Memory And Aging Project Research Articles

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.

Alzheimer’s disease genetics and real‐world patient data fuel target and drug discovery in European and African American ancestries

AbstractBackgroundTranslation of massive genetic and genomic data into Alzheimer’s target and drug discovery has not materialized. One challenge in this process is ethnicity‐based differences in the field of Alzheimer’s disease (AD). For example, African Americans (AAs) and European Americans (EAs) differ in AD prevalence, risk factors, and symptomatic presentation, and AAs have historically been less frequently enrolled in AD clinical trials.MethodWe conducted ancestry genetic‐specific target and drug discovery by gathering large genetic data from a diverse population with real‐world patient data to boost the likelihood of identifying disease‐modifying drug targets and treatments for AD. We analyzed genetic data from 275,540 AD cases and 1.55 million controls across 7 AD genome‐wide association studies (GWAS) datasets for both EA and AA ancestries, using Mendelian randomization. We utilized the genetic instruments from 9 expression quantitative trait loci (eQTL) and 3 protein quantitative trait loci (pQTL) datasets from three large human brain biobanks: a) Mount Sinai Brain Bank (MSBB), b) Mayo clinic (Mayo), and c) Religious Orders Study (ROS) or the Rush Memory and Aging Project (MAP) (ROS/MAP).ResultWe identified 25 drug targets in EAs and 6 new drug targets in AAs among 1,176 investigated druggable targets. Notably, the inflammatory target of epoxide hydrolase 2 (EPHX2) emerged as a potent AD target in EAs, and treatment of transgenic TgF344‐AD rats with an EPHX2 inhibitor was therapeutic. Among 6 AA‐specific targets, we identified that TRPV3 is a potent drug target for AA individuals with AD, and further replicated our finding in AA‐specific eQTL data. We additionally identified 23 candidate drugs associated with reduced risk of AD in mild cognitive impairment (MCI) patients after analysis of ∼80 million electronic health records. Using a propensity score‐matched design, we identified that usage of either apixaban (hazard ratio [HR] = 0.74, 95% confidence interval [CI] 0.69 – 0.80) or amlodipine (HR = 0.91, 95% CI 0.88 – 0.94) were both significantly associated with reduced progression to AD in people with MCI.ConclusionCombining genetics and real‐world patient data has identified ancestry‐specific therapeutic targets and medicines for AD.

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.

Effect of early‐ and mid‐life cognitive enrichment on Alzheimer’s disease pathology and late‐life cognition

AbstractBackgroundCognitive reserve and brain maintenance may explain individual differences in trajectories of cognitive and brain aging due to various life exposures (e.g., education, cognitive enrichment). Cognitive reserve refers to the advantages that life exposures exert on cognitive abilities despite brain aging or disease; brain maintenance refers to the protective effects of life exposures on the brain itself (e.g., reduced rate of neuropathology accumulation). Previous findings showed that early‐life cognitive enrichment (ELCE) was associated with slower cognitive decline, which was partially mediated through global Alzheimer’s disease pathology. Building on this work, this study investigated mediation by β‐amyloid and tau pathology (reflecting brain maintenance) as well as moderation by early‐ and mid‐life cognitive enrichment (ELCE, MLCE; reflecting cognitive reserve) on cognitive functioning at last visit proximate to death.MethodThere were 1015 community‐based participants (M baseline age = 82.57±6.35) from the Rush Memory and Aging Project (MAP) and Minority Aging Research Study (MARS) cohorts, who completed annual cognitive and clinical assessments. ELCE and MLCE composite measures were derived from z‐scored self‐reported indicators obtained at baseline (Table 1). Summary measures of β‐amyloid and tau burden were derived from immunohistochemistry at autopsy. Late‐life cognition was measured using a global composite of 19 z‐scored neuropsychological tests obtained at last visit. To test for cognitive reserve, separate linear regression models examined whether ELCE and MLCE moderated relations between β‐amyloid or tau and cognition, adjusted for age at death and sex. To test for brain maintenance, a series of mediation analyses examined whether β‐amyloid and/or tau burden mediated the relationship of ELCE and MLCE with cognition.ResultELCE (p = .005) and MLCE (p = .005) moderated the relationship between tau—but not β‐amyloid—and late‐life cognition proximate to death (Figure 1). Mediation analyses revealed an indirect effect of β‐amyloid—but not tau—on the relation between ELCE (B = 0.058, p = .004) and MLCE (B = 0.040, p = .03) and late‐life cognition (Figure 2).ConclusionELCE and MLCE improve late‐life cognition partially through reducing β‐amyloid, but not tau, accumulation (i.e., brain maintenance). In contrast, ELCE and MLCE are protective against late‐life cognitive impairment in the presence of tau pathology (i.e., cognitive reserve), but not β‐amyloid.

