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Introduction We report the effects of plasma exchange (PE) with albumin replacement on neuropsychological, neuropsychiatric, and quality-of-life (QoL) outcomes in mild-to-moderate Alzheimer's disease (AD) patients in a phase 2b/3 trial (Alzheimer's Management by Albumin Replacement [AMBAR] study). Methods Three hundred forty-seven patients were randomized into placebo (sham-PE) and three PE-treatment arms with low/high doses of albumin, with/without intravenous immunoglobulin (IVIG). Specific test measurements were performed at baseline; month 2 (weekly conventional PE); months 6, 9, and 12 (monthly low-volume PE [LVPE]); and month 14. Results The PE-treated mild-AD cohort improved their language fluency and processing speed versus placebo at month 14 (effect sizes: >100%; P-values: .03 to .001). The moderate-AD cohort significantly improved short-term verbal memory (effect sizes: 94% to >100%; P-values: .02 to .003). The progression of the neuropsychiatric symptoms of PE-treated was similar to placebo. Mild-AD patients showed improved QoL (P-values: .04 to .008). Discussion PE-treated AD patients showed improvement in memory, language abilities, processing speed, and QoL-AD. No worsening of their psychoaffective status was observed.

Purpose The association between CVD risk factors and mortality is well established, however, current tools for addressing subgroups have focused on the overall burden of disease. The identification of risky combinations of characteristics may lead to a better understanding of physiologic pathways that underlie morbidity and mortality in older adults. Methods Participants included 5067 older adults from the Cardiovascular Health Study, followed for up to 6 years. Using latent class analysis (LCA), we created CV damage phenotypes based on probabilities of abnormal brain infarctions, major echocardiogram abnormalities, N-terminal probrain natriuretic peptide, troponin T, interleukin-6, c reactive-protein, galectin-3, cystatin C. We assigned class descriptions based on the probability of having an abnormality among risk factors, such that a healthy phenotype would have low probabilities in all risk factors. Participants were assigned to phenotypes based on the maximum probability of membership. We used Cox-proportional hazards regression to evaluate the association between the categorical CV damage phenotype and all-cause and CVD-mortality. Results The analysis yielded 5 CV damage phenotypes consistent with the following descriptions: healthy (59%), cardio-renal (11%), cardiac (15%), multisystem morbidity (6%), and inflammatory (9%). All four phenotypes were statistically associated with a greater risk of all-cause mortality when compared with the healthy phenotype. The multisystem morbidity phenotype had the greatest risk of all-cause death (HR: 4.02; 95% CI: 3.44, 4.70), and CVD-mortality (HR: 4.90, 95% CI: 3.95, 6.06). Conclusions Five CV damage phenotypes emerged from CVD risk factor measures. CV damage across multiple systems confers a greater mortality risk compared to damage in any single domain.

Background Phospholipids are biomarkers of dietary fat intake and metabolism, linked to several cardiometabolic disorders. Few prospective studies have assessed plasma phospholipids in relation to dementia risk and cognitive function. Objectives We aimed to evaluate the association between a decrease in linoleic acid accompanied with an increase in other fatty acids and cognitive function and dementia risk. Methods We conducted a case-cohort study nested within the Ginkgo Evaluation of Memory Study. We included 1252 participants, 498 of whom who developed dementia during a mean of 5 y of follow-up. We measured 45 individual plasma phospholipids (as a percentage of total plasma phospholipid fatty acids) by GC and related these to Modified Mini-Mental State Examination (3MSE) scores at baseline and neurologist-adjudicated incidence of all-cause dementia and Alzheimer disease (AD), adjusting for sociodemographic and clinical characteristics. Results Substitution of 1% of SFAs for 1% of linoleic acid, the predominant polyunsaturated n-6 (ɷ-6) fatty acid, was associated with higher risk of dementia (HR per 1% of SFAs instead of linoleic acid = 1.03; 95% CI: 1.00, 1.07) and a 0.08 point lower 3MSE score at baseline (95% CI: -0.12, -0.03), signifying worse cognitive function. When compared with linoleic acid, we found no associations of total monounsaturated, n-3 polyunsaturated, or trans fatty acids with risk of dementia or AD. However, the substitution of 1% of the marine n-3 PUFA DHA for linoleic acid was associated with lower risk of dementia (HR = 0.86 per 1% of DHA instead of linoleic acid; 95% CI: 0.76, 0.96). These associations were not modified by apolipoprotein E genotype, mild cognitive impairment at baseline, age, or sex. Conclusions Specific elements of diet may be associated with late-life dementia, a hypothesis that requires formal testing in randomized controlled trials and that represents a possible preventive intervention.

We examined the association between APOE ɛ2/ɛ4 with incident Alzheimer’s disease (AD) and mild cognitive impairment (MCI) among African Americans using the national dataset from the National Alzheimer’s Coordinating Center (NACC) from 2005 to September 2019. Compared to ɛ3/ɛ3 carriers, ɛ2/ɛ4 carriers exhibited a similar risk of incident AD (adjusted hazard ratio [aHR] = 0.85, 95% CI [0.39, 1.84]) among the AD cohort and similar risk of incident MCI (aHR = 0.88, 95% CI [0.51, 1.50]) among the MCI cohort. Our findings suggest that, unlike the increased risk of AD and MCI in non-Latino whites, APOE ɛ2/ɛ4 genotype is not associated with the incidence of AD and MCI among African Americans.

Background Hemostasis is a key factor in cerebrovascular disease, but the association of hemostatic factors with cognitive decline is unclear.Objective To prospectively evaluate associations of 20 hemostatic factor levels with changes in cognition during >= 8 years of follow-up in the Cardiovascular Health Study (CHS) of older adults.Methods We included participants of an existing CHS cross-sectional substudy (n = 400) with hemostatic factors measured in 1989-1990. Between 1989-1990 and 1998-1999, cognitive function was measured using the Modified Mini-Mental State Examination (3MSE) and Digit Symbol Substitution Tests. Mixed-effects linear regression models estimated change in cognitive function over time, adjusting for sociodemographic and clinical factors and APOE genotype, using Bonferroni adjustment. We also derived principal components to account for the interrelationship among factors.Results Of 20 factors evaluated individually, only higher levels of plasmin-alpha(2)-antiplasmin complex (PAP), tissue factor pathway inhibitor (TFPI), and lower factor X (FXc) levels were associated with faster cognitive decline, estimated by annual change in 3MSE points (1 standard deviation PAP beta = -0.65, 95% confidence interval [CI]: -1.08 to -0.21; TFPI beta = -0.55, 95% CI: -0.90 to -0.19; FXc beta = 0.52, 95% CI: 0.21-0.84). One of four principal components, loading positively on D-dimer, prothrombin fragment 1.2 (F1.2), and PAP was significantly associated with change in 3MSE.Conclusions Levels of PAP, TPFI, and FXc and a combination of factors driven by PAP, D-dimer, and F1.2 were associated with cognitive decline. Whether these findings can be used to improve dementia prevention or prediction requires further study.

The potential benefit of the anti‐amyloid drug aducanumab based on results of recent EMERGE and ENGAGE clinical trials has generated great controversy and has very important implications for the future of anti‐amyloid drug therapies. The two trials of 18‐month duration were done in patients with mild cognitive impairment (MCI) and early dementia. The ENGAGE trial showed no benefit while the high‐dose EMERGE trial initially also showed no benefit but with longer follow‐up there was a significant positive benefit. A recent review form the U.S. Food and Drug Administration (FDA) Advisory Committee was negative while the FDA Office of Neurological Drugs was positive and the statisticians negative. This has generated debate about whether the drug should be approved, disapproved, require a new clinical trial, or approved for a subsample only. The implications for treating both MCI and Alzheimer's disease (AD) patients with anti‐amyloid drugs is very substantial as well as the brain amyloid‐AD‐dementia hypothesis.

In this review we examine, in the context of the amyloid, tau, and neurodegeneration framework, the available evidence and potential alternatives on how to establish tau positivity (T+) for multiple tau-imaging tracers in order to reach a consensus on normal and abnormal tau imaging values that can be universally implemented in clinical research and therapeutic trials.

