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Alzheimer’s disease (AD) has been associated with cardiovascular and cerebrovascular risk factors (CVRFs) during middle age and later and is frequently accompanied by cerebrovascular pathology at death. An interaction between CVRFs and genetic variants might explain the pathogenesis. Genome-wide, gene by CVRF interaction analyses for AD, in 6568 patients and 8101 controls identified FMNL2 (p = 6.6 × 10–7). A significant increase in FMNL2 expression was observed in the brains of patients with brain infarcts and AD pathology and was associated with amyloid and phosphorylated tau deposition. FMNL2 was also prominent in astroglia in AD among those with cerebrovascular pathology. Amyloid toxicity in zebrafish increased fmnl2a expression in astroglia with detachment of astroglial end feet from blood vessels. Knockdown of fmnl2a prevented gliovascular remodeling, reduced microglial activity and enhanced amyloidosis. APP/PS1dE9 AD mice also displayed increased Fmnl2 expression and reduced the gliovascular contacts independent of the gliotic response. Based on this work, we propose that FMNL2 regulates pathology-dependent plasticity of the blood–brain-barrier by controlling gliovascular interactions and stimulating the clearance of extracellular aggregates. Therefore, in AD cerebrovascular risk factors promote cerebrovascular pathology which in turn, interacts with FMNL2 altering the normal astroglial-vascular mechanisms underlying the clearance of amyloid and tau increasing their deposition in brain.

ImportanceCerebrospinal fluid (CSF) and plasma biomarkers can detect biological evidence of Alzheimer disease (AD), but their use in low-resource environments and among minority ethnic groups is limited.ObjectiveTo assess validated plasma biomarkers for AD among adults of Caribbean Hispanic ethnicity.Design, Setting, and ParticipantsIn this decision analytical modeling study, adults were recruited between January 1, 2018, and April 30, 2022, and underwent detailed clinical assessments and venipuncture. A subsample of participants also consented to lumbar puncture. Established CSF cut points were used to define AD biomarker-positive status, allowing determination of optimal cut points for plasma biomarkers in the same individuals. The performance of a panel of 6 plasma biomarkers was then assessed with respect to the entire group. Data analysis was performed in January 2023.Main Outcomes and MeasuresMain outcomes were the association of plasma biomarkers amyloid-β 1-42 (Aβ42), amyloid-β 1-40 (Aβ40), total tau (T-tau), phosphorylated tau181 (P-tau181), glial fibrillary acidic protein (GFAP), and neurofilament light chain (NfL) with AD diagnosis. These biomarkers allow assessment of amyloid (A), neurofibrillary degeneration (T), and neurodegeneration (N) aspects of AD. Statistical analyses performed included receiver operating characteristics, Pearson and Spearman correlations, t tests, and Wilcoxon rank-sum, chi-square, and Fisher exact tests.ExposuresExposures included age, sex, education, country of residence, apolipoprotein-ε4 (APOE-ε4) allele number, serum creatinine, blood urea nitrogen, and body mass index.ResultsThis study included 746 adults. Participants had a mean (SD) age of 71.0 (7.8) years, 480 (64.3%) were women, and 154 (20.6%) met clinical criteria for AD. Associations were observed between CSF and plasma P-tau181 (r = .47 [95% CI, 0.32-0.60]), NfL (r = 0.57 [95% CI, 0.44-0.68]), and P-tau181/Aβ42 (r = 0.44 [95% CI, 0.29-0.58]). For AD defined by CSF biomarkers, plasma P-tau181 and P-tau181/Aβ42 provided biological evidence of AD. Among individuals judged to be clinically healthy without dementia, biomarker-positive status was determined by plasma P-tau181 for 133 (22.7%) and by plasma P-tau181/Aβ42 for 104 (17.7%). Among individuals with clinically diagnosed AD, 69 (45.4%) had plasma P-tau181 levels and 89 (58.9%) had P-tau181/Aβ42 levels that were inconsistent with AD. Individuals with biomarker-negative clinical AD status tended to have lower levels of education, were less likely to carry APOE-ε4 alleles, and had lower levels of GFAP and NfL than individuals with biomarker-positive clinical AD.Conclusions and RelevanceIn this cross-sectional study, plasma P-tau181 and P-tau181/Aβ42 measurements correctly classified Caribbean Hispanic individuals with and without AD. However, plasma biomarkers identified individuals without dementia with biological evidence of AD, and a portion of those with dementia whose AD biomarker profile was negative. These results suggest that plasma biomarkers can augment detection of preclinical AD among asymptomatic individuals and improve the specificity of AD diagnosis.

Progranulin (GRN) mutations occur in frontotemporal lobar degeneration (FTLD) and in Alzheimer's disease (AD), often with TDP-43 pathology.We determined the frequency of rs5848 and rare, pathogenic GRN mutations in two autopsy and one family cohort. We compared Braak stage, β-amyloid load, hyperphosphorylated tau (PHFtau) tangle density and TDP-43 pathology in GRN carriers and non-carriers.Pathogenic GRN mutations were more frequent in all cohorts compared to the Genome Aggregation Database (gnomAD), but there was no evidence for association with AD. Pathogenic GRN carriers had significantly higher PHFtau tangle density adjusting for age, sex and APOE ε4 genotype. AD patients with rs5848 had higher frequencies of hippocampal sclerosis and TDP-43 deposits. Twenty-two rare, pathogenic GRN variants were observed in the family cohort.GRN mutations in clinical and neuropathological AD increase the burden of tau-related brain pathology but show no specific association with β-amyloid load or AD.

