.

OBJECTIVES: On average, adults racialized as non-Hispanic Black and Hispanic sleep more poorly than adults racialized as non-Hispanic White (hereafter, Black, Hispanic, White), but associations between factors that may moderate sleep-memory associations in these groups, such as neighborhood conditions, are unclear. Poorer neighborhood conditions (e.g. lower neighborhood cohesion) may be negatively associated with sleep quality and multiplicatively influence sleep-memory associations. We hypothesized lower ratings of neighborhood conditions would be associated with poorer sleep quality and moderate the association between sleep quality and episodic memory, especially in Black and Hispanic adults, who are disproportionately situated in poor neighborhood conditions. DESIGN: Seven-hundred-thirty-six adults across the adult lifespan (27-89 years) were recruited from the northern Manhattan community as a part of the Offspring Study of Racial and Ethnic Disparities in Alzheimer's disease. Sleep quality was assessed using a modified version of the Pittsburgh Sleep Quality Index, and episodic memory was evaluated with the Buschke Selective Reminding Test. With multiple regression models, we measured associations between perceived neighborhood conditions and sleep quality and the interaction between sleep quality and neighborhood conditions on episodic memory stratified by racial/ethnic and gender identity groups. RESULTS: Overall, poorer neighborhood conditions were associated with poorer sleep quality. In Black and Hispanic women, the sleep-memory association was moderated by neighborhood conditions. With more favorable neighborhood conditions, Black women showed an association between higher sleep quality and higher memory performance, and Hispanic women showed a protective effect of neighborhood (higher memory even when sleep quality was poor). CONCLUSION: Poorer neighborhood experiences may contribute to poorer sleep quality across groups. In Black and Hispanic women, the association between sleep quality and episodic memory performance was dependent upon neighborhood conditions. These findings may inform tailored, structural level sleep interventions, aimed to improve neighborhood experiences and thereby sleep quality and episodic memory.

Loneliness, cerebrovascular and Alzheimer's disease pathology, and cognition.

INTRODUCTION: Loneliness has a rising public health impact, but research involving neuropathology and representative cohorts has been limited. METHODS: Inverse odds of selection weights were generalized from the autopsy sample of Rush Alzheimer's Disease Center cohorts (N = 680; 89 ± 9 years old; 25% dementia) to the US-representative Health and Retirement Study (N = 8469; 76 ± 7 years old; 5% dementia) to extend external validity. Regressions tested cross-sectional associations between loneliness and (1) Alzheimer's disease (AD) and cerebrovascular pathology; (2) five cognitive domains; and (3) relationships between pathology and cognition, adjusting for depression. RESULTS: In weighted models, greater loneliness was associated with microinfarcts, lower episodic and working memory in the absence of AD pathology, lower working memory in the absence of infarcts, a stronger association of infarcts with lower episodic memory, and a stronger association of microinfarcts with lower working and semantic memory. DISCUSSION: Loneliness may relate to AD through multiple pathways involving cerebrovascular pathology and cognitive reserve. HIGHLIGHTS: Loneliness was associated with worse cognition in five domains. Loneliness was associated with the presence of microinfarcts. Loneliness moderated cognition-neuropathology associations. Transportability methods can provide insight into selection bias.

Microglia measured by TSPO PET are associated with Alzheimer's disease pathology and mediate key steps in a disease progression model.

INTRODUCTION: Evidence suggests microglial activation precedes regional tau and neurodegeneration in Alzheimer's disease (AD). We characterized microglia with translocator protein (TSPO) positron emission tomography (PET) within an AD progression model where global amyloid beta (Aß) precedes local tau and neurodegeneration, resulting in cognitive impairment. METHODS: Florbetaben, PBR28, and MK-6240 PET, T1 magnetic resonance imaging, and cognitive measures were performed in 19 cognitively unimpaired older adults and 22 patients with mild cognitive impairment or mild AD to examine associations among microglia activation, Aß, tau, and cognition, adjusting for neurodegeneration. Mediation analyses evaluated the possible role of microglial activation along the AD progression model. RESULTS: Higher PBR28 uptake was associated with higher Aß, higher tau, and lower MMSE score, independent of neurodegeneration. PBR28 mediated associations between tau in early and middle Braak stages, between tau and neurodegeneration, and between neurodegeneration and cognition. DISCUSSION: Microglia are associated with AD pathology and cognition and may mediate relationships between subsequent steps in AD progression.

