Rush Alzheimer Research Articles

Measuring Cognitive Function In-Person and Remotely in Round 4 of the National Social Life, Health, and Aging Project (NSHAP).

This paper describes the changes made to the collection of cognitive measures when the National Social Life, Health, and Aging Project (NSHAP) introduced remote modes of data collection. In Round 4 (2021-23), the longitudinal study transitioned from being conducted in-person to collecting data via multiple modes including in-person and remote modes: web, phone, and paper-and-pencil. The team began with the measures used in Rounds 2 and 3 of NSHAP-the survey-adapted Montreal Cognitive Assessment (MoCA-SA)-and evaluated which measures could be administered remotely, introducing new measures for each cognitive subdomain, as needed, to compensate for items that could not be administered remotely. Cognitive items used in Rounds 2 and 3 that could not be administered remotely were dropped from the respective modes, and items selected from the Rush Alzheimer's Disease Center's (RADC) global cognition battery were added as substitutes. For comparison, the RADC substitute items were added to the in-person mode making it longer in R4. The changes in cognitive measures resulted in different numbers of cognitive items across the four modes of survey administration in Round 4. Analysts should be aware of these changes when creating a single global cognition score for the entire NSHAP sample in Round 4, and aware that there may be mode effects that could impact cognition scores.

Participation in Physical, Cognitive, and Social Activities and the Association with Mobility Disability Transitions in Older Adults.

Development of late-life mobility disability is a dynamic process of transitions between worsening and improving. We tested associations between participation in physical, social, and cognitive activity with mobility disability transitions. Participants (N=2,758, age 78.1 years [SD: 7.7]) from two Rush Alzheimer's Disease Center cohorts completed annual mobility disability questionnaires for 7.6 (SD: 4.4) years. First-order Markov transition models tested associations between baseline self-reported physical, social, and cognitive activity with bidirectional transitions in mobility disability score increases (worsening) and decreases (improving) between consecutive visits. Overall, 75.5% of participants experienced ≥1 transition among 18,318 pairs of consecutive visits-4,174 of which were worsening and 2,606 were improving transitions. Adjusting for covariates, higher participation in each activity type was associated with lower odds of worsening (physical OR=0.71, 95% CI: 0.67-0.75; social OR=0.64, 95% CI: 0.58-0.70; and cognitive OR=0.79, 95% CI: 0.74-0.85), and higher odds of improving (physical OR=1.20, 95% CI: 1.11-1.28; social OR=1.45, 95% CI: 1.30-1.61; and cognitive OR=1.12, 95% CI: 1.03-1.22) in separate models. In combined models, physical and social activity remained associated with worsening and improving; cognitive activity was only associated with worsening. Physical, social, and cognitive activity engagement contributes to lower odds of worsening mobility disability and may promote recovery.

Correlates of missed or late versus timely diagnosis of dementia in healthcare settings.

There is limited evidence about factors related to the timeliness of dementia diagnosis in healthcare settings. In five prospective cohorts at Rush Alzheimer's Disease Center, we identified participants with incident dementia based on annual assessments and examined the timing of healthcare diagnoses in Medicare claims. We assessed sociodemographic, health, and psychosocial correlates of timely diagnosis. Of 710 participants, 385 (or 54%) received a timely claims diagnosis within 3 years prior to or 1 year following dementia onset. In logistic regressions accounting for demographics, we found Black participants (odds ratio [OR]=2.15, 95% confidence interval [CI]: 1.21 to 3.82) and those with better cognition at dementia onset (OR=1.48, 95% CI: 1.10 to 1.98) were at higher odds of experiencing a diagnostic delay, whereas participants with higher income (OR=0.89, 95% CI: 0.81 to 0.97) and more comorbidities (OR=0.94, 95% CI: 0.89 to 0.98) had lower odds. We identified characteristics of individuals who may miss the optimal window for dementia treatment and support. We compared the timing of healthcare diagnosis relative to the timing of incident dementia based on rigorous annual evaluation. Older Black adults with lower income, higher cognitive function, and fewer comorbidities were less likely to be diagnosed in a timely manner by the healthcare system.

Mercury and selenium distribution in human brain tissue using synchrotron micro-X-ray fluorescence.

Mercury is a well-recognized environmental contaminant and neurotoxin, having been associated with a number of deleterious neurological conditions including neurodegenerative diseases, such as Alzheimer's disease. To investigate how mercury and other metals behave in the brain, we used synchrotron micro-X-ray fluorescence to map the distribution pattern and quantify concentrations of metals in human brain. Brain tissue was provided by the Rush Alzheimer's Disease Center and samples originated from individuals diagnosed with Alzheimer's disease and without cognitive impairment. Data were collected at the 2-ID-E beamline at the Advanced Photon Source at Argonne National Laboratory with an incident beam energy of 13keV. Course scans were performed at low resolution to determine gross tissue features, after which smaller regions were selected to image at higher resolution. The findings revealed (1) the existence of mercury particles in the brain samples of two subjects; (2) co-localization and linear correlation of mercury and selenium in all particles; (3) co-localization of these particles with zinc structures; and (4) association with sulfur in some of these particles. These results suggest that selenium and sulfur may play protective roles against mercury in the brain, potentially binding with the metal to reduce the induced toxicity, although at different affinities. Our findings call for further studies to investigate the relationship between mercury, selenium, and sulfur, as well as the potential implications in Alzheimer's disease and related dementias.

