Memory And Aging Project Research Articles

Apolipoprotein E potently inhibits ferroptosis by blocking ferritinophagy.

Allelic 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. Here, we 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. These data support ferroptosis as a putative pathway to explain the major genetic risk associated with late onset AD.

Caffeine Consumption and Dementia: Are Lewy Bodies the Link?

ObjectiveThe objective of this study was to examine the association between caffeine intake and cognitive impairment. Caffeine‐neuropathology correlations and interactions with lifestyle and genetic factors impacting caffeine metabolism and response were also tested.MethodsWe included 888 participants aged 59+ years from the Rush Memory and Aging Project (MAP) and 303,887 participants aged 55+ years from the UK Biobank (UKB). MAP participants took part in annual cognitive testing. Diagnosis of dementia was based on clinical neurological examination and standardized criteria. A subset provided postmortem tissue for neuropathologic evaluation for common age‐related diseases (eg, Alzheimer's disease [AD], Lewy bodies, and vascular). For UKB, dementia was determined by linked hospital and death records. Self‐reported caffeine intake was estimated using food‐frequency questionnaires in both cohorts. Cox proportional hazard ratio (HR), regression, and mixed models were used to examine associations of caffeine intake with incident dementia, cognitive decline, and neuropathology.ResultsIn MAP, compared to ≤100 mg/day, caffeine intake >100 mg/day was associated with a significantly higher HR (95% confidence interval [CI]) of all‐cause (HR = 1.35, 95% CI = 1.03–1.76) and AD (HR = 1.41, 95% CI = 1.07–1.85) dementia. Caffeine intake was not associated with cognitive decline. In UKB, compared to ≤100 mg/day, the HRs (95% CI) of all‐cause dementia for consuming 100 ≤ 200, 200 ≤ 300, 300 ≤ 400, and > 400 mg/day were 0.83 (95% CI = 0.72–0.94), 0.74 (95% CI = 0.64–0.85), 0.74 (95% CI = 0.64–0.85), and 0.92 (95% CI = 0.79–1.08), respectively. Similar results were observed for Alzheimer's dementia. In MAP, caffeine intake was inversely associated with postmortem Lewy bodies but no other age‐related pathologies. Caffeine intake >100 mg/day was associated with lower neocortical type Lewy bodies (odds ratio (95%CI): 0.40 (95% CI = 0.21–0.75).InterpretationCaffeine intake was inconsistently associated with clinical dementia; potentially explained by cohort differences in underlying dementia etiology. Lewy bodies may link caffeine to lower risk in some persons. ANN NEUROL 2022;91:834–846

One in five community‐dwelling older adults will develop Alzheimer's dementia in five years

AbstractBackgroundAlzheimer's dementia (AD) is the most common form of dementia and a growing public health problem. By 2050, one in 85 adults globally will have the disease, for which there are few effective treatments. The objective of this study was to estimate the five‐year incidence rate of AD among predominantly White, community‐dwelling older adults.MethodData were included from 837 community‐dwelling older adults in the Rush Memory and Aging Project (MAP) with ≥2 cognitive assessments and clinical neurological exams, which were collected annually for up to 15 years (mean: 5.06; SE: 0.01). Enrollment for the current study began in 2004. Participants in MAP were community‐dwelling older adults recruited from >40 retirement communities in Chicago beginning in 1997 and followed until death, first diagnosis of probable AD, or until lost to follow‐up. A life table was used to estimate follow‐up time. Estimates of the incidence rate in this and prior MAP studies reporting incidence of AD based on cognitive testing (not autopsy) were pooled. Fixed and random effects models were used to estimate the pooled incidence rate using Episheet.ResultIn the current study, the mean age was 82.1 years (SE: 1.5 years) and respondents were predominantly non‐Hispanic White (n=776; 92.7%), 5.7% non‐Hispanic Black (n=48) and predominantly female (n=633, 75.6%). There were 200 cases of probable AD over 5,098 person‐years of follow‐up (incidence rate: 0.039; 95% CI: 0.034; 0.045 cases per year of follow‐up). Six studies, including an estimated total of 27,816 person‐years of follow‐up and 1,045 cases of probable AD, were included in the pooled analysis. The pooled incidence rate from fixed effects models was 0.038 cases/year (95% CI: 0.036; 0.040). The pooled incidence rate from random effects models was 0.037 cases/year (95% CI: 0.035, 0.041). The test of heterogeneity was p=0.128.ConclusionThese findings suggest that one in five (19%) predominantly White, community‐dwelling older adults will develop AD over five years. The burden of AD is already high but expected to increase significantly as the average age of the US population increases. This points to an urgent and growing need to find an effective treatment for Alzheimer’s dementia.