Longitudinal decline in semantic versus letter fluency, but not their ratio, marks incident Alzheimer's disease in Latinx Spanish-speaking older individuals.

OBJECTIVE: To compare longitudinal verbal fluency performance among Latinx Spanish speakers who develop Alzheimer's disease to those who do not develop dementia in absolute number of words produced on each task and their ratio to combine both scores. METHOD: Participants included 833 Latinx Spanish-speaking older adults from a community-based prospective cohort in Manhattan. We performed growth curve modeling to investigate the trajectories of letter and semantic fluency, and their ratio (i.e., 'semantic index'), between individuals who developed Alzheimer's disease and those who did not (i.e., controls). The semantic index quantifies the proportion of words generated for semantic fluency in relation to the total verbal fluency performance. RESULTS: Letter fluency performance did not decline in controls; we observed a linear decline in those who developed Alzheimer's disease. Semantic fluency declined in both groups and showed an increased rate of change over time in the incident Alzheimer's disease group; in comparison, the control group had a linear and slower decline. There were no group differences in the longitudinal trajectory (intercept and slope) of the semantic index. CONCLUSION: A decline in letter fluency and a more rapid and accelerating decline over time in semantic fluency distinguished people who developed Alzheimer's disease from controls. Using the semantic index was not a superior marker of incident Alzheimer's disease compared to examining the two fluency scores individually. Results suggest the differential decline in verbal fluency tasks, when evaluated appropriately, may be useful for early identification of Alzheimer's disease in Latinx Spanish speakers, a historically understudied population.

Patterns of tau pathology identified with 18 F-MK-6240 PET imaging.

INTRODUCTION: Positron emission tomography (PET) imaging for neurofibrillary tau allows investigation of the in vivo spatiotemporal progression of Alzheimer's disease (AD) pathology. We evaluated the suitability of 18 F-MK-6240 in a clinical sample and determined the relationships among 18 F-MK-6240 binding, age, cognition, and cerebrospinal fluid (CSF)-based AD biomarkers. METHODS: Participants (n = 101, 72 ± 9 years, 52% women) underwent amyloid PET, tau PET, structural T1-weighted magnetic resonance imaging, and neuropsychological evaluation. Twenty-one participants had lumbar puncture for CSF measurement of amyloid beta (Aß)42 , tau, and phosphorylated tau (p-tau). RESULTS: 18 F-MK-6240 recapitulated Braak staging and correlated with CSF tau and p-tau, normalized to Aß42 . 18 F-MK-6240 negatively correlated with age across Braak regions in amyloid-positive participants, consistent with greater tau pathology in earlier onset AD. Domain-specific, regional patterns of 18 F-MK-6240 binding were associated with reduced memory, executive, and language performance, but only in amyloid-positive participants. DISCUSSION: 18 F-MK-6240 can approximate Braak staging across the AD continuum and provide region-dependent insights into biomarker-based AD models.

Probing the proteome to explore potential correlates of increased Alzheimer's-related cerebrovascular disease in adults with Down syndrome.

Cerebrovascular disease is associated with symptoms and pathogenesis of Alzheimer's disease (AD) among adults with Down syndrome (DS). The cause of increased dementia-related cerebrovascular disease in DS is unknown. We explored whether protein markers of neuroinflammation are associated with markers of cerebrovascular disease among adults with DS. Participants from the Alzheimer's disease in Down syndrome (ADDS) study with magnetic resonance imaging (MRI) scans and blood biomarker data were included. Support vector machine (SVM) analyses examined the relationship of blood-based proteomic biomarkers with MRI-defined cerebrovascular disease among participants characterized as having cognitive decline (n = 36, mean age ± SD = 53 ± 6.2) and as being cognitively stable (n = 78, mean age = 49 ± 6.4). Inflammatory and AD markers were associated with cerebrovascular disease, particularly among symptomatic individuals. The pattern suggested relatively greater inflammatory involvement among cognitively stable individuals and greater AD involvement among those with cognitively decline. The findings help to generate hypotheses that both inflammatory and AD markers are implicated in cerebrovascular disease among those with DS and point to potential mechanistic pathways for further examination.