Late‐life social activity and subsequent risk of dementia and mild cognitive impairment

AbstractBackgroundPrevious research reported associations between more social engagement and better cognitive health. Social engagement is a multidimensional construct encompassing interrelated but distinct domains such as social activity, social network size, perceived social support, and loneliness. These domains are not equally amenable to interventions. We therefore focused on late‐life social activity, as a potentially modifiable facet of social engagement, and examined its relation to risks of dementia and MCI, independent of other aspects of social engagement, lifestyle, and health.MethodIn the Rush Memory and Aging Project (MAP), 1923 older adults without dementia at baseline were followed longitudinally, with annual clinical evaluation of dementia and MCI. The frequency of participation in six common social activities was assessed by a validated scale at baseline (mean = 2.6, range: 1‐4.3), as were size of social network, perceived social support, and perceived loneliness. A clinical diagnosis of MCI or dementia was rendered annually based on cognitive tests and diagnostic classification by a clinician. We used Cox proportional hazard models to quantify associations between social activity score and incident dementia or MCI. Primary models controlled for demographics; additional models included covariates for health, other social engagement indicators, and income. In secondary analyses, to consider reverse causality, we excluded participants who developed MCI or dementia within two years after baseline.ResultDuring a mean follow‐up of 6.7 (std = 4.7) years, 545 (28%) participants developed dementia, and 695 (49% of those without MCI at baseline) developed MCI. Each one‐unit increment in social activity score was associated with a 37% reduction in dementia risk [HR = 0.63, 95% CI: 0.53‐0.74] after adjusting for age, sex, education, race/ethnicity, and marital status (Figure 1A). Social activity was also related to a lower risk of MCI [HR = 0.77, 95% CI: 0.66‐0.89] (Figure 1B). Results were not meaningfully different after adjusting for vascular disease burden, BMI, ADL disability, physical activity, depressive symtoms, social network size, social support, social isolation, and income. Excluding participants who developed MCI or dementia soon after baseline did not change the patterns.ConclusionKeeping socially active at older age is related to lower dementia risk, possibly informing strategies for developing preventive interventions.

Capturing polygenic risk for Alzheimer’s disease using induced pluripotent stem cells

AbstractBackgroundOver 70 loci have been implicated in AD pathogenesis through genome‐wide association studies. Understanding of how these genetic variants interact with one another, as well as with unknown genetic variants of weak effect size to impinge upon biological processes and molecular pathway to affect risk and resilience to AD is key to unlocking appropriate therapeutic strategies for AD.MethodWe have generated iPSC lines from over 50 deceased individuals in the Religious Order Study (ROS) or Rush Memory and Aging Project (MAP) that span the clinical and neuropathological spectrum of aging. About one third of these individuals had clinical and neuropathological diagnoses of AD and Alzheimer’s dementia. We differentiated these lines into cortical neuronal fates, astrocyte fates and microglial fates and measured RNA and protein profiles as well as quantitative measures of APP cleavage products and tau species. In addition, we have measured autophagic and proteasome capacity, as well as synatic vesicle release and cytokine production.ResultWe identify specific proteins and pathways in neuronal and glial cultures that are associated with AD polygenic risk score (PRS), neuropathological burden, and/or cognitive trajectory in the donors and validate these findings through analyses of brain tissue. We identify an association of cognitive decline and measures of specific amyloid beta peptides and phospho‐tau species in iPSC‐derived neurons. We find that proteasome capacity and autophagic flux are influenced by genetic background, which in turn affects tau proteostasis. Intriguingly, different genetic backgrounds respond differentially to modulation of these protein degradation networks.ConclusionThe data presented establish this iPSC collection as a resource for investigating person‐specific processes in the brain that are encoded in part by polygenic risk for AD that can aid in identifying and validating molecular pathways underlying AD.

Financial Risk Aversion Among Older Black and White Adults.

