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Hippocampal sclerosis of aging (HS-Aging) is a high-morbidity brain disease in the elderly but risk factors are largely unknown. We report the first genome-wide association study (GWAS) with HS-Aging pathology as an endophenotype. In collaboration with the Alzheimer's Disease Genetics Consortium, data were analyzed from large autopsy cohorts: (#1) National Alzheimer's Coordinating Center (NACC); (#2) Rush University Religious Orders Study and Memory and Aging Project; (#3) Group Health Research Institute Adult Changes in Thought study; (#4) University of California at Irvine 90+ Study; and (#5) University of Kentucky Alzheimer's Disease Center. Altogether, 363 HS-Aging cases and 2,303 controls, all pathologically confirmed, provided statistical power to test for risk alleles with large effect size. A two-tier study design included GWAS from cohorts #1-3 (Stage I) to identify promising SNP candidates, followed by focused evaluation of particular SNPs in cohorts #4-5 (Stage II). Polymorphism in the ATP-binding cassette, sub-family C member 9 (ABCC9) gene, also known as sulfonylurea receptor 2, was associated with HS-Aging pathology. In the meta-analyzed Stage I GWAS, ABCC9 polymorphisms yielded the lowest p values, and factoring in the Stage II results, the meta-analyzed risk SNP (rs704178:G) attained genome-wide statistical significance (p = 1.4 × 10-9), with odds ratio (OR) of 2.13 (recessive mode of inheritance). For SNPs previously linked to hippocampal sclerosis, meta-analyses of Stage I results show OR = 1.16 for rs5848 (GRN) and OR = 1.22 rs1990622 (TMEM106B), with the risk alleles as previously described. Sulfonylureas, a widely prescribed drug class used to treat diabetes, also modify human ABCC9 protein function. A subsample of patients from the NACC database (n = 624) were identified who were older than age 85 at death with known drug history. Controlling for important confounders such as diabetes itself, exposure to a sulfonylurea drug was associated with risk for HS-Aging pathology (p = 0.03). Thus, we describe a novel and targetable dementia risk factor. © 2014 Springer-Verlag.

Socioeconomic disadvantages in childhood has been linked to dementia in late life. However, the underlying pathways through which childhood socioeconomic status (CSES) affects health in old age is unclear. CSES has been linked to age-related differences in regions affected by Alzheimer’s disease (AD; e.g., hippocampus). CSES varies across race/ethnicity; It is critical to examine the relationship between CSES and age-related brain structural changes across diverse aging populations. We used an established proxy for CSES, number of siblings (i.e., sibship size), to examine whether CSES buffered age-related changes in hippocampal volume in a community-based sample of racially/ethnically diverse older adults. Sibship size moderated age-related differences in hippocampal volume in Whites (β=-5.61[-11.09,-0.12]), but not in Blacks and Hispanics. Results indicate that Whites with no sibling (vs. Whites with siblings) show less age-related difference in hippocampal volume. Future analyses will examine other CSES factors (i.e., parental education/occupation) on age-related structural changes across race/ethnicity.

Alzheimer disease is the most common cause of dementia. It occurs worldwide and affects all ethnic groups. The incidence of Alzheimer disease is increasing due, in part, to increased life expectancy and the aging baby boomer generation. The average lifetime risk of developing Alzheimer disease is 10–12%. This risk at least doubles with the presence of a first-degree relative with the disorder. Despite its limited utility, patients express concern over their risk and, in some instances, request testing. Furthermore, research has demonstrated that testing individuals for apoli-poprotein E can be valuable and safe in certain contexts. However, because of the complicated genetic nature of the disorder, few clinicians are prepared to address the genetic risks of Alzheimer disease with their patients. Given the increased awareness in family history thanks to family history campaigns, the increasing incidence of Alzheimer disease, and the availability of direct to consumer testing, patient requests for information is increasing. This practice guideline provides clinicians with a framework for assessing their patients’ genetic risk for Alzheimer disease, identifying which individuals may benefit from genetic testing, and providing the key elements of genetic counseling for AD.

Objective The “healthy immigrant effect” pertains to findings that Hispanics/Latinos born outside of the US tend to be physically and emotionally healthier than individuals born in the US. However, immigrant Latino groups residing in the US have higher incidences of dementia (Tang et al., 2001). Sex/gender and years of education have been found to moderate the relationship between age of migration and cognitive functioning among immigrants born in Mexico (Garcia et al., 2017; Hill et al., 2012). While years of education has been the focus of many studies, literacy (ability to read/write) has been less frequently explored as a moderator of age of migration and cognitive change. We investigated the effect of age of migration on cognitive trajectory in a diverse Latino population and explored whether literacy influences the association between age of immigration and cognitive change. We hypothesize that literacy (ability to read/write) will buffer the effects of age of migration on cognitive (memory, language, motor speed, visuospatial) trajectory. Participants and Method Age at baseline, English fluency, country of birth, sex/gender, and years of education were included as time-invariant covariates and literacy was tested as a moderator via multiple group modeling. Results Results show that age of migration is marginally and inversely associated with baseline cognitive performance (p < .01). Thus, individuals who immigrated at an older age had lower baseline cognitive scores than their counterparts. Age of migration was not associated with cognitive change. Independent of covariates, literacy did not buffer the negative effects of later age at migration on cognitive function. Conclusions Results suggest that literacy confers a small advantage in premorbid cognition, but does not protect against cognitive decline over time. These findings also suggest that adults who immigrate at an older age present with lower cognitive scores at baseline, but do not experience faster rates of cognitive change. References Tang, M. X., Cross, P., Andrews, H., Jacobs, D. M., Small, S., Bell, K., ... & Mayeux, R. (2001). Incidence of AD in African-Americans, Caribbean Hispanics, and Caucasians in northern Manhattan. Neurology, 56, 49-56. Garcia, M. A., Reyes, A. M., Downer, B., Saenz, J. L., Samper-Ternent, R. A., & Raji, M. (2018). Age of migration and the incidence of cognitive impairment: A cohort study of elder Mexican-Americans. Innovation in aging, 1, igx037. https://doi.org/10.1093/geroni/igx037. Hill, T. D., Angel, J. L., Balistreri, K. S., & Herrera, A. P. (2012). Immigrant Status and Cognitive Functioning in Late Life: An Examination of Gender Variations in the Healthy Immigrant Effect. Social Science & Medicine (1982), 75, 2076–2084. http://doi.org/10.1016/j.socscimed.2012.04.005.