Alzheimer-Related Cerebrovascular Disease in Down Syndrome.

OBJECTIVE: Adults with Down syndrome (DS) develop Alzheimer disease (AD) pathology by their 5th decade. Compared with the general population, traditional vascular risks in adults with DS are rare, allowing examination of cerebrovascular disease in this population and insight into its role in AD without the confound of vascular risk factors. We examined in vivo magnetic resonance imaging (MRI)-based biomarkers of cerebrovascular pathology in adults with DS, and determined their cross-sectional relationship with age, beta-amyloid pathology, and mild cognitive impairment or clinical AD diagnostic status. METHODS: Participants from the Biomarkers of Alzheimer's Disease in Down Syndrome study (n = 138, 50 ± 7 years, 39% women) with MRI data and a subset (n = 90) with amyloid positron emission tomography (PET) were included. We derived MRI-based biomarkers of cerebrovascular pathology, including white matter hyperintensities (WMH), infarcts, cerebral microbleeds, and enlarged perivascular spaces (PVS), as well as PET-based biomarkers of amyloid burden. Participants were characterized as cognitively stable (CS), mild cognitive impairment-DS (MCI-DS), possible AD dementia, or definite AD dementia based on in-depth assessments of cognition, function, and health status. RESULTS: There were detectable WMH, enlarged PVS, infarcts, and microbleeds as early as the 5th decade of life. There was a monotonic increase in WMH volume, enlarged PVS, and presence of infarcts across diagnostic groups (CS < MCI-DS < possible AD dementia < definite AD dementia). Higher amyloid burden was associated with a higher likelihood of an infarct. INTERPRETATION: The findings highlight the prevalence of cerebrovascular disease in adults with DS and add to a growing body of evidence that implicates cerebrovascular disease as a core feature of AD and not simply a comorbidity. ANN NEUROL 2020;88:1165-1177.

Plasma p-tau181, p-tau217, and other blood-based Alzheimer's disease biomarkers in a multi-ethnic, community study.

INTRODUCTION: Blood-based Alzheimer's disease (AD) biomarkers provide opportunities for community studies and across ethnic groups. We investigated blood biomarker concentrations in the Washington Heights-Inwood Columbia Aging Project (WHICAP), a multi-ethnic community study of aging and dementia. METHODS: We measured plasma amyloid beta (Aß)40, Aß42, total tau (t-tau), phosphorylated tau (p-tau)181, and p-tau217, and neurofilament light chain (NfL) in 113 autopsied participants (29% with high AD neuropathological changes) and in 300 clinically evaluated individuals (42% with clinical AD). Receiver operating characteristics were used to evaluate each biomarker. We also investigated biomarkers as predictors of incident clinical AD. RESULTS: P-tau181, p-tau217, and NfL concentrations were elevated in pathologically and clinically diagnosed AD. Decreased Aß42/Aß40 ratio and increased p-tau217 and p-tau181 were associated with subsequent AD diagnosis. DISCUSSION: Blood-based AD biomarker concentrations are associated with pathological and clinical diagnoses and can predict future development of clinical AD, providing evidence that they can be incorporated into multi-ethnic, community-based studies.

Letter and Category Fluency Performance Correlates with Distinct Patterns of Cortical Thickness in Older Adults.