MIND Diet, Common Brain Pathologies, and Cognition in Community-Dwelling Older Adults.

MIND diet, a hybrid of the Mediterranean diet and the Dietary Approaches to Stop Hypertension diet, is associated with a slower cognitive decline and lower risk of Alzheimer's disease (AD) dementia in older adults. We aim to examine whether the association of the MIND diet with cognition is independent of common brain pathologies. Utilizing data from the Rush Memory and Aging Project (MAP), a longitudinal clinical-pathologic study, we studied 569 decedents with valid dietary data, cognitive testing proximate to death, and complete autopsy data at the time of these analyses. A series of regression analyses were used to examine associations of the MIND diet, dementia-related brain pathologies, and global cognition proximate to death adjusting for age, sex, education, APOEɛ4, late-life cognitive activities, and total energy intake. A higher MIND diet score was associated with better global cognitive functioning proximate to death (β= 0.119, SE = 0.040, p = 0.003), and neither the strength nor the significance of association changed substantially when AD pathology and other brain pathologies were included in the model. The β-estimate after controlling for global AD pathology was 0.111 (SE = 0.037, p = 0.003). The MIND diet-cognition relationship remained significant when we restricted our analysis to individuals without mild cognitive impairment at the baseline (β= 0.121, SE = 0.042, p = 0.005) or in people diagnosed with postmortem diagnosis of AD based on NIA-Reagan consensus recommendations (β= 0.114, SE = 0.050, p = 0.023). MIND diet is associated with better cognitive functioning independently of common brain pathology, suggesting that the MIND diet may contribute to cognitive resilience in the elderly.

A Genetic Study of Cerebral Atherosclerosis Reveals Novel Associations with NTNG1 and CNOT3.

Cerebral atherosclerosis is a leading cause of stroke and an important contributor to dementia. Yet little is known about its genetic basis. To examine the association of common single nucleotide polymorphisms with cerebral atherosclerosis severity, we conducted a genomewide association study (GWAS) using data collected as part of two community-based cohort studies in the United States, the Religious Orders Study (ROS) and Rush Memory and Aging Project (MAP). Both studies enroll older individuals and exclude participants with signs of dementia at baseline. From our analysis of 1325 participants of European ancestry who had genotype and neuropathologically assessed cerebral atherosclerosis measures available, we found a novel locus for cerebral atherosclerosis in NTNG1. The locus comprises eight SNPs, including two independent significant SNPs: rs6664221 (β = −0.27, 95% CI = (−0.35, −0.19), p = 1.29 × 10−10) and rs10881463 (β = −0.20, 95% CI = (−0.27, −0.13), p = 3.40 × 10−8). We further found that the SNPs may influence cerebral atherosclerosis by regulating brain protein expression of CNOT3. CNOT3 is a subunit of CCR4−NOT, which has been shown to be a master regulator of mRNA stability and translation and an important complex for cholesterol homeostasis. In summary, we identify a novel genetic locus for cerebral atherosclerosis and a potential mechanism linking this variation to cerebral atherosclerosis progression. These findings offer insights into the genetic effects on cerebral atherosclerosis.

Within-Person Associations of Self-Reports of Memory Impairment and Depressive Symptoms in Older Adults: Moderation of Relationships Over Time by Personality.