The influence of APOE status on rate of cognitive decline

BackgroundApolipoprotein (APOE) ɛ4 positivity and subjective cognitive decline (SCD) both increase risk of Alzheimer’s disease (AD) development. However, few studies have examined the relationship between SCD and APOE status, especially using longitudinal data. The current study examined whether APOE is associated with the rate of cognitive change in SCD and mild cognitive impairment (MCI).MethodsA sample of 3494 older adults (1990 normal controls, NC, 775 SCD, and 729 MCI) with a mean follow-up of 9.09 years were included from the Rush Alzheimer’s Disease Center Research Sharing Hub. Linear mixed effects models examined the relationship between APOE status and cognitive change in older adults with SCD normal controls, and people with MCI.ResultsThe presence of at least one ɛ2 allele in SCD and MCI results in cognitive change rates similar to a NC with the ɛ3ɛ3 genotype. Older adult SCD-ɛ4 individuals exhibited increased rate of cognitive decline compared to all groups, including NC-ɛ4 and MCI-ɛ4.ConclusionPeople with SCD with at least one ɛ4 allele experience increased rates of cognitive decline compared to cognitively healthy older adults and people with MCI. These findings have important implications for treatments and interventions and can improve future research and clinical trials by targeting people in the preclinical AD phase (i.e., SCD) who also possess at least one APOE ɛ4 allele.

Estimating dementia risk in an African American population using the DCTclock.

The prevalence of Alzheimer's disease (AD) and related dementias (ADRD) is increasing. African Americans are twice as likely to develop dementia than other ethnic populations. Traditional cognitive screening solutions lack the sensitivity to independently identify individuals at risk for cognitive decline. The DCTclock is a 3-min AI-enabled adaptation of the well-established clock drawing test. The DCTclock can estimate dementia risk for both general cognitive impairment and the presence of AD pathology. Here we performed a retrospective analysis to assess the performance of the DCTclock to estimate future conversion to ADRD in African American participants from the Rush Alzheimer's Disease Research Center Minority Aging Research Study (MARS) and African American Clinical Core (AACORE). We assessed baseline DCTclock scores in 646 participants (baseline median age = 78.0 ± 6.4, median years of education = 14.0 ± 3.2, 78% female) and found significantly lower baseline DCTclock scores in those who received a dementia diagnosis within 3 years. We also found that 16.4% of participants with a baseline DCTclock score less than 60 were significantly more likely to develop dementia in 5 years vs. those with the highest DCTclock scores (75-100). This research demonstrates the DCTclock's ability to estimate the 5-year risk of developing dementia in an African American population. Early detection of elevated dementia risk using the DCTclock could provide patients, caregivers, and clinicians opportunities to plan and intervene early to improve cognitive health trajectories. Early detection of dementia risk can also enhance participant selection in clinical trials while reducing screening costs.

RACE DIFFERENCES IN THE RELATIONSHIP BETWEEN HIGH AND VARIABLE BLOOD PRESSURE AND DOMAIN-SPECIFIC COGNITIVE CHANGE

Abstract Elevated blood pressure (BP), or hypertension, is a risk factor for several health conditions including Alzheimer’s disease. High BP in early- and mid-life is associated with cognitive decline, whereas research is mixed regarding BP and cognition in late-life. Moreover, hypertension disproportionately affects minority populations. Consequently, the effects of hypertension on cognition may differ by race. The present study investigates the relationship between BP and cognition. 4419 older adults (Black, n=1189; White, n= 3230), with 32116 follow-ups for a maximum of 10-years were included from the Rush Alzheimer’s Disease Center. Results reveal individuals with high BP exhibit significantly greater declines in global cognition compared to normal BP, regardless of race. When stratifying high BP by race, Blacks exhibit greater declines in working memory and perceptual speed, whereas Whites exhibit greater declines in episodic memory, semantic memory, and visuospatial ability compared to normal BP. Blacks with high BP exhibit greater decline in perceptual speed compared to variable BP, whereas no cognitive domain was worse in Whites with high BP compared to variable. When stratifying variable BP by race, Blacks exhibited greater decline in working memory compared to normal BP. Alternatively, Whites exhibited greater decline in episodic memory, semantic memory, working memory, and global cognition compared to normal and high BP counterparts. Our findings reveal racial differences in the relationship between BP and cognitive decline. Specifically, Blacks and Whites with high and variable BP experience cognitive decline in different cognitive domains, which may give insight into differences in disease trajectory and cognitive outcomes.

