Memory And Aging Project Research Articles

Associations of Vitamin D and Vitamin K and Their Metabolites Across Four Regions of the Human Brain: The Memory and Aging Project (MAP) (FS05-02-19)

ObjectivesVery little is known about the forms of vitamin D and vitamin K in the human brain. The objective of this study is to evaluate concentrations of vitamin D and vitamin K forms in human brain and their correlations across four human brain regions. MethodsVitamin D [D3, 25(OH)D and 1,25(OH)2D] and vitamin K [phylloquinone and menaquinone-4 (MK4)] concentrations were measured by LC/MS/MS and HPLC, respectively, in four brain regions from post-mortem samples obtained from participants in the Rush Memory and Aging Project (n = 130, mean age 82 yrs, 81% female). The brain regions analyzed were the mid-frontal cortex (MF) and mid-temporal cortex (MT) [two regions important for memory in Alzheimer’s Disease (AD)], the cerebellum (CR, a region not affected by AD), and the anterior watershed white matter (AWS, a region associated with vascular disease). The correlations among the vitamin forms across brain regions were calculated using Spearman rank order correlation coefficients. Significance was set at P < 0.001. ResultsThe average concentrations of vitamin D3, 25(OH)D and MK4 were 604 pg/g, 535 pg/g, and 3.4 pmol/g, respectively. 25(OH)D and MK4 were detected in >95% of the brain samples. Nearly 92% of 1,25(OH)2D and 80% of phylloquinone samples had concentrations below the limit of assay detection (LOD) 1,25(OH)2D = 20 ng/g, phylloquinone = 0.1 pmol/g). Vitamin D3 and 25(OH)D concentrations were positively correlated across all four regions (all Spearman r ≥ 0.78, P < 0.0001). The 1,25(OH)2D was significantly correlated between the MF and CR regions only (Spearman r = 0.30, P < 0.001, all other P ≥ 0.002). MK4 and PK were positively correlated across the four regions studied (MK4 all Spearman r ≥ 0.78, phylloquinone r ≥ 0.49, all P < 0.001). ConclusionsTo the best of our knowledge, this study is the first evaluation of the concentrations of vitamin D and vitamin K forms in multiple regions of the human brain. Overall, the vitamin D and vitamin K forms were each positively correlated across the four brain regions studied. Future studies are needed to clarify the roles of these nutrients in AD and dementia. Funding SourcesNational Institute of Aging.

Correlations of Vitamin D Forms and Vitamin K Forms Within Four Human Brain Regions: The Memory and Aging Project (MAP) (P14-025-19)

ObjectivesVitamins D and K are detected in the human brain, but the associations among the forms of vitamin D and vitamin K within brain region is unclear. The objective of this study is to evaluate the correlations of vitamin D forms and vitamin K forms within four regions of the human brain. MethodsPost-mortem brain samples were obtained from 130 participants in the Rush Memory and Aging Project, a prospective cohort of community-dwelling adults from Chicago, IL (age range 78–86 y; 81% Female). Vitamin D [D3, 25(OH)D and 1,25(OH)2D] and vitamin K (phylloquinone and MK4) concentrations were measured by LC/MS/MS and HPLC, respectively, in the following regions: middle frontal cortex (MF) and middle temporal cortex (MT) [two key memory regions affected by Alzheimer’s Disease (AD)], cerebellum, (CR, which is unaffected by AD), and the anterior watershed white matter (AWS, associated with vascular disease). The correlations among nutrient forms within each region were calculated using Spearman rank order correlation coefficients. Statistical significance was set at P < 0.001. ResultsWithin the MT region, D3, 25(OH)D, and 1,25(OH)2D were all positively correlated with one another (all Spearman r ≥ 0.35, P < 0.0001). Within the MF, AWS, and CR regions, 25(OH)D and D3 were positively correlated (Spearman r = 0.62, 0.61 and 0.46 respectively, all P < 0.0001), but 1,25(OH)2D was not significantly correlated with D3 or 25(OH)D (all Spearman r ≤ 0.21, P ≥ 0.02). No statistically significant correlations were detected between phylloquinone and MK4 (all Spearman r ≤ 0.17, P ≥ 0.05) in any region. ConclusionsVitamin D forms were significantly positively correlated within the four regions studied, but vitamin K forms were not. These data provide insight into a potential role for vitamin D and vitamin K in AD and dementia that merits future study. Funding SourcesSupported by the National Institute of Aging.