The current study examined within-person associations of self-reports of impaired current memory functioning and perceived decline with depressive symptoms in older adults without cognitive impairment, and whether these associations were moderated by individuals' levels of neuroticism, conscientiousness, and extraversion. Samples were drawn from the Einstein Aging Study, Rush Memory and Aging Project (MAP), Minority Aging Research Study (MARS), Health and Retirement Study (HRS), and National Health and Aging Trends Study (NHATS), with over 8,000 participants (65+ years) included across data sets. In a series of coordinated analyses, multilevel linear models tested within-person relationships over periods of up to 22 years. Across HRS and NHATS samples, self-reports of impaired current memory functioning covaried with depressive symptoms over time. This association was moderated by neuroticism, such that the association was stronger for individuals with higher levels of neuroticism. Across all samples, perceived memory decline covaried with depressive symptoms over time. This association was moderated by neuroticism in MAP/MARS, HRS, and NHATS, such that the association was stronger for individuals with higher levels of neuroticism. Self-reports of impaired current memory functioning and perceived memory decline are important determinants of older adults' psychological well-being. In our results, at times when older adults perceive poorer memory functioning or decline, they also tend to report more depressive symptoms. Further, results from two larger data sets suggest that individuals' level of neuroticism may determine the extent to which self-reports of memory impairment and depressive symptoms covary over time.

Risk factors for the progression of motoric cognitive risk syndrome to dementia: Retrospective cohort analysis of two populations.

Motoric cognitive risk syndrome (MCR) is a predementia syndrome characterized by cognitive complaints and slow gait. MCR is associated with increased risk of cognitive decline and incident dementia. Predictors of transition to dementia in MCR patients are still obscure. We examined clinical, biological and lifestyle parameters related to conversion to dementia using Cox models in 439 older adults with prevalent MCR (mean age 79.87±8.13years, 70% women) from two cohorts, 268 from the Chicago-based Rush Memory and Aging project (MAP) and 171 from the Religious Orders Study (ROS), which enrolled religious clergy across the United States. In the pooled sample, 439 (13.2%) had prevalent MCR (268 MAP and 171 ROS). There were 140 (31.9%) incident dementia cases over a median follow up of 4.0years. Age predicted conversion from MCR to dementia in both cohorts. Male gender was a risk factor only in ROS. In the pooled data, only higher depressive symptoms were associated with higher risk of conversion to dementia (adjusted hazard ratio [aHR] 1.13, 95% CI 1.03-1.24). Lower cognitive activity participation (aHR 0.59, 95% CI 0.44-0.79) and apolipoprotein E ε4 allele (aHR 2.57, 95% CI 1.48-4.45) predicted conversion to dementia in MAP. Depressive symptoms and other cohort-specific risk factors were identified as predictors of transition to dementia in individuals with MCR. These findings suggest common pathological mechanisms underlying mood, gait and cognitive declines in aging, which could help develop preventive strategies.

Hippocampal transcriptome deconvolution reveals differences in cell architecture of not demented elderly subjects underwent late-life physical activity

Recent findings demonstrated that physical exercise has a powerful role in improving cognitive function and delaying age-associated neurological decline. However, to date, there is a lack of information regarding the effect of physical activity (PA) on brain cells architecture.In this paper, we hypothesized that PA could play a role in the transcriptional changes of genes that enrich the main cells of central nervous system (CNS). From NCBI, we selected a microarray dataset composed of the human hippocampi (GSE110298) from 23 cognitively intact clinical cases (NDHSs) (aged 87.4 ± 6.3 years) selected to from the Rush Memory and Aging Project (MAP). The significantly expressed genes, obtained comparing hippocampi from subjects who underwent Low Physical Activity (LPA) vs those who performed High Physical Activity (HPA), were overlapped with the main genes enriching the CNS cells, obtained from the public human brain single-cell RNA-sequencing dataset (GSE67835), in order to determine the respective weighted percentages of significantly expression genes modulation (WPSEG).In NDHSs underwent HPA, the WPSEG was higher for Neurons, Dendritic Development, Synaptic transmission genes and Axon Development. In addition, in NDHSs underwent LPA we observed high expression of genes enriching Oligodendrocytes, Microglia, and Endothelial cells. Furthermore, neurogenesis and the decreasing of the T cell-mediated inflammatory process were the two main molecular mechanisms activated in the brains of NDHSs underwent HPA.From our results, it is possible to conclude that, in elderly subjects, the transcriptional profile of CNS cells changes as a function of the PA conducted during life. Performing PA periodically supports the maintenance of the physiological balance of neuronal cells and, consequently, improves the quality of life of the elderly.