Dementia and vascular mild cognitive impairment (VaMCI) currently impose a tremendous human and economic burden on patients from aging populations and their families worldwide. Understanding the interplay of cardiometabolic risk factors and apolipoprotein E (APOE) may direct us to a more personalized medicine and preventative care in MCI and dementia. Objective: To evaluate the relationship of cardiometabolic risk factors with MCI and assess the APOE genotype’s role in an elderly cohort in the Dominican Republic. Methods: We studied a cohort of 180 participants 65 years of age and older using a combined assessment of cardiometabolic risk factors, neuropsychological battery tests, and APOE genotyping. We used the number of failed tests as a proxy to predict MCI. Results: We found that patients with the ε3-ε4 APOE genotype had 2.91 higher number of failed cognitive tests (p=0.027) compared to patients with the ε3-ε3 genotyped. The rate of test failures increased 10% (p=0.025) per unit increase in HbA1c percentage. Conclusions: Increased Hemoglobin A1c levels and ε3-ε4 APOE genotypes seem to have an association with the development of VaMCI. RESUMO. A demência e o comprometimento cognitivo leve vascular (VaMCI) atualmente impõem uma enorme carga humana e econômica aos pacientes de populações envelhecidas e suas famílias em todo o mundo. Compreender a interação dos fatores de risco cardiometabólicos e apolipoproteína E (APOE) pode nos direcionar para uma medicina mais personalizada e de cuidados preventivos em MCI e demência. Objetivo: Avaliar a relação dos fatores de risco cardiometabólicos com o MCI e o papel do genótipo APOE em uma coorte de idosos na República Dominicana. Métodos: Estudamos uma coorte de 180 participantes com 65 anos de idade ou mais, utilizando uma avaliação combinada de fatores de risco cardiometabólicos, uma bateria de testes neuropsicológicos e genotipagem APOE. Adotou-se o número de testes com mau desempenho para o diagnóstico de MCI. Resultados: Verificou-se que os pacientes com o genótipo ε3-ε4 do APOE apresentaram 2,91 vezes mais testes cognitivos com mau desempenho (p=0,027) em comparação com os pacientes com o genótipo ε3-ε3. A taxa de falhas de teste aumentou 10% (p=0,025) por aumento de unidade na porcentagem de HbA1c. Conclusões: Níveis mais altos de HbA1c e os genótipos ε3-ε4 do APOE parecem estar associados ao desenvolvimento de VaMCI.

Introduction Less than 10% of early-onset Alzheimer's disease (EOAD) is explained by known mutations. Methods We conducted genetic linkage analysis of 68 well-phenotyped Caribbean Hispanic families without clear inheritance patterns or mutations in APP, PSEN1, and PSEN2 and with two or more individuals with EOAD. Results We identified 16 (logarithm of odds > 3.6) linked regions, including eight novel loci for EOAD (2p15, 5q14.1, 11p15.1, 13q21.22, 13q33.1, 16p12.1, 20p12.1, and 20q11.21) and eight regions previously associated with late-onset Alzheimer's disease. The strongest signal was observed at 16p12.1 (25 cM, 33 Mb; heterogeneity logarithm of odds = 5.3), ∼3 Mb upstream of the ceroid lipofuscinosis 3 (CLN3) gene associated with juvenile neuronal ceroid lipofuscinosis (JNCL), which functions in retromer trafficking and has been reported to alter intracellular processing of the amyloid precursor protein. Discussion This study supports the notion that the genetic architectures of unexplained EOAD and late-onset AD overlap partially, but not fully.

ObjectiveSynonymous variants can lead to disease; nevertheless, the majority of sequencing studies conducted in Alzheimer disease (AD) only assessed coding variation.MethodsTo detect synonymous variants modulating AD risk, we conducted a whole-genome sequencing study on 67 Caribbean Hispanic (CH) families multiply affected by AD. Identified disease-associated variants were further assessed in an independent cohort of CHs, expression quantitative trait locus (eQTL) data, brain autopsy data, and functional experiments.ResultsRare synonymous variants in 4 genes (CDH23, SLC9A3R1, RHBDD2,andITIH2) segregated with AD status in multiplex families and had a significantly higher frequency in these families compared with reference populations of similar ancestry. In comparison to subjects without dementia, expression ofCDH23(β = 0.53,p= 0.006) andSLC9A3R1(β = 0.50,p= 0.02) was increased, and expression ofRHBDD2(β = −0.70,p= 0.02) decreased in individuals with AD at death. In line with this finding, increased expression ofCDH23(β = 0.26 ± 0.08,p= 4.9E-4) and decreased expression ofRHBDD2(β = −0.60 ± 0.12,p= 5.5E-7) were related to brain amyloid load (p= 0.0025).SLC9A3R1expression was associated with burden of TDP43 pathology (β = 0.58 ± 0.17,p= 5.9E-4). Using eQTL data, theCDH23variant was in linkage disequilibrium with variants modulatingCDH23expression levels (top single nucleotide polymorphism: rs11000035,p= 4.85E-6, D' = 1.0). Using minigene splicing assays, theCDH23andSLC9A3R1variants affected splicing efficiency.ConclusionsThese findings suggest thatCDH23, SLC9A3R1, RHBDD2, and possiblyITIH2, which are involved in synaptic function, the glutamatergic system, and innate immunity, contribute to AD etiology. In addition, this study supports the notion that synonymous variants contribute to AD risk and that comprehensive scrutinization of this type of genetic variation is warranted and critical.

