Comprehensive assessment of TDP-43 neuropathology data in the National Alzheimer's Coordinating Center database.

TDP-43 proteinopathy is a salient neuropathologic feature in a subset of frontotemporal lobar degeneration (FTLD-TDP), in amyotrophic lateral sclerosis (ALS-TDP), and in limbic-predominant age-related TDP-43 encephalopathy neuropathologic change (LATE-NC), and is associated with hippocampal sclerosis of aging (HS-A). We examined TDP-43-related pathology data in the National Alzheimer's Coordinating Center (NACC) in two parts: (I) availability of assessments, and (II) associations with clinical diagnoses and other neuropathologies in those with all TDP-43 measures available. Part I: Of 4326 participants with neuropathology data collected using forms that included TDP-43 assessments, data availability was highest for HS-A (97%) and ALS (94%), followed by FTLD-TDP (83%). Regional TDP-43 pathologic assessment was available for 77% of participants, with hippocampus the most common region. Availability for the TDP-43-related measures increased over time, and was higher in centers with high proportions of participants with clinical FTLD. Part II: In 2142 participants with all TDP-43-related assessments available, 27% of participants had LATE-NC, whereas ALS-TDP or FTLD-TDP (ALS/FTLD-TDP) was present in 9% of participants, and 2% of participants had TDP-43 related to other pathologies ("Other TDP-43"). HS-A was present in 14% of participants, of whom 55% had LATE-NC, 20% ASL/FTLD-TDP, 3% Other TDP-43, and 23% no TDP-43. LATE-NC, ALS/FTLD-TDP, and Other TDP-43, were each associated with higher odds of dementia, HS-A, and hippocampal atrophy, compared to those without TDP-43 pathology. LATE-NC was associated with higher odds for Alzheimer's disease (AD) clinical diagnosis, AD neuropathologic change (ADNC), Lewy bodies, arteriolosclerosis, and cortical atrophy. ALS/FTLD-TDP was associated with higher odds of clinical diagnoses of primary progressive aphasia and behavioral-variant frontotemporal dementia, and cortical/frontotemporal lobar atrophy. When using NACC data for TDP-43-related analyses, researchers should carefully consider the incomplete availability of the different regional TDP-43 assessments, the high frequency of participants with ALS/FTLD-TDP, and the presence of other forms of TDP-43 pathology.

Neuropathologic changes at age 90+ related to sleep duration 19 to 40 years earlier: The 90+ Study.

INTRODUCTION: We investigated the association between sleep duration and neuropathologic changes 19 to 40 years later in oldest-old (age 90+) participants of The 90+ Study. METHODS: Participants self-reported sleep duration and underwent neuropathologic evaluation. We categorized sleep duration as < 7, 7 to 8 = reference, > 8 hours and dichotomized neuropathologic changes as present/absent. We estimated odds ratio (OR) and 95% confidence intervals (CI) using logistic regression. RESULTS: In 264 participants, mean age at sleep self-report was 69 years, mean age at autopsy was 98 years, and mean interval between sleep self-report and autopsy was 29 years (range: 19-40). Those reporting > 8 hours of sleep had lower likelihood of limbic-predominant age-related TDP-43 encephalopathy neuropathologic change (LATE-NC) inclusions (OR = 0.18; CI = 0.04-0.82) and amyloid beta deposits (OR = 0.34; 95% CI = 0.12-0.94). DISCUSSION: Long self-reported sleep is associated with lower odds of neurodegenerative neuropathologic changes 19 to 40 years later in the oldest-old, suggesting a potential role of sleep in accumulation of dementia-related neuropathologies. HIGHLIGHTS: Association of self-reported sleep with non-Alzheimer's disease neuropathologic changes has not been explored. Whether sleep duration is related to dementia neuropathologic changes decades later is unclear. Long self-reported sleep is associated with lower odds of Alzheimer's disease neuropathologic change 19 to 40 years later in the oldest-old. Long self-reported sleep is associated with lower odds of limbic-predominant age-related TDP-43 encephalopathy neuropathologic change 19 to 40 years later in the oldest-old.

White matter microstructural correlates of associative learning in the oldest-old.