Complex Neurological Phenotype in Female Carriers of NHE6 Mutations

Mutations in NHE6 (also termed SLC9A6) cause the X-linked neurological disorder Christianson syndrome (CS) in males. The purpose of this study was to examine the phenotypic spectrum of female carriers of NHE6 mutations. Twenty female carriers from 9 pedigrees were enrolled, ranging from approximately age 2 to 65. A subset of female carriers was assessed using standardized neuropsychological measures. Also, the association of NHE6 expression with markers of brain age was evaluated using 740 participants in the Religious Orders Study (ROS) and Rush Memory and Aging Project (MAP). A majority, but not all, female carriers demonstrated a deficit in at least one neurocognitive domain (85%). A recognizable neuropsychological profile emerged, revealing impairments in visuospatial function, attention, and executive function. Common neuropsychiatric diagnoses included: intellectual disability/developmental delay (20%), learning difficulties (31%), speech/language delays (30%), and attention-deficit/hyperactivity disorder (20%). Notable neurological diagnoses in aging CS female carriers include corticobasal degeneration and atypical parkinsonism. In postmortem brains from the ROS/MAP dataset of normal and pathological aging, decreased NHE6 expression was correlated with greater tau deposition. Our study provides an examination of the phenotypic range in female carriers of NHE6 mutations. The findings indicate that NHE6-related disease in females represents a new neurogenetic condition.

Subtypes Based on Neuropsychological Performance Predict Incident Dementia: Findings from the Rush Memory and Aging Project.

In a previous report, we used latent class analysis (LCA) to identify natural subgroups of older adults in the Einstein Aging Study (EAS) based on neuropsychological performance. These subgroups differed in demographics, genetic profile, and prognosis. Herein, we assess the generalizability of these findings to an independent sample, the Rush Memory and Aging Project (MAP), which used an overlapping, but distinct neuropsychological battery. Our aim was to identify the association of natural subgroups based on neuropsychological performance in the MAP cohort with incident dementia and compare them with the associations identified in the EAS. MAP is a community-dwelling cohort of older adults living in the northeastern Illinois, Chicago. Latent class models were applied to baseline scores of 10 neuropsychological measures across 1,662 dementia-free MAP participants. Results were compared to prior findings from the EAS. LCA resulted in a 5-class model: Mixed-Domain Impairment (n = 71, 4.3%), Memory-specific-Impairment (n = 274, 16.5%), Average (n = 767, 46.1%), Frontal Impairment (n = 222, 13.4%), and a class of Superior Cognition (n = 328, 19.7%). Similar to the EAS, the Mixed-Domain Impairment, the Memory-Specific Impairment, and the Frontal Impairment classes had higher risk of incident Alzheimer's disease when compared to the Average class. By contrast, the Superior Cognition had a lower risk of Alzheimer's disease when compared to the Average class. Natural cognitive subgroups in MAP are similar to those identified in EAS. These similarities, despite study differences in geography, sampling strategy, and cognitive tests, suggest that LCA is capable of identifying classes that are not limited to a single sample or a set of cognitive tests.

A multi-omic atlas of the human frontal cortex for aging and Alzheimer\u2019s disease research

We initiated the systematic profiling of the dorsolateral prefrontal cortex obtained from a subset of autopsied individuals enrolled in the Religious Orders Study (ROS) or the Rush Memory and Aging Project (MAP), which are jointly designed prospective studies of aging and dementia with detailed, longitudinal cognitive phenotyping during life and a quantitative, structured neuropathologic examination after death. They include over 3,322 subjects. Here, we outline the first generation of data including genome-wide genotypes (n=2,090), whole genome sequencing (n=1,179), DNA methylation (n=740), chromatin immunoprecipitation with sequencing using an anti-Histone 3 Lysine 9 acetylation (H3K9Ac) antibody (n=712), RNA sequencing (n=638), and miRNA profile (n=702). Generation of other omic data including ATACseq, proteomic and metabolomics profiles is ongoing. Thanks to its prospective design and recruitment of older, non-demented individuals, these data can be repurposed to investigate a large number of syndromic and quantitative neuroscience phenotypes. The many subjects that are cognitively non-impaired at death also offer insights into the biology of the human brain in older non-impaired individuals.

Evaluation of TDP-43 proteinopathy and hippocampal sclerosis in relation to APOE ε4 haplotype status: a community-based cohort study