Brain DNA Methylation Patterns in CLDN5 Associated With Cognitive Decline

BackgroundCognitive trajectory varies widely and can distinguish people who develop dementia from people who remain cognitively normal. Variation in cognitive trajectory is only partially explained by traditional neuropathologies. We sought to identify novel genes associated with cognitive trajectory using DNA methylation profiles from human postmortem brain. MethodsWe performed a brain epigenome-wide association study of cognitive trajectory in 636 participants from the ROS (Religious Orders Study) and MAP (Rush Memory and Aging Project) using DNA methylation profiles of the dorsolateral prefrontal cortex. To maximize our power to detect epigenetic associations, we used the recently developed Gene Association with Multiple Traits test to analyze the 5 measured cognitive domains simultaneously. ResultsWe found an epigenome-wide association for differential methylation of sites in the CLDN5 locus and cognitive trajectory (p = 9.96 × 10−7) that was robust to adjustment for cell type proportions (p = 8.52 × 10−7). This association was primarily driven by association with declines in episodic (p = 4.65 × 10−6) and working (p = 2.54 × 10−7) memory. This association between methylation in CLDN5 and cognitive decline was significant even in participants with no or little signs of amyloid-β and neurofibrillary tangle pathology. ConclusionsDifferential methylation of CLDN5, a gene that encodes an important protein of the blood-brain barrier, is associated with cognitive trajectory beyond traditional Alzheimer’s disease pathologies. The association between CLDN5 methylation and cognitive trajectory in people with low pathology suggests an early role for CLDN5 and blood-brain barrier dysfunction in cognitive decline and Alzheimer’s disease.

Relationship between objectively measured physical activity on neuropathology and cognitive outcomes in older adults: Resistance versus resilience?

IntroductionPhysical activity (PA) is associated with better cognitive and brain health. However, it remains unclear whether PA relates to accumulation of disease pathology (“resistance”) or indirectly moderates adverse effects of pathology on cognition (“cognitive resilience”).MethodsFive hundred thirteen Rush Memory and Aging Project (MAP) decedents completed longitudinal actigraphy monitoring, cognitive testing, and neuropathological examination. Cross‐sectional models tested the relationship between average PA and pathology, and the moderating effect of baseline PA on the association between pathology and cognition. Longitudinal models examined whether changes in PA moderated associations between pathology and cognition.ResultsPA was negatively associated with Lewy body disease (LBD), but positively associated with Alzheimer's disease (AD) burdens. Baseline PA attenuated the association between cerebrovascular pathology and cognition, whereas longitudinal change in PA attenuated associations between AD, cerebral amyloid angiopathy, TAR DNA‐binding protein 43, and atherosclerosis on cognitive decline.DiscussionWhereas PA relates to “cognitive resilience” against cerebrovascular disease, AD, and other neuropathologies, “resistance” effects were limited.