Verbal fluency tasks are generally thought to be mediated by frontal brain regions for letter fluency and temporal regions for category fluency. This idea, however, is primarily based on lesion studies and adapted versions of the fluency tasks in functional neuroimaging, without fundamental evidence from structural neuroimaging in healthy individuals. We investigated the cortical structural correlates of letter and category fluency, including overlapping and different regions, in 505 individuals who participated in a community-based study of healthy aging. The correlation between cortical thickness and verbal fluency in whole-brain analyses revealed distinct cortical signatures for letter fluency, primarily in frontal regions, and category fluency, in frontal and temporal-parietal regions. There was a dissociation in the left inferior frontal gyrus between letter and category fluency, with increased thickness in the posterior-dorsal versus anterior-ventral parts, respectively. These results distinguish the detailed anatomical correlates for verbal fluency within the coarse frontal-temporal distinction inferred from lesion studies and among the mixture of regions identified in functional neuroimaging. The evidence for the anatomical substrates of letter and category fluency, each recruiting slightly different language and cognitive processes, can serve both clinical applications as well as a deeper theoretical understanding of the organization of the cerebral cortex.

Further understanding the connection between Alzheimer's disease and Down syndrome.

Improved medical care of individuals with Down syndrome (DS) has led to an increase in life expectancy to over the age of 60 years. In conjunction, there has been an increase in age-related co-occurring conditions including Alzheimer's disease (AD). Understanding the factors that underlie symptom and age of clinical presentation of dementia in people with DS may provide insights into the mechanisms of sporadic and DS-associated AD (DS-AD). In March 2019, the Alzheimer's Association, Global Down Syndrome Foundation and the LuMind IDSC Foundation partnered to convene a workshop to explore the state of the research on the intersection of AD and DS research; to identify research gaps and unmet needs; and to consider how best to advance the field. This article provides a summary of discussions, including noting areas of emerging science and discovery, considerations for future studies, and identifying open gaps in our understanding for future focus.

[18 F]Nifene test-retest reproducibility in first-in-human imaging of α4ß2* nicotinic acetylcholine receptors.

The aim of this study was to examine the suitability of [18 F]nifene, a novel α4ß2* nicotinic acetylcholine receptor (nAChR) radiotracer, for in vivo brain imaging in a first-in-human study. METHODS: Eight healthy subjects (4 M,4 F;21-69,44 ± 21 yrs) underwent a [18 F]nifene positron emission tomography scan (200 ± 3.7 MBq), and seven underwent a second scan within 58 ± 31 days. Regional estimates of DVR were measured using the multilinear reference tissue model (MRTM2) with the corpus callosum as reference region. DVR reproducibility was evaluated with test-retest variability (TRV) and intraclass correlation coefficient (ICC). RESULTS: The DVR ranged from 1.3 to 2.5 across brain regions with a TRV of 0-7%, and did not demonstrate a systematic difference between test and retest. The ICCs ranged from 0.2 to 0.9. DVR estimates were stable after 40 min. CONCLUSION: The binding profile and tracer kinetics of [18 F]nifene make it a promising α4ß2* nAChR radiotracer for scientific research in humans, with reliable DVR test-retest reproducibility.

The effects of normal aging on amyloid-ß deposition in nondemented adults with Down syndrome as imaged by carbon 11-labeled Pittsburgh compound B.

INTRODUCTION: In Down syndrome (DS), the overproduction of amyloid precursor protein is hypothesized to predispose young adults to early expression of Alzheimer-like neuropathology. METHODS: PET imaging with carbon 11-labeled Pittsburgh compound B examined the pattern of amyloid-ß deposition in 68 nondemented adults with DS (30-53 years) to determine the relationship between deposition and normal aging. Standard uptake value ratio (SUVR) images were created with cerebellar gray matter as the reference region. RESULTS: Multiple linear regression revealed slight but highly significant (corrected P < .05) positive correlations between SUVR and age. The striatum showed the strongest correlation, followed by precuneus, parietal cortex, anterior cingulate, frontal cortex, and temporal cortex. CONCLUSION: There is an age-related amyloid-ß deposition in the DS population, but as a pattern of elevated cortical retention becomes apparent, the correlation of SUVR with age ceases to be significant. Factors unrelated to aging may drive an increase in deposition during early Alzheimer's disease pathogenesis.

Deficient import of acetyl-CoA into the ER lumen causes neurodegeneration and propensity to infections, inflammation, and cancer.