The ability to learn associations between events is critical for everyday functioning (e.g., decision making, social interactions) and has been attributed to structural differences in white matter tracts connecting cortical regions to the hippocampus (e.g., fornix) and striatum (e.g., internal capsule) in younger-old adults (ages 65-85 years). However, evidence of associative learning has not been assessed within oldest-old adults (ages 90+ years), despite its relevance to other extensively characterized cognitive abilities in the oldest-old and the relatively large effect of advanced age on the microstructural composition of these white matter tracts. We acquired multicompartment diffusion-weighted magnetic resonance imaging data from 22 oldest-old adults without dementia (mean age = 92.91 ± 1.44 years) who also completed an associative learning task. Behavioral results revealed significantly better associative learning performance during later task stages, as expected if participants incidentally learned the cue-cue-target associations for frequently occurring event triplets. Moreover, better learning performance was significantly predicted by better microstructure of cortico-striatal white matter (posterior limb of the internal capsule). Finding that associative learning abilities in the 10th decade of life are supported by better microstructure of white matter tracts connecting the cortex to the striatum underscores their importance to learning performance across the entire lifespan.

Characterization of hippocampal sclerosis of aging and its association with other neuropathologic changes and cognitive deficits in the oldest-old.

Hippocampal sclerosis of aging (HS-A) is a common age-related neuropathological lesion characterized by neuronal loss and astrogliosis in subiculum and CA1 subfield of hippocampus. HS-A is associated with cognitive decline that mimics Alzheimer's disease. Pathological diagnosis of HS-A is traditionally binary based on presence/absence of the lesion. We compared this traditional measure against our novel quantitative measure for studying the relationship between HS-A and other neuropathologies and cognitive impairment. We included 409 participants from The 90+ study with neuropathological examination and longitudinal neuropsychological assessments. In those with HS-A, we examined digitized H&E and LFB stained hippocampal slides. The length of HS-A in each subfield of hippocampus and subiculum, each further divided into three subregions, was measured using Aperio eSlide Manager. For each subregion, the proportion affected by HS-A was calculated. Using regression models, both traditional/binary and quantitative measures were used to study the relationship between HS-A and other neuropathological changes and cognitive outcomes. HS-A was present in 48 (12%) of participants and was always focal, primarily affecting CA1 (73%), followed by subiculum (9%); overlapping pathology (subiculum and CA1) affected 18% of individuals. HS-A was more common in the left (82%) than the right (25%) hemisphere and was bilateral in 7% of participants. HS-A traditional/binary assessment was associated with limbic-predominant age-related TDP-43 encephalopathy (LATE-NC; OR = 3.45, p < 0.001) and aging-related tau astrogliopathy (ARTAG; OR = 2.72, p = 0.008). In contrast, our quantitative approach showed associations between the proportion of HS-A (CA1/subiculum/combined) and LATE-NC (p = 0.001) and arteriolosclerosis (p = 0.005). While traditional binary assessment of HS-A was associated with impaired memory (OR = 2.60, p = 0.007), calculations (OR = 2.16, p = 0.027), and orientation (OR = 3.56, p < 0.001), our quantitative approach revealed additional associations with impairments in language (OR = 1.33, p = 0.018) and visuospatial domains (OR = 1.37, p = 0.006). Our novel quantitative method revealed associations between HS-A and vascular pathologies and impairment in cognitive domains that were not detected using traditional/binary measures.

LATE-NC staging in routine neuropathologic diagnosis: an update.

An international consensus report in 2019 recommended a classification system for limbic-predominant age-related TDP-43 encephalopathy neuropathologic changes (LATE-NC). The suggested neuropathologic staging system and nomenclature have proven useful for autopsy practice and dementia research. However, some issues remain unresolved, such as cases with unusual features that do not fit with current diagnostic categories. The goal of this report is to update the neuropathologic criteria for the diagnosis and staging of LATE-NC, based primarily on published data. We provide practical suggestions about how to integrate available genetic information and comorbid pathologies [e.g., Alzheimer's disease neuropathologic changes (ADNC) and Lewy body disease]. We also describe recent research findings that have enabled more precise guidance on how to differentiate LATE-NC from other subtypes of TDP-43 pathology [e.g., frontotemporal lobar degeneration (FTLD) and amyotrophic lateral sclerosis (ALS)], and how to render diagnoses in unusual situations in which TDP-43 pathology does not follow the staging scheme proposed in 2019. Specific recommendations are also made on when not to apply this diagnostic term based on current knowledge. Neuroanatomical regions of interest in LATE-NC are described in detail and the implications for TDP-43 immunohistochemical results are specified more precisely. We also highlight questions that remain unresolved and areas needing additional study. In summary, the current work lays out a number of recommendations to improve the precision of LATE-NC staging based on published reports and diagnostic experience.