The incidence and prevalence of Alzheimer's disease (AD) dementia are higher among Caribbean Hispanics than among non-Hispanic Whites. The causes of this health disparity remain elusive, partially because of the relative limited capacity for biomedical research in the developing countries that comprise Caribbean Latin America. To begin to address this issue, we were awarded a Development Research Award from the US NIH and Fogarty International Center in order to establish the local capacity to integrate magnetic resonance imaging (MRI) into studies of cognitive aging and dementia in Dominican Republic, establish collaborations with Dominican investigators, and conduct a pilot study on the role of cerebrovascular markers in the clinical expression of AD. Ninety older adult participants with and without AD dementia and with and without a strong family history of AD dementia received MRI scans and clinical evaluation. We quantified markers of cerebrovascular disease (white matter hyperintensities [WMH], presence of infarct, and presence of microbleed) and neurodegeneration (entorhinal cortex volume) and compared them across groups. Patients with AD dementia had smaller entorhinal cortex and greater WMH volumes compared with controls, regardless of family history status. This study provides evidence for the capacity to conduct MRI studies of cognitive aging and dementia in Dominican Republic. The results are consistent with the hypothesis that small vessel cerebrovascular disease represents a core feature of AD dementia, as affected participants had elevated WMH volumes irrespective of family history status.

In a whole-exome sequencing study of multiplex Alzheimer's disease (AD) families, we investigated three neuronal ceroid lipofuscinosis genes that have been linked to retromer, an intracellular trafficking pathway associated with AD: ceroid lipofuscinosis 3 (CLN3), ceroid lipofuscinosis 5 (CLN5), and cathepsin D (CTSD). We identified a missense variant in CLN5 c.A959G (p.Asn320Ser) that segregated with AD. We find that this variant causes glycosylation defects in the expressed protein, which causes it to be retained in the endoplasmic reticulum with reduced delivery to the endolysosomal compartment, CLN5's normal cellular location. The AD-associated CLN5 variant is shown here to reduce the normal processing of cathepsin D and to decrease levels of full-length amyloid precursor protein (APP), suggestive of a defect in retromer-dependent trafficking.

Inbreeding can be associated with a modification of disease risk due to excess homozygosity of recessive alleles affecting a wide range of phenotypes. We estimated the inbreeding coefficient in Caribbean Hispanics and examined its effects on risk of late-onset Alzheimer disease.The inbreeding coefficient was calculated in 3,392 subjects (1,451 late-onset Alzheimer disease patients and 1,941 age-matched healthy controls) of Caribbean Hispanic ancestry using 177,997 nearly independent single-nucleotide polymorphisms from genome-wide array. The inbreeding coefficient was estimated using the excess homozygosity method with and without adjusting for admixture.The average inbreeding coefficient in Caribbean Hispanics without accounting for admixture was F = 0.018 (±0.048), suggesting a mating equivalent to that of second cousins or second cousins once removed. Adjusting for admixture from three parent populations, the average inbreeding coefficient was found to be 0.0034 (±0.019) or close to third-cousin mating. Inbreeding coefficient was a significant predictor of Alzheimer disease when age, sex, and APOE genotype were used as adjusting covariates (P = 0.03).The average inbreeding coefficient of this population is significantly higher than that of the general Caucasian populations in North America. The high rate of inbreeding resulting in increased frequency of recessive variants is advantageous for the identification of rare variants associated with late-onset Alzheimer disease.Genet Med 17 8, 639-643.

Objective To detect rare coding variants underlying loci detected by genome-wide association studies (GWAS) of late onset Alzheimer disease (LOAD). Methods We conducted targeted sequencing of ABCA7, BIN1, CD2AP, CLU, CR1, EPHA1, MS4A4A/MS4A6A, and PICALM in 3 independent LOAD cohorts: 176 patients from 124 Caribbean Hispanics families, 120 patients and 33 unaffected individuals from the 129 National Institute on Aging LOAD Family Study; and 263 unrelated Canadian individuals of European ancestry (210 sporadic patients and 53 controls). Rare coding variants found in at least 2 data sets were genotyped in independent groups of ancestry-matched controls. Additionally, the Exome Aggregation Consortium was used as a reference data set for population-based allele frequencies. Results Overall we detected a statistically significant 3.1-fold enrichment of the nonsynonymous mutations in the Caucasian LOAD cases compared with controls (p = 0.002) and no difference in synonymous variants. A stop-gain mutation in ABCA7 (E1679X) and missense mutation in CD2AP (K633R) were highly significant in Caucasian LOAD cases, and mutations in EPHA1 (P460L) and BIN1 (K358R) were significant in Caribbean Hispanic families with LOAD. The EPHA1 variant segregated completely in an extended Caribbean Hispanic family and was also nominally significant in the Caucasians. Additionally, BIN1 (K358R) segregated in 2 of the 6 Caribbean Hispanic families where the mutations were discovered. Interpretation Targeted sequencing of confirmed GWAS loci revealed an excess burden of deleterious coding mutations in LOAD, with the greatest burden observed in ABCA7 and BIN1. Identifying coding variants in LOAD will facilitate the creation of tractable models for investigation of disease-related mechanisms and potential therapies. Ann Neurol 2015;78:487–498