Multimodal lifestyle engagement patterns support cognitive stability beyond neuropathological burden

BackgroundModifiable lifestyle behaviors account for a large proportion of dementia risk. However, the combined contributions of multidomain lifestyle patterns to cognitive aging are poorly understood, as most studies have examined individual lifestyle behaviors in isolation and without neuropathological characterization. This study examined data-driven patterns of lifestyle behaviors across multiple domains among older adults and tested their associations with disease-specific neuropathological burden and cognitive decline.MethodsParticipants included 2059 older adults enrolled in the longitudinal Memory and Aging Project (MAP) at the Rush Alzheimer’s Disease Center; none of whom had dementia at baseline (73% no cognitive impairment (NCI), 27% mild cognitive impairment [MCI]). All participants completed cognitive testing annually. Lifestyle factors were measured during at least one visit and included (1) actigraphy-measured physical activity, as well as self-reported (2) sleep quality, (3) life space, (4) cognitive activities, (5) social activities, and (6) social network. A subset of participants (n = 791) had autopsy data for which burden of Alzheimer’s disease (AD), cerebrovascular disease (CVD), Lewy body disease, and hippocampal sclerosis/TDP-43 was measured. Latent profile analysis across all 2059 participants identified distinct subgroups (i.e., classes) of lifestyle patterns. Linear mixed-effects models examined relationships between lifestyle classes and global cognitive trajectories, with and without covarying for all neuropathologies. Classes were also compared on rates of incident MCI/dementia.ResultsFive classes were identified: Class 1Low Life Space (lowest lifestyle engagement), Class 2PA (high physical activity), Class 3Low Avg (low to average lifestyle engagement), Class 4Balanced (high average lifestyle engagement), and Class 5Social (large social network). Classes 4Balanced and 5Social had the lowest AD burden, and Class 2PA had the lowest CVD burden. Classes 2–5 had significantly less steep global cognitive decline compared to Class 1Low Life Space, with comparable effect sizes before and after covarying for neuropathological burden. Classes 4Balanced and 5Social exhibited the lowest rates of incident MCI/dementia.ConclusionsLifestyle behavior patterns among older adults account for differential rates of cognitive decline and clinical progression. Those with at least average engagement across all lifestyle domains exhibit greater cognitive stability after adjustment for neuropathology, highlighting the importance of engagement in multiple healthy lifestyle behaviors for later life cognitive health.

Sensitivity and Specificity of the Boston Criteria Version 2.0 for the Diagnosis of Cerebral Amyloid Angiopathy in a Community-Based Sample.

The Boston criteria are a set of clinical and neuroimaging features that enable accurate diagnosis of cerebral amyloid angiopathy (CAA) without invasive methods such as brain biopsies or autopsy. The last updates to the Boston criteria, named version 2.0, were recently released and incorporated new nonhemorrhagic MRI features. These criteria have been validated in symptomatic samples, with improved diagnostic yield. We set out to investigate the accuracy of the Boston criteria v2.0 for the diagnosis of CAA in a community-based sample. Participants were recruited from longitudinal clinical-pathologic studies of aging conducted at the Rush Alzheimer's Disease Center in Chicago: the Religious Orders Study and the Rush Memory and Aging Project. Deceased participants with in vivo 3T MRI and detailed pathologic data available were included in the analysis. We compared the diagnostic yield of the current and earlier versions of the Boston criteria in our sample. Among those classified as probable CAA according to the Boston criteria v2.0, we investigated the ability of each neuroimaging marker to distinguish between false-positive and true-positive cases. In total, 134 individuals were included in the study (mean age = 82.4 ± 6.0 years; 69.4% F), and 49 of them were considered pathology-proven definite cases with CAA (mean age = 82.9 ± 6.0 years; 63.3% F). The Boston criteria versions 1.0 and 1.5 yielded similar sensitivity (26.5%, both), specificity (90.6% and 89.4%, respectively), and predictive values (negative: 68.1% and 67.9%; positive: 61.9% and 59.1%, respectively). The recently released Boston criteria v2.0 offered higher sensitivity (38.8%) and slightly lower specificity (83.5%). Among those classified as probable CAA (v2.0), pathology-proven true-positive cases had higher numbers of strictly cortical lobar microbleeds compared with false-positive cases (p = 0.004). Similar to findings from symptomatic samples, the inclusion of nonhemorrhagic neuroimaging markers in the updated Boston criteria offered a 12.3% gain in sensitivity among community-dwelling individuals, at the expense of a 5.9% drop in specificity. In cases with probable CAA, the cortical location of microbleeds may represent a promising distinguishing feature between true-positive and false-positive cases. Despite its improved performance, the diagnostic sensitivity of the updated criteria in a community-based sample remains limited. This study provides Class II evidence that the Boston criteria v2.0 accurately distinguishes people with CAA from those without CAA.