Transactive response DNA-binding protein of 43 kDa (TDP-43) proteinopathy in older adults frequently coexists with Alzheimer's disease pathology and hippocampal sclerosis. It is unclear whether there is a link between APOE ε4 and TDP-43 proteinopathy, and the role of APOE ε4 in the association of TDP-43 proteinopathy with hippocampal sclerosis remains to be examined. We investigated the relationships of TDP-43 proteinopathy and hippocampal sclerosis with APOE ε4. We used data from two community-based cohort studies of ageing and dementia: the Religious Orders Study (ROS) and the Rush Memory and Aging Project (MAP). A battery of cognitive tests examining multiple cognitive domains is given to ROS-MAP participants each year, and a measure of annual global cognitive function for each participant is derived by averaging Z scores of these tests. The final clinical diagnosis is assigned after death by a neurologist using all available clinical data without access to post-mortem pathology. Amyloid-β, paired helical filament tau, Lewy bodies, TDP-43, and hippocampal sclerosis were microscopically evaluated in the midbrain, medial temporal, and neocortical regions that capture the progression of each neuropathology. TDP-43 proteinopathy topographic stage was recorded as an ordinal variable, and TDP-43 burden was defined by averaging a semi-quantitative six-point scale across six brain regions. The relationships among APOE ε4, TDP-43 proteinopathy, and hippocampal sclerosis were tested with regression models controlled for sex and age at death, and they were further explored with a mediation analysis using the quasi-Bayesian Monte Carlo method. ROS began data collection in 1994, and MAP began data collection in 1997. The data included in this study were analysed from Jan 16, 2017, to July 12, 2017. When analysis began in January, 2017, a total of 1059 ROS-MAP participants who were deceased had APOE genotype and complete pathological measures for amyloid-β, paired helical filament tau, and TDP-43 proteinopathy stage. After excluding 15 participants with other pathological diagnoses, 1044 participants, 1042 of whom also had measures of Lewy body pathology, were included in this study (470 from ROS and 574 from MAP). APOE ε4 count was associated with higher TDP-43 proteinopathy stage (odds ratio [OR] 2·0, 95% CI 1·6-2·6; p=1·9 × 10-9) and TDP-43 burden (0·40, 0·28-0·52; p=1·2 × 10-10). Amyloid-β, paired helical filament tau, or Lewy body pathology did not fully explain this association. APOE ε4 increased the odds of hippocampal sclerosis (OR 2·1, 95% CI 1·4-3·0; p=1·7 × 10-4); this effect was largely mediated by TDP-43 burden (mediated effect p<1·0 × 10-4) but not directly by APOE ε4 (direct effect p=0·40). APOE ε4 was associated with worse global cognition proximate to death even after adjusting for amyloid-β and paired helical filament tau (estimated effect -0·18, 95% CI -0·31 to -0·04; p=0·010), but this association was attenuated by additionally adjusting for TDP-43 burden (-0·09, -0·22 to 0·04; p=0·18). APOE ε4 seems to increase TDP-43 burden, and this effect in turn was associated with higher odds of hippocampal sclerosis, a pathology potentially downstream of TDP-43 proteinopathy. TDP-43 proteinopathy contributes to the detrimental effect of APOE ε4 on late-life cognition through mechanisms independent of Alzheimer's disease pathology, and future research should consider that TDP-43 proteinopathy might be an integral component of APOE-related neurodegeneration. US National Institute on Aging and Alzheimer's Association.

Instrumental neutron activation analysis, a technique for measurement of Se, Hg, Fe, Zn, K, Mn, Br, and the Hg:Se ratio in brain tissue samples with results from the Memory and Aging Project (MAP)

An INAA method for measurement of Se, Hg, Fe, Cr, Zn, Mn, K, and Br in autopsy cerebellum, anterior putamen, white matter, mid-frontal cortex, and inferior temporal lobe. Se, Hg, Fe, Cr, and Zn were measured autopsy samples collected from participants of the Memory and Aging Project. The first study examined the association between seafood consumption, brain Hg and Se, Apolipoprotein E (APOE-e4) status, and brain neuropathology. Following the initial study, the samples were archived. A subsequent method was developed to measure Mn, K, and Br in the archived brain tissue samples.

Loneliness 5 years ante-mortem is associated with disease-related differential gene expression in postmortem dorsolateral prefrontal cortex

Subjective social isolation, loneliness, is associated with poor mental and physical health, but the underlying molecular mechanisms are poorly understood. Here we analyzed loneliness data collected on average 5 years ante-mortem and RNA gene expression at death in postmortem dorsolateral prefrontal cortex (DLPFC) from 181 participants in the Rush Memory and Aging Project (MAP), a longitudinal, prospective cohort study of common chronic conditions of aging. Our analytic protocol controlled for biographical variables (age, sex, education), psychological and health variables (depressive symptoms, interval between assessment and autopsy, slope of cognitive decline, AD pathology, presence of infarcts) and RNA integrity. Our results are based on a pre-ranked Gene Set Enrichment Analysis (GSEA) at FDR-corrected q-values <0.05, using these collections from the Molecular Signatures Database (v6.0 MSigDB): (1) Hallmarks, (2) Canonical, (3) Gene Ontology (GO), (4) Chemical and Genetic Perturbations, (5) Immunologic Signatures, (6) Oncogenic Signatures, and (7) Cancer Modules. We now report on 337 up-regulated and 43 down-regulated gene sets, among which the most significant ones were associated with Alzheimer’s disease, psychiatric illness, immune dysfunction, and cancer. These gene sets constitute attractive targets for future studies into the molecular mechanisms by which loneliness exacerbates a wide range of neurodegenerative, psychiatric, and somatic illnesses.