Alzheimer's Disease Neuropathologic Change and Vitamin Supplement Use Decades Earlier: The 90+ Study.

BACKGROUND: Alzheimer's disease (AD) is the most common cause of dementia. AD neuropathologic change (ADNC) likely begins decades before clinical manifestations. One mechanism implicated in AD is oxidative stress. We explored the potential association of ADNC with antioxidant vitamin supplements taken about 30 years before death. METHODS: The 264 brain-autopsied participants were part of The 90+ Study, a longitudinal study of aging among people aged 90+ years, and originally members of the Leisure World Cohort Study, a population-based health study established in the 1980s. Intake of supplemental vitamins A, C, and E was collected by the Leisure World Cohort Study about 30 years before ADNC assessment. Odds ratios of ADNC (intermediate/high vs. none/low) for vitamin intake were estimated using logistic regression. RESULTS: The adjusted odds ratio (95% CI) of ADNC was 0.52 (0.29-0.92) for vitamin E supplements and 0.51 (0.27-0.93) for vitamin C supplements. Supplemental vitamin E intake was the first variable, after education, to enter the stepwise model. Intake of vitamin A or C did not improve the model fit. CONCLUSIONS: The observed association of ADNC and supplemental vitamin E intake decades earlier suggests a beneficial effect and supports further investigation into a nutritional approach to preventing AD with vitamin supplementation.

Self-reported sleep in relation to risk of dementia a quarter of a century later at age 90+: The 90+ Study.

OBJECTIVE: To examine sex-specific associations of sleep duration and napping self-reported at mean age of 69 years (range: 53-81) with risk of incident dementia 24 years later at age 90 +. METHOD: Analytic sample included individuals from a population-based study who reported sleep and napping once in the 1980s and 24 years later (range: 16-38) joined The 90+ Study and were evaluated in-person. Those without dementia at baseline of The 90+ Study were prospectively followed. Hazard ratios [HR] and 95% confidence intervals [CI] of dementia risk were estimated by Cox regression. RESULTS: Of 574 participants 71% were women, mean age at start of dementia follow-up with The 90+ Study was 93 years (range: 90-102). After 3.3 years (range: 0.4-13.8) of follow-up 47% developed dementia. Higher risk of dementia at age 90+ was seen in women with <6 hours of self-reported sleep per night (adjusted HR = 2.00; 95% CI = 1.15-3.50; p = .01) compared with 8 hours. Lower risk of dementia at 90+ was seen in men with short-to-moderate (<60 minutes) self-reported naps compared with no naps (HR = 0.33; 95% CI = 0.18-0.63; p < .01). CONCLUSIONS: Sleep and nap 24 years earlier are important risk factors for dementia after age 90.

Assessing cognitive impairment in an ethnically diverse cohort of oldest-old: the life after 90 study.

BACKGROUND: Though dementia rates vary by racial or ethnic groups, it is unknown if these disparities remain among those aged 90 or older. AIMS: To test this hypothesis, we used baseline clinical evaluation of 541 ethnically and racially diverse individuals participating in the LifeAfter90 Study to assess how associations between core demographic characteristics and measures of physical and cognitive performance differ across the racial/ethnic groups. METHODS: Participants in this study were long-term non-demented members of Kaiser Permanente Northern California. They were clinically evaluated and diagnosed with normal or impaired cognition (mild cognitive impairment and dementia) through an in-person comprehensive clinical assessment consisting of a detailed medical history, physical and neurological examination, functional, and cognitive tests. RESULTS: The average age at enrollment was 93.0 ± 2.6 years, 62.4% female and 34.2% non-Hispanic White. At initial evaluation 301 participants had normal cognition and 165 had mild cognitive impairment (MCI) and despite screening, 69 participants were determined to have dementia. Age, education, 3MS, FAQ and CDR scores were significantly associated with cognitive impairment (normal versus MCI and dementia), but not gender. There was a significant univariate association between race/ethnicity and cognitive impairment (p < 0.02) being highest among Black (57.4%) and lowest among Asian (32.7%) individuals. After adjustment for age, gender, and education, however, prevalence of cognitive impairment was not influenced by race or ethnicity. CONCLUSION: Our results confirm the ability to reliably assess clinical diagnosis in a diverse sample of very old individuals.