Risk aversion has a substantial impact on decision making and is associated with key demographic characteristics. However, few studies have investigated whether risk aversion varies by race. We investigated racial differences in financial risk aversion in 684 older Black and White adults without dementia in the Minority Aging Research Study and Rush Memory and Aging Project matched for age, education, sex, and cognition using Mahalanobis distance. We also investigated whether select contextual factors (self-reported discrimination, socioeconomic status, and literacy) mediated or affective factors (trust, loneliness, and neuroticism) moderated any observed racial differences. In regression models adjusted for age, education, sex, and cognitive function, older Black adults were more risk averse than older White adults (Beta = 0.1264, standard error = 0.0227, p value ≤ .00001). None of the contextual or affective factors mediated or moderated this association. Older Black adults are more financially risk averse than older White adults. Because risk aversion may be associated with important financial and health outcomes in older age, more research is needed to investigate the reasons for this difference.

Bone mineral density and the risk of incident dementia: A meta-analysis.

It is not known whether bone mineral density (BMD) measured at baseline or as the rate of decline prior to baseline (prior bone loss) is a stronger predictor of incident dementia or Alzheimer's disease (AD). We performed a meta-analysis of three longitudinal studies, the Framingham Heart Study (FHS), the Rotterdam Study (RS), and the Rush Memory and Aging Project (MAP), modeling the time to diagnosis of dementia as a function of BMD measures accounting for covariates. We included individuals with one or two BMD assessments, aged ≥60 years, and free of dementia at baseline with follow-up available. BMD was measured at the hip femoral neck using dual-energy X-ray absorptiometry (DXA), or at the heel calcaneus using quantitative ultrasound to calculate estimated BMD (eBMD). BMD at study baseline ("baseline BMD") and annualized percentage change in BMD prior to baseline ("prior bone loss") were included as continuous measures. The primary outcome was incident dementia diagnosis within 10 years of baseline, and incident AD was a secondary outcome. Baseline covariates included age, sex, body mass index, ApoE4 genotype, and education. The combined sample size across all three studies was 4431 with 606 incident dementia diagnoses, 498 of which were AD. A meta-analysis of baseline BMD across three studies showed higher BMD to have a significant protective association with incident dementia with a hazard ratio of 0.47 (95% CI: 0.23-0.96; p = 0.038) per increase in g/cm2 , or 0.91 (95% CI: 0.84-0.995) per standard deviation increase. We observed a significant association between prior bone loss and incident dementia with a hazard ratio of 1.30 (95% CI: 1.12-1.51; p < 0.001) per percent increase in prior bone loss only in the FHS cohort. Baseline BMD but not prior bone loss was associated with incident dementia in a meta-analysis across three studies.

21 Socioeconomic Influences on Instrumental Activities of Daily Living in Older Black Adults

Objective:Socioeconomic factors, spanning from childhood to mid-adulthood, were examined in an older adult Black cohort to better understand their influence on the ability to complete instrumental activities of daily living. Previous research with socioeconomic factors has primarily focused on cognitive changes rather than everyday functioning. Additionally, research that has been conducted examining functioning has been with predominantly White samples.Participants and Methods:Data on Black participants were obtained from Rush University’s Memory and Aging Project (MAP), Minority Aging Research Study (MARS), and the Latino CORE study (CORE). Participants (n = 1,273) were predominately female (79.9%) and ranged in age from 54 - 97 years (M = 73 years old). Participants were stratified into two groups based on their consensus diagnosis: no cognitive impairment (NCI; 76.1%) and mild cognitive impairment (MCI). Linear regression analyses were utilized on each group to examine predictors of decreased functioning in instrumental activities of daily living. Predictors included income levels during childhood, at age 40, and current income level. Additionally, sex, education level, and parental education levels were included in the models.Results:Impairment of functioning in instrumental activities of daily living was predicted by the age of the participants at the time of their visit in both NCI and MCI groups (p &lt; 0.001). Current income levels for the NCI participants significantly predicted functioning in IADLs (p &lt; 0.001). This relationship was not present for the MCI group, rather, total family income at age 40 better predicted functioning (p = 0.043).Conclusions:Previous research has found that early and mid-life socioeconomic circumstances have cascading and complex effects on late life cognition. These same associations may be applicable to functioning with instrumental activities of daily living as they are with cognition. In the present study, current income levels were influential on the functioning of participants without cognitive impairment. Although, when examining those with mild cognitive impairment, mid-life economic circumstances were more impactful on everyday functioning. While the economic status of both groups were predictors of functioning, these findings highlight the importance of better understanding socioeconomic factors across the lifespan and all levels of cognition.