The Alzheimer's Disease Sequencing Project: Study design and sample selection.

Late-onset Alzheimer disease (LOAD) is the leading cause of dementia worldwide, with substantial economic and public health implications.1 LOAD is a neurodegenerative disease characterized by progressive dementia typically manifesting in the seventh to ninth decades. Neuropathological changes precede clinical symptoms by 10–20 years, resulting in clinically asymptomatic individuals carrying neuropathologic features of LOAD.2 Much of the heritability of LOAD remains unexplained, despite LOAD having a high heritability (60%–80%) and despite the identification of the APOE locus, a major genetic determinant for LOAD.3 Genetic analyses have identified more than 25 other variants associated with smaller individual effects on disease risk.4 Acknowledgment: The Alzheimer's Disease Sequencing Project (ADSP) comprises 2 Alzheimer's Disease (AD) genetics consortia and 3 National Human Genome Research Institute (NHGRI)-funded Large Scale Sequencing and Analysis Centers (LSAC). The 2 AD genetics consortia are the Alzheimer's Disease Genetics Consortium (ADGC) funded by the NIA (U01 AG032984), and the Cohorts for Heart and Aging Research in Genomic Epidemiology (CHARGE) funded by the NIA (R01 AG033193), the National Heart, Lung, and Blood Institute (NHLBI), other NIH institutes, and other foreign governmental and nongovernmental organizations. The Discovery Phase analysis of sequence data is supported through UF1AG047133 (to G. Schellenberg, L.A. Farrer, M.A. Pericak-Vance, R. Mayeux, and J.L. Haines); U01AG049505 to S. Seshadri; U01AG049506 to E. Boerwinkle; U01AG049507 to E. Wijsman; and U01AG049508 to A. Goate. Data generation and harmonization in the Follow-up Phases is supported by U54AG052427 (to G. Schellenberg and Wang). The ADGC cohorts include Adult Changes in Thought (ACT), the Alzheimer's Disease Centers (ADC), the Chicago Health and Aging Project (CHAP), the Memory and Aging Project (MAP), Mayo Clinic (MAYO), Mayo Parkinson's Disease controls, the University of Miami, the Multi-Institutional Research in Alzheimer's Genetic Epidemiology Study (MIRAGE), the National Cell Repository for Alzheimer's Disease (NCRAD), the National Institute on Aging Late Onset Alzheimer's Disease Family Study (NIA-LOAD), the Religious Orders Study (ROS), the Texas Alzheimer's Research and Care Consortium (TARC), Vanderbilt University/Case Western Reserve University (VAN/CWRU), the Washington Heights-Inwood Columbia Aging Project (WHICAP) and the Washington University Sequencing Project (WUSP), the Columbia University Hispanic–Estudio Familiar de Influencia Genetica de Alzheimer (EFIGA), the University of Toronto (UT), and Genetic Differences (GD). The CHARGE cohorts with funding provided by 5RC2HL102419 and HL105756, include the following: the Atherosclerosis Risk in Communities (ARIC) Study which is conducted as a collaborative study supported by NHLBI contracts (HHSN268201100005C, HHSN268201100006C, HHSN268201100007C, HHSN268201100008C, HHSN268201100009C, HHSN268201100010C, HHSN268201100011C, and HHSN268201100012C), the Austrian Stroke Prevention Study (ASPS), the Cardiovascular Health Study (CHS), the Erasmus Rucphen Family Study (ERF), the Framingham Heart Study (FHS), and the Rotterdam Study (RS). The 3 LSACs are the Human Genome Sequencing Center at the Baylor College of Medicine (U54 HG003273), the Broad Institute Genome Center (U54HG003067), and the Washington University Genome Institute (U54HG003079). Biological samples and associated phenotypic data used in primary data analyses were stored at Study Investigators institutions and at the National Cell Repository for Alzheimer's Disease (NCRAD, U24AG021886) at Indiana University funded by the NIA. Associated Phenotypic Data used in primary and secondary data analyses were provided by Study Investigators, the NIA-funded Alzheimer's Disease Centers (ADCs), and the National Alzheimer's Coordinating Center (NACC, U01AG016976) and the National Institute on Aging Genetics of Alzheimer's Disease Data Storage Site (NIAGADS, U24AG041689) at the University of Pennsylvania, funded by the NIA and at the Database for Genotypes and Phenotypes (dbGaP) funded by the NIH. This research was supported in part by the Intramural Research Program of the NIH and the National Library of Medicine. Contributors to the Genetic Analysis Data included Study Investigators on projects that were individually funded by the NIA and other NIH institutes, and by private U.S. organizations, or foreign governmental or nongovernmental organizations.