Study of neuropathological changes and dementia in 100 centenarians in The 90+ Study.

INTRODUCTION: The association between neuropathological changes and dementia among centenarians and nonagenarians remains unclear. METHODS: We examined brain tissue from 100 centenarians and 297 nonagenarians from The 90+ Study, a community-based longitudinal study of aging. We determined the prevalence of 10 neuropathological changes and compared their associations with dementia and cognitive performance between centenarians and nonagenarians. RESULTS: A total of 59% of centenarians and 47% of nonagenarians had at least four neuropathological changes. In centenarians, neuropathological changes were associated with higher odds of dementia and, compared to nonagenarians, the odds were not attenuated. For each additional neuropathological change, the Mini-Mental State Examination score was lower by 2 points for both groups. DISCUSSION: Neuropathological changes continue to be strongly related to dementia in centenarians, highlighting the importance of slowing or preventing the development of multiple neuropathological changes in the aging brain to maintain cognitive health. HIGHLIGHTS: Individual and multiple neuropathological changes are frequent in centenarians. These neuropathological changes are strongly associated with dementia. There is no attenuation of this association with age.

Pragmatic approaches to handling practice effects in longitudinal cognitive aging research.

INTRODUCTION: The challenge of accounting for practice effects (PEs) when modeling cognitive change was amplified by the COVID-19 pandemic, which introduced period and mode effects that may bias the estimation of cognitive trajectory. METHODS: In three Kaiser Permanente Northern California prospective cohorts, we compared predicted cognitive trajectories and the association of grip strength with cognitive decline using three approaches: (1) no acknowledgment of PE, (2) inclusion of a wave indicator, and (3) constraining PE based on a preliminary model (APM) fit using a subset of the data. RESULTS: APM-based correction for PEs based on balanced, pre-pandemic data, and with current age as the timescale produced the smallest discrepancy between within-person and between-person estimated age effects. Estimated associations between grip strength and cognitive decline were not sensitive to the approach used. DISCUSSION: Constraining PEs based on a preliminary model is a flexible, pragmatic approach allowing for meaningful interpretation of cognitive change. HIGHLIGHTS: The magnitude of practice effects (PEs) varied widely by study. When PEs were present, the three PE approaches resulted in divergent estimated age-related cognitive trajectories. Estimated age-related cognitive trajectories were sometimes implausible in models that did not account for PEs. The associations between grip strength and cognitive decline did not differ by the PE approach used. Constraining PEs based on estimates from a preliminary model allows for a meaningful interpretation of cognitive change.

Cognition, function, and prevalent dementia in centenarians and near-centenarians: An individual participant data (IPD) meta-analysis of 18 studies.

INTRODUCTION: There are limited data on prevalence of dementia in centenarians and near-centenarians (C/NC), its determinants, and whether the risk of dementia continues to rise beyond 100. METHODS: Participant-level data were obtained from 18 community-based studies (N = 4427) in 11 countries that included individuals ≥95 years. A harmonization protocol was applied to cognitive and functional impairments, and a meta-analysis was performed. RESULTS: The mean age was 98.3 years (SD = 2.67); 79% were women. After adjusting for age, sex, and education, dementia prevalence was 53.2% in women and 45.5% in men, with risk continuing to increase with age. Education (OR 0.95;0.92-0.98) was protective, as was hypertension (odds ratio [OR] 0.51;0.35-0.74) in five studies. Dementia was not associated with diabetes, vision and hearing impairments, smoking, and body mass index (BMI). DISCUSSION: Among the exceptional old, dementia prevalence remains higher in the older participants. Education was protective against dementia, but other factors for dementia-free survival in C/NC remain to be understood.

Hippocampal dentate gyrus integrity revealed with ultrahigh resolution diffusion imaging predicts memory performance in older adults.