A Microsimulation of Well-Being and Literacy Interventions to Reduce Scam Susceptibility in Older Adults.

Poor financial and health literacy and poor psychological well-being are significant correlates of scam susceptibility in older adults; yet, no research has examined whether interventions that target these factors may effectively reduce susceptibility. Using longitudinal data from older adults in the Rush Memory and Aging Project (MAP) (N = 1,231), we used microsimulations to estimate the causal effect of hypothetical well-being and literacy interventions on scam susceptibility over six years. Microsimulations can simulate a randomized trial to estimate intervention effects using observational data. We simulated hypotheticalinterventions that improved well-being or literacy scores by either 10% or 30% from baseline, or to the maximum scores, for an older adult population and for income and education subgroups. Simulations suggest thathypotheticalinterventions that increase well-being or literacy cause statistically significant reductions in scam susceptibility of older adults over time, but improving well-being caused a greater-albeit not significantly different-reduction compared to improving literacy.

Evaluating genomic signatures of aging in brain tissue as it relates to Alzheimer’s disease

Telomere length (TL) attrition, epigenetic age acceleration, and mitochondrial DNA copy number (mtDNAcn) decline are established hallmarks of aging. Each has been individually associated with Alzheimer’s dementia, cognitive function, and pathologic Alzheimer’s disease (AD). Epigenetic age and mtDNAcn have been studied in brain tissue directly but prior work on TL in brain is limited to small sample sizes and most studies have examined leukocyte TL. Importantly, TL, epigenetic age clocks, and mtDNAcn have not been studied jointly in brain tissue from an AD cohort. We examined dorsolateral prefrontal cortex (DLPFC) tissue from N = 367 participants of the Religious Orders Study (ROS) or the Rush Memory and Aging Project (MAP). TL and mtDNAcn were estimated from whole genome sequencing (WGS) data and cortical clock age was computed on 347 CpG sites. We examined dementia, MCI, and level of and change in cognition, pathologic AD, and three quantitative AD traits, as well as measures of other neurodegenerative diseases and cerebrovascular diseases (CVD). We previously showed that mtDNAcn from DLPFC brain tissue was associated with clinical and pathologic features of AD. Here, we show that those associations are independent of TL. We found TL to be associated with β-amyloid levels (beta = − 0.15, p = 0.023), hippocampal sclerosis (OR = 0.56, p = 0.0015) and cerebral atherosclerosis (OR = 1.44, p = 0.0007). We found strong associations between mtDNAcn and clinical measures of AD. The strongest associations with pathologic measures of AD were with cortical clock and there were associations of mtDNAcn with global AD pathology and tau tangles. Of the other pathologic traits, mtDNAcn was associated with hippocampal sclerosis, macroscopic infarctions and CAA and cortical clock was associated with Lewy bodies. Multi-modal age acceleration, accelerated aging on both mtDNAcn and cortical clock, had greater effect size than a single measure alone. These findings highlight for the first time that age acceleration determined on multiple genomic measures, mtDNAcn and cortical clock may have a larger effect on AD/AD related disorders (ADRD) pathogenesis than single measures.

CogDrisk, ANU-ADRI, CAIDE, and LIBRA Risk Scores for Estimating Dementia Risk.