Objective In the context of late-onset Alzheimer's disease (LOAD) over 20 genes have been identified but, aside APOE, all show small effect sizes, leaving a large part of the genetic component unexplained. Admixed populations, such as Caribbean Hispanics, can provide a valuable contribution because of their unique genetic profile and higher incidence of the disease. We aimed to identify novel loci associated with LOAD. Methods About 4514 unrelated Caribbean Hispanics (2451 cases and 2063 controls) were selected for genome-wide association analysis. Significant loci were further tested in the expanded cohort that also included related family members (n = 5300). Two AD-like transgenic mice models (J20 and rTg4510) were used to study gene expression. Independent data sets of non-Hispanic Whites and African Americans were used to further validate findings, along with publicly available brain expression data sets. Results A novel locus, rs75002042 in FBXL7 (5p15.1), was found genome-wide significant in the case–control cohort (odd ratio [OR] = 0.61, P = 6.19E-09) and confirmed in the related members cohorts (OR = 0.63, P = 4.7E-08). Fbxl7 protein was overexpressed in both AD-like transgenic mice compared to wild-type littermates. Publicly available microarray studies also showed significant overexpression of Fbxl7 in LOAD brains compared to nondemented controls. single-nucleotide polymorphism (SNP) rs75002042 was in complete linkage disequilibrium with other variants in two independent non-Hispanic White and African American data sets (0.0005

Alzheimer's disease (AD) has a major impact by limiting the ability to live independently. This condition of dependency involves all members of the family, particularly those who take direct care of patients. The changes that take place in caregivers' lives may alter their health and have an effect on the care of the sick. OBJECTIVE: To determine the presence of burden, anxiety and depression in caregivers of Alzheimer's patients. METHOD: A descriptive cross-sectional study was performed in 67 family caregivers from the Alzheimer's Clinic Research Unit, Memory and Alzheimer, in the city of Santiago, Dominican Republic. Caregivers were evaluated for burden intensity with the Zarit scale and for both depression and anxiety using the respective Hamilton scales. Descriptive statistical analysis and Pearson correlation were used. RESULTS: 84% of caregivers were female, and 52% were older than 50 years. A total of 36% exhibited caregiver burden; 19% anxiety symptoms; and 43% depressive symptoms. No statistical significance was found between age, sex and number of hours of care. A significant association was found in the Pearson correlation coefficient between caregiver burden, anxiety and depression. CONCLUSION: Caregiver burden was associated with anxiety and depression. It is important for health professionals to include caregiver assessments in the treatment protocols of dementia. Policy should include support programs for carers. A doença de Alzheimer (DA) tem um grande impacto, limitando a capacidade de viver de forma independente. Esta condição de dependência envolve todos os membros da família, particularmente aqueles que realizam o cuidado direto. As mudanças que ocorrem na vida dos cuidadores podem alterar a sua saúde e ter um efeito sobre o cuidado dos doentes. OBJETIVO: Determinar a presença de sobrecarga, ansiedade e depressão em cuidadores de pacientes com doença de Alzheimer. MÉTODO: Um estudo descritivo transversal foi realizado em 67 cuidadores familiares na Unidade de Pesquisa Clínica em Memória e Alzheimer, na cidade de Santiago, República Dominicana. Eles foram avaliados com relação a sobrecarga com a escala Zarit; quanto a depressão e ansiedade, com as respectivas escalas de Hamilton. Foram utilizadas análise estatística descritiva e correlação de Pearson. RESULTADOS: 84% dos cuidadores eram do sexo feminino, e 52% tinham mais de 50 anos; 36% apresentavam sobrecarga do cuidador; 19% sintomas de ansiedade; e 43% sintomas depressivos. Não foram encontradas significâncias estatísticas entre idade, sexo e número de horas de cuidados. Foi encontrada associação significativa no coeficiente de correlação de Pearson entre sobrecarga do cuidador, ansiedade e depressão. CONCLUSÃO: A sobrecarga do cuidador está associada a ansiedade e depressão. É importante que os profissionais de saúde incluam avaliações de cuidadores nos protocolos de tratamento de demência. A política deve incluir programas de apoio a cuidadores.