Medial temporal lobe (MTL) atrophy is a core feature of age-related cognitive decline and Alzheimer's disease (AD). While regional volumes and thickness are often used as a proxy for neurodegeneration, they lack the sensitivity to serve as an accurate diagnostic test and indicate advanced neurodegeneration. Here, we used a submillimeter resolution diffusion weighted MRI sequence (ZOOMit) to quantify microstructural properties of hippocampal subfields in older adults (63-98 years old) using tensor derived measures: fractional anisotropy (FA) and mean diffusivity (MD). We demonstrate that the high-resolution sequence, and not a standard resolution sequence, identifies dissociable profiles for CA1, dentate gyrus (DG), and the collateral sulcus. Using ZOOMit, we show that advanced age is associated with increased MD of the CA1 and DG as well as decreased FA of the DG. Increased MD of the DG, reflecting decreased cellular density, mediated the relationship between age and word list recall. Further, increased MD in the DG, but not DG volume, was linked to worse spatial pattern separation. Our results demonstrate that ultrahigh-resolution diffusion imaging enables the detection of microstructural differences in hippocampal subfield integrity and will lead to novel insights into the mechanisms of age-related memory loss.

Frequency of LATE neuropathologic change across the spectrum of Alzheimer's disease neuropathology: combined data from 13 community-based or population-based autopsy cohorts.

Limbic-predominant age-related TDP-43 encephalopathy neuropathologic change (LATE-NC) and Alzheimer's disease neuropathologic change (ADNC) are each associated with substantial cognitive impairment in aging populations. However, the prevalence of LATE-NC across the full range of ADNC remains uncertain. To address this knowledge gap, neuropathologic, genetic, and clinical data were compiled from 13 high-quality community- and population-based longitudinal studies. Participants were recruited from United States (8 cohorts, including one focusing on Japanese-American men), United Kingdom (2 cohorts), Brazil, Austria, and Finland. The total number of participants included was 6196, and the average age of death was 88.1 years. Not all data were available on each individual and there were differences between the cohorts in study designs and the amount of missing data. Among those with known cognitive status before death (n = 5665), 43.0% were cognitively normal, 14.9% had MCI, and 42.4% had dementia-broadly consistent with epidemiologic data in this age group. Approximately 99% of participants (n = 6125) had available CERAD neuritic amyloid plaque score data. In this subsample, 39.4% had autopsy-confirmed LATE-NC of any stage. Among brains with "frequent" neuritic amyloid plaques, 54.9% had comorbid LATE-NC, whereas in brains with no detected neuritic amyloid plaques, 27.0% had LATE-NC. Data on LATE-NC stages were available for 3803 participants, of which 25% had LATE-NC stage > 1 (associated with cognitive impairment). In the subset of individuals with Thal Aß phase = 0 (lacking detectable Aß plaques), the brains with LATE-NC had relatively more severe primary age-related tauopathy (PART). A total of 3267 participants had available clinical data relevant to frontotemporal dementia (FTD), and none were given the clinical diagnosis of definite FTD nor the pathological diagnosis of frontotemporal lobar degeneration with TDP-43 inclusions (FTLD-TDP). In the 10 cohorts with detailed neurocognitive assessments proximal to death, cognition tended to be worse with LATE-NC across the full spectrum of ADNC severity. This study provided a credible estimate of the current prevalence of LATE-NC in advanced age. LATE-NC was seen in almost 40% of participants and often, but not always, coexisted with Alzheimer's disease neuropathology.

Addressing the disparities in dementia risk, early detection and care in Latino populations: Highlights from the second Latinos & Alzheimer's Symposium.

The Alzheimer's Association hosted the second Latinos & Alzheimer's Symposium in May 2021. Due to the COVID-19 pandemic, the meeting was held online over 2 days, with virtual presentations, discussions, mentoring sessions, and posters. The Latino population in the United States is projected to have the steepest increase in Alzheimer's disease (AD) in the next 40 years, compared to other ethnic groups. Latinos have increased risk for AD and other dementias, limited access to quality care, and are severely underrepresented in AD and dementia research and clinical trials. The symposium highlighted developments in AD research with Latino populations, including advances in AD biomarkers, and novel cognitive assessments for Spanish-speaking populations, as well as the need to effectively recruit and retain Latinos in clinical research, and how best to deliver health-care services and to aid caregivers of Latinos living with AD.