Single‐cell Transcriptomes Reveal Cell‐type Specific Roles of VEGF Family Genes in the Pathogenesis of Alzheimer’s Disease

AbstractBackgroundThe role of the vascular endothelial growth factors (VEGFs) in the pathogenesis of Alzheimer’s disease (AD) has been recently described, including notable changes along the VEGFB/FLT1 signaling pathway. Yet, cell‐specific alterations are not well characterized. To disentangle VEGFs’ cell‐specific effect on AD‐related traits, we performed association analyses of mRNA expression from 10 VEGF genes with cognitive performance and AD pathology in eight brain cell types using a large single nucleus RNA sequencing dataset from human brain.MethodThis project utilized recently published single‐cell transcriptomes derived from dorsolateral prefrontal cortex tissues of 424 donors collected at Rush Alzheimer’s Disease Center. Processed single cell RNA sequencing data were acquired from AD Knowledge Portal (syn2580853). Mean age at death was 89 years, 68% were females, and 37% were AD cases. Negative binomial lognormal mixed models implemented in the NEBULA R package were used to detect differential expression between AD cases and cognitively normal controls, and to analyze the associations with immunohistochemical amyloid and tangles, and finally to assess cross‐sectional and longitudinal global cognitive scores. Correction for multiple comparisons was completed using the false discovery rate procedure (Pfdr<0.05).ResultPrefrontal cortical FLT1 expression was upregulated in AD participants compared to cognitively normal controls in both endothelial (endo) and microglial (micro) cells. Higher micro‐FLT1, endo‐FLT4, and oligodendrocyte (oligo) VEGFB expression was associated with greater β‐amyloid burden in AD samples, whereas higher VEGFB expression in inhibitory neurons was associated with lower β‐amyloid burden. Higher expression of micro‐FLT1 and oligo‐VEGFB associated with worse cognitive trajectories. Higher micro‐ and endo‐ expression of FLT1 associated with lower cognition scores at the last clinic visit before death. Lastly, higher astrocyte‐expressed NRP1 was associated with lower tangle burden.ConclusionConsistent with our previously reported bulk tissue results, prefrontal cortical expression of FLT1 and FLT4 were associated with global cognition, longitudinal cognitive trajectories, and AD neuropathology, and these associations appear to be limited to endothelial and microglial cells. In contrast, VEGFB expression seems to have opposite effects on amyloid burden depending on the cell types, suggesting its more dynamic role in AD physiopathology.

Relationship between metabolic disease and Alzheimer’s disease

AbstractBackgroundDiabetes is an enormous and growing global public health problem, associated with poor health outcomes including dementia. Mechanisms underlying the relationship of diabetes to dementia are less well understood.MethodsWe leveraged several large, ongoing community‐based cohorts of older women and men with and without diabetes, taking part in longitudinal, clinical‐pathologic studies of aging at the Rush Alzheimer’s Disease Center. Participants undergo annual clinical evaluations including detailed neuropsychological testing, and brain autopsy at time of death. We examined the relation of diabetes and related clinical variables (e.g., medications, body mass index [BMI], hypertension), and blood and brain biomarkers of insulin resistance and other measures (e.g., epigenetics), to brain outcomes. Level and change in global cognition and five cognitive domains were based on neuropsychological tests, and dementia status was classified. Postmortem human brain specimens of deceased persons were systematically evaluated for neuropathology, including neurodegenerative (e.g., Alzheimer’s disease [AD]) and cerebrovascular disease (e.g., infarcts).ResultsDiabetes, present in 15‐20% of our cohorts, is associated a two‐fold increased risk of dementia and relates to cognitive decline (particularly in some cognitive domains more than others), and these observations are found in both Black and White participants. Some diabetes‐related clinical variables (e.g., BMI) are associated with faster cognitive decline, while others such as medications (metformin) are associated with slower cognitive decline. Regarding human postmortem neuropathologic outcomes, diabetes is associated with cerebrovascular pathologies, and small subcortical infarcts in particular. But, while we have not found clear associations of diabetes with neurodegenerative pathologies such as AD, some brain molecular markers in the insulin signaling pathway (AKT1) are associated with AD (including amyloid‐beta and tau tangles) and cognition (memory). Recently, using blood and brain specimens, we show that genome‐wide 5‐hydroxymethylcytosine profiling uncovers epigenetic features and biologic pathways related to nucleotide sugar metabolism linking diabetes to diabetes‐associated AD.ConclusionDiabetes is a potentially‐modifiable risk factor for dementia and cognitive decline. Clinical, neuropathologic, and epigenetic factors are at play in the underlying mechanisms. A better understanding of mechanisms will inform future research and offer opportunities for precision medicine and dementia prevention (supported by NIH: R01NS084965, RF1AG059621, RF1AG074549, R01AG022018, P30AG10161, P30AG072975, R01AG15819, R01AG17917).

Cerebral amyloid angiopathy is associated with higher gray matter regional R2 relaxation rate: An ex‐vivo MRI and pathology study