ARTS: A novel In-vivo classifier of arteriolosclerosis for the older adult brain

Brain arteriolosclerosis, one of the main pathologies of cerebral small vessel disease, is common in older adults and has been linked to lower cognitive and motor function and higher odds of dementia. In spite of its frequency and associated morbidity, arteriolosclerosis can only be diagnosed at autopsy. Therefore, the purpose of this work was to develop an in-vivo classifier of arteriolosclerosis based on brain MRI. First, an ex-vivo classifier of arteriolosclerosis was developed based on features related to white matter hyperintensities, diffusion anisotropy and demographics by applying machine learning to ex-vivo MRI and pathology data from 119 participants of the Rush Memory and Aging Project (MAP) and Religious Orders Study (ROS), two longitudinal cohort studies of aging that recruit non-demented older adults. The ex-vivo classifier showed good performance in predicting the presence of arteriolosclerosis, with an average area under the receiver operating characteristic curve AUC = 0.78. The ex-vivo classifier was then translated to in-vivo based on available in-vivo and ex-vivo MRI data on the same participants. The in-vivo classifier was named ARTS (short for ARTerioloSclerosis), is fully automated, and provides a score linked to the likelihood a person suffers from arteriolosclerosis. The performance of ARTS in predicting the presence of arteriolosclerosis in-vivo was tested in a separate, 91% dementia-free group of 79 MAP/ROS participants and exhibited an AUC = 0.79 in persons with antemortem intervals shorter than 2.4 years. This level of performance in mostly non-demented older adults is notable considering that arteriolosclerosis can only be diagnosed at autopsy. The scan-rescan reproducibility of the ARTS score was excellent, with an intraclass correlation of 0.99, suggesting that application of ARTS in longitudinal studies may show high sensitivity in detecting small changes. Finally, higher ARTS scores in non-demented older adults were associated with greater decline in cognition two years after baseline MRI, especially in perceptual speed which has been linked to arteriolosclerosis and small vessel disease. This finding was shown in a separate group of 369 non-demented MAP/ROS participants and was validated in 72 non-demented Black participants of the Minority Aging Research Study (MARS) and also in 244 non-demented participants of the Alzheimer's Disease Neuroimaging Initiative 2 and 3. The results of this work suggest that ARTS may have broad implications in the advancement of diagnosis, prevention and treatment of arteriolosclerosis. ARTS is publicly available at https://www.nitrc.org/projects/arts/.

Within-Person Associations Among Self-Perceptions of Memory, Depressive Symptoms, and Activity Participation in Older Adults

Self-perceptions of memory problems may impact older adults' mood as well as their activity participation, thereby negatively affecting health and well-being. We examined within-person associations among self-reported memory, depressive symptoms, as well as physical, social, and cognitive activity participation in older adults without cognitive impairment. Samples were drawn from the Einstein Aging Study (EAS), National Health and Aging Trends Study (NHATS), Rush Memory and Aging Project (MAP), and Minority Aging Research Study (MARS), with over 8,000 participants (65+ years) included across data sets. In a series of coordinated analyses, multilevel structural equation modeling was used to examine within-person relationships over periods of up to 20 years. Across EAS, NHATS, and MAP/MARS samples, we found that older adults' self-perceptions of memory did not directly covary with activity participation over time. However, we did find an indirect association in NHATS such that within-person changes in depressive symptoms were associated with changes in self-reported memory, and these contributed to lower physical as well as social activity participation. Older adults' activity participation is important for health, but maximizing engagement requires understanding potentially impeding factors. We found some evidence that as self-perceptions of memory change over time, associated depressive symptoms may contribute to lower activity participation. Inconsistent findings across data sets, however, suggest future research is needed to understand individual characteristics that may influence these relationships.

Identifying gene expression signatures in individuals with minimal cognitive impairment in the presence of advanced Alzheimer's disease pathology

AbstractBackgroundThe pathological hallmarks of Alzheimer’s disease such as amyloid plaques and neurofibrillary tau tangles are usually associated with the primary clinical manifestation of cognitive decline. Recent studies implicate that a subset of “resistant” individuals have high burden of AD pathology, yet do not exhibit dementia (cognitive decline). Here, we compared the publicly available gene expression profiles of these resilient individuals and susceptible individuals (showing both AD pathology and cognitive decline) in dorsolateral prefrontal cortex (DLPFC) brain tissue obtained from individuals enrolled in the Religious Orders Study (ROS) or the Rush Memory and Aging Project (MAP).MethodWe conducted bulk RNA‐Seq analysis on data from the DLPFC of 239 individuals with differing AD pathological findings and clinical consensus diagnosis. This data set is available through the Synapse portal (AMP‐AD consortium). The patients were subdivided into four groups of control, weakly resilient, strongly resilient, and susceptible, according to their degree of pathology (Braak stage) and clinical cognitive diagnosis. The control group included individuals with no cognitive impairment and initial braak stages; 0 and 1. The weakly and strongly resilient groups included individuals with no and mild cognitive impairment with advanced Braak stages respectively, while the susceptible group comprised individuals with AD‐dementia and advanced tauopathy (Braak stage>4). We used DESeq2 between these groups with a multiple factor approach that corrected for sex and age of death.ResultOur findings provide insight into genes that may be attributable to weak or strong resilience in the presence of relatively advanced AD pathology. Some of these candidate genes, such as SERPINA5 and GIPR, have previously been associated AD pathology and other neurodegenerative diseases, but we also identified a set of less well‐characterized genes that may be involved in cognition specific contributions to AD resilience.ConclusionOur study recapitulates genes with known associations with AD pathology, and also identifies new candidate genes and pathways worth pursuing further as potential therapeutic targets to mitigate cognitive decline associated with AD. As ongoing proteomics and snRNA‐seq data is generated, these candidates may be further refined through an integrative approach, yielding new insights into pathways involved in AD pathology‐mediated decline and cognitive resilience.