IMPORTANCE: Genetic causes of late-onset Alzheimer disease (LOAD) are not completely explained by known genetic loci. Whole-exome and whole-genome sequencing can improve the understanding of the causes of LOAD and provide initial steps required to identify potential therapeutic targets. OBJECTIVE: To identify the genetic loci for LOAD across different ethnic groups. DESIGN, SETTING, AND PARTICIPANTS: This multicenter cohort study was designed to analyze whole-exome sequencing data from a multiethnic cohort using a transethnic gene-kernel association test meta-analysis, adjusted for sex, age, and principal components, to identify genetic variants associated with LOAD. A meta-analysis was conducted on the results of 2 independent studies of whole-exome and whole-genome sequence data from individuals of European ancestry. This group of European American, African American, and Caribbean Hispanic individuals participating in an urban population-based study were the discovery cohort; the additional cohorts included affected individuals and control participants from 2 publicly available data sets. Replication was achieved using independent data sets from Caribbean Hispanic families with multiple family members affected by LOAD and the International Genetics of Alzheimer Project. MAIN OUTCOMES AND MEASURES: Late-onset Alzheimer disease. RESULTS: The discovery cohort included 3595 affected individuals, while the additional cohorts included 5931 individuals with LOAD and 5504 control participants. Of 3916 individuals in the discovery cohort, we included 3595 individuals (1397 with LOAD and 2198 cognitively healthy controls; 2451 [68.2%] women; mean [SD] age, 80.3 [6.83] years). Another 321 individuals (8.2%) were excluded because of non-LOAD diagnosis, age younger than 60 years, missing covariates, duplicate data, or genetic outlier status. Gene-based tests that compared affected individuals (n = 7328) and control participants (n = 7702) and included only rare and uncommon variants annotated as having moderate-high functional effect supported PINX1 (8p23.1) as a locus with gene-wide significance (P = 2.81 × 10(−6)) after meta-analysis across the 3 studies. The PINX1 finding was replicated using data from the family-based study and the International Genetics of Alzheimer Project. Full meta-analysis of discovery and replication cohorts reached a P value of 6.16 × 10(−7) for PINX1 (in 7620 affected individuals vs 7768 control participants). We also identified TREM2 in an annotation model that prioritized highly deleterious variants with a combined annotation dependent depletion greater than 20 (P= 1.0 × 10(−7)). CONCLUSIONS AND RELEVANCE: This gene-based, transethnic approach identified PINX1, a gene involved in telomere integrity, and TREM2, a gene with a product of an immune receptor found in microglia, as associated with LOAD. Both genes have well-established roles in aging and neurodegeneration.

Key Points Question Can rare genetic variants for Alzheimer disease be identified using nonstatistical approaches? Findings In this genetic association study, variants with high functional effect were observed in participants with Alzheimer disease but not in controls in NOTCH3, a gene previously associated with cerebral autosomal-dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL), and TREM2 (Q33X) that in homozygous form causes Nasu-Hakola disease. Meaning Different mutations in the same gene or variable dose of a particular mutation may be associated with dissimilar types of dementia., Importance Some of the unexplained heritability of Alzheimer disease (AD) may be due to rare variants whose effects are not captured in genome-wide association studies because very large samples are needed to observe statistically significant associations. Objective To identify genetic variants associated with AD risk using a nonstatistical approach. Design, Setting, and Participants Genetic association study in which rare variants were identified by whole-exome sequencing in unrelated individuals of European ancestry from the Alzheimer’s Disease Sequencing Project (ADSP). Data were analyzed between March 2017 and September 2018. Main Outcomes and Measures Minor alleles genome-wide and in 95 genes previously associated with AD, AD-related traits, or other dementias were tabulated and filtered for predicted functional impact and occurrence in participants with AD but not controls. Support for several findings was sought in a whole-exome sequencing data set comprising 19 affected relative pairs from Utah high-risk pedigrees and whole-genome sequencing data sets from the ADSP and Alzheimer’s Disease Neuroimaging Initiative. Results Among 5617 participants with AD (3202 [57.0%] women; mean [SD] age, 76.4 [9.3] years) and 4594 controls (2719 [59.0%] women; mean [SD] age, 86.5 [4.5] years), a total of 24 variants with moderate or high functional impact from 19 genes were observed in 10 or more participants with AD but not in controls. These variants included a missense mutation (rs149307620 [p.A284T], n = 10) in NOTCH3, a gene in which coding mutations are associated with cerebral autosomal-dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL), that was also identified in 1 participant with AD and 1 participant with mild cognitive impairment in the whole genome sequencing data sets. Four participants with AD carried the TREM2 rs104894002 (p.Q33X) high-impact mutation that, in homozygous form, causes Nasu-Hakola disease, a rare disorder characterized by early-onset dementia and multifocal bone cysts, suggesting an intermediate inheritance model for the mutation. Compared with controls, participants with AD had a significantly higher burden of deleterious rare coding variants in dementia-associated genes (2314 vs 3354 cumulative variants, respectively; P = .006). Conclusions and Relevance Different mutations in the same gene or variable dose of a mutation may be associated with result in distinct dementias. These findings suggest that minor differences in the structure or amount of protein may be associated with in different clinical outcomes. Understanding these genotype-phenotype associations may provide further insight into the pathogenic nature of the mutations, as well as offer clues for developing new therapeutic targets., This genetic association study uses whole-exome sequencing to identify genetic variants associated with the risk of Alzheimer disease in Alzheimer’s Disease Sequencing Project participants of European ancestry.