AbstractBackgroundCerebral amyloid angiopathy (CAA) is characterized by accumulation of amyloid‐ß (Aß) protein in the walls of cortical and meningeal small vessels. CAA is common in older adults. It has been linked to intracerebral hemorrhage and cognitive decline. In this study, the association of CAA with the transverse relaxation rate R2 values was investigated in gray matter regions from a large number of community‐based older adults.MethodCerebral hemispheres from 802 older adults participating in four cohort studies of aging, the Rush Memory and Aging Project, the Minority Aging Research Study, the Religious Orders Study, and the Clinical Core of the Rush Alzheimer’s Disease Research Center (Fig. 1a) were included in this work. All hemispheres were imaged ex‐vivo using 3T MRI scanners. R2 maps were generated from multi‐echo spin‐echo images. Gray matter was segmented into 34 cortical and 8 subcortical regions. Median R2 values were obtained from each region. Following ex‐vivo MRI, all hemispheres underwent detailed neuropathologic assessment (Fig. 1b). Evaluated neuropathologies included: CAA, Aß plaques, neurofibrillary tangles, gross infarcts, microinfarcts, TDP‐43 pathology, hippocampal sclerosis, Lewy bodies, atherosclerosis, and arteriolosclerosis. Multiple linear regression was conducted in each segmented gray matter region separately to test the association of the corresponding median R2 value with the global CAA score, controlling for all other neuropathologies, age at death, sex, education, postmortem interval to fixation and to imaging, and scanners. False discovery rate (FDR) was used to correct for multiple comparisons. Statistical significance was set at p<0.05.ResultA significant positive association of median R2 with CAA pathology was found in several cortical regions of the temporal and frontal lobes as well as in subcortical structures (Fig. 2,3). No gray matter region showed lower median R2 for higher CAA score. Furthermore, we obtained similar findings when also controlling in the linear regression models for normalized regional volume and for clinical variables such as history of hypertension, diabetes, smoking, blood pressure levels, and the presence of the APOE‐e4 allele.ConclusionThis investigation showed that CAA is independently associated with elongated R2 in cortical regions of the temporal and frontal lobes as well as in subcortical structures.

Brain MRI diffusion abnormalities associated with arteriolosclerosis pathology

AbstractBackgroundBrain arteriolosclerosis is one of the main pathologies of cerebral small vessel disease. It involves the thickening of the vessel wall and stenosis of arterioles causing lower cognitive and motor function, and higher odds of dementia. This work intends to explore the independent association of brain arteriolosclerosis with diffusion abnormalities in the white matter (WM) of community‐based older adults.MethodParticipants comprised community‐dwelling older adults (N = 175) from four studies of aging (Rush Memory and Aging Project, Religious Orders Study, Minority Aging Research Study, and Clinical Core of the Rush Alzheimer’s Disease Research Center) (Fig.1A). Whole brain 3D T1w MPRAGE, T2w FLAIR, and diffusion‐weighted MRI (2×2×2mm3, b = 1,000s/mm2 for 40 diffusion gradient directions, and 6 b = 0s/mm2 volumes) data were acquired in‐vivo using 3T MRI scanners. The fractional anisotropy (FA) and trace maps were transformed to the space of the IIT Human Brain Atlas v.5.0 and projected onto the WM skeleton of the IIT atlas. Following a participant’s death, the extracted brain underwent a detailed evaluation by a neuropathologist. Assessed neuropathologies included arteriolosclerosis, Alzheimer’s pathology, LATE‐NC, gross and microscopic infarcts, atherosclerosis, and cerebral amyloid angiopathy (Fig.1B). Linear regression was used in voxels of the WM skeleton to test the association of FA or trace with the severity of arteriolosclerosis controlling for all other neuropathologies, white matter hyperintensities (WMH), demographic variables (age at scan, sex, years of education), antemortem interval to imaging, and scanner. The statistical analyses were carried out using FSL’s PALM tool with 5,000 permutations and threshold‐free cluster enhancement. The significance level was set at p<0.05, after family‐wise error rate (FWER) correction for multiple testing.ResultArteriolosclerosis score was associated with lower FA (Fig.2) and higher trace (Fig.3) of the diffusion tensor throughout the brain in multiple WM regions, even in areas typically free of WMH. Other neuropathologies or the effects of WMH on diffusion characteristics had no impact on these relationships.ConclusionThe current study showed that, regardless of the impact of other neuropathologies or visible WMH, brain arteriolosclerosis in older persons is associated with diffusion abnormalities that extend throughout the WM.

Brain MRI diffusion abnormalities associated with arteriolosclerosis pathology

AbstractBackgroundBrain arteriolosclerosis is one of the main pathologies of cerebral small vessel disease. It involves the thickening of the vessel wall and stenosis of arterioles causing lower cognitive and motor function, and higher odds of dementia. This work intends to explore the independent association of brain arteriolosclerosis with diffusion abnormalities in the white matter (WM) of community‐based older adults.MethodParticipants comprised community‐dwelling older adults (N = 175) from four studies of aging (Rush Memory and Aging Project, Religious Orders Study, Minority Aging Research Study, and Clinical Core of the Rush Alzheimer’s Disease Research Center) (Fig.1A). Whole brain 3D T1w MPRAGE, T2w FLAIR, and diffusion‐weighted MRI (2×2×2mm3, b = 1,000s/mm2 for 40 diffusion gradient directions, and 6 b = 0s/mm2 volumes) data were acquired in‐vivo using 3T MRI scanners. The fractional anisotropy (FA) and trace maps were transformed to the space of the IIT Human Brain Atlas v.5.0 and projected onto the WM skeleton of the IIT atlas. Following a participant’s death, the extracted brain underwent a detailed evaluation by a neuropathologist. Assessed neuropathologies included arteriolosclerosis, Alzheimer’s pathology, LATE‐NC, gross and microscopic infarcts, atherosclerosis, and cerebral amyloid angiopathy (Fig.1B).Linear regression was used in voxels of the WM skeleton to test the association of FA or trace with the severity of arteriolosclerosis controlling for all other neuropathologies, white matter hyperintensities (WMH), demographic variables (age at scan, sex, years of education), antemortem interval to imaging, and scanner. The statistical analyses were carried out using FSL’s PALM tool with 5,000 permutations and threshold‐free cluster enhancement. The significance level was set at p<0.05, after family‐wise error rate (FWER) correction for multiple testing.ResultArteriolosclerosis score was associated with lower FA (Fig.2) and higher trace (Fig.3) of the diffusion tensor throughout the brain in multiple WM regions, even in areas typically free of WMH. Other neuropathologies or the effects of WMH on diffusion characteristics had no impact on these relationships.ConclusionThe current study showed that, regardless of the impact of other neuropathologies or visible WMH, brain arteriolosclerosis in older persons is associated with diffusion abnormalities that extend throughout the WM.