Across Latin American and Caribbean countries (LACs), the fight against dementia faces pressing challenges, such as heterogeneity, diversity, political instability, and socioeconomic disparities. These can be addressed more effectively in a collaborative setting that fosters open exchange of knowledge. In this work, the Latin American and Caribbean Consortium on Dementia (LAC-CD) proposes an agenda for integration to deliver a Knowledge to Action Framework (KtAF). First, we summarize evidence-based strategies (epidemiology, genetics, biomarkers, clinical trials, nonpharmacological interventions, networking, and translational research) and align them to current global strategies to translate regional knowledge into transformative actions. Then we characterize key sources of complexity (genetic isolates, admixture in populations, environmental factors, and barriers to effective interventions), map them to the above challenges, and provide the basic mosaics of knowledge toward a KtAF. Finally, we describe strategies supporting the knowledge creation stage that underpins the translational impact of KtAF. Fil: Parra, Mario Alfredo. Universidad Autónoma del Caribe; Colombia Fil: Baez, Sandra. Universidad de los Andes; Colombia Fil: Sedeño, Lucas. Consejo Nacional de Investigaciones Científicas y Técnicas; Argentina Fil: Gonzalez Campo, Cecilia. Universidad de San Andrés; Argentina Fil: Santamaría García, Hernando. Pontificia Universidad Javeriana; Colombia Fil: Aprahamian, Ivan. No especifíca; Fil: Bertolucci, Paulo. Universidade Federal de Sao Paulo; Brasil Fil: Bustin, Julian. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Houssay. Instituto de Neurociencia Cognitiva. Fundación Favaloro. Instituto de Neurociencia Cognitiva; Argentina Fil: Camargos Bicalho, Maria Aparecida. Universidade Federal de Minas Gerais; Brasil Fil: Cano Gutierrez, Carlos. Hospital Universitario San Ignacio; Colombia Fil: Caramelli, Paulo. Universidade Federal de Minas Gerais; Brasil Fil: Chaves, Marcia L. F.. Universidade Federal do Rio Grande do Sul; Brasil Fil: Perez Cogram, Patricia. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Houssay. Instituto de Neurociencia Cognitiva. Fundación Favaloro. Instituto de Neurociencia Cognitiva; Argentina Fil: Beber, Bárbara Costa. Universidade Federal do Rio Grande do Sul; Brasil Fil: Court, Felipe A.. Universidad Mayor; Chile Fil: de Souza, Leonardo Cruz. Universidade Federal de Minas Gerais; Brasil Fil: Custodio, Nilton. Peruvian Institute of Neurosciences; Perú Fil: Damian, Andres. Universidad de la República; Uruguay Fil: de la Cruz, Myriam. University of California; Estados Unidos Fil: Diehl Rodriguez, Roberta. Universidade de Sao Paulo; Brasil Fil: Dozzi Brucki, Sonia Maria. Universidade de Sao Paulo; Brasil Fil: Fajersztajn, Lais. Universidade de Sao Paulo; Brasil Fil: Farías, Gonzalo A.. Universidad de Chile; Chile Fil: De Felice, Fernanda G.. Universidade Federal do Rio de Janeiro; Brasil Fil: Ferrari, Raffaele. Colegio Universitario de Londres; Reino Unido Fil: Ferreira de Oliveira, Fabricio. Universidade de Sao Paulo; Brasil Fil: Ferreira, Sergio Teixeira. Universidade Federal do Rio de Janeiro; Brasil Fil: Ferretti, Ceres. Universidade de Sao Paulo; Brasil Fil: Figueredo Balthazar, Marcio Luiz. Universidade Estadual de Campinas; Brasil Fil: Ferreira Frota, Norberto Anizio. Universidade de Fortaleza; Brasil Fil: Fuentes, Patricio. No especifíca; Fil: García, Adolfo Martín. Universidad Nacional de Cuyo; Argentina. Universidad de San Andrés; Argentina. Consejo Nacional de Investigaciones Científicas y Técnicas; Argentina Fil: Garcia, Patricia J.. Cayetano Heredia University; Perú Fil: de Gobbi Porto, Fábio Henrique. Universidade de Sao Paulo; Brasil Fil: Duque Peñailillo, Lissette. Ecuadorian Dementia Association; Ecuador Fil: Engler, Henry Willy. Universidad de la República; Uruguay Fil: Maier, Irene. Universidad de Chile; Chile Fil: Mata, Ignacio F.. University of Pittsburgh; Estados Unidos Fil: González Billault, Christian. Universidad de Chile; Chile Fil: Lopez, Oscar L.. University of Pittsburgh; Estados Unidos Fil: Morelli, Laura. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Parque Centenario. Instituto de Investigaciones Bioquímicas de Buenos Aires. Fundación Instituto Leloir. Instituto de Investigaciones Bioquímicas de Buenos Aires; Argentina Fil: Nitrini, Ricardo. Universidade de Sao Paulo; Brasil Fil: Quiroz, Yakeel T.. Harvard Medical School; Estados Unidos Fil: Guerrero Barragan, Alejandra. Universidad de la Sabana; Colombia Fil: Huepe, David. Universidad Adolfo Ibañez; Chile Fil: Pio, Fabricio Joao. Hospital Governador Celso Ramos; Brasil Fil: Suemoto, Claudia Kimie. Universidade de Sao Paulo; Brasil Fil: Kochhann, Renata. Pontificia Universidade Católica do Rio Grande do Sul; Brasil Fil: Kochen, Sara Silvia. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Houssay. Instituto de Biología Celular y Neurociencia "Prof. Eduardo de Robertis". Universidad de Buenos Aires. Facultad de Medicina. Instituto de Biología Celular y Neurociencia; Argentina Fil: Kumfor, Fiona. University of Western Sydney; Australia Fil: Lanata, Serggio. University of California; Estados Unidos Fil: Miller, Bruce. University of California; Estados Unidos Fil: Lessa Mansur, Leticia. Universidade de Sao Paulo; Brasil Fil: Lie Hosogi, Mirna. Universidade de Sao Paulo; Brasil Fil: Lillo, Patricia. Universidad de Chile; Chile Fil: Llibre Guerra, Jorge. University of California; Estados Unidos Fil: Lira, David. Peruvian Institute of Neurosciences; Perú Fil: Lopera, Francisco. Universidad de Antioquia; Colombia Fil: Comas, Adelina. No especifíca; Fil: Avila Funes, José Alberto. Instituto Nacional de Ciencias Médicas y Nutrición Salvador Zubirán; México Fil: Sosa, Ana Luisa. Instituto Nacional de Neurología y Neurocirugía; México Fil: Ramos, Claudia. University of California; Estados Unidos Fil: de Paula França Resende, Elisa. University of California; Estados Unidos Fil: Snyder, Heather M.. No especifíca; Fil: Tarnanas, Ioannis. University of California; Estados Unidos Fil: Yokoyama, Jenifer. University of California; Estados Unidos Fil: Llibre, Juan. Centro de Estudios de Alzheimer; Cuba Fil: Cardona Londoño, Juan Felipe. Universidad del Valle; Colombia. Consejo Nacional de Investigaciones Científicas y Técnicas; Argentina Fil: Possin, Kate. University of California; Estados Unidos Fil: Kosik, Kenneth. University of California; Estados Unidos Fil: Montesinos, Rosa. Peruvian Institute of Neurosciences; Perú Fil: Moguilner, Sebastian Gabriel. University of California; Estados Unidos Fil: Solis, Patricia Cristina Lourdes. Provincia de Buenos Aires. Ministerio de Salud. Hospital Alta Complejidad en Red El Cruce Dr. Néstor Carlos Kirchner Samic; Argentina. Universidad Nacional Arturo Jauretche; Argentina. Universidad de Buenos Aires; Argentina Fil: de Lucena Ferretti Rebustini, Renata Eloah. Universidade de Sao Paulo; Brasil Fil: Ramirez, Jeronimo Martin. No especifíca; Fil: Matallana, Diana. Pontificia Universidad Javeriana; Colombia Fil: Mbakile Mahlanza, Lingani. University of California; Estados Unidos Fil: Mendonça Marques Ton, Alyne. Universidade Federal do Rio de Janeiro; Brasil Fil: Melo Tavares, Ronnielly. Centro Universitario de Belo Horizonte.; Brasil Fil: Miotto, Eliane C.. Universidade de Sao Paulo; Brasil Fil: Muniz-Terrera, Graciela. University of Edinburgh; Reino Unido Fil: MuñozN evárez, Luis Arnoldo. University of California; Estados Unidos Fil: Orozco, David. Universidad Nacional del Sur; Argentina Fil: Okada de Oliveira, Maira. University of California; Estados Unidos Fil: Piguet, Olivier. University of Western Sydney; Australia Fil: Pintado Caipa, Maritza. University of California; Estados Unidos Fil: Piña Escudero, Stefanie Danielle. University of California; Estados Unidos Fil: Porcello Schilling, Lucas. Pontificia Universidade Católica do Rio Grande do Sul; Brasil Fil: Rodrigues Palmeira, André Luiz. Hospital Ernesto Dornelles; Brasil Fil: Sanches Yassuda, Mônica. Universidade de Sao Paulo; Brasil Fil: Santacruz Escudero, Jose Manuel. Pontificia Universidad Javeriana; Colombia Fil: Serafim, Rodrigo Bernardo. Universidade Federal do Rio de Janeiro; Brasil Fil: Smid, Jerusa. Universidade de Sao Paulo; Brasil Fil: Slachevsky, Andrea. Universidad de Chile; Chile Fil: Serrano, Cecilia Mariela. No especifíca; Fil: Soto Añari, Marcio. Universidad Católica San Pablo; Perú Fil: Takada, Leonel Tadao. Universidade de Sao Paulo; Brasil Fil: Tenenholz Grinberg, Lea. Universidade de Sao Paulo; Brasil Fil: Teixeira, Antonio Lucio. Universidade Federal de Minas Gerais; Brasil Fil: Tonidandel Barbosa, Maira. Universidade Federal de Minas Gerais; Brasil Fil: Trépel, Dominic. Trinity College; Estados Unidos Fil: Ibañez, Agustin Mariano. Universidad Autónoma del Caribe; Colombia. Universidad Adolfo Ibañez; Chile. Universidad de San Andrés; Argentina. Consejo Nacional de Investigaciones Científicas y Técnicas; Argentina

To characterize the influence of APOE genotype on cerebral Aβ load and longitudinal Aβ trajectories, [(11)C]PiB PET imaging studies were performed in a cohort of 428 participants with known APOE genotype and a range of clinical diagnoses from cognitively normal elderly to Alzheimer’s disease (AD). [(11)C]PiB PET imaging was used to assess amyloid load in a clinically heterogeneous cohort of 428 elderly participants. Serial [(11)C]PiB data and a repeated measures model were used to model amyloid trajectories in a subset of 235 participants classified on the basis of APOE genotype. We found that APOE-ε4 was associated with increased Aβ burden and an earlier age of onset of Aβ positivity, whereas APOE-ε2 appeared to have modest protective effects against Aβ. APOE class did not predict rates of Aβ accumulation. The present study suggests that APOE modifies AD risk through a direct influence on amyloidogenic processes, which manifests as an earlier age-of-onset of Aβ positivity, although it is likely that other genetic, environmental, and lifestyle factors are important.