Quantifying cognitive resilience in Alzheimer's Disease: The Alzheimer's Disease Cognitive Resilience Score.

Even though there is a clear link between Alzheimer’s Disease (AD) related neuropathology and cognitive decline, numerous studies have observed that healthy cognition can exist in the presence of extensive AD pathology, a phenomenon sometimes called Cognitive Resilience (CR). To better understand and study CR, we develop the Alzheimer’s Disease Cognitive Resilience Score (AD-CR Score), which we define as the difference between the observed and expected cognition given the observed level of AD pathology. Unlike other definitions of CR, our AD-CR Score is a fully non-parametric, stand-alone, individual-level quantification of CR that is derived independently of other factors or proxy variables. Using data from two ongoing, longitudinal cohort studies of aging, the Religious Orders Study (ROS) and the Rush Memory and Aging Project (MAP), we validate our AD-CR Score by showing strong associations with known factors related to CR such as baseline and longitudinal cognition, non AD-related pathology, education, personality, APOE, parkinsonism, depression, and life activities. Even though the proposed AD-CR Score cannot be directly calculated during an individual’s lifetime because it uses postmortem pathology, we also develop a machine learning framework that achieves promising results in terms of predicting whether an individual will have an extremely high or low AD-CR Score using only measures available during the lifetime. Given this, our AD-CR Score can be used for further investigations into mechanisms of CR, and potentially for subject stratification prior to clinical trials of personalized therapies.

Association of Heel Bone Mineral Density With Incident Disability and Mortality in Community-Dwelling Older Adults.

ABSTRACTAge‐related bone loss is common in older adults. However, the association of low bone mass with incident disability and mortality is not well established. A sample of 738 participants in the Rush Memory and Aging Project (MAP) was evaluated at baseline for bone mineral density (BMD) using quantitative ultrasound at the calcaneus. An annual interview assessed basic activities of daily living (BADL), instrumental activities of daily living (IADL), mobility disability, and history of hip fracture. The associations between baseline BMD and risk of death; incident BADL, IADL, and mobility disability; and hip fracture were investigated using Cox hazard models, adjusting for age, sex, education, race, and body mass index (BMI). The robustness of our findings was evaluated by adjusting for confounding factors and health conditions including joint pain, musculoskeletal medications, smoking status, motor function, global cognition, falls, cardiovascular events, and diabetes. Participants were on average (mean ± SD) 80.9 ± 7.0 years old, 72% female, and 3.8% black, with a baseline BMI of 27.3 ± 5.4 kg/m2, and a baseline of BMD of 0.44 ± 0.14 g/cm2. In models adjusted for age, sex, education, race, and BMI, lower BMD was associated with a higher rate of death (hazard ratio [HR] 1.20; 95% confidence interval [CI], 1.08–1.33), incident BADL disability (HR 1.20; 95% CI, 1.05–1.37), and hip fracture (HR 2.57; 95% CI, 1.72–3.82), but not of IADL disability (HR 1.00; 95% CI, 0.85–1.17) or mobility disability (HR 1.13; 95% CI, 0.97–1.32). The association between BMD and mortality was not significant in fully adjusted models, but the BMD and BADL associations remained significant in models adjusting for both demographic variables and BMD‐modifying health conditions. BMD is associated with incident disability in older adults. © 2020 The Authors. JBMR Plus published by Wiley Periodicals LLC on behalf of American Society for Bone and Mineral Research.