Objective: To identify rare coding variants segregating with late-onset Alzheimer disease (LOAD) in Caribbean Hispanic families. Methods: Whole-exome sequencing (WES) was completed in 110 individuals from 31 Caribbean Hispanic families without APOE ε4 homozygous carriers. Rare coding mutations segregating in families were subsequently genotyped in additional families and in an independent cohort of Caribbean Hispanic patients and controls. SRCAP messenger RNA (mRNA) expression was assessed in whole blood from mutation carriers with LOAD, noncarriers with LOAD, and healthy elderly controls, and also from autopsied brains in 2 clinical neuropathologic cohort studies of aging and dementia. Results: Ten ultra-rare missense mutations in the Snf2-related CREBBP, activator protein (SRCAP), were found in 12 unrelated families. Compared with the frequency in Caribbean Hispanic controls and the Latino population in the Exome Aggregation Consortium, the frequency of SRCAP mutations among Caribbean Hispanic patients with LOAD was significantly enriched (p = 1.19e-16). mRNA expression of SRCAP in whole blood was significantly lower in mutation carriers with LOAD, while the expression in whole blood and in the brain was significantly higher in nonmutation carriers with LOAD. Brain expression also correlated with clinical and neuropathologic endophenotypes. Conclusions: WES in Caribbean Hispanic families with LOAD revealed ultra-rare missense mutations in SRCAP, a gene expressed in the brain and mutated in Floating-Harbor syndrome. SRCAP is a potent coactivator of the CREB-binding protein and a regulator of DNA damage response involving ATP-dependent chromatin remodeling. We hypothesize that increased expression in LOAD suggests a compensatory mechanism altered in mutation carriers.

Pathogenic mutations in the three known genes – the amyloid precursor protein (APP), presenilin 1 (PSEN1), presenilin 2 (PSEN2) – are known to cause familial Alzheimer's disease (AD) and tend to be associated with early-onset AD. However, the frequency and risk associated with these mutations vary widely. In addition, mutations in the frontotemporal lobar degeneration (FTLD) genes – the microtubule-associated protein tau (MAPT), granulin (GRN) – have also been found to be associated with clinical AD. Here, we conducted targeted resequencing of the exons in genes encoding APP, PSEN1, PSEN2, GRN, and MAPT in 183 individuals from families with four or more affected relatives, presumed to be AD, and living in the Dominican Republic and Puerto Rico. We then performed linkage and family-based association analyses in carrier families, and genotyped 498 similarly aged unrelated controls from the same ethnic background. Twelve potentially pathogenic mutations were found to be associated with disease in 53 individuals in the five genes. The most frequently observed mutation was the p.Gly206Ala variant in PSEN1 present in 30 (57%) of those sequenced. In the combined linkage and association analyses several rare variants were associated with dementia. In Caribbean Hispanics with familial AD, potentially pathogenic variants were present in 29.2%, four were novel mutations, while eight had been previously observed. In addition, some family members carried variants in the GRN and MAPT genes which are associated with FTLD.

"El presente trabajo ofrece información actualizada sobre el registro fósil de los ofiuroideos (Ordovícico-Holoceno) en el Continente Americano. Estos datos permiten evaluar la abundancia y distribución de los ofiuroideos fósiles por edad y por país, así como identi- ficar las edades y regiones mejor estudiadas. También se muestran datos sobre los distintos tipos de fósiles que componen el registro, tales como las especies descritas e identificadas, osículos disgregados, capas de ofiuroideos, icnoespecies y datos donde únicamente se reporta la presencia de estos ejemplares en localidades fosilíferas. Aunado a esto, se realiza un análisis sobre el tipo de trabajo (sistemático, ecológico/tafonómico, evolutivo, conductual o estratigráfico) en el que se ha reportado por primera vez la presencia de ofiuroideos fósiles en un país, así como las décadas con mayor número de publicaciones de este tipo. Por último, se proporciona una lista de las especies descritas y la bibliografía correspondiente para cada país del continente."

Objective:To investigate the association between a genetic risk score (GRS) and familial late-onset Alzheimer disease (LOAD) and its predictive value in families multiply affected by the disease.Methods:Using data from the National Institute on Aging Genetics Initiative for Late-Onset Alzheimer Disease (National Institute on Aging–Late-Onset Alzheimer's Disease Family Study), mixed regression models tested the association of familial LOAD with a GRS based on single nucleotide polymorphisms (SNPs) previously associated with LOAD. We modeled associations using unweighted and weighted scores with estimates derived from the literature. In secondary models, we adjusted subsequent models for presence of the APOE ε4 allele and further tested the interaction between APOE ε4 and the GRS. We constructed a similar GRS in a cohort of Caribbean Hispanic families multiply affected by LOAD by selecting the SNP with the strongest p value within the same regions.Results:In the NIA-LOAD families, the GRS was significantly associated with LOAD (odds ratio [OR] 1.29; 95% confidence interval 1.21–1.37). The results did not change after adjusting for APOE ε4. In Caribbean Hispanic families, the GRS also significantly predicted LOAD (OR 1.73; 1.57–1.93). Higher scores were associated with lower age at onset in both cohorts.Conclusions:High GRS increases the risk of familial LOAD and lowers the age at onset, regardless of ethnic group.