Declining estrogen levels before, during, and after menopause can affect memory and risk for Alzheimer's disease. Undesirable side effects of hormone variations emphasize a role for hormone therapy (HT) where possible benefits include a delay in the onset of dementia—yet findings are inconsistent. Effects of HT may be mediated by estrogen receptors found throughout the brain. Effects may also depend on lifestyle factors, timing of use, and genetic risk. We studied the impact of self‐reported HT use on brain volume in 562 elderly women (71–94 years) with mixed cognitive status while adjusting for aforementioned factors. Covariate‐adjusted voxelwise linear regression analyses using a model with 16 predictors showed HT use as positively associated with regional brain volumes, regardless of cognitive status. Examinations of other factors related to menopause, oophorectomy and hysterectomy status independently yielded positive effects on brain volume when added to our model. One interaction term, HTxBMI, out of several examined, revealed significant negative association with overall brain volume, suggesting a greater reduction in brain volume than BMI alone. Our main findings relating HT to regional brain volume were as hypothesized, but some exploratory analyses were not in line with existing hypotheses. Studies suggest lower levels of estrogen resulting from oophorectomy and hysterectomy affect brain volume negatively, and the addition of HT modifies the relation between BMI and brain volume positively. Effects of HT may depend on the age range assessed, motivating studies with a wider age range as well as a randomized design., Declining estrogen levels for women in all stages of menopause can affect memory and risk of Alzheimer's Disease (AD), emphasizing a role for hormone therapy (HT). Effects may differ due to several factors including lifestyle and cardiovascular risk, genetic makeup, and timing and duration of HT. We addressed this hypothesis using self‐reported HT in 562 elderly women with mixed cognitive status, covarying for aforementioned factors. Voxelwise regression showed HT use as correlated with higher brain volume regardless of cognitive status

Objectives To examine the relationship between duration of the cognitive symptoms, from the earliest reported symptom to death, and hippocampal sclerosis (HS) and TAR‐DNA binding protein of 43kDA (TDP‐43) in Alzheimer’s disease (AD) patients. Methods The study was conducted in 359 cognitively impaired patients who met the pathological criteria for AD (NIA‐Reagan intermediate or high). The mean age at onset was 69.5 ± 8.8 years (range 37‐95) and the mean duration of the symptoms was 10.5 ± 4.2 years. The association between symptoms duration and HS and TDP‐43 was examined with logistic regression analyses controlling for age at death, atherosclerosis in the Circle of Willis (CW), cerebral infarcts, gender, baseline Mini Mental State Examination scores, APOE‐4 allele, and presence of Lewy bodies (LB). Results HS was present in 18% (n = 64) and TDP‐43 in 51.5% (n = 185) of the patients. HS and TDP‐43 were more frequent in patients whose symptoms lasted more than 10 years. LBs were present in 72% of the patients with HS and in 64% of the patients with TDP‐43. Age at onset was not associated with TDP‐43 or HS. HS was associated with duration of symptoms and LB, TDP‐43, and atherosclerosis in the CW. TDP‐43 was associated with duration of symptoms, LB, and HS. Interpretation HS and TDP‐43 are present in early and late onset AD. However, their presence is mainly driven by the duration of symptoms and the presence of LB. This suggests that HS and TDP‐43 are part of the later neuropathological changes in AD.

ObjectiveTo test the hypothesis that orthostatic hypotension (OH) might cause cerebral hypoperfusion and injury, we examined the longitudinal relationship between OH or orthostatic symptoms and incident neurologic outcomes in a community population of older adults.MethodsCardiovascular Health Study participants (≥65 years) without dementia or stroke had blood pressure (BP) measured after lying down for 20 minutes and after standing 3 for minutes. Participants reported dizziness immediately upon standing and any dizziness in the past 2 weeks. OH was defined as a drop in standing systolic/diastolic BP ≥20/≥10 mm Hg. We determined the association between OH or dizziness with (1) MRI brain findings (ventricular size, white matter hyperintensities, brain infarcts) using linear or logistic regression, (2) cognitive function (baseline and over time) using generalized estimating equations, and (3) prospective adjudicated events (dementia, stroke, death) using Cox models. Models were adjusted for demographic characteristics and OH risk factors. We used multiple imputation to account for missing OH or dizziness (n = 534).ResultsPrior to imputation, there were 5,007 participants (mean age 72.7 ± 5.5 years, 57.6% women, 10.9% Black, 16% with OH). OH was modestly associated with death (hazard ratio [HR] 1.11; 95% confidence interval 1.02–1.20), but not MRI findings, cognition, dementia, or stroke. In contrast, dizziness upon standing was associated with lower baseline cognition (β = −1.20; −1.94 to −0.47), incident dementia (HR 1.32; 1.04–1.62), incident stroke (HR 1.22; 1.06–1.41), and death (HR 1.13; 1.06–1.21). Similarly, dizziness over the past 2 weeks was associated with higher white matter grade (β = 0.16; 0.03–0.30), brain infarcts (OR 1.31; 1.06–1.63), lower baseline cognition (β = −1.18; −2.01 to −0.34), and death (HR 1.13; 1.04–1.22).ConclusionsDizziness was more consistently associated with neurologic outcomes than OH 3 minutes after standing. Delayed OH assessments may miss pathologic information related to cerebral injury.

Introduction This phase 2b/3 trial examined the effects of plasma exchange (PE) in patients with mild‐to‐moderate Alzheimer's disease (AD). Methods Three hundred forty‐seven patients (496 screened) were randomized (1:1:1:1) into three PE treatment arms with different doses of albumin and intravenous immunoglobulin replacement (6‐week period of weekly conventional PE followed by a 12‐month period of monthly low‐volume PE), and placebo (sham). Results PE‐treated patients performed significantly better than placebo for the co‐primary endpoints: change from baseline of Alzheimer's Disease Cooperative Study–Activities of Daily Living (ADCS‐ADL; P = .03; 52% less decline) with a trend for Alzheimer's Disease Assessment Scale–Cognitive Subscale (ADAS‐Cog; P = .06; 66% less decline) scores at month 14. Moderate‐AD patients (baseline Mini‐Mental State Examination [MMSE] 18‐21) scored better on ADCS‐ADL (P = .002) and ADAS‐Cog (P = .05), 61% less decline both. There were no changes in mild‐AD patients (MMSE 22‐26). PE‐treated patients scored better on the Clinical Dementia Rating Sum of Boxes (CDR‐sb) (P = .002; 71% less decline) and Alzheimer's Disease Cooperative Study‐Clinical Global Impression of Change (ADCS‐CGIC) (P

Introduction Recent studies suggest that Alzheimer's disease (AD) biomarker disclosure has no discernable psychological impact on cognitively healthy persons. Far less is known about how such results affect symptomatic individuals and their caregivers. Methods Randomized controlled trial of 82 mild cognitive impairment (MCI) patient and caregiver dyads (total n = 164) to determine the effect of receiving amyloid positron emission tomography results on understanding of, and perceived efficacy to cope with, MCI over 52 weeks of follow-up. Results Gains in the primary outcomes were not consistently observed. Amyloid negative patients reported greater perceived ambiguity regarding MCI at follow-up, while moderate and sustained emotional distress was observed in patients, and to a lesser extent, caregivers, of those who were amyloid positive. There was no corresponding increase in depressive symptoms. Discussion These findings point to the possibility that both MCI patients and caregivers may need emotional support after the disclosure of amyloid scan results.