SummaryCerebrospinal fluid (CSF) tau, tau phosphorylated at threonine 181 (ptau), and Aβ42 are established biomarkers for Alzheimer’s disease (AD) and have been used as quantitative traits for genetic analyses. We performed the largest genome-wide association study for cerebrospinal fluid (CSF) tau/ptau levels published to date (n = 1,269), identifying three genome-wide significant loci for CSF tau and ptau: rs9877502 (p = 4.89 × 10−9 for tau) located at 3q28 between GEMC1 and OSTN, rs514716 (p = 1.07 × 10−8 and p = 3.22 × 10−9 for tau and ptau, respectively), located at 9p24.2 within GLIS3 and rs6922617 (p = 3.58 × 10−8 for CSF ptau) at 6p21.1 within the TREM gene cluster, a region recently reported to harbor rare variants that increase AD risk. In independent data sets, rs9877502 showed a strong association with risk for AD, tangle pathology, and global cognitive decline (p = 2.67 × 10−4, 0.039, 4.86 × 10−5, respectively) illustrating how this endophenotype-based approach can be used to identify new AD risk loci.

Recent genome wide association studies have identified CLU, CR1, ABCA7 BIN1, PICALM and MS4A6A/MS4A6E in addition to the long established APOE, as loci for Alzheimer's disease. We have systematically examined each of these loci to assess whether common coding variability contributes to the risk of disease. We have also assessed the regional expression of all the genes in the brain and whether there is evidence of an eQTL explaining the risk. In agreement with other studies we find that coding variability may explain the ABCA7 association, but common coding variability does not explain any of the other loci. We were not able to show that any of the loci had eQTLs within the power of this study. Furthermore the regional expression of each of the loci did not match the pattern of brain regional distribution in Alzheimer pathology. Although these results are mainly negative, they allow us to start defining more realistic alternative approaches to determine the role of all the genetic loci involved in Alzheimer's disease. © 2013 Blackwell Publishing Ltd/University College London.

Objective: To evaluate the association of late-life depression with mild cognitive impairment (MCI) and dementia in a multiethnic community cohort. Design and Setting: A cohort study was conducted in Northern Manhattan, New York, New York. Participants: A total of 2160 community-dwelling Medicare recipients aged 65 years or older were included in the study. Methods: Depression was assessed using the 10-item version of the Center for Epidemiological Studies Depression scale (CES-D) and defined by a CES-D score of 4 or more. We used logistic regression for cross-sectional association analyses and proportional hazards regression for longitudinal analyses. Main Outcome Measures: Mild cognitive impairment dementia, and progression from MCI to dementia were the main outcome measures. We also used subcategories of MCI (amnestic and nonamnestic), and dementia (probable Alzheimer disease and vascular dementia, including possible Alzheimer disease with stroke). Results: Baseline depression was associated with prevalent MCI (odds ratio, 1.4; 95% CI, 1.1-1.9) and dementia (2.2; 1.6-3.1). Baseline depression was associated with an increased risk of incident dementia (hazard ratio [HR], 1.7; 95% CI, 1.2-2.3) but not with incident MCI (0.9; 0.7-1.2). Persons with MCI and coexisting depression at baseline had a higher risk of progression to dementia (HR, 2.0; 95% CI, 1.2-3.4), especially vascular dementia (4.3; 1.1-17.0), but not Alzheimer disease (1.9; 1.0-3.6). Conclusion: The association of depression with prevalent MCI and with progression from MCI to dementia, but not with incident MCI, suggests that depression accompanies cognitive impairment but does not precede it. JAMA Neurol. 2013;70(3):383-389. Published online December 31, 2012. doi:10.1001/jamaneurol.2013.603

Objective: To characterize the clinical and molecular effect of mutations in the sortilin-related receptor ( SORL1 ) gene. Methods: We performed whole-exome sequencing in early-onset Alzheimer disease (EOAD) and late-onset Alzheimer disease (LOAD) families followed by functional studies of select variants. The phenotypic consequences associated with SORL1 mutations were characterized based on clinical reviews of medical records. Functional studies were completed to evaluate β-amyloid (Aβ) production and amyloid precursor protein (APP) trafficking associated with SORL1 mutations. Results: SORL1 alterations were present in 2 EOAD families. In one, a SORL1 T588I change was identified in 4 individuals with AD, 2 of whom had parkinsonian features. In the second, an SORL1 T2134 alteration was found in 3 of 4 AD cases, one of whom had postmortem Lewy bodies. Among LOAD cases, 4 individuals with either SORL1 A528T or T947M alterations had parkinsonian features. Functionally, the variants weaken the interaction of the SORL1 protein with full-length APP, altering levels of Aβ and interfering with APP trafficking. Conclusions: The findings from this study support an important role for SORL1 mutations in AD pathogenesis by way of altering Aβ levels and interfering with APP trafficking. In addition, the presence of parkinsonian features among select individuals with AD and SORL1 mutations merits further investigation.

Introduction African Americans' (AAs) late-onset Alzheimer's disease (LOAD) genetic risk profile is incompletely understood. Including clinical covariates in genetic analyses using informed conditioning might improve study power. Methods We conducted a genome-wide association study (GWAS) in AAs employing informed conditioning in 1825 LOAD cases and 3784 cognitively normal controls. We derived a posterior liability conditioned on age, sex, diabetes status, current smoking status, educational attainment, and affection status, with parameters informed by external prevalence information. We assessed association between the posterior liability and a genome-wide set of single-nucleotide polymorphisms (SNPs), controlling for APOE and ABCA7 , identified previously in a LOAD GWAS of AAs. Results Two SNPs at novel loci, rs112404845 ( P = 3.8 × 10 −8 ), upstream of COBL , and rs16961023 ( P = 4.6 × 10 −8 ), downstream of SLC10A2 , obtained genome-wide significant evidence of association with the posterior liability. Discussion An informed conditioning approach can detect LOAD genetic associations in AAs not identified by traditional GWAS.