While the Australian National University-Alzheimer Disease Risk Index (ANU-ADRI), Cardiovascular Risk Factors, Aging, and Dementia (CAIDE), and Lifestyle for Brain Health (LIBRA) dementia risk tools have been widely used, a large body of new evidence has emerged since their publication. Recently, Cognitive Health and Dementia Risk Index (CogDrisk) and CogDrisk for Alzheimer disease (CogDrisk-AD) risk tools have been developed for the assessment of dementia and AD risk, respectively, using contemporary evidence; comparison of the relative performance of these risk tools is limited. To evaluate the performance of CogDrisk, ANU-ADRI, CAIDE, LIBRA, and modified LIBRA (LIBRA with age and sex estimates from ANU-ADRI) in estimating dementia and AD risks (with CogDrisk-AD and ANU-ADRI). This population-based cohort study obtained data from the Rush Memory and Aging Project (MAP), the Cardiovascular Health Study Cognition Study (CHS-CS), and the Health and Retirement Study-Aging, Demographics and Memory Study (HRS-ADAMS). Participants who were free of dementia at baseline were included. The factors were component variables in the risk tools that included self-reported baseline demographics, medical risk factors, and lifestyle habits. The study was conducted between November 2021 and March 2023, and statistical analysis was performed from January to June 2023. Risk scores were calculated based on available factors in each of these cohorts. Area under the receiver operating characteristic curve (AUC) was calculated to measure the performance of each risk score. Multiple imputation was used to assess whether missing data may have affected estimates for dementia risk. Among the 6107 participants in 3 validation cohorts included for this study, 2184 participants without dementia at baseline were available from MAP (mean [SD] age, 80.0 [7.6] years; 1606 [73.5%] female), 548 participants without dementia at baseline were available from HRS-ADAMS (mean [SD] age, 79.5 [6.3] years; 288 [52.5%] female), and 3375 participants without dementia at baseline were available from CHS-CS (mean [SD] age, 74.8 [4.9] years; 1994 [59.1%] female). In all 3 cohorts, a similar AUC for dementia was obtained using CogDrisk, ANU-ADRI, and modified LIBRA (MAP cohort: CogDrisk AUC, 0.65 [95% CI, 0.61-0.69]; ANU-ADRI AUC, 0.65 [95% CI, 0.61-0.69]; modified LIBRA AUC, 0.65 [95% CI, 0.61-0.69]; HRS-ADAMS cohort: CogDrisk AUC, 0.75 [95% CI, 0.71-0.79]; ANU-ADRI AUC, 0.74 [95% CI, 0.70-0.78]; modified LIBRA AUC, 0.75 [95% CI, 0.71-0.79]; CHS-CS cohort: CogDrisk AUC, 0.70 [95% CI, 0.67-0.72]; ANU-ADRI AUC, 0.69 [95% CI, 0.66-0.72]; modified LIBRA AUC, 0.70 [95% CI, 0.68-0.73]). The CAIDE and LIBRA also provided similar but lower AUCs than the 3 aforementioned tools (eg, MAP cohort: CAIDE AUC, 0.50 [95% CI, 0.46-0.54]; LIBRA AUC, 0.53 [95% CI, 0.48-0.57]). The performance of CogDrisk-AD and ANU-ADRI in estimating AD risks was also similar. CogDrisk and CogDrisk-AD performed similarly to ANU-ADRI in estimating dementia and AD risks. These results suggest that CogDrisk and CogDrisk-AD, with a greater range of modifiable risk factors compared with other risk tools in this study, may be more informative for risk reduction.

Apolipoprotein E potently inhibits ferroptosis by blocking ferritinophagy

AbstractBackgroundAllelic variation to the APOE gene confers the greatest genetic risk for sporadic Alzheimer’s disease (AD). Independent of genotype, low abundance of apolipoprotein E (apoE), is characteristic of AD CSF, and predicts cognitive decline. The mechanisms underlying the genotype and apoE level risks are uncertain. Recent fluid and imaging biomarker studies have revealed an unexpected link between apoE and brain iron, which also forecasts disease progression, possibly through ferroptosis, an iron‐dependent regulated cell death pathway.MethodFerroptosis was induced in the N27 neuronal cell model of ferroptosis using multiple agents (erastin, RSL3, iron, cysteine depletion). The severity of ferroptosis was measured by several toxicity assays (MTT, LDH) and lipid peroxide probe (C11BODIPY). Iron levels in the temporal inferior cortex was gathered from 608 deceased subjects in the memory and aging project (MAP, Chicago, USA). Iron levels were quantified and analyzed using multiple regression models stratified by APOE genotype.ResultWe report that apoE is a potent inhibitor of ferroptosis (EC50≈10 nM; N27 neurons). We demonstrate that apoE signals to activate the PI3K/AKT pathway that then inhibits the autophagic degradation of ferritin (ferritinophagy), thus averting iron‐dependent lipid peroxidation. Using postmortem inferior temporal brain cortex tissue from deceased subjects from the Rush Memory and Aging Project (MAP) (N = 608), we found that the association of iron with pathologically confirmed clinical Alzheimer’s disease was stronger among those with the adverse APOE‐ε4 allele. While protection against ferroptosis did not differ between apoE isoforms in vitro, other features of ε4 carriers, such as low abundance of apoE protein and higher levels of polyunsaturated fatty acids (which fuel ferroptosis) could mediate the ε4 allele’s heighted risk of AD.ConclusionWe show that apoE protects against ferroptic neurodegeneration through regulating autophagy and identified an increased risk of AD diagnosis associated with the apoE risk allele in a clinical study. These findings support ferroptosis as a putative pathway to explain the major genetic risk associated with late onset AD.