The import of acetyl-CoA into the ER lumen by AT-1/SLC33A1 is essential for the N(ε)-lysine acetylation of ER-resident and ER-transiting proteins. A point-mutation (S113R) in AT-1 has been associated with a familial form of spastic paraplegia. Here, we report that AT-1S113R is unable to form homodimers in the ER membrane and is devoid of acetyl-CoA transport activity. The reduced influx of acetyl-CoA into the ER lumen results in reduced acetylation of ER proteins and an aberrant form of autophagy. Mice homozygous for the mutation display early developmental arrest. In contrast, heterozygous animals develop to full term, but display neurodegeneration and propensity to infections, inflammation, and cancer. The immune and cancer phenotypes are contingent on the presence of pathogens in the colony, whereas the nervous system phenotype is not. In conclusion, our results reveal a previously unknown aspect of acetyl-CoA metabolism that affects the immune and nervous systems and the risk for malignancies.

Psychotic symptoms are associated with elevated tau PET signal in the amygdala independent of Alzheimer's disease clinical severity and amyloid burden.

Background: Psychosis in Alzheimer's disease (AD) is associated with worse outcomes, yet no established biomarkers exist for early diagnosis and intervention. We compared tau PET burden across older individuals with and without psychotic symptoms. Methods: [18F]AV1451 tau PET binding was compared between 26 Alzheimer's Disease Neuroimaging Initiative (ADNI) subjects with psychotic symptoms (delusions and/or hallucinations) and 26 ADNI subjects without psychotic symptoms, matched for age, sex, race/ethnicity, and clinical severity. Tau was assessed on a region-of-interest and voxel level, corrected for amyloid PET burden. Results: Tau was greater in individuals with psychotic symptoms in the amygdala in region-of-interest analyses, and in amygdala, thalamus, putamen, right hippocampus, right entorhinal cortex, and right frontal cortex in voxel-based analyses. When considering different onset and type of psychotic symptoms, tau binding was greatest in those with concurrent delusions. Conclusion: Elevated tau in limbic regions may be relevant for psychotic symptoms in aging and AD.

Small vessel cerebrovascular disease is associated with cognition in prospective Alzheimer's clinical trial participants.

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.

Cerebrovascular disease emerges with age and Alzheimer's disease in adults with Down syndrome.

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.

A pathway linking pulse pressure to dementia in adults with Down syndrome.

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.

PET imaging of acetylcholinesterase inhibitor-induced effects on α4ß2 nicotinic acetylcholine receptor binding.

Acetylcholinesterase inhibitors (AChEIs) are drugs that increase synaptic acetylcholine (ACh) concentrations and are under investigation as treatments for symptoms accompanying Alzheimer's disease. The goal of this work was to use PET imaging to evaluate alterations of in vivo α4ß2 nicotinic acetylcholine receptor (nAChR) binding induced by the AChEIs physostigmine (PHY) and galanthamine (GAL). The α4ß2 nAChR-specific radioligand [(18)F]nifene was used to examine the effects of 0.1-0.2 mg/kg PHY, 5 mg/kg GAL, and saline in three separate experiments all performed on each of two rat subjects. A 60-min bolus-infusion protocol was used with drug administered after 30 min. Data from the thalamus and cortex were analyzed with a graphical model accounting for neurotransmitter activation using the cerebellum as a reference region to test for transient competition with bound [(18) F]nifene. Significant [(18) F]nifene displacement was detected in both regions during one PHY and both GAL studies, while no significant competition was observed in both saline studies. This preliminary work indicates the viability of [(18) F]nifene in detecting increases in synaptic ACh induced by AChEIs.

Brain Aging Among Racially and Ethnically Diverse Middle-Aged and Older Adults.