What have we learned from cognition in the oldest-old.

PURPOSE OF REVIEW: People over 90 are the fastest growing segment of the population with the highest rates of dementia. This review highlights recent findings that provide insight to our understanding of dementia and cognition at all ages. RECENT FINDINGS: Risk factors for Alzheimer's disease (AD) and dementia differ by age, with some factors, like the development of hypertension, actually becoming protective in the oldest-old. At least half of all dementia in this age group is due to non AD pathologies, including microinfarcts, hippocampal sclerosis and TDP-43. The number of pathologic changes found in the brain is related to both risk and severity of dementia, but many people in this age group appear to be 'resilient' to these pathologies. Resilience to Alzheimer pathology, in part, may be related to absence of other pathologies, and imaging and spinal fluid biomarkers for AD have limited utility in this age group. SUMMARY: Studies of dementia in the oldest-old are important for our understanding and eventual treatment or prevention of dementia at all ages.

Norms and equivalences for MoCA-30, MoCA-22, and MMSE in the oldest-old.

BACKGROUND: Cognitive screening is important for the oldest-old (age 90 +). This age group is the fastest growing and has the highest risk of dementia. However, norms and score equivalence for screening tests are lacking for this group. AIMS: To provide norms and score equivalence for commonly used cognitive screening tests for the oldest-old. METHODS: Data on 157 participants of the Center for Healthy Aging Longevity Study aged 90 + were analyzed. First, we derived norms for (1) subtests and cognitive domains of the in-person Montreal Cognitive Assessment having a maximum score of 30 (MoCA-30) and (2) the total MoCA-22 score, obtained from the in-person MoCA-30 by summing the subtests that do not require visual input to a maximum score of 22. These norms were derived from 124 participants with a Mini-Mental State Examination (MMSE) ≥ 27. Second, we derived score equivalences for MMSE to MoCA-30 and MoCA-22, and MoCA-30 to MoCA-22 using equipercentile equating method with log-linear smoothing, based on all 157 participants. RESULTS: MoCA-22 total score norms are: mean = 18.3(standard deviation = 2.2). An MMSE score of 27 is equivalent to a MoCA-30 score of 22 and a MoCA-22 score of 16. DISCUSSION AND CONCLUSIONS: Subtest, domain and MoCA-22 norms will aid in evaluation of the oldest-old who cannot complete the MoCA-30 or are tested over the phone. The equivalences of the three cognitive tests (MMSE, MoCA-30, MoCA-22) in the oldest-old will facilitate continuity of cognitive tracking of individuals tested with different tests over time and comparison of the studies that use different cognitive tests.

Utility of MRI in the identification of hippocampal sclerosis of aging.

INTRODUCTION: Hippocampal sclerosis of aging (HS) is a common pathology often misdiagnosed as Alzheimer's disease. We tested the hypothesis that participants with HS would have a magnetic resonance imaging (MRI)-detectable hippocampal pattern of atrophy distinct from participants without HS, both with and without Alzheimer's disease neuropathology (ADNP). METHODS: Query of the National Alzheimer's Coordinating Center database identified 198 participants with MRI and autopsy. Hippocampal subfields were segmented with FreeSurfer v6. Analysis of covariance for subfield volumes compared HS+ participants to those without HS, both with ADNP (HS-/ADNP+) and without (HS-/ADNP-). RESULTS: HS+ participants (N = 27, 14%) showed atrophied cornu ammonis 1 (CA1; left P < .001, ηp2  = 0.14; right P = .001, ηp2  = 0.09) and subiculum (left P < .001, ηp2  = 0.139; right P = .001, ηp2  = 0.085) compared to HS-/ADNP+ (N = 100, 51%). Compared to HS-/ADNP- (N = 71, 36%), HS+ also had atrophy in subiculum (left P < .001, ηp2  = 0.235; right P = .002, ηp2  = 0.137) and CA1 (left P < .001, ηp2  = 0.137; right P = .006, ηp2  = 0.070). DISCUSSION: Subiculum and CA1 atrophy from clinical MRI may be a promising in vivo biomarker for HS.

Apolipoprotein E/Amyloid-ß Complex Accumulates in Alzheimer Disease Cortical Synapses via Apolipoprotein E Receptors and Is Enhanced by APOE4.