The Stability of Vitamins D and K of the Human Brain During Freezer Storage: The Memory and Aging Project (MAP)

Abstract Objectives Vitamins D and K are present in human brain tissue, and evidence is emerging that these nutrients may have a role in neurodegenerative disease. Given the increasing interest in conducting analyses of archived brain samples, it is important to evaluate the stability of these nutrients in brain tissue over long-term storage. Therefore, we evaluated the influence of freezer storage time on vitamin D and vitamin K concentrations in human brain samples. Methods Post-mortem brain samples were obtained from 500 participants in the Rush Memory and Aging Project (mean age 91 yrs, 71% female). At autopsy and brain dissection, the tissues were immediately frozen on brass plates atop dry ice then stored at −80o C until analysis. Storage time was categorized in 1-year increments. Vitamin D [25(OH)D] and vitamin K [menaquinone-4 (MK4)] concentrations were measured in four regions (mid-temporal cortex, mid-frontal cortex, cerebellum, anterior watershed white matter) using LC/MS/MS and HPLC, respectively. We calculated the mean 25(OH)D and MK4 concentrations across the four regions and then applied a natural-log transformation to the means to improve normality. Analysis of variance was used to determine if the geometric mean ± SEM 25(OH)D and MK4 concentrations differed according to storage time. The samples stored ≤1.0 year served as the reference group. Results The mean 25(OH)D concentration in brains stored >6.0 years (n = 203; 0.8 ± 0.05 pmol/g), was significantly lower than the concentration in brains stored ≤1.0 year (n = 79; 1.2 ± 0.09 pmol/g, P ≤ 0.004). The 25(OH)D in the brains stored ≤1.0 year did not differ from the concentration in brains stored for 1.1–6.0 years (n = 212; 1.2 ± 0.05 pmol/g, P ≥ 0.37). The mean MK4 concentration in the brains stored ≥9.0 years (n = 81; 0.7 ± 0.6 pmol/g) was significantly lower than that in the brains stored ≤1.0 year (1.2 ± 1.3 pmol/g; P ≤ 0.01). The MK4 in brains stored ≤1.0 year did not differ from the concentration in brains stored for 1.1–9.0 years (n = 339; 1.3 ± 0.8 pmol/g; P ≥ 0.11). Conclusions 25(OH)D and MK4 appear to be stable in brain tissue stored at −80 °C for up to 6 and 9 years, respectively, but not longer. This should be considered in the design and interpretation of studies linking brain concentrations of these nutrients to neurodegenerative diseases. Funding Sources Supported by the National Institute of Aging.

Dietary flavonols and risk of Alzheimer dementia.

To determine whether dietary intake of flavonols is associated with Alzheimer dementia. The study was conducted among 921 participants of the Rush Memory and Aging Project (MAP), an ongoing community-based, prospective cohort. Participants completed annual neurologic evaluations and dietary assessments using a validated food frequency questionnaire. Among 921 MAP participants who initially had no dementia in the analyzed sample, 220 developed Alzheimer dementia. The mean age of the sample was 81.2 years (SD 7.2), with the majority (n = 691, 75%) being female. Participants with the highest intake of total flavonols had higher levels of education and more participation in physical and cognitive activities. In Cox proportional hazards models, dietary intakes of flavonols were inversely associated with incident Alzheimer dementia in models adjusted for age, sex, education, APOE ɛ4, and participation in cognitive and physical activities. Hazard ratios (HRs) for the fifth vs first quintiles of intake were as follows: for total flavonol, 0.52 (95% confidence interval [CI], 0.33-0.84); for kaempferol, 0.49 (95% CI, 0.31-0.77); for myricetin, 0.62 (95% CI, 0.4-0.97); and for isorhamnetin, 0.62 (95% CI, 0.39-0.98). Quercetin was not associated with Alzheimer dementia (HR, 0.69; 95% CI, 0.43-1.09). Higher dietary intakes of flavonols may be associated with reduced risk of developing Alzheimer dementia.