BACKGROUND: Histologic and molecular differences between primary breast cancer and their subsequent metastases are well-established. Characterization of this heterogeneity may provide important information for both diagnosis and prognosis. Tissue donation via autopsy can aid in characterizing the microenvironment and understanding organ tropism. We describe the implementation, results, and challenges of a cohesive program of post-mortem tissue procurement in patients with breast cancer. METHODS: Prior to formalization of the program, three autopsies were performed without specific operating procedures. In 2016, formal input from patients, their families, clinicians, and pathology technicians helped to operationalize a formal tissue donation program. Ten autopsies have been performed to date. Demographic and clinical data were collected for these patients through retrospective chart reviews. When available, primary tumor tissue and any prior metastasis which were biopsied or surgically resected were acquired from clinical archives at our institution, or requested from outside facilities for future analyses. RESULTS: Between October 2011 and April 2019, autopsies were performed on 1 male and 9 female patients. Time from primary to metastatic disease was an average of 4 years. The median age at the time of death was 56 years (range 37-73). The average time from diagnosis of metastatic disease to consent to autopsy was 30 months. Although the majority of patients died outside the hospital (70%), the mean time between death and the start of autopsy was 4.7 hours. Samples of metastatic tissue were collected in all patients postmortem. There was an average of 16 samples collected from various sites that included both normal and metastatic tissue. The most common sites were the liver (80%), lung (70%), and lymph nodes (70%). Immunohistochemical analysis of metastatic tumors revealed intrapatient heterogeneity in ER, HER2 and Ki67 staining. TABLE 1: CLINICAL COURSE OF PATIENTSN=10 patientsPatients (%)Age at Diagnosis, years (median)46.7 (24.9-57.8)GenderFemale9 (90)Male1 (10)AJCC stage at initial presentationStage 13 (30)Stage 23 (30)Stage 33 (30)Stage 41 (10)Molecular SubtypesHR+/HER 2-6 (60)HR+/HER 2+2 (20)HR-/HER 2-2 (20)HR-/HER 2+0 (0)Time from initial diagnosis to metastatic disease, years (median)4.3 (0-12.8)Tissue of Metastases Obtained While AliveYes4 (40)No6 (60)Median age at time of death, years56.5 (37-73)Total Survival (dx to death), years (median)7.7Metastatic Survival (mets to death), years (median)3.3 TABLE 2: POST MORTEM TISSUE DONATION PROGRAMTime from Metastatic Diagnosis to Consent for Autopsy, months (median)30.3Time from Consent for Autopsy to Death, months (median)10.25Location of DeathHome5 (50)Hospital3 (30)Inpatient Hospice Facility2 (20)Time from death to starting autopsy, hours (median)4.68Time to complete autopsy, hours (median) N=72.82Number of Samples Collected During Autopsy (median)16.2 (3-27)Sites for Metastatic Tissue Procurement Postmortem8 (80)Liver7 (70)Lung7 (70)Lymph Nodes4 (40)Brain4 (40)Ascitic Fluid3 (30)Bone2 (20)Adrenal2 (20)Pericardium2 (20)Pleural Effusion1 (10)Chest Wall1 (10)Gall Bladder1 (10) CONCLUSION: Post-mortem tissue donation programs allow procurement of tissue that would otherwise be inaccessible in the living patient. Histological examination and immunohistochemical assessment of key biomarkers will be used to further characterize the tissue collected ante-mortem and post-mortem. This data combined with the clinical history and longitudinal specimens will help us better understand how intra- and inter-tumor heterogeneity play a role in the clinical course of breast cancer. Also, as we establish the program, we will identify barriers that need to be addressed in order to optimize the process. Citation Format: Tara Hyder, Lori Miller, Jennifer M Atkinson, Zoe Wecht, Ashuvinee Elangovan, Kai Ding, Nolan Priedigkeit, Zheqi Li, Tiantong Liu, Laura Savariau, Fangyuan Chen, Oscar Lopez, Dayne Ashman, Daniel Geisler, Jacob A Smith, Rachel Jankowitz, Priscilla F McAuliffe, Shannon Puhalla, Humberto E Trejo Bittar, Jeffrey S Nine, Peter C Lucas, Adam Brufsky, Steffi Oesterreich, Adrian V Lee, Margaret Rosenzweig. Implementation of a breast cancer post-mortem tissue donation program [abstract]. In: Proceedings of the 2019 San Antonio Breast Cancer Symposium; 2019 Dec 10-14; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2020;80(4 Suppl):Abstract nr P2-21-02.

Tau PET tracers exhibit varying levels of specific signal and distinct off-target binding patterns that are more diverse than amyloid PET tracers. This study compared 2 frequently used tau PET tracers, (18)F-flortaucipir and (18)F-MK-6240, in the same subjects. Methods: (18)F-flortaucipir and (18)F-MK-6240 scans were collected within 2 mo in 15 elderly subjects varying in clinical diagnosis and cognition. FreeSurfer, version 5.3, was applied to 3-T MR images to segment Braak pathologic regions (I–VI) for PET analyses. Off-target binding was assessed in the choroid plexus, meninges, and striatum. SUV ratio (SUVR) outcomes were determined over 80–100 min ((18)F-flortaucipir) or 70–90 min ((18)F-MK-6240) normalized to cerebellar gray matter. Masked visual interpretation of images was performed by 5 raters for both the medial temporal lobe and the neocortex, and an overall (majority) rating was determined. Results: Overall visual ratings showed complete concordance between radiotracers for both the medial temporal lobe and the neocortex. SUVR outcomes were highly correlated (r(2) > 0.92; P ≪ 0.001) for all Braak regions except Braak II. The dynamic range of SUVRs in target regions was approximately 2-fold higher for (18)F-MK-6240 than for (18)F-flortaucipir. Cerebellar SUVs were similar for (18)F-MK-6240 and (18)F-flortaucipir, suggesting that differences in SUVRs are driven by specific signals. Apparent off-target binding was observed often in the striatum and choroid plexus with (18)F-flortaucipir and most often in the meninges with (18)F-MK-6240. Conclusion: Both (18)F-MK-6240 and (18)F-flortaucipir are capable of quantifying signal in a common set of brain regions that develop tau pathology in Alzheimer disease; these tracers perform equally well in visual interpretations. Each also shows distinct patterns of apparent off-target binding. (18)F-MK-6240 showed a greater dynamic range in SUVR estimates, which may be an advantage in detecting early tau pathology or in performing longitudinal studies to detect small interval changes.

This individual participant data analysis assesses the cross-sectional and longitudinal associations of baseline thyroid dysfunction with cognitive function and dementia., Key Points Question Is thyroid dysfunction associated with cognitive decline? Findings In this individual participant data analysis of 23 cohorts including 74 565 participants with cognitive function and/or dementia measurements, subclinical thyroid dysfunction was not associated with global cognitive function at baseline (standardized mean difference, −0.02 for subclinical hyperthyroidism and 0.05 for subclinical hypothyroidism) or annual decline (standardized mean difference, −0.02 for subclinical hyperthyroidism and −0.00 for subclinical hypothyroidism). Meaning These findings do not support the need for screening for subclinical thyroid dysfunction for prevention of cognitive decline or dementia., Importance In clinical guidelines, overt and subclinical thyroid dysfunction are mentioned as causal and treatable factors for cognitive decline. However, the scientific literature on these associations shows inconsistent findings. Objective To assess cross-sectional and longitudinal associations of baseline thyroid dysfunction with cognitive function and dementia. Design, Setting, and Participants This multicohort individual participant data analysis assessed 114 267 person-years (median, 1.7-11.3 years) of follow-up for cognitive function and 525 222 person-years (median, 3.8-15.3 years) for dementia between 1989 and 2017. Analyses on cognitive function included 21 cohorts comprising 38 144 participants. Analyses on dementia included eight cohorts with a total of 2033 cases with dementia and 44 573 controls. Data analysis was performed from December 2016 to January 2021. Exposures Thyroid function was classified as overt hyperthyroidism, subclinical hyperthyroidism, euthyroidism, subclinical hypothyroidism, and overt hypothyroidism based on uniform thyrotropin cutoff values and study-specific free thyroxine values. Main Outcomes and Measures The primary outcome was global cognitive function, mostly measured using the Mini-Mental State Examination. Executive function, memory, and dementia were secondary outcomes. Analyses were first performed at study level using multivariable linear regression and multivariable Cox regression, respectively. The studies were combined with restricted maximum likelihood meta-analysis. To overcome the use of different scales, results were transformed to standardized mean differences. For incident dementia, hazard ratios were calculated. Results Among 74 565 total participants, 66 567 (89.3%) participants had normal thyroid function, 577 (0.8%) had overt hyperthyroidism, 2557 (3.4%) had subclinical hyperthyroidism, 4167 (5.6%) had subclinical hypothyroidism, and 697 (0.9%) had overt hypothyroidism. The study-specific median age at baseline varied from 57 to 93 years; 42 847 (57.5%) participants were women. Thyroid dysfunction was not associated with global cognitive function; the largest differences were observed between overt hypothyroidism and euthyroidism—cross-sectionally (−0.06 standardized mean difference in score; 95% CI, –0.20 to 0.08; P = .40) and longitudinally (0.11 standardized mean difference higher decline per year; 95% CI, –0.01 to 0.23; P = .09). No consistent associations were observed between thyroid dysfunction and executive function, memory, or risk of dementia. Conclusions and Relevance In this individual participant data analysis of more than 74 000 adults, subclinical hypothyroidism and hyperthyroidism were not associated with cognitive function, cognitive decline, or incident dementia. No rigorous conclusions can be drawn regarding the role of overt thyroid dysfunction in risk of dementia. These findings do not support the practice of screening for subclinical thyroid dysfunction in the context of cognitive decline in older adults as recommended in current guidelines.