Associations of subcortical shapes with age‐related neuropathologies in community‐based older adults

AbstractBackgroundAge‐related neuropathologies lead to substantial atrophy of subcortical brain regions. However, the effects of age‐related neuropathologies on the shape of subcortical brain structures are not well understood because a) definitive diagnosis of most neuropathologies is only possible at autopsy and b) multiple neuropathologies often coexist in the brain of older adults. The purpose of this work was to integrate ex‐vivo MRI and detailed neuropathologic examination in a large number of community‐based older adults.Method Participants and Data Cerebral hemispheres from 842 older adults participating in four longitudinal, clinical‐pathologic cohort studies of aging: the Rush Memory and Aging Project (MAP), the Religious Orders Study (ROS), the Minority Aging Research Study (MARS) and the Clinical Core (CC) of the Rush Alzheimer’s Disease Research Center (ADRC)1,2 (Fig.1) were included in this work. All hemispheres were imaged at room temperature while immersed in 4% formaldehyde solution using clinical 3T MRI scanners approximately 30 days postmortem. After ex‐vivo MRI, each hemisphere underwent detailed neuropathologic examination by a board‐certified neuropathologist (Fig.1). Ex‐vivo MRI and Shape Estimation The subcortical structures were segmented in ex‐vivo T2‐weighted MR images from all participants. Shape analysis was performed using SPHARM‐PDM3. For each subcortical structure, signed shape differences were computed from the average mesh for all vertices and all participants. Statistical Analysis Vertex‐wise linear regression was performed for each subcortical structure, modeling the signed shape difference at each vertex (dependent variable) as a function of neuropathologies (specifically amyloid‐β plaques, neurofibrillary tangles, limbic‐predominant age‐related TDP‐43 encephalopathy neuropathological change (LATE‐NC), Lewy bodies, arteriolosclerosis, atherosclerosis, gross and microscopic infarcts, and cerebral amyloid angiopathy), and controlling for age at death, sex, years of education, postmortem interval to fixation, postmortem interval to imaging, and scanner. The statistical analysis was conducted using PALM4 with family‐wise error rate correction.ResultThe results are shown in Figure 2. These findings for tangles and LATE‐NC were in good agreement with our previous work5,6. Finally, although MRI was conducted ex‐vivo, we expect the results to translate well to in‐vivo7.ConclusionThe differences in spatial patterns of the effects of various neuropathologies may contribute towards the development of tools for in‐vivo prediction of these neuropathologies.

Associations of subcortical shapes with age‐related neuropathologies in community‐based older adults

AbstractBackgroundAge‐related neuropathologies lead to substantial atrophy of subcortical brain regions. However, the effects of age‐related neuropathologies on the shape of subcortical brain structures are not well understood because a) definitive diagnosis of most neuropathologies is only possible at autopsy and b) multiple neuropathologies often coexist in the brain of older adults. The purpose of this work was to integrate ex‐vivo MRI and detailed neuropathologic examination in a large number of community‐based older adults.MethodParticipants and Data Cerebral hemispheres from 842 older adults participating in four longitudinal, clinical‐pathologic cohort studies of aging: the Rush Memory and Aging Project (MAP), the Religious Orders Study (ROS), the Minority Aging Research Study (MARS) and the Clinical Core (CC) of the Rush Alzheimer’s Disease Research Center (ADRC)1,2 (Fig.1) were included in this work. All hemispheres were imaged at room temperature while immersed in 4% formaldehyde solution using clinical 3T MRI scanners approximately 30 days postmortem. After ex‐vivo MRI, each hemisphere underwent detailed neuropathologic examination by a board‐certified neuropathologist (Fig.1). Ex‐vivo MRI and Shape Estimation The subcortical structures were segmented in ex‐vivo T2‐weighted MR images from all participants. Shape analysis was performed using SPHARM‐PDM3. For each subcortical structure, signed shape differences were computed from the average mesh for all vertices and all participants. Statistical Analysis Vertex‐wise linear regression was performed for each subcortical structure, modeling the signed shape difference at each vertex (dependent variable) as a function of neuropathologies (specifically amyloid‐ß plaques, neurofibrillary tangles, limbic‐predominant age‐related TDP‐43 encephalopathy neuropathological change (LATE‐NC), Lewy bodies, arteriolosclerosis, atherosclerosis, gross and microscopic infarcts, and cerebral amyloid angiopathy), and controlling for age at death, sex, years of education, postmortem interval to fixation, postmortem interval to imaging, and scanner. The statistical analysis was conducted using PALM4 with family‐wise error rate correction.ResultThe results are shown in Figure 2. These findings for tangles and LATE‐NC were in good agreement with our previous work5,6. Finally, although MRI was conducted ex‐vivo, we expect the results to translate well to in‐vivo7.ConclusionThe differences in spatial patterns of the effects of various neuropathologies may contribute towards the development of tools for in‐vivo prediction of these neuropathologies.