THE ROLE OF FRAILTY IN DEMENTIA EXPRESSION: EVIDENCE FROM CLINICAL-PATHOLOGIC COHORT STUDIES

A growing body of evidence suggests that pathological features of dementia are diverse and don’t wholly explain variability in dementia incidence. Objective: discuss the role of frailty in dementia expression using evidence from clinical-pathologic cohort studies. Methods: Cross-sectional relationships between neuropathology (Braak, CERAD staging), frailty (frailty index at last study visit before death), and dementia diagnosis at death were performed using data from the Rush Memory and Aging Project (MAP) and the Cambridge City Over 75s Cohort study (CC75C). Results: Participants were 89.7±6.2 and 92.2±4.5 years in MAP (n=451) and CC75C (n=177) and mostly female (69.4-70.1%). Most had dementia (52.8%-59.3%). Frailty was normally distributed (mean FI0.42±0.18 in MAP and 0.34±0.16 in CC75C). Frailty was associated with dementia in MAP (OR=1.88, p<0.001) and CC75C (OR=1.30, p=0.03) after controlling for age, sex, time to death, and neuropathology. Longitudinal analysis is in progress. Frailty appears to play a meaningful role in dementia expression.

Cognitive function and neuropathological outcomes: a forward-looking approach.

To evaluate the risk of Alzheimer's disease-related neuropathology burden at autopsy given older adults' current cognitive state. Participants included 1,303 individuals who enrolled in the Religious Orders Study (ROS) and 1,789 who enrolled in the Rush Memory and Aging Project (MAP). Cognitive status was evaluated via standardized assessments of global cognition and episodic memory. At the time of analyses, about 50% of participants were deceased with the remaining numbers right censored. Using multi-state Cox proportional hazard models, we compared the cognitive status of all subjects alive at a given age and estimated future risk of dying with different AD-related neuropathologies. Endpoints considered were Braak Stages (0-2, 3-4, 5-6), CERAD (0, 1, 2, 3), and TDP-43 (0, 1, 2, 3) level. For all three pathological groupings (Braak, CERAD, TDP-43), we found that a cognitive test score one standard deviation below average put individuals at up to three times the risk for being diagnosed with late stage AD at autopsy according to pathological designations. The effect remained significant after adjusting for sex, APOE-e4 status, smoking status, education level, and vascular health scores. Applying multi-state modeling techniques, we were able to identify those at risk of exhibiting specific levels of neuropathology based on current cognitive test performance. This approach presents new and approachable possibilities in clinical settings for diagnosis and treatment development programs.

HIGH LIFESPAN COGNITIVE RESERVE IS ASSOCIATED WITH A REDUCED DEMENTIA RISK, INDEPENDENTLY OF BRAIN PATHOLOGIES

Cognitive reserve (CR) has been proposed as compensatory mechanisms to cope with brain damages. However, evidence on the association between lifespan CR with dementia is limited, and the role of brain pathologies in the association is unknown. Within the Rush Memory and Aging Project (MAP), 1638 dementia-free older adults (mean age=79) were followed for up to 20 years to detect incident dementia cases. Information on CR factors (education, cognitive activities at early, mid- and late-life, and social activities in late life) was obtained at the study entry. Based on these factors, lifespan CR was captured by a latent variable which was divided into tertiles: lowest, middle and highest. During the follow-up, 633 participants died and underwent neuropathologic evaluations for Alzheimer's disease and other brain pathologies. Data were analyzed using structural equation model, Cox model and logistic regression. During the follow-up, 386 participants developed dementia (357 Alzheimer's dementia). The multi-adjusted hazards ratios (HR, 95% CI) of dementia were 0.77 (0.59–0.99, p=0.048) for middle CR, and 0.61 (0.47–0.81) for highest CR compared to lowest CR. The risk reduction by highest CR was greater in APOE ε4 carriers than non-ε4 carriers (attributable proportion due to interaction=0.43, 95% CI 0.16–0.71). In autopsied participants, middle and highest CR were not related to the burden of AD pathologies and most of other brain pathologies comparing to lowest CR. The association between high CR and dementia remained significant (HR=0.60, 95% CI 0.42–0.86) after additional adjustment for the pathologies. Middle to highest lifespan CR is associated with a reduced dementia risk, independent of brain pathologies. High CR may mitigate APOE ɛ4 related dementia risk.