The Alzheimer’s Disease Neuroimaging Initiative showed that Japanese had significantly lower brain Aβ burden than Americans among a cognitively normal population. This cross-sectional study aimed to compare vascular disease burden, Aβ burden, and neurodegeneration between cognitively normal elderly Japanese and Americans. Japanese and American participants were matched for age (±4-year-old), sex, and Apolipoprotein E (APOE) genotype. Brain vascular disease burden and brain Aβ burden were measured using white matter lesions (WMLs) and 11C-labeled Pittsburgh Compound B (PiB) retention, respectively. Neurodegeneration was measured using hippocampal volumes and cortical thickness. A total of 95 Japanese and 95 Americans were recruited (50.5% men, mean age = 82). Compared to Americans, Japanese participants had larger WMLs, and a similar global Aβ standardized uptake value ratio (SUVR), cortical thickness and hippocampal volumes. Japanese had significantly lower regional Aβ SUVR in the anterior ventral striatum, posterior cingulate cortex, and precuneus. Cognitively normal elderly Japanese and Americans had different profiles regarding vascular disease and Aβ burden. This suggests that multiple risk factors are likely to be involved in the development of dementia. Additionally, Japanese might have a lower risk of dementia due to lower Aβ burden than Americans. Longitudinal follow-up of these cohorts is warranted to ascertain the predictive accuracy of these findings.

ObjectiveTo determine changes in the incidence of dementia between 1988 and 2015.MethodsThis analysis was performed in aggregated data from individuals >65 years of age in 7 population-based cohort studies in the United States and Europe from the Alzheimer Cohort Consortium. First, we calculated age- and sex-specific incidence rates for all-cause dementia, and then defined nonoverlapping 5-year epochs within each study to determine trends in incidence. Estimates of change per 10-year interval were pooled and results are presented combined and stratified by sex.ResultsOf 49,202 individuals, 4,253 (8.6%) developed dementia. The incidence rate of dementia increased with age, similarly for women and men, ranging from about 4 per 1,000 person-years in individuals aged 65–69 years to 65 per 1,000 person-years for those aged 85–89 years. The incidence rate of dementia declined by 13% per calendar decade (95% confidence interval [CI], 7%–19%), consistently across studies, and somewhat more pronouncedly in men than in women (24% [95% CI 14%–32%] vs 8% [0%–15%]).ConclusionThe incidence rate of dementia in Europe and North America has declined by 13% per decade over the past 25 years, consistently across studies. Incidence is similar for men and women, although declines were somewhat more profound in men. These observations call for sustained efforts to finding the causes for this decline, as well as determining their validity in geographically and ethnically diverse populations.

Introduction Both high or low plasma amyloid levels have been associated with risk of dementia in nondemented subjects. Methods We examined baseline plasma β-amyloid (Aβ) levels in relationship to incident dementia during a period of 8.5 years in 2840 subjects age >75 years; 2381 were cognitively normal (CN) and 450 mild cognitive impairment. Results Increased plasma Aβ1-40 and Aβ1-42 levels were associated with gender (women), age, low education, creatinine levels, history of stroke, and hypertension. CN participants who developed dementia had lower levels of Aβ1-42 and Aβ1-42/Aβ1-40 ratio compared with those who did not. Aβ levels did not predict dementia in mild cognitive impairment participants. Discussion There was an inverse association between Aβ1-42 and Aβ1-42/Aβ1-40 ratio to risk of dementia in CN participants. Cerebral and cardiovascular disease and renal function are important determinants of increased Aβ levels and must be considered in evaluations of relationship of plasma Aβ and subsequent risk of dementia.

Background:Observational studies in Asia show that dietary intake of soy isoflavones had a significant inverse association with coronary heart disease (CHD). A recent randomized controlled trial (RCT) of soy isoflavones on atherosclerosis in the US, however, failed to show their benefit. The discrepancy may be due to the much lower prevalence of S-equol producers in Westerners: Only 20-30% of Westerners produce S-equol in contrast to 50-70% in Asians. S-equol is a metabolite of dietary soy isoflavone daidzein by gut microbiome and possesses the most antiatherogenic properties among all isoflavones. Several short-duration RCTs documented that soy isoflavones improves arterial stiffness. Accumulating evidence shows that both atherosclerosis and arterial stiffness are positively associated with cognitive decline/dementia. Therefore, potentially, soy isoflavones, especially S-equol, are protective against cognitive decline/dementia. Methods/Results: This narrative review of clinical and epidemiological studies provides an overview of the health benefits of soy isoflavones and introduces S-equol. Second, we review recent evidence on the association of soy isoflavones and S-equol with CHD, atherosclerosis, and arterial stiffness as well as the association of atherosclerosis and arterial stiffness with cognitive decline/ dementia. Third, we highlight recent studies that report the association of soy isoflavones and S-equol with cognitive decline/dementia. Lastly, we discuss the future directions of clinical and epidemiological research on the relationship of S-equol and CHD and dementia.Conclusions:Evidence from observational studies and short-term RCTs suggests that S-equol is anti-atherogenic and improves arterial stiffness and may prevent CHD and cognitive impairment/ dementia. Well-designed long-term (≥ 2years) RCTs should be pursued.

Introduction Preliminary studies have shown that treatment with plasma exchange (PE) plus therapeutic albumin replacement in patients with Alzheimer's disease (AD) induced mobilization of plasma and cerebrospinal fluid amyloid β protein, associated with an improvement in memory and language functions, as well as the stabilization of brain perfusion, which persisted after treatment discontinuation. Methods Alzheimer's Management By Albumin Replacement (AMBAR) is a multicenter, randomized, blinded and placebo-controlled, parallel-group, phase IIb/III trial enrolling patients with mild to moderate AD. The study evaluates PE with different replacement volumes of therapeutic albumin (5% and 20% Albutein®, Grifols), with or without intravenous immunoglobulin (Flebogamma® 5% DIF, Grifols). Patients are randomized to one of three active treatment groups or one control (sham PE) group (1:1:1:1). The intervention regime includes a first 6-week stage of intensive treatment, followed by a second 12-month stage of maintenance treatment. The change from the baseline to the end of treatment periods in the ADAS-Cog and ADCS-ADL scores are the coprimary efficacy variables. Secondary efficacy variables include change from the baseline in scores on cognitive, functional, behavioral, and overall progression tests; changes in plasma and cerebrospinal fluid levels of amyloid β and tau protein; and assessment of structural and functional changes in brain areas of interest. Safety and tolerability are assessed. Results The study has enrolled 496 patients from 41 centers (19 in Spain and 22 in the USA); 347 of these patients were randomized and underwent close to 5000 PEs, of which approximately 25% were sham PEs. Discussion We present an innovative approach for treating AD. The study has been designed to demonstrate clinical efficacy, defined as slow decline of the patient's cognition and brain function. The sample size has adequate power to detect differences between any of the active treatment groups and the control group, as well as between the three active treatment groups combined and the control group., Highlights • AMBAR approaches Alzheimer's disease with plasma exchange plus albumin replacement. • Clinical efficacy is to slow decline of the patient's cognition and brain function. • Sample size has power to detect differences between treatments and controls. • Interim results showed a safety profile similar to other plasma exchange indications.

Introduction Systemic inflammation has been increasingly implicated in the pathogenesis of Alzheimer’s disease (AD), yet the mechanistic and temporal specificity of this relationship is poorly understood. We aimed to characterize the cross-sectional and longitudinal associations between peripheral inflammatory biomarkers, cognition, and Aβ deposition in oldest-old cognitively unimpaired (CU) adults. Methods A large sample of 139 CU older adults (mean age (range) = 85.4 (82–95)) underwent neuropsychological testing, Pittsburgh compound-B (PiB)-PET imaging and structural MRI. Hierarchical regression models examined associations between circulating inflammatory biomarkers (Interleukin-6 (IL-6), soluble Tumor Necrosis Factor receptors 1 and 2 (sTNFr1 and sTNFr2), soluble cluster of differentiation 14 (sCD14), C-reactive protein (CRP)), cognition, and global and regional Aβ deposition at baseline and over follow-up. Indices of preclinical disease, including pathologic Aβ status and hippocampal volume, were incorporated to assess conditional associations. Results At baseline evaluation, higher concentrations of IL-6 and sTNFr2 were associated with greater global Aβ burden in those with lower hippocampal volume. In longitudinal models, IL-6 predicted subsequent conversion to MCI and both IL-6 and CRP predicted greater change in global and regional Aβ deposition specifically among participants PiB-positive at baseline. These relationships withstood adjustment for demographic factors, anti-hypertensive medication use, history of diabetes, heart disease, APOE e4 carrier status, and white matter lesions. Discussion In a large prospective sample of CU adults aged 80 and over, peripheral inflammatory biomarkers were associated with and predictive of the progression of Aβ deposition. This was specific to those with biomarker evidence of preclinical AD at baseline, supporting recent evidence of disease-state-dependent differences in inflammatory expression profiles. Chronic, low-level systemic inflammation may exacerbate the deposition of Aβ pathology among those with emerging disease processes, and place individuals at a higher risk of developing clinically significant cognitive impairment.

