IntroductionLate-onset Alzheimer's disease (LOAD, onset age > 60 years) is the most prevalent dementia in the elderly 1 , and risk is partially driven by genetics 2 . Many of the loci responsible for this genetic risk were identified by genome-wide association studies (GWAS) [3][4][5][6][7][8] . To identify additional LOAD risk loci, the we performed the largest GWAS to date (89,769 individuals), analyzing both common and rare variants. We confirm 20 previous LOAD risk loci and identify four new genome-wide loci (IQCK, ACE, ADAM10, and ADAMTS1). Pathway analysis of these data implicates the immune system and lipid metabolism, and for the first time tau binding proteins and APP metabolism. These findings show that genetic variants affecting APP and Aβ processing are not only associated with early-onset autosomal dominant AD but also with LOAD. Analysis of AD risk genes and pathways show enrichment for rare variants (P = 1.32 x 10 -7 ) indicating that additional rare variants remain to be identified. Main TextOur previous work identified 19 genome-wide significant common variant signals in addition to APOE 9 , that influence risk for LOAD. These signals, combined with 'subthreshold' common variant associations, account for ~31% of the genetic variance of LOAD 2 , leaving the majority of genetic risk uncharacterized 10 . To search for additional signals, we conducted a GWAS metaanalysis of non-Hispanic Whites (NHW) using a larger sample (17 new, 46 total datasets) from our group, the International Genomics of Alzheimer's Project (IGAP) (composed of four AD consortia: ADGC, CHARGE, EADI, and GERAD). This sample increases our previous discovery sample (Stage 1) by 29% for cases and 13% for controls (N=21,982 cases; 41,944 controls) ( Supplementary Table 1 and 2, and Supplementary Note). To sample both common and rare variants (minor allele frequency MAF ≥ 0.01, and MAF < 0.01, respectively), we imputed the discovery datasets using a 1000 Genomes reference panel consisting of . CC-BY-NC-ND 4.0 International license peer-reviewed) is the author/funder. It is made available under a 11 36,648,992 single-nucleotide variants, 1,380,736 insertions/deletions, and 13,805 structural variants. After quality control, 9,456,058 common variants and 2,024,574 rare variants were selected for analysis (a 63% increase from our previous common variant analysis in 2013).Genotype dosages were analyzed within each dataset, and then combined with meta-analysis ( Supplementary Figures 1 and 2 and Supplementary Table 3). The Stage 1 discovery metaanalysis was first followed by Stage 2 using the I-select chip we previously developed in Lambert et al (including 11,632 variants, N=18,845) and finally stage 3A (N=6,998). The final sample was 33,692 clinical AD cases and 56,077 controls.Meta-analysis of Stages 1 and 2 produced 21 associations with P ≤ 5x10 -8 (Table 1 and Figure 1). Of these, 18 were previously reported as genome-wide significant and three of them are signals not initially described in Lambert et al: the rare R47H TREM2 coding va...

Background Innovative approaches to the widespread delivery of evidence-based dementia care are needed. The aims of this study were to determine whether a telephone screening method could efficiently identify individuals in the community in need of care for dementia and to develop a multidimensional needs assessment tool for identifying the type and frequency of unmet needs related to memory disorders in the home setting. Methods This was a cross-sectional evaluation of 292 community-residing individuals aged 70 and older in Maryland. Participants were given a brief cognitive telephone screen. A subsample (n=43) received a comprehensive in-home assessment for dementia and dementia-related needs. Cognitive, functional, behavioral, and clinical factors were assessed. The Johns Hopkins Dementia Care Needs Assessment was used to identify unmet needs related to dementia. Results Telephone screening for the sample took 350 hours, and 27% screened positive for dementia. Virtually all participants with dementia who received an in-home assessment had at least one unmet need, with the most frequent unmet needs being for a dementia workup, general medical care, environmental safety, assistance with ADL impairments, and access to meaningful activities. Caregivers, when present, also had a number of unmet needs, with the most common being caregiver education about dementia, knowledge of community resources, and caregiver mental health care. Conclusions Effective and efficient means for identifying community-residing individuals with dementia are needed so that Dementia Care interventions can be provided to address unmet care needs of patients and their caregivers.

The objective of this study was to describe the prevalence and course of depressive symptoms before AIDS in HIV-infected homosexual men. A descriptive and comparative analysis of data from HIV-infected and -uninfected homosexual men in the Multicenter AIDS Cohort Study was performed. The Center for Epidemiologic Studies Depression Scale (CES-D) was the primary measure of depressive symptoms. The prevalence of depressive symptoms and CES-D caseness estimates in the AIDS-free HIV-infected homosexual men were stable over time. Small differences between HIV seropositive and seronegative men were detected on the CES-D and on three of its subscales. These were mostly accounted for by less hope, and by more fearfulness, insomnia, and anorexia in the seropositive cohort. We concluded that there does not appear to be an overall increase in depressive symptoms in HIV-infected homosexual men from the time of infection until prior to AIDS. However, this group of men consistently report specific depressive symptoms more often. Implications of these findings for the clinical care of HIV-infected patients is discussed.

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