Purpose in Life May Lead to Better Sleep

Purpose in Life May Lead to Better Sleep

Is purpose in life associated with less sleep disturbance in older adults?

BackgroundPrevious work has shown that purpose in life can be protective against numerous negative health outcomes including sleep disturbances. Given that sleep disturbances are common among older adults and African Americans, the aim of the present study was to examine the relationship between purpose in life, overall sleep quality, and the presence of sleep disorders in a community-based bi-racial sample of older adults.MethodsParticipants were 825 non-demented older African Americans (n = 428) and Whites (n = 397) from two cohort studies, the Minority Aging Research Study (MARS) and the Rush Memory and Aging Project (MAP). Participants completed a 32-item questionnaire assessing sleep quality and symptoms of Sleep Apnea, Restless Leg Syndrome (RLS) and REM Behavior Disorder (RBD). Purpose in life was assessed with a 10-item measure modified from Ryff & Keyes’s scales of Psychological Well Being.ResultsIn a series of hierarchical multiple linear regressions controlling for the demographic covariates of age, sex, race, and education, higher levels of purpose in life were associated with better sleep quality at baseline. Using longitudinal follow-up data, higher levels of purpose in life was associated with lower risk of sleep apnea at baseline, 1-year follow-up, and 2-year follow-up, as well as reduced symptoms of RLS at 1-year and 2-year follow-up.ConclusionsThese findings provide support for the hypothesis that a higher level of meaning and purpose in life among older adults is related to better sleep quality and appears to be protective against symptoms of sleep apnea and RLS.

THE ROLE OF COMPLEMENT C3 AND C3AR RECEPTOR IN TAU PATHOLOGY IN ALZHEIMER’S DISEASE

Besides the pathological hallmarks of β-amyloid (Aβ) plaques and neurofibrillary tangles (NFTs), increasing evidence suggests that neuroinflammation plays a significant role in AD pathogenesis. The complement pathway is a key regulator of innate immunity. Recent findings from our laboratory showed that the central complement component C3 is upregulated in astrocytes of AD patients and mouse models. Moreover, elevated astroglial C3 can modulate Aβ dynamics and pathology and reduce dendritic morphology and synaptic function through microglial and neuronal C3a receptor (C3aR), respectively. Giving the importance of the C3-C3aR axis in the CNS, we are interested in understanding whether the complement pathway also impacts the NFT pathology. We analyzed the expression patterns of complement pathway genes in AD, MCI and non-cognitive impaired brain samples obtained from the Religious Orders Study (ROS) and Rush Memory and Aging Project (MAP) cohorts and in the PS19 mouse model of tauopathy before or after the onset of NFT pathology. Next, we studied the functional effects of the C3-C3aR pathway on reactive gliosis and NFT pathology by genetically deleting C3aR or overexpressing neuronal C3aR in PS19 animals. Finally, we utilized RNA sequencing and reverse-phase proteomics (RPPA) to identify C3aR downstream signaling pathways that promote such effects. Analysis of RNA sequencing datasets from human brains revealed a strong upregulation of complement pathway genes that is highly correlated with Braak staging and cognitive decline. Prominent complement upregulation was also observed in PS19 mice in response to NFT pathology. AAV-driven neuronal overexpression of C3aR exacerbates tau/NFT pathology in PS19 animals. Conversely, knocking out C3aR in PS19 mice results in significant reduction of inflammation, phospho-tau levels and associated pathology and improved behavioral deficits of PS19 animals. Mechanistically, we identify the Jak-Stat3 pathway as a potent regulator of reactive gliosis and tau pathology in PS19 mice downstream of C3aR.