Psychotic symptoms, defined as the occurrence of delusions or hallucinations, are frequent in Alzheimer disease (AD), affecting ~40 to 60% of individuals with AD (AD with psychosis (AD+P)). In comparison with AD subjects without psychosis, AD+P subjects have more rapid cognitive decline and poor outcomes. Prior studies have estimated the heritability of psychosis in AD at 61%, but the underlying genetic sources of this risk are not known. We evaluated a Discovery Cohort of 2876 AD subjects with (N=1761) or without psychosis (N=1115). All subjects were genotyped using a custom genotyping array designed to evaluate single-nucleotide polymorphisms (SNPs) with evidence of genetic association with AD+P and include SNPs affecting or putatively affecting risk for schizophrenia and AD. Results were replicated in an independent cohort of 2194 AD subjects with (N=734) or without psychosis (N=1460). We found that AD+P is associated with polygenic risk for a set of novel loci and inversely associated with polygenic risk for schizophrenia. Among the biologic pathways identified by the associations of schizophrenia SNPs with AD+P are endosomal trafficking, autophagy and calcium channel signaling. To the best of our knowledge, these findings provide the first clear demonstration that AD+P is associated with common genetic variation. In addition, they provide an unbiased link between polygenic risk for schizophrenia and a lower risk of psychosis in AD. This provides an opportunity to leverage progress made in identifying the biologic effects of schizophrenia alleles to identify novel mechanisms protecting against more rapid cognitive decline and psychosis risk in AD.

ImportanceIdentifying individuals at risk for developing Alzheimer’s disease (AD) is of utmost importance. Although genetic studies have identified APOE and other AD associated single nucleotide polymorphisms (SNPs), genetic information has not been integrated into an epidemiological framework for personalized risk prediction.ObjectiveTo develop, replicate and validate a novel polygenic hazard score for predicting age-specific risk for AD.SettingMulti-center, multi-cohort genetic and clinical data.ParticipantsWe assessed genetic data from 17,008 AD patients and 37,154 controls from the International Genetics of Alzheimer’s Project (IGAP), and 6,409 AD patients and 9,386 older controls from Phase 1 Alzheimer’s Disease Genetics Consortium (ADGC). As independent replication and validation cohorts, we also evaluated genetic, neuroimaging, neuropathologic, CSF and clinical data from ADGC Phase 2, National Institute of Aging Alzheimer’s Disease Center (NIA ADC) and Alzheimer’s Disease Neuroimaging Initiative (ADNI) (total n = 20,680)Main Outcome(s) and Measure(s)Use the IGAP cohort to first identify AD associated SNPs (at p < 10-5). Next, integrate these AD associated SNPs into a Cox proportional hazards model using ADGC phase 1 genetic data, providing a polygenic hazard score (PHS) for each participant. Combine population based incidence rates, and genotype-derived PHS for each individual to derive estimates of instantaneous risk for developing AD, based on genotype and age. Finally, assess replication and validation of PHS in independent cohorts.ResultsIndividuals in the highest PHS quantiles developed AD at a considerably lower age and had the highest yearly AD incidence rate. Among APOE ε3/3 individuals, PHS modified expected age of AD onset by more than 10 years between the lowest and highest deciles. In independent cohorts, PHS strongly predicted empirical age of AD onset (p = 1.1 x 10-26), longitudinal progression from normal aging to AD (p = 1.54 x 10-10) and associated with markers of AD neurodegeneration.ConclusionsWe developed, replicated and validated a clinically usable PHS for quantifying individual differences in age-specific risk of AD. Beyond APOE, polygenic architecture plays an important role in modifying AD risk. Precise quantification of AD genetic risk will be useful for early diagnosis and therapeutic strategies.

OBJECTIVES: To investigate the association between mortality and heritability of a rescaled Fried frailty index, the Scale of Aging Vigor in Epidemiology (SAVE), to determine its value for genetic analyses. DESIGN: Longitudinal, community-based cohort study. SETTING: The Long Life Family Study (LLFS) in the United States and Denmark. PARTICIPANTS: Long-lived individuals (N = 4,875, including 4,075 genetically related individuals) and their families (N = 551). MEASUREMENTS: The SAVE was administered to 3,599 participants and included weight change, weakness (grip strength), fatigue (questionnaire), physical activity (days walked in prior 2 weeks), and slowness (gait speed); each component was scored 0, 1, or 2 using approximate tertiles, and summed (range 0 (vigorous) to 10 (frail)). Heritability was determined using a variance component-based family analysis using a polygenic model. Association with mortality in the proband generation (N = 1,421) was calculated using Cox proportional hazards mixed-effect models. RESULTS: Heritability of the SAVE was 0.23 (P < .001) overall (n = 3,599), 0.31 (P < .001) in probands (n = 1,479), and 0.26 (P < .001) in offspring (n = 2,120). In adjusted models, higher SAVE scores were associated with higher mortality (score 5-6: hazard ratio (HR) = 2.83, 95% confidence interval (CI) = 1.46-5.51; score 7-10: HR = 3.40, 95% CI = 1.72-6.71) than lower scores (0-2). CONCLUSION: The SAVE was associated with mortality and was moderately heritable in the LLFS, suggesting a genetic component to age-related vigor and frailty and supporting its use for further genetic analyses. OBJECTIVES: To investigate the association between mortality and heritability of a rescaled Fried frailty index, the Scale of Aging Vigor in Epidemiology (SAVE), to determine its value for genetic analyses.DESIGN: Longitudinal, community-based cohort study.SETTING: The Long Life Family Study (LLFS) in the United States and Denmark.PARTICIPANTS: Long-lived individuals (N = 4,875, including 4,075 genetically related individuals) and their families (N = 551).MEASUREMENTS: The SAVE was administered to 3,599 participants and included weight change, weakness (grip strength), fatigue (questionnaire), physical activity (days walked in prior 2 weeks), and slowness (gait speed); each component was scored 0, 1, or 2 using approximate tertiles, and summed (range 0 (vigorous) to 10 (frail)). Heritability was determined using a variance component-based family analysis using a polygenic model. Association with mortality in the proband generation (N = 1,421) was calculated using Cox proportional hazards mixed-effect models.RESULTS: Heritability of the SAVE was 0.23 (P < .001) overall (n = 3,599), 0.31 (P < .001) in probands (n = 1,479), and 0.26 (P < .001) in offspring (n = 2,120). In adjusted models, higher SAVE scores were associated with higher mortality (score 5-6: hazard ratio (HR) = 2.83, 95% confidence interval (CI) = 1.46-5.51; score 7-10: HR = 3.40, 95% CI = 1.72-6.71) than lower scores (0-2).CONCLUSION: The SAVE was associated with mortality and was moderately heritable in the LLFS, suggesting a genetic component to age-related vigor and frailty and supporting its use for further genetic analyses.