Late-life depression (LLD) is associated with an increased risk of developing dementia; however, it is not known whether individuals with a history of LLD exhibit a more rapid rate of cognitive decline. We aimed to determine whether those with LLD experienced faster cognitive decline compared with never-depressed control (NDC) participants from the community and whether stratification of LLD into early-onset depression (EOD) and late-onset depression (LOD) subtypes revealed differing rates and domain-specific expression of cognitive decline. We conducted a prospective, longitudinal study where 185 participants with LLD (remitted) and 114 NDC were followed for 5 years on average. EOD was defined as having first lifetime depressive episode at

Introduction: Plant-based diets rich in fruits and vegetables have been associated with lower risk of dementia, but the specific role of antioxidants, a key class of bioactive phytochemicals, has not been well ascertained.Methods: We measured antioxidants in a case-cohort study nested within the Ginkgo Evaluation of Memory Study. We included 996 randomly selected participants and 521 participants who developed dementia, of which 351 were diagnosed with Alzheimer's disease (AD) during a median of 5.9 years of follow-up. We measured baseline plasma levels of retinol, α-, and γ-tocopherol; zeaxanthin and lutein (combined); beta-cryptoxanthin; cis-lycopene; trans-lycopene; α-carotene; and trans-β-carotene by organic phase extraction followed by chromatographic analysis and related these to neurologist-adjudicated risks of all-cause dementia and AD.Results: Plasma retinol, α-, and γ-tocopherol, and carotenoids were not significantly related to risk of dementia or AD. Associations were not significant upon Bonferroni correction for multiple testing and were consistent within strata of sex, age, apolipoprotein E ε4 genotype, mild cognitive impairment at baseline, and intake of multivitamin, vitamin A or β-carotene, or vitamin E supplements. Higher trans-β-carotene tended to be related to a higher risk of dementia (adjusted hazard ratio [HR] per 1 standard deviation [SD] higher trans-β-carotene: 1.10; 95% confidence interval [CI]: 1.00, 1.20) and α-carotene tended to be associated with higher risk of AD only (adjusted HR per 1 SD higher α-carotene: 1.15; 95% CI: 1.02, 1.29).Discussion: Plasma antioxidants were not significantly associated with risk of dementia or AD among older adults. Similar studies in younger populations are required to better understand the association between plasma antioxidants and dementia risk.

Background: African American/Black adults have a disproportionate incidence of Alzheimer’s disease (AD) and are underrepresented in biomarker discovery efforts. Objective: This study aimed to identify potential diagnostic biomarkers for AD using a combination of proteomics and machine learning approaches in a cohort that included African American/Black adults. Methods: We conducted a discovery-based plasma proteomics study on plasma samples (N = 113) obtained from clinically diagnosed AD and cognitively normal adults that were self-reported African American/Black or non-Hispanic White. Sets of differentially-expressed proteins were then classified using a support vector machine (SVM) to identify biomarker candidates. Results: In total, 740 proteins were identified of which, 25 differentially-expressed proteins in AD came from comparisons within a single racial and ethnic background group. Six proteins were differentially-expressed in AD regardless of racial and ethnic background. Supervised classification by SVM yielded an area under the curve (AUC) of 0.91 and accuracy of 86%for differentiating AD in samples from non-Hispanic White adults when trained with differentially-expressed proteins unique to that group. However, the same model yielded an AUC of 0.49 and accuracy of 47%for differentiating AD in samples from African American/Black adults. Other covariates such as age, APOE4 status, sex, and years of education were found to improve the model mostly in the samples from non-Hispanic White adults for classifying AD. Conclusion: These results demonstrate the importance of study designs in AD biomarker discovery, which must include diverse racial and ethnic groups such as African American/Black adults to develop effective biomarkers.

Here we present a plasma proteomics dataset that was generated to understand the importance of self-reported race for biomarker discovery in Alzheimer's disease. This dataset is related to the article “Why inclusion matters for Alzheimer's disease biomarker discovery in plasma” [1]. Plasma samples were obtained from clinically diagnosed Alzheimer's disease and cognitively normal adults of African American/Black and non-Hispanic White racial and ethnic backgrounds. Plasma was immunodepleted, digested, and isobarically tagged with commercial reagents. Tagged peptides were fractionated using high pH fractionation and resulting fractions analysed by liquid chromatography – mass spectrometry (LC-MS/MS & MS3) analysis on an Orbitrap Fusion Lumos mass spectrometer. The resulting data was processed using Proteome Discoverer to produce a list of identified proteins with corresponding tandem mass tag (TMT) intensity information.

Alzheimer's disease (AD) disproportionately affects certain racial and ethnic subgroups, such as African American/Black and Hispanic adults. Genetic, comorbid, and socioeconomic risk factors contribute to this disparity; however, the molecular contributions have been largely unexplored. Herein, we conducted a pilot proteomics study of postmortem brains from African American/Black and non-Hispanic White adults neuropathologically diagnosed with AD compared to closely-matched cognitively normal individuals. Examination of hippocampus, inferior parietal lobule, and globus pallidus regions using quantitative proteomics resulted in 568 differentially-expressed proteins in AD. These proteins were consistent with the literature and included glial fibrillary acidic protein, peroxiredoxin-1, and annexin A5. In addition, 351 novel proteins in AD were identified, which could partially be due to cohort diversity. From linear regression analyses, we identified 185 proteins with significant race x diagnosis interactions across various brain regions. These differences generally were reflective of differential expression of proteins in AD that occurred in only a single racial/ethnic group. Overall, this pilot study suggests that disease understanding can be furthered by including diversity in racial/ethnic groups; however, this must be done on a larger scale.

Introduction: Air pollution is associated with reduced cognitive performance and accelerated cognitive decline in older adults. Less is known regarding air pollution’s contribution to all-cause dem...

Psychotic symptoms, defined as the occurrence of delusions or hallucinations, are frequent in Alzheimer disease (AD with psychosis, AD+P). AD+P affects ∼50% of individuals with AD, identifies a subgroup with poor outcomes, and is associated with a greater degree of cognitive impairment and depressive symptoms, compared to subjects without psychosis (AD-P). Although the estimated heritability of AD+P is 61%, genetic sources of risk are unknown. We report a genome-wide meta-analysis of 12,317 AD subjects, 5,445 AD+P. Results showed common genetic variation accounted for a significant portion of heritability. Two loci, one in ENPP6 (rs9994623, O.R. (95%CI) 1.16 (1.10, 1.22), p=1.26×10−8) and one spanning the 3’-UTR of an alternatively spliced transcript of SUMF1 (rs201109606, O.R. 0.65 (0.56-0.76), p=3.24×10−8), had genome-wide significant associations with AD+P. Gene-based analysis identified a significant association with APOE, due to the APOE risk haplotype ε4. AD+P demonstrated negative genetic correlations with cognitive and educational attainment and positive genetic correlation with depressive symptoms. We previously observed a negative genetic correlation with schizophrenia; instead, we now found a stronger negative correlation with the related phenotype of bipolar disorder. Analysis of polygenic risk scores supported this genetic correlation and documented a positive genetic correlation with risk variation for AD, beyond the effect of ε4. We also document a small set of SNPs likely to affect risk for AD+P and AD or schizophrenia. These findings provide the first unbiased identification of the association of psychosis in AD with common genetic variation and provide insights into its genetic architecture.

Background Age, human immunodeficiency virus (HIV) infection, illicit drug use, and central nervous system (CNS) opportunistic infections can affect brain structure, with the striatum being particularly sensitive to HIV effects. Nevertheless, the impact of non-CNS AIDS-defining illness (ADI) on brain structure has been less investigated. We examined ADI and HIV effects on brain volume. Methods In a cross-sectional study, including 95 virally suppressed seropositive and 84 demographically matched, seronegative participants, we examined serostatus and ADI effects. Cortical and subcortical gray matter volume (GMV) regions of interest were estimated with computational neuroanatomy techniques applied to high-resolution, T1-weighted magnetic resonance imaging data. Linear regression was used to model HIV serostatus and ADI effects on global and regional GMV, adjusting for age, sex, CD4 nadir, drug use, and total intracranial volume. Results While HIV serostatus was associated with lower striatal volume (B = −.59 [95% confidence interval {CI}, −1.08 to −.10]), co-occurring ADI was independently associated with lower striatal volume (B = −.73 [95% CI, −1.36 to −.09]). ADI was also associated with lower global (B = −19.35 [95% CI, −32.42 to −6.29]) and regional GMV. Conclusions While HIV infection is associated with a localized effect on striatal structure, having a prior ADI is a strong predictor of smaller global and regional GMV. The lack of interaction between HIV serostatus or ADI with age suggests that chronic HIV infection and ADI have independent effects on brain structure, without associated accelerated lower volume with age. ADI history should be incorporated into statistical adjustments in HIV neuroimaging analysis. These findings also lend support to current HIV treatment guidelines urging prompt antiretroviral therapy initiation after HIV diagnosis.