Amyloid β (Aβ), the putative culprit in Alzheimer’s disease (AD) is produced by successive β-secretase (BACE) cleavage of the amyloid precursor protein (APP) at the N-terminus of the Aβ peptide followed by γ-secretase cleavage of the membrane-bound C-terminal APP fragment.1 This mechanism explains Aβ accumulation in early-onset familial AD due to mutations in the APP2 presenilin 1 (PSEN1),3 and presenilin 2 (PSEN2)4 genes. The explanation for the accumulation of Aβ40 and Aβ42 in the common late-onset form of the disease remains largely unknown. APP and the secretases are integral transmembrane proteins. They are dynamically sorted into the plasma membrane and the membranes of intracellular organelles.5,6 As a consequence, sorting mechanisms that cause APP and the secretases to colocalize in the same cellular compartment are expected to play important roles in the regulation of Aβ production. During the last 2 decades, the trans-Golgi network and the endosome were identified as the key organelles managing the complex movement of the transmembrane proteins via secretory and endocytic pathways.7,8 We and others have previously reported9–16 that variants in the Sortilin-related receptor (SORL1), which maps to chromosome 11q23.3, are associated with AD, that SORL1 is involved in trafficking of APP from the cell surface to the Golgi-endoplasmic reticulum complex, and that under expression of SORL1 leads to overexpression of Aβ and an increased risk of AD.9 SORL1 belongs to the mammalian Vps10p-domain sorting receptor family, which is a group of 5 type-I membrane homologs (SORL1, Sortilin, SorCS1, SorCS2, and SorCS3).17–20 All 5 proteins are characterized by a luminal, extracellular VPS10 domain. In sortilin, the VPS10 domain is the only luminal, extracellular module. In SORL1 the VPS10 domain is followed by low-density lipoprotein (LDL) receptor-like regions and fibronectin type-III domains. In the homologous SorCS1, SorCS2, and SorCS3 the transmembrane domain is preceded by a leucine-rich module.21 Following the extracellular and transmembrane segment, each receptor carries a short (40–80 amino acids) cytoplasmic domain comprising typical motifs for interaction with cytosolic adaptor molecules. All of these receptors are prominently expressed in the nervous system and particularly high in the brain, and may be important for neuronal activity,22,23 although their precise function remains elusive. We hypothesized that genetic variants in SORL1 homologues, in particular SORCS1, might also affect the risk of AD. This was supported by the facts that: (1) we previously observed an association of single nucleotide polymorphism (SNP) rs7082289 in SORCS1 (p = 0.013) in late-onset AD families9; and that (2) Li et al.24 examined a Canadian dataset of 753 AD cases and 736 controls, and SNP rs601883 in SORCS1 was associated with AD risk (hazard ratio [HR], 3.41; 95% confidence interval [CI], 1.87–6.23), and SNP rs7907690 was also significant in logistic regression analyses (p = 0.05). In a chromosome 10–specific association study with 1,412 SNPs in 4 independent Caucasian datasets,25 SNP rs600879 in SORCS1 was significantly associated with AD in an exploratory sample set and an independent replication sample set, although the authors used replication rather than correction for multiple testing for evidence of association (uncorrected p-value across datasets: 0.0043). In a case-control dataset of 506 cases and 558 controls, rs17277986 in SORCS1 was significant in the overall datasets (p = 0.0025) and most significant in the female subset (allelic association p = 0.00002) in single-marker and haplotype analyses.26 The goal of this study was to analyze the genetic associations between AD and SORCS1 in 6 independent data sets that had sufficient power to detect modest gene effects. We focused on the SNPs that had been reported by the previous studies as described above, adding SNP rs7082289 at 108,357,010bp that was associated with AD in a previous report by us.9 We also compared SorCS1 expression levels of affected and unaffected brain regions in AD and control brains in expanded microarray gene expression and real-time polymerase chain reaction (RT-PCR) sets, explored the effects of significant SORCS1-SNPs on SorCS1 brain expression levels, and explored the effect of suppression and overexpression of the common SorCS1 isoforms on APP processing and Aβ generation.

On the basis of six articulated individuals from the middle to late Albian lithographic limestone at Tlayua near Tepexi de Rodro´guez (Puebla, Mexico), a new species of ophiuroid, Ophiactis applegatei, is described. The mate- rial adds to the rather poor record of Early Cretaceous brittlestars and represents the oldest known member of the family Ophiactidae, being based on well-preserved and articulated specimens and thus reasonably well defined morphologically. The rarity of ophiuroids, their complete preservation as well as the unnatural contortions of their arms suggest these specimens to be allochthonous, having been transported into a hostile environment where burial was rapid.

Familial Alzheimer's disease (AD [MIM 104300]) has been a focus of intense investigation, primarily in Caucasian families from Europe and North America families. Although the late-onset form of familial AD, beginning after age 65 years, has been linked to regions on chromosomes 10q and 12p, the specific genetic variants have not yet been consistently identified. Using a unique cohort of families of Caribbean Hispanics ancestry, we screened the genome using 340 markers on 490 family members from 96 families with predominantly late-onset AD. We observed the strongest support for linkage on 18q (LOD=3.14). However, 17 additional markers (chromosomes 1-6, 8, 10, 12, and 14) exceeded a two-point LOD score of 1.0 under the affecteds-only autosomal dominant model or affected sibpair model. As we previously reported the fine-mapping effort on 12p showing modest evidence of linkage, we focused our fine-mapping efforts on two other candidate regions in the current report, namely 10q and 18q. We added 31 family members and eight additional Caribbean Hispanic families to fine map 10q and 18q. With additional microsatellite markers, the evidence for linkage for 18q strengthened near 112 cM, where the two-point LOD score for D18S541 was 3.37 and the highest NPL score in that region was 3.65 (P=0.000177). This narrow region contains a small number of genes expressed in the brain. However, at 10q (134-138 cM), the NPL score decreased from 3.15 (P=0.000486) to 2.1 (P=0.0218), but two broad peaks remained overlapping with previously reported peaks. Our results provide modest support for linkage on 10q and 12p in this cohort of Caribbean Hispanic families with familial Alzheimer's disease, and strong evidence for a new locus on 18q.