Apolipoprotein E (apoE) colocalizes with amyloid-ß (Aß) in Alzheimer disease (AD) plaques and in synapses, and evidence suggests that direct interactions between apoE and Aß are important for apoE's effects in AD. The present work examines the hypothesis that apoE receptors mediate uptake of apoE/Aß complex into synaptic terminals. Western blot analysis shows multiple SDS-stable assemblies in synaptosomes from human AD cortex; apoE/Aß complex was markedly increased in AD compared with aged control samples. Complex formation between apoE and Aß was confirmed by coimmunoprecipitation experiments. The apoE receptors low-density lipoprotein receptor (LDLR) and LDLR-related protein 1 (LRP1) were quantified in synaptosomes using flow cytometry, revealing up-regulation of LRP1 in early- and late-stage AD. Dual-labeling flow cytometry analysis of LRP1- and LDLR positives indicate most (approximately 65%) of LDLR and LRP1 is associated with postsynaptic density-95 (PSD-95)-positive synaptosomes, indicating that remaining LRP1 and LDLR receptors are exclusively presynaptic. Flow cytometry analysis of Nile red labeling revealed a reduction in cholesterol esters in AD synaptosomes. Dual-labeling experiments showed apoE and Aß concentration into LDLR and LRP1-positive synaptosomes, along with free and esterified cholesterol. Synaptic Aß was increased by apoE4 in control and AD samples. These results are consistent with uptake of apoE/Aß complex and associated lipids into synaptic terminals, with subsequent Aß clearance in control synapses and accumulation in AD synapses.

Neuropsychological Test Norms in Cognitively Intact Oldest-Old.

OBJECTIVES: Individuals aged 90 or older (oldest-old), the fastest growing segment of the population, are at increased risk of developing cognitive impairment compared with younger old. Neuropsychological evaluation of the oldest-old is important yet challenging in part because of the scarcity of test norms for this group. We provide neuropsychological test norms for cognitively intact oldest-old. METHODS: Test norms were derived from 403 cognitively intact participants of The 90+ Study, an ongoing study of aging and dementia in the oldest-old. Cognitive status of intact oldest-old was determined at baseline using cross-sectional approach. Individuals with cognitive impairment no dementia or dementia (according to DSM-IV criteria) were excluded. Participants ranged in age from 90 to 102 years (mean=94). The neuropsychological battery included 11 tests (Mini-Mental Status Examination, Modified Mini-Mental State Examination, Boston Naming Test - Short Form, Letter Fluency Test, Animal Fluency Test, California Verbal Learning Test-II Short Form, Trail Making Tests A/B/C, Digit Span Forward and Backwards Test, Clock Drawing Test, CERAD Construction Subtests), and the Geriatric Depression Scale. RESULTS: Data show significantly lower scores with increasing age on most tests. Education level, sex, and symptoms of depression were associated with performance on several tests after accounting for age. CONCLUSIONS: Provided test norms will help to distinguish cognitively intact oldest-old from those with cognitive impairment. (JINS, 2019, 25, 530-545).

Incidence of dementia after age 90 in a multiracial cohort.

INTRODUCTION: Little is known about dementia incidence in diverse populations of oldest-old, the age group with highest dementia incidence. METHODS: Incident dementia diagnoses from 1/1/2010 to 9/30/2015 were abstracted from medical records for 2350 members of an integrated health care system in California (n = 1702 whites, n = 375 blacks, n = 105 Latinos, n = 168 Asians) aged ≥90 in 2010. We estimated race/ethnicity-specific age-adjusted dementia incidence rates and implemented Cox proportional hazards models and Fine and Gray competing risk of death models adjusted for demographics and comorbidities in midlife and late-life. RESULTS: Dementia incidence rates (n = 771 cases) were lowest among Asians (89.9/1000 person-years), followed by whites (96.9/1000 person-years), Latinos (105.8/1000 person-years), and blacks (121.5/1000 person-years). Cox regression and competing risk models estimated 28% and 36% higher dementia risk for blacks versus whites adjusting for demographics and comorbidities. DISCUSSION: Patterns of racial/ethnic disparities in dementia seen in younger older adults continue after the age of 90 years, though smaller in magnitude.