BACKGROUND: Reliable cerebral blood flow (CBF) biomarkers using a noninvasive imaging technique are sought to facilitate early diagnosis and intervention in early Alzheimer’s disease (AD). OBJECTIVE: We aim to identify brain regions in which CBF values are affected and related to cognitive decline in early AD using a large cohort. METHODS: Perfusion MRIs using continuous arterial spin labeling (CASL) were acquired at 1.5 T in 58 normal controls (NC), 50 mild cognitive impairments (MCI), and 40 AD subjects from the Cardiovascular Health Study (CHS) Cognition Study. Regional absolute CBF and normalized CBF (rCBF) values, without and with correction of partial volume effects (PVE), were compared across three groups. Association between regional CBF values and Modified Mini-Mental State Examination (3MSE) were investigated by multiple linear regression analyses adjusted for cardiovascular risk factors. RESULTS: After correcting for PVE and cardiovascular risk factors, ADs exhibited decreased rCBF with the strongest reduction in the bilateral posterior cingulate and precuneus (BPCP) region (p

Cardiovascular disease risk factors, including age, hypertension, and diabetes, contribute to aortic stiffness and subclinical cardiovascular and brain disease, increasing dementia risk. Aortic stiffness, measured by carotid-femoral pulse wave velocity (cfPWV), reduces the buffering of pulsatile blood flow, exposing cerebral small arteries to microvascular damage. High cfPWV is related to white matter hyperintensities and brain amyloid deposition, and to cognitive decline, but it is unclear whether cfPWV independently predicts incident dementia. Therefore, we tested the hypothesis that cfPWV predicts incident dementia in older adults, independent of potential confounders. The Cardiovascular Health Study Cognition Study followed 532 non-demented older adults with annual cognitive exams from 1998-99 through 2013. CfPWV was measured on 356 (mean age = 78, 59% women) between 1996-2000. Over 15 years, 212 (59.6%) developed dementia (median time from cfPWV measurement = 4 years). In age and sex-adjusted Cox models, cfPWV was significantly associated with increased risk of dementia, but systolic blood pressure, mean arterial pressure and pulse pressure were not. CfPWV (transformed as - 1/cfPWV) remained significantly associated with dementia risk when further adjusted for education, race, APOEɛ4, diabetes, body mass index, mean arterial pressure, and anti-hypertensive medication (hazard ratio = 1.60, 95% CI = 1.02, 2.51). Results were similar when further adjusted for baseline global cognition, subclinical brain measures, and coronary artery calcification. Finally, higher cfPWV was related to lower physical activity intensity and higher systolic blood pressure, heart rate, and waist circumference measured 5 years prior. An important unanswered question is whether interventions to slow arterial stiffening can reduce the risk of dementia.

The presence of psychosis in Alzheimer's disease denotes a phenotype with more rapid cognitive deterioration than in Alzheimer's disease without psychosis. Discovery of novel pharmacotherapies that engage therapeutic targets for prevention or treatment of Alzheimer's disease with psychosis would benefit from identifying the neurobiology of resilience to psychosis in Alzheimer's disease. The primary objective of this study was to determine whether alterations in the synaptic proteome were associated with resilience to psychotic symptoms in Alzheimer's disease and, if present, were independent of neuropathologic burden.Quantitative immunohistochemistry was used to measure multiple neuropathologies in dorsolateral prefrontal cortex from subjects with early and middle-stage Alzheimer's disease who differed in psychosis status. Synaptic proteins were quantified by liquid chromatography-mass spectrometry in gray matter homogenates from these subjects and from neuropathologically unaffected subjects. The synaptic proteome was similarly evaluated in cortical gray matter homogenate and in postsynaptic density fractions from an APPswe/PSEN1dE9 mouse model of amyloidosis with germline reduction in Kalrn, which has been shown to confer resilience to progression of psychosis-associated behaviors relative to APPswe/PSEN1dE9 alone.Subjects resilient to psychotic symptoms in Alzheimer's disease had higher levels of synaptic proteins compared with those with psychosis and unaffected control subjects. Neuropathologic burden predicted less than 20% of the variance in psychosis status and did not account for the synaptic protein level differences between groups. Reduction of Kalrn in APPswe/PSEN1dE9 mice resulted in higher levels of synaptic proteins in cortical homogenate and normalized protein levels in the postsynaptic density.Accumulation of synaptic proteins, particularly those that are enriched in the postsynaptic density, is associated with resilience to psychosis in Alzheimer's disease. One candidate mechanism for this synaptic proteome compensation is alteration in levels of proteins that facilitate the transport of synaptic proteins to and from the postsynaptic density.

Inflammatory processes may contribute to risk for Alzheimer's disease (AD) and age-related brain degeneration. Metabolic and genetic risk factors, and physical activity may, in turn, influence these inflammatory processes. Some of these risk factors are modifiable, and interact with each other. Understanding how these processes together relate to brain aging will help to inform future interventions to treat or prevent cognitive decline. We used brain magnetic resonance imaging (MRI) to scan 335 older adult humans (mean age 77.3 ± 3.4 years) who remained non-demented for the duration of the 9-year longitudinal study. We used structural equation modeling (SEM) in a subset of 226 adults to evaluate whether measures of baseline peripheral inflammation (serum C-reactive protein levels; CRP), mediated the baseline contributions of genetic and metabolic risk, and physical activity, to regional cortical thickness in AD-relevant brain regions at study year 9. We found that both baseline metabolic risk and AD risk variant apolipoprotein E e4 (APOE4), modulated baseline serum CRP. Higher baseline CRP levels, in turn, predicted thinner regional cortex at year 9, and mediated an effect between higher metabolic risk and thinner cortex in those regions. A higher polygenic risk score composed of variants in immune-associated AD risk genes (other than APOE) was associated with thinner regional cortex. However, CRP levels did not mediate this effect, suggesting that other mechanisms may be responsible for the elevated AD risk. We found interactions between genetic and environmental factors and structural brain health. Our findings support the role of metabolic risk and peripheral inflammation in age-related brain decline.

Introduction Given mounting calls to disclose biomarker test results to research participants, we explored factors underlying decisions by patients with mild cognitive impairment to receive amyloid imaging results. Methods Prospective, qualitative interviews were conducted with 59 participants (30 = mild cognitive impairment patients, 29 = care partners) from the scan arm of a randomized controlled trial on the effects of amyloid PET results disclosure in an Alzheimer Disease Research Center setting. Results Sixty-three percent of the participants were female, with an average age of 72.9 years, and most had greater than a high school level of education (80%). Primary motivations included: (1) better understanding one's mild cognitive impairment etiology and prognosis to plan ahead, and (2) learning one's brain amyloid status for knowledge's sake, regardless of whether the information is actionable. Most participants demonstrated an adequate understanding of the scan's limitations, yet instances of characterizing amyloid PET as a definitive test for Alzheimer's disease occurred. Mention of potential drawbacks, such as negative psychological outcomes, was minimal, even among care partners. Discussion Findings demonstrate a risk of disproportionate focus on possible benefits of testing among amyloid scan candidates and suggest a need to clearly emphasize the limitations of amyloid PET when counseling cognitively impaired patients and their families before testing. Future research should examine whether minimizing drawbacks at the pre-imaging stage has adverse consequences on results disclosure.

The positron emission tomography (PET) radiotracer Pittsburgh Compound B ([C-11]PiB) demonstrates a high affinity for fibrillary amyloid-beta (Aβ) aggregates. However, [C-11]PiB's in vivo sensitivity and specificity is an ongoing area of investigation in correlation studies with postmortem measures of Aβ pathology. One potential confound in PET-to-postmortem correlation studies is the limited spatial resolution of PET and resulting partial volume effects (PVEs). In this work, we evaluated the impact of three partial volume correction (PVC) techniques – the Meltzer, the modified Müller-Gärtner, and the Region-Based Voxel-Wise – on correlations between region-matched in vivo [C-11]PiB standardized uptake value ratios (SUVRs) and postmortem measures of Aβ pathology in a unique cohort of nine subjects. Postmortem Aβ pathology was assessed histologically as percent area coverage of 6-CN-PiB positive and Aβ immunoreactive (4G8 antibody) deposits. The application of all three PVC techniques resulted in minimally reduced PET-to-postmortem correlations relative to no PVC. However, correlations to both 6-CN-PiB and 4G8 percent area across all PVC techniques and no PVC were statistically significant at p, Highlights • Three partial volume correction techniques are applied to PiB PET SUVR data. • Corrected and uncorrected data are correlated to postmortem measures of Aβ load. • All 3 correction methods minimally impact PET-to-postmortem correlations.