Importance: Neuroimaging studies have documented racial and ethnic disparities in brain health in old age. It remains unclear whether these disparities are apparent in midlife. Objective: To assess racial and ethnic disparities in magnetic resonance imaging (MRI) markers of cerebrovascular disease and neurodegeneration in midlife and late life. Design, Setting, and Participants: Data from 2 community-based cohort studies, Washington Heights-Inwood Columbia Aging Project (WHICAP) and the Offspring Study of Racial and Ethnic Disparities in Alzheimer Disease (Offspring), were used. Enrollment took place from March 2011 and June 2017, in WHICAP and Offspring, respectively, to January 2021. Of the 822 Offspring and 1254 WHICAP participants approached for MRI scanning, 285 and 176 refused participation in MRI scanning, 36 and 76 were excluded for contraindications/ineligibility, and 4 and 32 were excluded for missing key variables, respectively. Main Outcomes and Measures: Cortical thickness in Alzheimer disease-related regions, white matter hyperintensity (WMH) volume. Results: The final sample included 1467 participants. Offspring participants (497 [33.9%]) had a mean (SD) age of 55 (10.7) years, had a mean (SD) of 13 (3.5) years of education, and included 117 Black individuals (23.5%), 348 Latinx individuals (70%), 32 White individuals (6.4%), and 324 women (65.2%). WHICAP participants (970 [66.1%]) had a mean (SD) age of 75 (6.5) years, had a mean (SD) of 12 (4.7) years of education, and included 338 Black individuals (34.8%), 389 Latinx individuals (40.1%), 243 White individuals (25.1%), and 589 women (65.2%). Racial and ethnic disparities in cerebrovascular disease were observed in both midlife (Black-White: B = 0.357; 95% CI, 0.708-0.007; P = .046) and late life (Black-Latinx: B = 0.149, 95% CI, 0.068-0.231; P < .001; Black-White: B = 0.166; 95% CI, 0.254-0.077; P < .001), while disparities in cortical thickness were evident in late life only (Black-Latinx: B = -0.037; 95% CI, -0.055 to -0.019; P < .001; Black-White: B = -0.064; 95% CI -0.044 to -0.084; P < .001). Overall, Black-White disparities were larger than Latinx-White disparities for cortical thickness and WMH volume. Brain aging, or the association of age with MRI measures, was greater in late life compared with midlife for Latinx (cortical thickness: B = 0.006; 95% CI, 0.004-0.008; P < .001; WMH volume: B = -0.010; 95% CI, -0.018 to -0.001; P = .03) and White (cortical thickness: B = 0.005; 95% CI, 0.002-0.008; P = .001; WMH volume: B = -0.021; 95% CI -0.043 to 0.002; P = .07) participants but not Black participants (cortical thickness: B = 0.001; 95% CI, -0.002 to 0.004; P =.64; WMH volume: B = 0.003; 95% CI, -0.010 to 0.017; P = .61), who evidenced a similarly strong association between age and MRI measures in midlife and late life. Conclusions and Relevance: In this study, racial and ethnic disparities in small vessel cerebrovascular disease were apparent in midlife. In Latinx and White adults, brain aging was more pronounced in late life than midlife, whereas Black adults showed accelerated pattern of brain aging beginning in midlife.

Posterior white matter hyperintensities are associated with reduced medial temporal lobe subregional integrity and long-term memory in older adults.

White matter hyperintensities are a marker of small vessel cerebrovascular disease that are strongly related to cognition in older adults. Similarly, medial temporal lobe atrophy is well-documented in aging and Alzheimer's disease and is associated with memory decline. Here, we assessed the relationship between lobar white matter hyperintensities, medial temporal lobe subregional volumes, and hippocampal memory in older adults. We collected MRI scans in a sample of 139 older adults without dementia (88 females, mean age (SD) = 76.95 (10.61)). Participants were administered the Rey Auditory Verbal Learning Test (RAVLT). Regression analyses tested for associations among medial temporal lobe subregional volumes, regional white matter hyperintensities and memory, while adjusting for age, sex, and education and correcting for multiple comparisons. Increased occipital white matter hyperintensities were related to worse RAVLT delayed recall performance, and to reduced CA1, dentate gyrus, perirhinal cortex (Brodmann area 36), and parahippocampal cortex volumes. These medial temporal lobe subregional volumes were related to delayed recall performance. The association of occipital white matter hyperintensities with delayed recall performance was fully mediated statistically only by perirhinal cortex volume. These results suggest that white matter hyperintensities may be associated with memory decline through their impact on medial temporal lobe atrophy. These findings provide new insights into the role of vascular pathologies in memory loss in older adults and suggest that future studies should further examine the neural mechanisms of these relationships in longitudinal samples.