Association of short tandem repeats with neuropathological features in late‐onset of Alzheimer’s disease brains

AbstractBackgroundLate‐Onset Alzheimer’s Disease (LOAD) is characterized by genetic heterogeneity and there is no single model explaining the genetic mode of inheritance. Short tandem repeats (STRs), which are hyper‐mutable sequences in the human genome could explain some of the missing heritability in LOAD. STRs are involved in several neuro‐degenerative disorders. We systematically evaluated the impact of 31 disease‐associated STRs on neuropathological LOAD features.MethodFrom whole‐genome sequencing (WGS) data in for 1,134 unrelated individuals of European ancestry from Religious Orders Study (ROS) and Rush Memory and Aging project (MAP) cohorts, we identified known pathogenic STRs in 31 loci using ExpansionHunter. WGS was generated from DNA extracted from blood and brain tissues. We tested the association of STRs with a) neuropathological LOAD status, b) beta‐amyloid levels, c) neurofibrillary tangle (NFT) burden, d) global measure of pathology based on the scaled scores of 5 brain regions and e) estimated slope of global cognition using longitudinal measurements. Regression models adjusting for age, sex and first three principal components. Subsequently, we examined if STRs influenced gene expression in dorsolateral prefrontal cortex (DLPFC), posterior cingulate cortex (PCC) and the anterior cingulate (AC) and tested if the association of STRs with neuropathological traits were mediated by altered gene expression.ResultTGC repeat in ATXN1 was associated with cognitive decline (b = ‐0.007, p = 0.014) and risk of clinical AD (b = 0.126, p = 0.03). Variation in CAG repeats in ATN1 was associated with cognition (b = 0.004, p = 0.022) and risk of pathological AD (b = ‐0.069, p = 0.035). Longer Repeats at ATXN1 increased gene expression in DLPFC (b = 0.012, p = 0.049) and PCC (b = 0.019, p = 0.006) and repeats in ATN1 altered DLPFC (b = 0.01, p = 0.016) and PCC (b = 0.01, p = 0.026) expression. Mediation analysis determined that the effect of the CAG repeats in ATN1 on tau was mediated by gene expression in PCC (p = 0.004).ConclusionWe demonstrate that disease causing STRs influence the underlying gene expression in brain and are associated with neuropathological and cognitive endophenotypes of AD. This suggests that STRs could explain some of the missing heritability in LOAD.

Ultra-high field imaging, plasma markers and autopsy data uncover a specific rostral locus coeruleus vulnerability to hyperphosphorylated tau

Autopsy data indicate that the locus coeruleus (LC) is one of the first sites in the brain to accumulate hyperphosphorylated tau pathology, with the rostral part possibly being more vulnerable in the earlier stages of the disease. Taking advantage of recent developments in ultra-high field (7 T) imaging, we investigated whether imaging measures of the LC also reveal a specific anatomic correlation with tau using novel plasma biomarkers of different species of hyperphosphorylated tau, how early in adulthood these associations can be detected and if are associated with worse cognitive performance. To validate the anatomic correlations, we tested if a rostro-caudal gradient in tau pathology is also detected at autopsy in data from the Rush Memory and Aging Project (MAP). We found that higher plasma measures of phosphorylated tau, in particular ptau231, correlated negatively with dorso-rostral LC integrity, whereas correlations for neurodegenerative plasma markers (neurofilament light, total tau) were scattered throughout the LC including middle to caudal sections. In contrast, the plasma Aβ42/40 ratio, associated with brain amyloidosis, did not correlate with LC integrity. These findings were specific to the rostral LC and not observed when using the entire LC or the hippocampus. Furthermore, in the MAP data, we observed higher rostral than caudal tangle density in the LC, independent of the disease stage. The in vivo LC-phosphorylated tau correlations became significant from midlife, with the earliest effect for ptau231, starting at about age 55. Finally, interactions between lower rostral LC integrity and higher ptau231 concentrations predicted lower cognitive performance. Together, these findings demonstrate a specific rostral vulnerability to early phosphorylated tau species that can be detected with dedicated magnetic resonance imaging measures, highlighting the promise of LC imaging as an early marker of AD-related processes.