Effective prevention of Alzheimer's disease (AD) requires the development of risk prediction tools permitting preclinical intervention. We constructed a genetic risk score (GRS) comprising common genetic variants associated with AD, evaluated its association with incident AD and assessed its capacity to improve risk prediction over traditional models based on age, sex, education, and APOE epsilon 4. In eight prospective cohorts included in the International Genomics of Alzheimer's Project (IGAP), we derived weighted sum of risk alleles from the 19 top SNPs reported by the IGAPGWAS in participants aged 65 and older without prevalent dementia. Hazard ratios (HR) of incident AD were estimated in Cox models. Improvement in risk prediction was measured by the difference in C-index (Delta-C), the integrated discrimination improvement (IDI) and continuous net reclassification improvement (NRI>0). Overall, 19,687 participants at risk were included, of whom 2,782 developed AD. The GRS was associated with a 17% increase in AD risk (pooled HR=1.17; 95% CI = [1.13-1.21] per standard deviation increase in GRS; p-value = 2.86x10(-16)). This association was stronger among persons with at least one APOE epsilon 4 allele (HRGRS = 1.24; 95% CI = [1.15-1.34]) than in others (HRGRS = 1.13; 95% CI = [1.08-1.18]; p(interaction) = 3.45x10(-2)). Risk prediction after seven years of follow-up showed a small improvement when adding the GRS to age, sex, APOE epsilon 4, and education (Delta-Cindex = 0.0043 [0.0019-0.0067]). Similar patterns were observed for IDI and NRI>0. In conclusion, a risk score incorporating common genetic variation outside the APOE epsilon 4 locus improved AD risk prediction and may facilitate risk stratification for prevention trials.

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.

Objective: To identify a causative variant(s) that may contribute to Alzheimer disease (AD) in African Americans (AA) in the ATP-binding cassette, subfamily A ( ABC1 ), member 7 ( ABCA7 ) gene, a known risk factor for late-onset AD. Methods: Custom capture sequencing was performed on ∼150 kb encompassing ABCA7 in 40 AA cases and 37 AA controls carrying the AA risk allele (rs115550680). Association testing was performed for an ABCA7 deletion identified in large AA data sets (discovery n = 1,068; replication n = 1,749) and whole exome sequencing of Caribbean Hispanic (CH) AD families. Results: A 44-base pair deletion (rs142076058) was identified in all 77 risk genotype carriers, which shows that the deletion is in high linkage disequilibrium with the risk allele. The deletion was assessed in a large data set (531 cases and 527 controls) and, after adjustments for age, sex, and APOE status, was significantly associated with disease ( p = 0.0002, odds ratio [OR] = 2.13 [95% confidence interval (CI): 1.42–3.20]). An independent data set replicated the association (447 cases and 880 controls, p = 0.0117, OR = 1.65 [95% CI: 1.12–2.44]), and joint analysis increased the significance ( p = 1.414 × 10 −5 , OR = 1.81 [95% CI: 1.38–2.37]). The deletion is common in AA cases (15.2%) and AA controls (9.74%), but in only 0.12% of our non-Hispanic white cohort. Whole exome sequencing of multiplex, CH families identified the deletion cosegregating with disease in a large sibship. The deleted allele produces a stable, detectable RNA strand and is predicted to result in a frameshift mutation (p.Arg578Alafs) that could interfere with protein function. Conclusions: This common ABCA7 deletion could represent an ethnic-specific pathogenic alteration in AD.

Background: Previous research has identified multiple risk and protective factors for late onset Alzheimer’s disease (LOAD). However, it is not known whether these risk and protective factors differ for individuals who are cognitively stable versus those already experiencing declines. Objective: This study examined how dementia risk factors differ across subgroups of older adults defined by memory trajectory. This line of research may lead to more individualized risk profiles. Methods: Risk factors for incident LOAD were compared across previously-validated groups of older adults exhibiting different memory trajectories (“Stable-High,” “Stable-Low,” “Decliner,” “Rapid Decliner”) using stratified Cox regressions. Participants included 2,593 racially/ethnically diverse older adults (mean age of 76 at study entry) in the Washington HeightsInwood Columbia Aging Project. Results: Predictors of incident dementia differed across trajectory groups: older age only incurred independent risk in stable groups, education did not incur independent protection in the rapidly declining group, depression only incurred independent risk in the stable-low group, stroke incurred independent risk in the two extreme groups, and APOE-4 only incurred independent risk in the rapidly declining group. Conclusion: The finding that different risk factors for LOAD were associated with specific memory trajectories may reflect the existence of resilience or vulnerability factors that modify the individual influences of risk/protective factors. This study highlights the utility of considering interactions between dementia risk factors and a patient’s unique cognitive history.