WATERSHED MICROINFARCT PATHOLOGY AND COGNITION IN OLDER PERSONS

Brain microinfarcts are common in aging and are associated with cognitive impairment. Watershed regions (border zones between anterior, middle, and posterior cerebral arterial territories) are considered to be more vulnerable to the effects of hypoxia-ischemia than other brain regions. However, little is known about the frequency of microinfarcts in these regions and how they relate to cognition in aging. Participants (n = 213) from the Rush Memory and Aging Project (MAP), a community-based clinical-pathologic study of aging, underwent detailed annual clinical testing, including 19 neuropsychological tests, to measure cognition proximate to death (mean age of death, 91 years; 26% men). Neuropathological examination provided measures for microinfarcts, from 2 anterior watershed regions (midfrontal cortex and adjacent white matter), one posterior watershed region (parieto-occipital cortex with underlying white matter), and 8 non-watershed regions (midtemporal, entorhinal, inferior parietal, calcarine, and anterior cingulate cortices, hippocampus, basal ganglia, and thalamus), AD pathology, and macroinfarcts. Linear regression models controlling for demographics and other age-related pathologies were used to simultaneously examine the association of watershed vs. non-watershed microinfarcts with cognition, including global cognition and 5 cognitive domains. Microinfarcts in one or more of the 11 brain regions (3 watershed; 8 non-watershed) were present in 90 (42%) participants, of which 32 (36%) showed microinfarcts in watershed regions and 73 (81%) in non-watershed regions. Microinfarcts in watershed regions were associated with lower global cognition (estimate, -0.380; SE, 0.15; p = 0.012) after controlling for demographics and age-related pathologies including Alzheimer's disease and macroscopic infarcts, whereas in the same model, non-watershed microinfarcts were not related to global cognition. Microinfarcts in watershed regions were related to all 5 cognitive domains, including visuospatial skills (estimate, -0.505; SE, 0.14; p<0.001), semantic memory (estimate, -0.418; SE, 0.18; p = 0.021), perceptual speed (estimate, -0.345; SE, 0.14; p = 0.014), and episodic memory, the presumed hallmark of clinical AD (estimate, -0.331; SE, 0.17; p = 0.047). In comparison, non-watershed microinfarcts were not associated with any of the 5 cognitive domains. These data suggest that microinfarcts in brain watershed regions contribute to age-related cognitive impairment and impairment in multiple cognitive domains. Further study of watershed microinfarcts in aging is warranted.

Association of Cancer History with Alzheimer's Disease Dementia and Neuropathology.

Cancer and Alzheimer's disease (AD) are common diseases of aging and share many risk factors. Surprisingly, however, epidemiologic data from several recent independent cohort studies suggest that there may be an inverse association between these diseases. To determine the relationship between history of cancer and odds of dementia proximate to death and neuropathological indices of AD. Using data from two separate clinical-pathologic cohort studies of aging and AD, the Religious Orders Study (ROS) and the Rush Memory and Aging Project (MAP), we compared odds of AD dementia proximate to death among participants with and without a history of cancer. We then examined the relation of history of cancer with measures of AD pathology at autopsy, i.e., paired helical filament tau (PHFtau) neurofibrillary tangles and amyloid-β load. Participants reporting a history of cancer had significantly lower odds of AD (OR 0.70 [0.55-0.89], p = 0.0040) proximate to death as compared to participants reporting no prior history of cancer. The results remained significant after adjusting for multiple risk factors including age, sex, race, education, and presence of an APOEɛ4 allele. At autopsy, participants with a history of cancer had significantly fewer PHFtau tangles (p < 0.001) than participants without a history of cancer, but similar levels of amyloid-β. Cancer survivors have reduced odds of developing AD and a lower burden of neurofibrillary tangle deposition.

Self-Reported Sleep in Older African Americans and White Americans.

Assess the relationship of self-reported sleep quality and possible sleep disorders with disability in a racially diverse sample of community-dwelling older adults. Participants included 943 non-demented older African Americans (n=452) and Whites (n=491) from two cohort studies, the Minority Aging Research Study (MARS) and the Rush Memory and Aging Project (MAP). Participants completed a 32-item questionnaire assessing sleep quality and the possible presence of three sleep disorders (sleep apnea, restless leg syndrome [RLS] and REM behavior disorder [RBD]). Disability was assessed with scales that quantified the ability to perform instrumental activities of daily living (IADL), basic activities of daily living (ADL), and physical mobility activities. More than half of the participants reported impaired sleep quality (51%), or the possible presence of at least one sleep disorder (57%; sleep apnea 44%, RLS 25% and RBD 7%). Sleep quality was rated poorer in African Americans, those with advancing age and fewer years of education (all P<.05). Only sleep apnea risk was associated with age (P<.02). In logistic regression models adjusted for age, sex, years of education, and race, both sleep quality and disorders were associated with disability (sleep quality with mobility disability (P<.001), sleep apnea risk with mobility disability and IADL disability (all P<.001) and RLS symptoms with mobility disability (P<.01). Results indicate that self-assessed impaired sleep is common in old age and is associated with disability.

Association of Traumatic Brain Injury With Late-Life Neurodegenerative Conditions and Neuropathologic Findings.