68 Interactive Effects of Sleep Apnea and Depression Symptoms on Cognition in Older Adults

Objective:Sleep deprivation and depressive symptoms have been shown to negatively impact cognitive function within older adult populations (Gilley, 2022; Donovan et al., 2016). However, there is minimal research on interactions between sleep disturbance and depressive symptoms in relation to their shared impact on cognitive impairment. The purpose of this study is to examine possible interactions between sleep disorders and depression and their relationship with cognition among relatively good functioning and healthy older adults.Participants and Methods:The sample was obtained from the Memory and Aging Project (Rush Alzheimer's Disease Center, Rush University, 2019) and consisted of 3,345 community dwelling older adults. The study analyzed data from 2552 women (76.3%) and 1093 men (23.7%). The average age of participants was 80 years and ranged from 45 to 98 years old. Measures used included the Berlin Questionnaire (risk for sleep apnea), Center for Epidemiological Studies Depression Scale (CES-D; depression), and a neuropsychological battery (visuospatial ability/perceptual reasoning and processing speed).Results:ANOVA analyses exhibited a significant main effect of depression on visuospatial ability/perceptual reasoning (p <.001), processing speed (p <.001), and semantic memory (p <.001). No significant main effect was found for sleep apnea on these cognitive domains. However, when sleep apnea was analyzed between those with any depressive symptoms versus those without, significant interactions were found for visuospatial ability/perceptual reasoning (p =.027), processing speed (p <.001), and semantic memory (p =.016). Sleep apnea symptoms had a greater detrimental effect on visuospatial skills and perceptual reasoning (F=4.90; p=.027) only when any depression symptom is present. In contrast, there was a steeper decline of processing speed when only depressive symptoms were present apart from sleep apnea symptoms (F=10.34; p =.001) Similarly, depressive symptoms had a greater negative effect on semantic memory for older adults who reported no sleep apnea symptoms compare to those who did (F=5.83, p=.016).Conclusions:The current study indicated that while sleep apnea was negatively related to several cognitive domains, the impact became greater with the presence of depression on visuospatial skills and perceptual reasoning among older adults. However, the detrimental impact of sleep apnea was somewhat less with the presence of depression for processing speed and semantic memory. This may be due to likely higher endorsements of depressive symptoms compared to sleep apnea symptoms within the study sample. These findings suggest that there are differential interactive effects of sleep impairment and depressive symptoms on cognitive domains among older adults. Considering the relationship that exists between depression and increased disease burden among older adults, it is crucial for clinicians to also take sleep behaviors into account when examining and treating their patients. Clinicians should be mindful of their older patient's sleep health and depression measures when cognitive declines are suspected. They also suggest that cognitive performance may be improved with treating any symptoms of sleep apnea and depression in older adults.

23 Subjective Cognition in African American and White Older Adults: Interactions with Psychosocial Factors

Objective:Given that African American older adults are disproportionately at risk for the development of dementia, identifications of sensitive risk and protective factors are of high importance. Subjective decline in cognition is a potentially easy to assess clinical marker, as it has been previously associated with increased risk of converting to MCI and/or dementia. Subjective decline in cognition is complex though, in that it has also been associated with psychosocial factors. Given this, and the fact that the bulk of research on subjective decline in cognition has been conducted in older white adults, research in diverse samples is needed. The present study sought to address these gaps by examining interactions between race and psychosocial risk (dysphoria) and protective (social activity) factors in the prediction of subjective cognition.Participants and Methods:Older white (n = 350) and African American (n = 478) participants completed questionnaires via Qualtrics Panels (m age = 65.9). Subjective decline in cognition was assessed via the Multifactorial Memory Questionnaire (MMQ). Dysphoria was assessed via the Inventory of Depression and Anxiety Symptoms-II Dysphoria subscale (IDAS). Frequency of late life social activity was assessed via a validated series of questions used by the Rush Alzheimer’s Disease Center. Race, dysphoria, late life social activity, and interactions between race and dysphoria and race and social activity were analyzed as predictors of subjective decline in cognition via linear regression.Results:The overall model accounted for a significant portion of the variance in subjective decline in cognition, F(6, 713) = 38.38, p < .01, with an R2 of .24. The interaction between race and dysphoria was significant, such that the relationship between dysphoria and subjective decline in cognition was stronger for older adults who are African American. Race, dysphoria, social activity, and the interaction between race and social activity were not significant predictors.Conclusions:While dysphoria and related negative affect variables have been previously associated with subjective cognition, interactions with race are rarely analyzed. Our results show that the relationship between dysphoria and subjective decline in cognition were stronger for African American older adults. This result is of clinical importance, as dysphoria is central to many internalizing disorders, which have been associated with subjective cognition and the development of MCI and dementia. Future research should seek to analyze drivers for this associations and if interventions for dysphoria may reduce subjective decline in cognition for African American older adults.