BACKGROUND: The Long Life Family Study (LLFS) is an international study to identify the genetic components of various healthy aging phenotypes. We hypothesized that pedigree-specific rare variants at longevity-associated genes could have a similar functional impact on healthy phenotypes.METHODS: We performed custom hybridization capture sequencing to identify the functional variants in 464 candidate genes for longevity or the major diseases of aging in 615 pedigrees (4,953 individuals) from the LLFS, using a multiplexed, custom hybridization capture. Variants were analyzed individually or as a group across an entire gene for association to aging phenotypes using family based tests.RESULTS: We found significant associations to three genes and nine single variants. Most notably, we found a novel variant significantly associated with exceptional survival in the 3' UTR OBFC1 in 13 individuals from six pedigrees. OBFC1 (chromosome 10) is involved in telomere maintenance, and falls within a linkage peak recently reported from an analysis of telomere length in LLFS families. Two different algorithms for single gene associations identified three genes with an enrichment of variation that was significantly associated with three phenotypes (GSK3B with the Healthy Aging Index, NOTCH1 with diastolic blood pressure and TP53 with serum HDL).CONCLUSIONS: Sequencing analysis of family-based associations for age-related phenotypes can identify rare or novel variants. BACKGROUND: The Long Life Family Study (LLFS) is an international study to identify the genetic components of various healthy aging phenotypes. We hypothesized that pedigree-specific rare variants at longevity-associated genes could have a similar functional impact on healthy phenotypes.METHODS: We performed custom hybridization capture sequencing to identify the functional variants in 464 candidate genes for longevity or the major diseases of aging in 615 pedigrees (4,953 individuals) from the LLFS, using a multiplexed, custom hybridization capture. Variants were analyzed individually or as a group across an entire gene for association to aging phenotypes using family based tests.RESULTS: We found significant associations to three genes and nine single variants. Most notably, we found a novel variant significantly associated with exceptional survival in the 3' UTR OBFC1 in 13 individuals from six pedigrees. OBFC1 (chromosome 10) is involved in telomere maintenance, and falls within a linkage peak recently reported from an analysis of telomere length in LLFS families. Two different algorithms for single gene associations identified three genes with an enrichment of variation that was significantly associated with three phenotypes (GSK3B with the Healthy Aging Index, NOTCH1 with diastolic blood pressure and TP53 with serum HDL).CONCLUSIONS: Sequencing analysis of family-based associations for age-related phenotypes can identify rare or novel variants.

Background Autosomal dominant familial Alzheimer's disease (ADAD) is a rare disorder with non-amnestic neurological symptoms in some clinical presentations. We aimed to compile and compare data from symptomatic participants in the Dominantly Inherited Alzheimer Network observational study (DIAN-OBS) with those reported in the literature to estimate the prevalences of non-amnestic neurological symptoms in participants with ADAD. Methods We prospectively collected data from the DIAN-OBS database, which recruited participants from study centres in the USA, Europe, and Australia, between Feb 29, 2008, and July 1, 2014. We also did a systematic review of publications to extract individual-level clinical data for symptomatic participants with ADAD. We used data for age of onset (from first report of cognitive decline), disease course from onset to death, and the presence of 13 neurological findings that have been reported in association with ADAD. Using multivariable linear regression, we investigated the prevalences of various non-amnestic neurological symptoms and the contributions of age of onset and specific mutation type on symptoms. Findings The DIAN-OBS dataset included 107 individuals with detailed clinical data (forming the DIAN-OBS cohort). Our systematic review yielded 188 publications reporting on 1228 symptomatic individuals, with detailed neurological examination descriptions available for 753 individuals (forming the published data cohort). The most prevalent non-amnestic cognitive manifestations in participants in the DIAN-OBS cohort were those typical of mild to moderate Alzheimer's disease, including visual agnosia (55·1%, 95% CI 45·7–64·6), aphasia (57·9%, 48·6–67·3), and behavioural changes (61·7%, 51·5–70·0). Non-amnestic cognitive manifestations were less prevalent in the published data cohort (eg, visual agnosia [5·6%, 3·9–7·2], aphasia [23·0%, 20·0–26·0], and behavioural changes [31·7%, 28·4–35·1]). Prevalence of non-cognitive neurological manifestations in the DIAN-OBS cohort was low, including myoclonus and spasticity (9·3%, 95% CI 3·8–15·0), and seizures (2·8%, 0·5–5·9) and moderate for parkinsonism (11·2%, 5·3–17·1). By constrast, prevalence was higher in the published data cohort for myoclonus and spasticity (19·4%, 16·6–22·2 and 15·0%, 12·5–17·6, respectively), parkinsonism (12·5%, 10·1–15·0), and seizures (20·3%, 17·4–23·2). In an analysis of the published data cohort, ischaemic stroke was more prevalent at older ages of onset of symptoms of ADAD (odds ratio 1·09 per 1 year increase in age of onset, 95% CI 1·04–1·14, p=0·0003); and motor symptoms were more common at younger age of onset (myoclonus 0·93, 0·90–0·97, p=0·0007; seizures 0·95, 0·92–0·98, p=0·0018; corticobulbar deficits 0·91, 0·86–0·96, p=0·0012; and cerebellar ataxia 0·82, 0·74–0·91, p=0·0002). In the DIAN-OBS cohort, non-cognitive symptoms were more common at more severe stages of disease. Interpretation The non-cognitive clinical manifestations of Alzheimer's disease seem to affect a small proportion of participants with mild to moderate ADAD, and are probably influenced by disease severity, environmental, and genetic factors. When evaluating patients with potential ADAD, clinicians should note that cognitive symptoms typical of sporadic Alzheimer's disease are the most consistent finding, with some patients manifesting non-cognitive neurological symptoms. Future work is needed to determine the environmental and genetic factors that cause these neurological symptoms. Funding National Institutes of Health and German Center for Neurodegenerative Diseases. Fil: Tang, Mengxuan. Washington University. School of Medicine; Estados Unidos Fil: Ryman, Davis C.. Washington University. School of Medicine; Estados Unidos Fil: McDade, Eric. Washington University. School of Medicine; Estados Unidos Fil: Jasielec, Mateusz S.. Washington University. School of Medicine; Estados Unidos Fil: Buckles, Virginia D.. Washington University. School of Medicine; Estados Unidos Fil: Cairns, Nigel J.. Washington University. School of Medicine; Estados Unidos Fil: Fagan, Anne M.. Washington University. School of Medicine; Estados Unidos Fil: Goate, Alison. Washington University. School of Medicine; Estados Unidos Fil: Marcus, Daniel S.. Washington University. School of Medicine; Estados Unidos Fil: Xiong, Chengjie. Washington University. School of Medicine; Estados Unidos Fil: Allegri, Ricardo Francisco. Consejo Nacional de Investigaciones Científicas y Técnicas; Argentina Fil: Chhatwal, Jasmeer P.. Brigham and Women’s Hospital; Estados Unidos Fil: Danek, Adrian. Ludwig-Maximilians Universität Munich. Neurologische Klinik; Alemania Fil: Farlow, Martin R.. Indiana University; Estados Unidos Fil: Fox, Nick C.. University College London; Estados Unidos Fil: Ghetti, Bernardino. Indiana University; Estados Unidos Fil: Graff-Radford, Neill R.. Mayo Clinic; Estados Unidos Fil: Laske, Christopher. German Center for Neurodegenerative Diseases and Hertie Institute for Clinical Brain Research; Alemania Fil: Martins, Ralph N.. Edith Cowan University. School of Exercise, Biomedical and Health Sciences. Centre of Excellence for Alzheimer’s Disease Research and Care; Australia Fil: Masters, Colin L.. University of Melbourne. Mental Health Research Institute; Australia Fil: Mayeux, Richard P.. Columbia University Medical Center. Taub Institute for Research on Alzheimer’s Disease and the Aging Brain; Estados Unidos Fil: Ringman, John M.. University of Southern California. Keck School of Medicine; Estados Unidos Fil: Rossor, Martin N.. University College London; Estados Unidos Fil: Salloway, Stephen P.. Brown University. Warren Alpert Medical School; Estados Unidos Fil: Schofield, Peter R.. University of New South Wales; Australia Fil: Morris, John C.. University of Washington; Estados Unidos Fil: Bateman, Randall J.. University of Washington; Estados Unidos