Objective:To identify rare coding variants segregating with late-onset Alzheimer disease (LOAD) in Caribbean Hispanic families.Methods:Whole-exome sequencing (WES) was completed in 110 individuals from 31 Caribbean Hispanic families without APOE ε4 homozygous carriers. Rare coding mutations segregating in families were subsequently genotyped in additional families and in an independent cohort of Caribbean Hispanic patients and controls. SRCAP messenger RNA (mRNA) expression was assessed in whole blood from mutation carriers with LOAD, noncarriers with LOAD, and healthy elderly controls, and also from autopsied brains in 2 clinical neuropathologic cohort studies of aging and dementia.Results:Ten ultra-rare missense mutations in the Snf2-related CREBBP, activator protein (SRCAP), were found in 12 unrelated families. Compared with the frequency in Caribbean Hispanic controls and the Latino population in the Exome Aggregation Consortium, the frequency of SRCAP mutations among Caribbean Hispanic patients with LOAD was significantly enriched (p = 1.19e-16). mRNA expression of SRCAP in whole blood was significantly lower in mutation carriers with LOAD, while the expression in whole blood and in the brain was significantly higher in nonmutation carriers with LOAD. Brain expression also correlated with clinical and neuropathologic endophenotypes.Conclusions:WES in Caribbean Hispanic families with LOAD revealed ultra-rare missense mutations in SRCAP, a gene expressed in the brain and mutated in Floating-Harbor syndrome. SRCAP is a potent coactivator of the CREB-binding protein and a regulator of DNA damage response involving ATP-dependent chromatin remodeling. We hypothesize that increased expression in LOAD suggests a compensatory mechanism altered in mutation carriers.

Background: Anxiety disorders affect 18% of Americans, and their managements remain to be a great challenge for the society. Aside from the anxiety disorders, there are many diseases, including Alzheimer’s disease (AD), that have anxiety as one of their clinic symptoms.Mechanistic and therapeutic studies of the anxiety disorders often begin at animal level, such as rodent. For the latter, the anxiety level is most commonly assessed by elevated plus maze (EPM). However, the existing anxiety assessment methods, including EPM, display limited sensitivity, often due to very high in-group variations. Thus a more sensitive method is needed for better assessing animal anxiety. Methods: We created a novel elevated platform (EP) with open edges. The platform was divided into three consecutive concentric ring zones so that the anxiety challenge increased in a continuous gradient from the central zone towards the outer zone. For comparisons, the anxiety levels of APPsw (Tg2576) mice and GRK5 +/mice were assessed with open field (OF), EPM and the new EP.Results:Neither the OF, nor the EPM was able to reveal significant difference between any groups, but the EP did discover that APPsw mice displayed statistically significant higher anxiety level than the wild type controls.Conclusions: The EP is more sensitive than the OF and EPM in assessing the animal anxiety.

Importance Late-onset Alzheimer disease (LOAD), defined as onset of symptoms after age 65 years, is the most common form of dementia. Few reports investigate incidence rates in large family-based studies in which the participants were selected for family history of LOAD. Objective To determine the incidence rates of dementia and LOAD in unaffected members in the National Institute on Aging Genetics Initiative for Late-Onset Alzheimer Disease/National Cell Repository for Alzheimer Disease (NIA-LOAD/NCRAD) and Estudio Familiar de Influencia Genetica en Alzheimer (EFIGA) family studies. Design, Setting, and Participants Families with 2 or more affected siblings who had a clinical or pathological diagnosis of LOAD were recruited as a part of the NIA-LOAD/NCRAD Family Study. A cohort of Caribbean Hispanics with familial LOAD was recruited in a different study at the Taub Institute for Research on Alzheimer’s Disease and the Aging Brain in New York and from clinics in the Dominican Republic as part of the EFIGA study. Main Outcomes and Measures Age-specific incidence rates of LOAD were estimated in the unaffected family members in the NIA-LOAD/NCRAD and EFIGA data sets. We restricted analyses to families with follow-up and complete phenotype information, including 396 NIA-LOAD/NCRAD and 242 EFIGA families. Among the 943 at-risk family members in the NIA-LOAD/NCRAD families, 126 (13.4%) developed dementia, of whom 109 (86.5%) met criteria for LOAD. Among 683 at-risk family members in the EFIGA families, 174 (25.5%) developed dementia during the study period, of whom 145 (83.3%) had LOAD. Results The annual incidence rates of dementia and LOAD in the NIA-LOAD/NCRAD families per person-year were 0.03 and 0.03, respectively, in participants aged 65 to 74 years; 0.07 and 0.06, respectively, in those aged 75 to 84 years; and 0.08 and 0.07, respectively, in those 85 years or older. Incidence rates in the EFIGA families were slightly higher, at 0.03 and 0.02, 0.06 and 0.05, 0.10 and 0.08, and 0.10 and 0.07, respectively, in the same age groups. Contrasting these results with the population-based estimates, the incidence was increased by 3-fold for NIA-LOAD/NCRAD families (standardized incidence ratio, 3.44) and 2-fold among the EFIGA compared with the NIA-LOAD/NCRAD families (1.71). Conclusions and Relevance The incidence rates for familial dementia and LOAD in the NIA-LOAD/NCRAD and EFIGA families are significantly higher than population-based estimates. The incidence rates in all groups increase with age. The higher incidence of LOAD can be explained by segregation of Alzheimer disease–related genes in these families or shared environmental risks.