The late effects of traumatic brain injury (TBI) are of great interest, but studies characterizing these effects are limited. To determine whether TBI with loss of consciousness (LOC) is associated with an increased risk for clinical and neuropathologic findings of Alzheimer disease (AD), Parkinson disease (PD), and other dementias. This study analyzed data from the Religious Orders Study (ROS), Memory and Aging Project (MAP), and Adult Changes in Thought study (ACT). All ROS and MAP participants and a subset of ACT participants consent to autopsy. Studies performed annual (ROS and MAP) or biennial (ACT) cognitive and clinical testing to identify incident cases of dementia and AD. The 7130 participants included members of a Seattle-area health care delivery system (ACT), priests and nuns living in orders across the United States (ROS), and Chicago-area adults in retirement communities (MAP). Of these, 1589 underwent autopsy. Primary hypothesis was that TBI with LOC would be associated with increased risk for AD and neurofibrillary tangles. Data were accrued from 1994 to April 1, 2014. Self-reported TBI when the participant was free of dementia, categorized as no more than 1 vs more than 1 hour of LOC. Clinical outcomes included incident all-cause dementia, AD, and PD in all studies and incident mild cognitive impairment and progression of parkinsonian signs in ROS and MAP. Neuropathologic outcomes included neurofibrillary tangles, neuritic plaques, microinfarcts, cystic infarcts, Lewy bodies, and hippocampal sclerosis in all studies. Of 7130 participants (2879 [40.4%] men; overall mean [SD] age, 79.9 [6.9] years), 865 reported a history of TBI with LOC. In 45 190 person-years of follow-up, 1537 incident cases of dementia and 117 of PD were identified. No association was found between TBI with LOC and incident dementia (ACT: HR for TBI with LOC ≤1 hour, 1.03; 95% CI, 0.83-1.27; HR for TBI with LOC >1 hour, 1.18; 95% CI, 0.77-1.78; ROS and MAP: HR for TBI with LOC ≤1 hour, 0.87; 95% CI, 0.58-1.29; HR for TBI with LOC >1 hour, 0.84; 95% CI, 0.44-1.57) or AD (findings similar to those for dementia). Associations were found for TBI with LOC and incident PD in ACT (HR for TBI with LOC >1 hour, 3.56; 95% CI, 1.52-8.28) and progression of parkinsonian signs in ROS and MAP (odds ratio [OR] for TBI with LOC ≤1 hour, 1.65; 95% CI, 1.23-2.21; OR for TBI with LOC >1 hour, 2.23; 95% CI, 1.16-4.29). Traumatic brain injury with LOC was associated with Lewy bodies (any Lewy body in ACT: RR for TBI with LOC >1 hour, 2.64; 95% CI, 1.40-4.99; Lewy bodies in substantia nigra and/or locus ceruleus in ACT: RR for TBI with LOC >1 hour, 3.30; 95% CI, 1.71-6.38; Lewy bodies in frontal or temporal cortex in ACT: RR for TBI with LOC >1 hour, 5.73; 95% CI, 2.18-15.0; ROS and MAP: RR for TBI with LOC ≤1 hour, 1.64; 95% CI, 1.00-2.70; pooled RR for TBI with LOC ≤1 hour, 1.59; 95% CI, 1.06-2.39) and microinfarcts (any cortical microinfarct in ROS and MAP: RR for TBI with LOC >1 hour, 2.12; 95% CI, 1.12-4.01; pooled RR for TBI with LOC >1 hour, 1.58; 95% CI, 1.06-2.35). Pooled clinical and neuropathologic data from 3 prospective cohort studies indicate that TBI with LOC is associated with risk for Lewy body accumulation, progression of parkinsonism, and PD, but not dementia, AD, neuritic plaques, or neurofibrillary tangles.

AFRICAN AMERICANS REPORT LESS LONELINESS THAN WHITE ADULTS IN OLD AGE

Loneliness increases with age and is associated with a two-fold increase in dementia. While loneliness in older White adults has been studied, little is known about loneliness in older African Americans. Older African Americans may show lower rates of loneliness due to greater interpersonal contact within social networks. Here we tested the hypothesis that African Americans would report lower levels of loneliness than demographically-matched older White participants, and that this race difference would interact with cognitive function. One thousand one hundred and eighty participants without dementia (mean age=74.85, mean education=14.46, male/female=265/915, mean MMSE=27.95) from the Rush Memory and Aging Project (MAP) and Minority Aging Research Study (MARS) completed a battery of clinical measures and a series of questions assessing loneliness. In the sample, 590 older nondemented African Americans (mean age=74.81, mean education=14.48, male/female=140/450, mean MMSE=27.51) were demographically matched with 590 older nondemented White participants (mean age=74.88, mean education=14.43, male/female=125/465, mean MMSE=28.38) according to age, education, and sex using propensity score matching procedures. Multiple regression analyses adjusting for the effects of age, education, and sex revealed older African Americans reported less loneliness than White adults (estimate=-0.1336, SE=0.0361, p <0.001). This effect remained significant even after further adjusting for the effects of cognitive function and socioeconomic status (estimate=-0.2158, SE=0.0387, p <0.001). In additional models, loneliness was associated with lower cognitive function (estimate=-0.0542, SE=0.0247, p=0.028); however, there was no evidence observed for a race by loneliness interaction. Older African Americans endorsed lower levels of loneliness than demographically matched older White adults, even after adjusting further for socioeconomic status and cognitive function. Loneliness was associated with lower cognitive function; however, this did not differ by race. More research is needed to determine the underlying mechanisms contributing to race differences in loneliness in old age.