Gait speed is associated with multiple adverse outcomes of aging. White matter hyperintensities (WMH) on magnetic resonance imaging (MRI) have been associated with gait speed, though few studies have examined changes in gait speed over time in population-based studies comprising participants from diverse cultural backgrounds. The purpose of this study was to examine the association between a decline in gait speed and total and regional WMH volumes in a community-based study of aging. Participants (n = 701) underwent gait-speed measurement via a 4-m walk test at the time of initial enrollment and MRI at a second time interval (mean 4.7 [SD = 0.5] years apart). Logistic regression was used to examine the association between large WMH volume and regional WMH volume with gait speed

Pancreatitis is a complex, progressively destructive inflammatory disorder. Alcohol was long thought to be the primary causative agent, but genetic contributions have been of interest since the discovery that rare PRSS1, CFTR and SPINK1 variants were associated with pancreatitis risk. We now report two associations at genome-wide significance identified and replicated at PRSS1-PRSS2 (P < 1 × 10(-12)) and X-linked CLDN2 (P < 1 × 10(-21)) through a two-stage genome-wide study (stage 1: 676 cases and 4,507 controls; stage 2: 910 cases and 4,170 controls). The PRSS1 variant likely affects disease susceptibility by altering expression of the primary trypsinogen gene. The CLDN2 risk allele is associated with atypical localization of claudin-2 in pancreatic acinar cells. The homozygous (or hemizygous in males) CLDN2 genotype confers the greatest risk, and its alleles interact with alcohol consumption to amplify risk. These results could partially explain the high frequency of alcohol-related pancreatitis in men (male hemizygote frequency is 0.26, whereas female homozygote frequency is 0.07).

A B S T R AC T BACKGROUND The order and magnitude of pathologic processes in Alzheimer’s disease are not well understood, partly because the disease develops over many years. Autosomal dominant Alzheimer’s disease has a predictable age at onset and provides an opportunity to determine the sequence and magnitude of pathologic changes that culminate in symptomatic disease. METHODS In this prospective, longitudinal study, we analyzed data from 128 participants who underwent baseline clinical and cognitive assessments, brain imaging, and cerebrospinal fluid (CSF) and blood tests. We used the participant’s age at baseline assessment and the parent’s age at the onset of symptoms of Alzheimer’s disease to calculate the estimated years from expected symptom onset (age of the participant minus parent’s age at symptom onset). We conducted cross-sectional analyses of baseline data in relation to estimated years from expected symptom onset in order to determine the relative order and magnitude of pathophysiological changes. RESULTS Concentrations of amyloid-beta (Aβ)42 in the CSF appeared to decline 25 years before expected symptom onset. Aβ deposition, as measured by positron-emission tomography with the use of Pittsburgh compound B, was detected 15 years before expected symptom onset. Increased concentrations of tau protein in the CSF and an increase in brain atrophy were detected 15 years before expected symptom onset. Cerebral hypometabolism and impaired episodic memory were observed 10 years before expected symptom onset. Global cognitive impairment, as measured by the Mini–Mental State Examination and the Clinical Dementia Rating scale, was detected 5 years before expected symptom onset, and patients met diagnostic criteria for dementia at an average of 3 years after expected symptom onset. CONCLUSIONS We found that autosomal dominant Alzheimer’s disease was associated with a series of pathophysiological changes over decades in CSF biochemical markers of Alzheimer’s disease, brain amyloid deposition, and brain metabolism as well as progressive cognitive impairment. Our results require confirmation with the use of longitudinal data and may not apply to patients with sporadic Alzheimer’s disease. (Funded by the National Institute on Aging and others; DIAN ClinicalTrials.gov number, NCT00869817.)