Worse objective and subjective sleep‐wake metrics are associated with locus coeruleus hypopigmentation: a retrospective post‐mortem study

AbstractBackgroundThe brainstem locus coeruleus (LC) was recently put forward as a key nucleus to connect early sleep‐wake disruption and Alzheimer’s disease (AD) pathophysiological processes. Here, we sought to investigate the relationships between post‐mortem LC hypopigmentation, reflecting LC neurodegeneration, and retrospective subjective/objective sleep‐wake regulation metrics in two longitudinal datasets.MethodLC pigmentation ratings were extracted from autopsy data across 517 Rush Memory and Aging Project (MAP) and 637 National Alzheimer’s Coordinating Center (NACC) cases. Actigraphy‐derived intradaily variability, an objective measure of rest‐activity rhythm fragmentation, was obtained in the MAP dataset, and subjective evaluations of sleep quality were retrieved from the NACC cohort. For both studies, sleep‐wake measures were extracted at the furthest and closest available time points, on average 6.8 y. and 2.5 y. before death, respectively. Logistic regressions adjusted for age at death, sex, race, and post‐mortem interval were used to assess whether sleep‐wake variables could predict post‐mortem LC pigmentation ratings. In the next step, additional models including AD‐related variables of APOE genotype and cortical neuropathology (amyloid‐beta and tau burden) were further performed to test for independence in the relationships between sleep‐wake measures and LC pigmentation.ResultsIn the MAP cohort, higher rest‐activity rhythm fragmentation at both time points was significantly associated with greater odds of LC hypopigmentation at autopsy (Table 1). In models considering additional AD‐related variables, these relationships remained significant independently of the effects of APOE and cortical AD neuropathology (Table 1). In the NACC dataset, worse subjective sleep quality at the closest time point, but not at the furthest, was significantly linked to greater odds of LC hypopigmentation at autopsy (Table 2). Likewise, additional models indicated that this relationship is independent of APOE and cortical AD neuropathology (Table 2).ConclusionThese findings highlight the utility of evaluating sleep and wakefulness, especially with objective measurements, to predict LC neurodegenerative processes in older populations, as far as 6.8 years before death and beyond the effects of APOE genotype and cortical AD neuropathology. Our results thus have implications for improved detection of at‐risk individuals.

Neurofibrillary Tangles Prediction Based On MRI

AbstractBackgroundNeurofibrillary tangles, one of the hallmark pathologies of Alzheimer’s disease, are closely related to brain atrophy and cognitive decline. The purpose of this work was to develop an MRI‐based classifier of neurofibrillary tangles by combining ex‐vivo MRI and neuropathology in brain autopsies from a large number of community‐based older adults.MethodCerebral hemispheres from 878 older adults participating in three longitudinal, clinical pathologic cohort studies of aging: the Rush Memory and Aging Project (MAP), the Religious Orders Study (ROS), and the Minority Aging Research Study (MARS) (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, once within 24 hours postmortem and a second time approximately 30 days postmortem followed by detailed neuropathologic examination.An SVM classifier with l2 regularization was trained to distinguish participants at a Braak stage of V‐VI from those at a Braak stage of 0‐IV, based on features extracted from ex‐vivo MRI as well as demographic information (age, sex). The MRI features included volumetric, cortical thickness, subcortical shape, diffusion, and R2 measurements. When a feature contained multiple measurements per person, they were used to train a separate model that generated a separate risk score which was used as a feature in the final model. Because different groupings of features were available on different subgroups of the participants, the performance of the classifier was tested in a total of 74 participants (Fig. 2) that had measurements on all features.ResultThe average AUC of the classifier based on all MRI and demographic features was 0.87 with 82% mean sensitivity and 77% mean specificity (Fig. 3). In comparison, recently published work combining in‐vivo MRI and pathology data trained an MRI‐based classifier of people at Braak stage V‐VI vs. 0‐II and achieved an AUC=0.69 [1].ConclusionSuccessful completion of ex‐vivo to in‐vivo translation of our work may result in a non‐invasive classifier of neurofibrillary tangles aiding in refined participant selection and targeted therapies. Reference: [1] Dallaire‐Théroux, Caroline et al., Braak neurofibrillary tangle staging prediction from in vivo MRI metrics, Alzheimer's &amp; dementia, vol. 11, 2019.

Subjective socioeconomic status is associated with risk aversion in a community-based cohort of older adults without dementia.