Background Familial aggregation of dementia with Lewy bodies (DLB) remains unclear. Objectives To determine the degree of family aggregation of DLB by comparing DLB risk between siblings of probands with clinically diagnosed DLB and siblings of probands with clinically diagnosed Alzheimer disease in a cohort of Caribbean Hispanic families and to explore the degree of aggregation of specific clinical manifestations (ie, cognitive fluctuations, visual hallucinations, and parkinsonism) in DLB. Design Familial cohort study. Setting Academic research. Patients We separately compared risks of possible DLB, probable DLB, and clinical core features of DLB (cognitive fluctuations, visual hallucinations, and parkinsonism) between siblings of probands with clinically diagnosed DLB (n = 344) and siblings of probands with clinically diagnosed Alzheimer disease (n = 280) in 214 Caribbean Hispanic families with extended neurologic and neuropsychological assessment. Main Outcome Measures We applied general estimating equations to adjust for clustering within families. In these models, age and proband disease status were independent variables, and disease status of siblings was the measure of disease risk and the dependent variable. Results Compared with siblings of probands having clinically diagnosed Alzheimer disease, siblings of probands having clinically diagnosed DLB had higher risks of probable DLB (odds ratio [OR], 2.29; 95% confidence interval [CI], 1.04-5.04) and visual hallucinations (2.32; 1.16-4.64). They also had increased risks of possible DLB (OR, 1.51; 95% CI, 0.97-2.34) and cognitive fluctuations (1.55; 0.95-2.53). Conclusions Dementia with Lewy bodies and core features of DLB aggregate in families. Compared with siblings of probands having clinically diagnosed AD, siblings of probands having clinically diagnosed DLB are at increased risks of DLB and visual hallucinations. These findings are an important step in elucidating the genetic risk factors underlying DLB and in delineating DLB from other neurodegenerative diseases, such as Alzheimer disease.

Numerous genome-wide association studies (GWAS) have been published for late-onset Alzheimer disease (LOAD).1–13 Aside from APOE, additional candidate susceptibility genes identified using GWAS methods for LOAD have included GAB2, GALP, 14q32.13, LOC651924, PGBD1, TNK1, CR1, CLU, PICALM, and BIN1.14,15 In addition, variants in SORL1 identified by Rogaeva et al16 have been replicated in several independent cohorts and were significantly associated with LOAD in a meta-analysis.17 Difficulties inherent to the genetics of complex diseases (eg, etiologic heterogeneity, gene × environment and gene × gene interactions, and methylation) remain with these studies, and much work needs to be done. For example, the strength of association, or effect size, as measured by odds ratios (ORs) varies widely across studies and is generally small. Yet, these GWAS have identified a number of candidate genes that need to be replicated and their functional roles determined. Despite the increasing number of identified susceptibility genetic variants, a relatively large proportion of genetic variance remains unexplained. 18 This has much to do with both the complexity of the genetics and inadequacy of heritability as a measure of genetic contribution. Similar phenomena have been observed in other common, complex genetic diseases and invoked a term, genetic dark matter, in GWAS.19,20 In the current study, we report the results of a GWAS in unrelated patients with LOAD and controls of Caribbean Hispanic ancestry. This population was selected because the prevalence and incidence rate of LOAD is higher than in white, non-Hispanic individuals living in the same community21 and because we had previously identified numerous large families multiply affected by LOAD. We first examined unrelated cases and controls in the Caribbean Hispanic individuals and then replicated the associations using the publicly available GWAS data from the National Institute on Aging Late-Onset Alzheimer’s Disease (NIA-LOAD) Family Study (E. M. Wijsman, PhD, N. Pankratz, PhD, Y. Choi, PhD, J. H. Rothstein, MS, K. Faber, MS, R.C., J.H.L., T. D. Bird, MD, D. A. Bennett, MD, R. Diaz-Arrastia, MD, A. M. Goate, DPhil, M. Farlow, MD, B. Ghetti, MD, R. A. Sweet, MD, T. M. Foroud, PhD, and R.P.M.; for the NIA-LOAD/NCRAD Family Study Group. “Genome-wide Association of Familial Late-Onset Alzheimer’s Disease Replicates BIN1 and CLU and Nominates CUGBP2 in Interaction with APOE,” unpublished data). This approach allowed us to further assess the role of genetic admixture in the Caribbean Hispanic population. To our knowledge, this is the only GWAS of Alzheimer disease that focuses exclusively on a Caribbean Hispanic population.