We examined whether late-life depression, including depressive symptoms and antidepressant use, was associated with smaller total brain volume, smaller hippocampal volume, and larger white matter hyperintensity (WMH) volume in a large community-based cohort of old persons without dementia. Within the Washington/Hamilton Height-Inwood Columbia Aging Project (WHICAP), a community-based cohort study in northern Manhattan, 630 persons without dementia (mean age 80 years, SD = 5) had volumetric measures of the total brain, hippocampus, and WMH at 1.5 Tesla MRI and data on current depression, defined as a score of 4 or higher on the 10-item Center for Epidemiologic Studies-Depression (CES-D) scale, or use of antidepressants. Multiple linear regression analyses adjusted for age, gender, ethnicity, education, cardiovascular disease history, and MRI parameters showed that subjects with current depression had smaller relative total brain volume (B = -0.86%; 95% CI -1.68 to -0.05%; p < 0.05), smaller relative hippocampal volume (B = -0.07 ml; 95% CI -0.14 to 0.00 ml; p = 0.05), and larger relative WMH volume (natural logtransformed B = 0.19 ml; 95% CI 0.02 to 0.35 ml; p < 0.05). When examined separately, antidepressant use was significantly associated with smaller total brain, smaller hippocampal, and larger WMH volume, while high CES-D scores were not significantly associated with any of the brain measures, although the direction of association was similar as for antidepressant use. With the caveat that analyses were cross-sectional and we had no formal diagnosis of depression, our findings suggest that in this community-based sample of old persons without dementia, late-life depression is associated with more brain atrophy and more white matter lesions, which was mainly driven by antidepressant use.

Recently genome-wide association studies have identified significant association between Alzheimer’s disease (AD) and variations in CLU, PICALM, BIN1, CR1, MS4A4/MS4A6E, CD2AP, CD33, EPHA1, and ABCA7. However, the pathogenic variants in these loci have not yet been found. We conducted a genome-wide scan for large copy number variation (CNV) in a dataset of Caribbean Hispanic origin (554 controls and 559 AD cases that were previously investigated in a SNP-based genome-wide association study using Illumina HumanHap 650Y platform). We ran four CNV calling algorithms to obtain high-confidence calls for large CNVs (>100 kb) that were detected by at least two algorithms. Global burden analyses did not reveal significant differences between cases and controls in CNV rate, distribution of deletions or duplications, total or average CNV size; or number of genes affected by CNVs. However, we observed a nominal association between AD and a ∼470 kb duplication on chromosome 15q11.2 (P = 0.037). This duplication, encompassing up to five genes (TUBGCP5, CYFIP1, NIPA2, NIPA1, and WHAMML1) was present in 10 cases (2.6%) and 3 controls (0.8%). The dosage increase of CYFIP1 and NIPA1 genes was further confirmed by quantitative PCR. The current study did not detect CNVs that affect novel AD loci identified by recent genome-wide association studies. However, because the array technology used in our study has limitations in detecting small CNVs, future studies must carefully assess novel AD genes for the presence of disease-related CNVs.

Objective To examine genetic associations of polymorphisms in the dopamine receptor D2 ( DRD2 ) and D3 ( DRD3 ) genes with risk of Parkinson's disease (PD). Methods The study included 1325 newly diagnosed patients with PD and 1735 controls from a consortium of five North American case–control studies. We collected risk factor information by in-person or telephone interview. Six DRD2 and two DRD3 polymorphisms were genotyped using a common laboratory. Odds ratios were estimated using logistic regression. Results Among non-Hispanic whites, homozygous carriers of Taq1A DRD2 (rs1800497) polymorphism had an increased risk of PD compared to homozygous wildtype carriers (OR = 1.5, 95% CI 1.0–2.3). In contrast, the direction of association for Taq1A polymorphism was opposite for African–Americans, showing an inverse association with PD risk (OR = 0.10, 95% CI 0.2–0.7). Among white Hispanics who carried two alleles, the Ser9Gly DRD3 (rs6280) polymorphism was associated with a decreased risk of PD (OR = 0.4, 95% CI 0.2–0.8). The inverse association of smoking with PD risk was not modified by any of the DRD2 or DRD3 polymorphisms. Conclusions DRD2 polymorphisms are unlikely to be true disease-causing variants; however, three DRD2 polymorphisms (including Taq1A) may be in linkage disequilibrium with possible disease associated variants in the DRD2-ANKK1-NCAM1-TTC12 gene cluster.

Objective: To evaluate the relations between PET Pittsburgh compound B (PiB-PET) binding (amyloid imaging) and plasma Aβ in patients with mild cognitive impairment (MCI) and similarly aged controls. Methods: In 20 patients with MCI and 19 cognitively intact controls (case-control study), PiB binding potential (BP nd ) was assessed in 4 regions, and total brain excluding cerebellum, referenced to cerebellar binding. The mean of plasma Aβ levels measured in duplicate was analyzed. Results: Plasma Aβ42/Aβ40 ratio was decreased in MCI compared to controls (mean 0.15 SD 0.04 vs mean 0.19 SD 0.07, p = 0.03) but Aβ40 ( p = 0.3) and Aβ42 ( p = 0.06) levels did not differ between the 2 groups. PiB BP nd was increased in MCI compared to controls in the cingulate ( p = 0.02), parietal ( p = 0.02), and total brain ( p = 0.03), but not in prefrontal cortex ( p = 0.08) or parahippocampal gyrus ( p = 0.07). Linear regression analyses adjusting for age, sex, and cognitive test scores showed that low Aβ42/Aβ40 ratio was associated with high cingulate, parietal, and total brain PiB binding (0.01 p ≤ 0.05). These associations between PiB binding and the Aβ42/Aβ40 ratio were strongest in PiB-positive subjects and within the MCI group. Conclusions: Though cross-sectional, the findings support the “sink” hypothesis that increased brain Aβ is accompanied by lower peripheral levels of Aβ, particularly the Aβ42/Aβ40 ratio in patients with MCI. The association between PiB binding and the plasma Aβ42/Aβ40 ratio suggests possible use of plasma Aβ combined with PiB binding as a risk biomarker with potential clinical application.