Attitudes towards risk impact financial decisions that are critical in older adulthood. Socioeconomic status (SES) influences an individual's level of risk aversion; however, the association of subjective SES (i.e., social standing relative to others) with risk aversion has not been explored. We examined whether subjective SES is associated with risk aversion independent of objective SES (i.e., income, education). Participants were 933 older adults without dementia from the Rush Memory and Aging Project (MAP) or Minority Aging Research Study (MARS), two longitudinal epidemiologic studies of aging. Participants completed assessments of risk aversion, subjective SES, and cognition. We examined associations of subjective SES with risk aversion using mixed models adjusting for participant characteristics, objective markers of SES and global cognition. In bivariate analyses, lower global cognitive functioning, lower income, female sex, Black race, and lower subjective SES were associated with greater risk aversion. Results of the nonlinear mixed effects model revealed that higher subjective SES was associated with less risk aversion (Estimate = -0.238, SE = 0.083, p = 0.004), after controlling for covariates. Age, sex, race, and global cognition were also associated with risk aversion in the mixed effects model (ps 0.03), although income and education were not (ps 0.27) The relationship between subjective SES and risk aversion did not differ by sex or race (ps 0.31). Findings suggest that subjective SES contributes to risk aversion regardless of sex or race. Findings support the importance of considering subjective indicators of SES as they may impact an older adult's economic preferences.

Body Mass Index Trajectories Preceding Incident Mild Cognitive Impairment and Dementia

Body mass index (BMI) trajectories before the onset of mild cognitive impairment (MCI) and during the progression from MCI to dementia remain unclear. To assess the long-term BMI trajectories preceding incident MCI and dementia and explore whether they are associated with brain pathologies. The Rush Memory and Aging Project (MAP) was an ongoing community-based cohort study. This study included cognitively intact participants aged 60 to 90 years at baseline with annual follow-up from October 1997 to December 2020 (maximum follow-up of 22 years). During the follow-up, participants underwent brain autopsies. Data were analyzed from August 2021 to February 2022 using mixed-effect models. BMI was calculated using height and weight measured at baseline and follow-ups. Incident MCI and dementia were diagnosed following standard criteria. Neuropathological assessments (including global Alzheimer disease and vascular pathology) were performed for autopsies. A total of 1390 participants (mean [SD] age, 78.4 [6.5] years; 1063 female [76.5%]) were included in the study. In the analysis of BMI trajectories before MCI (n = 939), during the follow-up (median [IQR] duration, 6 [3-9] years), 371 participants (39.5%) developed MCI, of whom 88 (23.7%) progressed to dementia. Those who developed MCI were older (mean [SD] age, 79.6 [5.9] years vs 76.9 [6.6] years), consumed less alcohol (median [IQR] consumption, 0 [0-5.8] g/day vs 1.1 [0-6.9] g/day), had a lower BMI (mean [SD], 27.2 [4.9] vs 28.2 [5.9]), and were more likely to be apolipoprotein E (APOE) ε4 carriers (89 of 371 [24.0%] vs 98 of 568 [17.3%]) compared with those who remained cognitively intact over follow-up. Those who developed dementia were older (mean [SD] age, 81.0 [5.2] years vs 79.1 [6.0] years), had a lower level of physical activity (median [IQR] activity, 1.0 [0-2.5] h/week vs 1.8 [0.2-3.8] h/week), and were more likely to be APOE ε4 carriers than those who were dementia-free (33 of 88 [37.5%] vs 56 of 283 [19.8%]). Compared with participants who remained cognitively intact, in those with incident MCI, BMI tended to decline earlier and faster. From 7 years before diagnosis, people with incident MCI had an associated significantly lower BMI (mean difference, -0.96; 95% CI, -1.85 to -0.07) than those who were cognitively intact. Among people with incident MCI, the slopes of BMI decline did not differ significantly between those who did and did not develop dementia (β, -0.03; 95% CI, -0.21 to 0.15). In the analysis of BMI trajectories before autopsy (n = 358), BMI was associated with a faster declination among participants with a high burden of global Alzheimer disease pathology (β for pathology × time highest vs lowest tertile, -0.14; 95% CI, -0.26 to -0.02) or vascular pathology (β for pathology × time2 highest vs lowest tertile, 0.02; 95% CI, 0-0.05). Results of this cohort study suggest that among cognitively intact people, significantly lower BMI occurs beginning approximately 7 years before MCI diagnosis. After MCI diagnosis, BMI declines at the same pace in people who develop dementia and those who do not. High brain pathologies may underly the BMI decline preceding dementing disorders.