Food for Thought: Hypertension-Control Diet Also Slowed Cognitive Decline

Food for Thought: Hypertension-Control Diet Also Slowed Cognitive Decline

Principal components methods for narrow‐sense heritability in the analysis of multidimensional longitudinal cognitive phenotypes

Genetic association studies of longitudinal cognitive phenotypes are an alternate approach to discovering genetic risk factors for Alzheimer's disease (AD). However, the standard linear mixed model approach is limited in the face of multidimensional longitudinal data and multiple genotypes. In this setting, the principal components of heritability (PCH) approach may increase efficiency by deriving a linear combination of phenotypes to maximize the heritability attributable to a particular genetic locus. The current study investigated the performance of two PCH methods, the Principal Components of Heritability Association Test (PCHAT) and C2BAT, in detecting association of the known AD susceptibility allele APOE-ϵ4 with cognitive function at baseline and decline in cognition over time. PCHAT, C2BAT, and standard linear mixed models were used to test for association between APOE-ϵ4 allele and performance on 19 neuropsychological tests using subjects without dementia at baseline from the Religious Orders Study (ROS) (n = 693) and Memory and Aging Project (MAP) (n = 778). Analyses were conducted across the three methods for three nested phenotype definitions (all 19 measures, executive function and episodic memory measures, and episodic memory only), and for baseline data only versus longitudinal change. In all cases, APOE-ϵ4 was significantly associated with baseline level of and change over time in cognitive function, and PCHAT and C2BAT yielded evidence of association comparable to or stronger than conventional methods. PCHAT, C2BAT, and other PCH methods may have utility for genetic association studies of multidimensional cognitive and other phenotypes by maximizing genetic information while limiting multiple comparisons.

Abstract TP171: Purpose in Life and Risk of Cerebral Infarction

Background: Purpose in life (PIL), the sense that life has meaning and direction, is associated with a reduced risk of Alzheimer’s disease, incident disability, and mortality among community-dwelling older persons. Objective: To test the hypothesis that PIL is associated with reduced risk of cerebral infarction. Methods: Longitudinal clinical-pathologic cohort study. Subjects were from the Rush Memory and Aging Project (MAP). Older persons without dementia completed a standard measure of PIL using a structured interview and 10-item scale derived from Ryff’s Scales of Psychological Well-Being. The number of chronic gross &amp; microscopic cerebral infarctions (each expressed as 0,1, or &gt;1) were identified on a uniform neuropathologic examination blinded to clinical information. Semiquantitative assessments (0 to 3) of atherosclerosis and lipohyalinosis were also performed. The associations of PIL with cerebral infarction, cerebral vessel pathology were examined using linear regression and mixed models adjusted for age, sex, &amp; education. Results: 347 subjects had both PIL and brain pathology assessed. Scores on the measure of PIL ranged from 2.1 to 5.0 (mean 3.5, SD 0.48). On postmortem examination, gross/macroscopic cerebral infarcts were found in 112 (32.28%) persons (51 with 1, 61 with &gt;1) and microinfarcts were found in 84 (24.21%) (54 with 1, 30 with &gt; 1). PIL was associated with a reduced odds of gross cerebral infarcts (estimate = 0.57, SE = 0.24, p = 0.02) and there was a trend (p = 0.096) toward an association with microinfarcts. PIL was not related to the type or severity of cerebral vessel pathology. In subsequent logistic regression models, the association of PIL with gross cerebral infarcts persisted after adjustment for depressive symptoms, BMI, smoking, diabetes, and measures of socioeconomic status. However, the association of PIL with gross infarcts was reduced to a trend (estimate = 0.46, SE = 0.26, p = 0.08) after adjustment for systolic blood pressure, suggesting partial mediation. Conclusions: Lower PIL may be a risk factor for macroscopic cerebral infarction in old age without a direct effect on atherosclerotic cerebral vessel pathology.