Introduction We investigated the effect of antihypertensive (aHTN) medications and cholinesterase inhibitors (ChEIs) on the cognitive decline in patients with Alzheimer's disease (AD) and analyzed synergism by chemogenomics systems pharmacology mapping. Methods We compared the effect of aHTN drugs on Mini-Mental State Examination scores in 617 AD patients with hypertension, and studied the synergistic effects. Results The combination of diuretics, calcium channel blockers, and renin-angiotensin-aldosterone system blockers showed slower cognitive decline compared with other aHTN groups (Δβ = +1.46, P, Highlights • Combination of three antihypertensive drug classes slowed down cognitive decline. • Antihypertensives and cholinesterase inhibitor showed synergistic cognitive benefit. • Computational systems pharmacology revealed molecular mechanisms for synergism.

Introduction Apolipoproteins of demonstrated importance to brain cholesterol and s-amyloid metabolism may serve as novel risk markers for Alzheimer's pathology. Methods We measured apolipoproteins (apoE, apoJ, apoA-I, and apoC-III and their uniquely defined subspecies) by enzyme-linked immunosorbent assay in plasma collected in 2000 and 2008 from 176 dementia-free participants of the Ginkgo Evaluation of Memory Study and related these to s-amyloid on positron emission tomography scans, hippocampal volume, and white matter lesion volume in 2009. Results Higher apoE was associated with lower s-amyloid deposition. Despite apoA-I being unrelated to hippocampal volume, subspecies of apoA-I containing or lacking apoJ or apoC-III showed opposite associations with hippocampal volume. Higher apoJ and apoE lacking apoJ were associated with higher hippocampal volume and higher white matter lesion volume, respectively. Associations were similar in participants without cognitive impairment or APOE e4 noncarrier and when analyzing apolipoproteins in 2000–2002. Discussion Apolipoproteins may be important minimally invasive biomarkers indicative of Alzheimer's pathology.

ObjectiveTo update the 2001 American Academy of Neurology (AAN) guideline on mild cognitive impairment (MCI).MethodsThe guideline panel systematically reviewed MCI prevalence, prognosis, and treatment articles according to AAN evidence classification criteria, and based recommendations on evidence and modified Delphi consensus.ResultsMCI prevalence was 6.7% for ages 60–64, 8.4% for 65–69, 10.1% for 70–74, 14.8% for 75–79, and 25.2% for 80–84. Cumulative dementia incidence was 14.9% in individuals with MCI older than age 65 years followed for 2 years. No high-quality evidence exists to support pharmacologic treatments for MCI. In patients with MCI, exercise training (6 months) is likely to improve cognitive measures and cognitive training may improve cognitive measures.Major recommendationsClinicians should assess for MCI with validated tools in appropriate scenarios (Level B). Clinicians should evaluate patients with MCI for modifiable risk factors, assess for functional impairment, and assess for and treat behavioral/neuropsychiatric symptoms (Level B). Clinicians should monitor cognitive status of patients with MCI over time (Level B). Cognitively impairing medications should be discontinued where possible and behavioral symptoms treated (Level B). Clinicians may choose not to offer cholinesterase inhibitors (Level B); if offering, they must first discuss lack of evidence (Level A). Clinicians should recommend regular exercise (Level B). Clinicians may recommend cognitive training (Level C). Clinicians should discuss diagnosis, prognosis, long-term planning, and the lack of effective medicine options (Level B), and may discuss biomarker research with patients with MCI and families (Level C).

International audience; Several studies have reported a decline in incidence of dementia which may have large implications for the projected burden of disease, and provide important guidance to preventive efforts. However, reports are conflicting or inconclusive with regard to the impact of gender and education with underlying causes of a presumed declining trend remaining largely unidentified. The Alzheimer Cohorts Consortium aggregates data from nine international population-based cohorts to determine changes in the incidence of dementia since 1990. We will employ Poisson regression models to calculate incidence rates in each cohort and Cox proportional hazard regression to compare 5-year cumulative hazards across study-specific epochs. Finally, we will meta-analyse changes per decade across cohorts, and repeat all analysis stratified by sex, education and APOE genotype. In all cohorts combined, there are data on almost 69,000 people at risk of dementia with the range of follow-up years between 2 and 27. The average age at baseline is similar across cohorts ranging between 72 and 77. Uniting a wide range of disease-specific and methodological expertise in research teams, the first analyses within the Alzheimer Cohorts Consortium are underway to tackle outstanding challenges in the assessment of time-trends in dementia occurrence.

Background Previous studies have shown that individuals with diabetes exhibit accelerated cognitive decline. However, methodological limitations have limited the quality of this evidence. Heterogeneity in study design, cognitive test administration, and methods of analysis of cognitive data have made it difficult to synthesize and translate findings to practice. We analyzed longitudinal data from the Ginkgo Evaluation of Memory Study to test our hypothesis that older adults with diabetes have greater test-specific and domain-specific cognitive declines compared to older adults without diabetes. Methods Tests of memory, visuo-spatial construction, language, psychomotor speed, and executive function were administered. Test scores were standardized to z-scores and averaged to yield domain scores. Linear random effects models were used to compare baseline differences and changes over time in test and domain scores among individuals with and without diabetes. Results Among the 3,069 adults, aged 72-96 years, 9.3% reported diabetes. Over a median follow-up of 6.1 years, participants with diabetes exhibited greater baseline differences in a test of executive function (trail making test, Part B) and greater declines in a test of language (phonemic verbal fluency). For the composite cognitive domain scores, participants with diabetes exhibited lower baseline executive function and global cognition domain scores, but no significant differences in the rate of decline. Conclusions Identifying cognitive domains most affected by diabetes can lead to targeted risk modification, possibly in the form of lifestyle interventions such as diet and physical activity, which we know to be beneficial for improving vascular risk factors, such as diabetes, and therefore may reduce the risk of executive dysfunction and possible dementia.

Background Mild cognitive impairment (MCI) has an uncertain etiology and prognosis and may be challenging for clinicians to discuss with patients and families. Amyloid imaging may aid specialists in determining MCI etiology and prognosis, but creates novel challenges related to disease labeling. Methods We convened a workgroup to formulate recommendations for clinicians providing care to MCI patients. Results Clinicians should use the MCI diagnosis to validate patient and family concerns and educate them that the patient’s cognitive impairment is not normal for his or her age and education level. The MCI diagnosis should not be used to avoid delivering a diagnosis of dementia. For patients who meet Appropriate Use Criteria after standard-of-care clinical workup, amyloid imaging may position specialists to offer more information about etiology and prognosis. Clinicians must set appropriate expectations, including ensuring that patients and families understand the limitations of amyloid imaging. Communication of negative results should include that patients remain at elevated risk for dementia and that negative scans do not indicate a specific diagnosis or signify brain health. Positive amyloid imaging results should elicit further monitoring and conversations about appropriate advance planning. Clinicians should offer written summaries, including referral to appropriate social services. Conclusions In patients with MCI, there is a need to devote considerable time and attention to patient education and shared decision-making. Amyloid imaging may be a tool to aid clinicians. Careful management of patient expectations and communication of scan results will be critical to the appropriate use of amyloid imaging information.

Objective Higher levels of physical activity (PA) reduce the risk of cognitive impairment, but the underlying mechanisms are unclear. Using longitudinal data from the Cardiovascular Health Study, we examined whether PA predicted plasma Aβ levels and risk for cognitive decline 9–13 years later. Methods Linear and logistic regressions (controlling for APOE status, age, gender, body mass index, cardiovascular disease, brain white matter lesions, and cystatin C levels) tested associations between PA, Aβ, and cognitive impairment in a sample of 149 cognitively normal older adults (mean age 83 years). Results More PA at baseline predicted lower levels of Aβ 9–13 years later. Higher Aβ levels at year 9 predicted greater risk for cognitive impairment at year 13. Levels of Aβ at year 9 mediated the relationship between PA and cognitive impairment. Interpretation Greater PA may reduce plasma levels of a neurotoxic peptide at an age when the risk for cognitive impairment is especially high.

Background:Previous research regarding anxiety as a predictor of future cognitive decline in older adults is limited and inconsistent. We examined the independent relationship between anxiety symptoms and subsequent cognitive decline.Methods:We included 2,818 community-dwelling older men (mean age = 76.1, SD ±5.3 years) who were followed on an average for 3.4 years. We assessed anxiety symptoms at baseline using the Goldberg Anxiety Scale (GAS; range = 0–9). We assessed cognitive function at baseline and at two subsequent visits using the Modified Mini-Mental State Examination (3MS; global cognition) and the Trails B test (executive function).Results:At baseline, there were 690 (24%) men with mild anxiety symptoms (GAS 1–4) and 226 (8%) men with moderate/severe symptoms (GAS 5–9). Men with anxiety symptoms were more likely to have depressed mood, poor sleep, more chronic medical conditions, and more impairment in activities of daily living compared to those with no anxiety symptoms. Compared to those with no anxiety symptoms at baseline, men with any anxiety symptoms were more likely to have substantial worsening in Trails B completion time (OR = 1.56, 95% CI 1.19, 2.05). The association was attenuated after adjusting for potential confounders, including depression and poor sleep, but remained significant (OR = 1.40, 95% CI 1.04, 1.88).Conclusion:In cognitively healthy older men, mild anxiety symptoms may potentially predict future decline in executive functioning. Anxiety is likely a manifestation of an underlying neurodegenerative process rather than a cause.