4 Interactions of Inflammation and Psychosocial Stress on White Matter Integrity Over Time in Older Black Adults

Objective:Higher levels of inflammation are associated with risk factors for Alzheimer’s disease and related dementias (ADRD) in older Black adults including psychosocial stressors (e.g., discrimination and early life adversity) and white matter alterations. Yet, limited work has investigated these risk factors together in a longitudinal neuroimaging study, despite the well-known ADRD disparity in older Black adults. Using data from the Minority Aging Research Study and African American Clinical Core of the Rush Alzheimer’s Disease Center, we examined interactions of psychosocial stressors and change in inflammation on changes in white matter integrity as measured via diffusion tensor imaging (DTI).Participants and Methods:Older Black adults (n=102) without known dementia at baseline (age=75.8±6.1 years; 87.3% female; education=15.4±2.7 years) completed blood draws at two time points (follow-up=2.4±0.7 years), neuroimaging at two or more time points (follow-up=3.7±1.8 years), and psychosocial questionnaires at one time point coinciding with the first blood draw/neuroimaging. Blood serum was assayed using highly-sensitive multiplexed sandwich ELISA for interleukin-6, c-reactive protein (CRP), and tumor necrosis factor-alpha (TNF-a) and a change score was calculated for each inflammatory marker (T2 - T1). The Williams Everyday Discrimination Scale quantified experiences of discrimination in all participants and a 16-item questionnaire of emotional and physical trauma from age 0-18 assessed early life adversity in a participant subset (n=63). DTI-derived tract-based spatial statistics (TBSS) slope change measures for trace of the diffusion tensor, fractional anisotropy (FA), axial diffusivity (AD), and radial diffusivity (RD) were calculated, with the first two scans matched in time to blood assays. Linear regression models investigated interactions of each inflammatory marker change score (separately) and either discrimination or early life adversity (separately) on trace, FA, AD, and RD slopes as individual outcomes adjusting for age, sex, education, white matter hyperintensities (total volume and voxelwise), cardiovascular risk factors, statin and analgesic medications, thyroid conditions, and depression. Statistical significance was determined at p<0.05 using family wise error correction and threshold free cluster enhancement.Results:Discrimination moderated the relationship between TNF-a and AD whereby those with increasing TNF-a and higher levels of discrimination had increasing levels of AD over time in white matter tracts connecting the left and right cerebellum, the left pallidum and medulla, and the left superior frontal gyrus and left thalamus. Both discrimination and early life adversity moderated associations between CRP and AD, where increases in CRP and higher psychosocial stressors (of either type) resulted in decreasing AD over time in tracts involving cingulate, frontal, and parietal regions. Discrimination and early life adversity also moderated associations between CRP and RD, where increasing CRP combined with greater psychosocial stressors resulted in decreasing RD in right hemisphere association and projection tracts connecting frontal, parietal, central, and subcortical regions.Conclusions:TNF-a and CRP interacted with measures of psychosocial stress to associate with DTI-derived TBSS slope change measures of AD and RD in differential, and at times, paradoxical ways. Findings suggest that both risk and resilience as related to brain connectivity may be co-occurring in the presence of psychosocial stressors for older Black adults.

B - 98 Interactive Effects of Sleep Apnea and Depression Symptoms on Cognition in Older Adults.

This study examined interactions between symptoms of sleep apnea and depression in predicting cognition in healthy older adults. From the Memory and Aging Project (Rush Alzheimer's Disease Center, Rush University, 2019), the sample consisted of 3345 community dwelling older adults including 2552 women (76.3%) and 1093 men (23.7%) with an average age of 80years. Measures included the Berlin Questionnaire (for sleep apnea symptoms, Center for Epidemiological Studies Depression Scale, and neuropsychological measures of semantic memory, visuospatial ability, and processing speed. ANOVAs indicated significant main effects of depression on visuospatial ability, processing speed, and semantic memory (p's < 0.001), and no main effect for sleep apnea. However, when sleep apnea was analyzed between those with any depressive symptoms versus those without, significant interactions were found for visuospatial ability, processing speed, and semantic memory (ps < 0.05). Sleep apnea symptoms had a detrimental effect on visuospatial skills (p = 0.027) only when any depression symptom was present. In contrast, sleep apnea symptoms predicted slower processing speed when depressive symptoms were not present (p = 0.001) Similarly, depression symptoms had a greater negative effect on semantic memory for those who reported no sleep apnea symptoms compared to those who did (p = 0.016). There seems to be differential main and interactive effects of sleep apnea symptoms and depression on semantic memory, visuospatial ability, and processing speed. Clinicians may need to consider even mild symptoms of sleep problems and depression if they suspect changes in these cognitive domains in older adults.