Limited ancestral diversity has impaired our ability to detect risk variants more prevalent in ancestry groups of predominantly non-European ancestral background in genome-wide association studies (GWAS). We construct and analyze a multi-ancestry GWAS dataset in the Alzheimer’s Disease Genetics Consortium (ADGC) to test for novel shared and population-specific late-onset Alzheimer’s disease (LOAD) susceptibility loci and evaluate underlying genetic architecture in 37,382 non-Hispanic White (NHW), 6728 African American, 8899 Hispanic (HIS), and 3232 East Asian individuals, performing within ancestry fixed-effects meta-analysis followed by a cross-ancestry random-effects meta-analysis. We identify 13 loci with cross-population associations including known loci at/near CR1, BIN1, TREM2, CD2AP, PTK2B, CLU, SHARPIN, MS4A6A, PICALM, ABCA7, APOE, and two novel loci not previously reported at 11p12 (LRRC4C) and 12q24.13 (LHX5-AS1). We additionally identify three population-specific loci with genome-wide significance at/near PTPRK and GRB14 in HIS and KIAA0825 in NHW. Pathway analysis implicates multiple amyloid regulation pathways and the classical complement pathway. Genes at/near our novel loci have known roles in neuronal development (LRRC4C, LHX5-AS1, and PTPRK) and insulin receptor activity regulation (GRB14). Using cross-population GWAS meta-analyses, we identify novel LOAD susceptibility loci in/near LRRC4C and LHX5-AS1, both with known roles in neuronal development, as well as several novel population-unique loci. Reflecting the power of diverse ancestry in GWAS, we detect the SHARPIN locus with only 13.7

center dot PURPOSE: To investigate whether associations between diabetic retinopathy (DR) and dementia and Alzheimer's disease (AD) remain significant after controlling for sev-eral measures of diabetes severity.center dot DESIGN: Retrospective cohort study.center dot METHODS: Adult Changes in Thought (ACT) is a prospective cohort study of adults aged >65 years, ran-domly selected and recruited from the membership rolls of Kaiser Permanente Washington, who are dementia free at enrollment and followed biennially until incident demen-tia. The ACT participants were included in this study if they had type 2 diabetes mellitus at enrollment or devel-oped it during follow-up, and data were collected through September, 2018 (3516 person-years of follow-up). Di-abetes was defined by > 2 diabetes medication fills in 1 year. Diagnosis of DR was based on International Clas-sification of Diseases Ninth and Tenth Revision codes. Estimates of microalbuminuria, long-term glycemia, and renal function from longitudinal laboratory records were used as indicators of diabetes severity. Alzheimer's dis-ease and dementia were diagnosed using research criteria at expert consensus meetings.center dot RESULTS: A total of 536 participants (median baseline age 75 [interquartile range 71-80], 54% women) met in-clusion criteria. Significant associations between DR >5 years duration with dementia (hazard ratio 1.81 [95% CI 1.23, 2.65]) and AD (1.80 [1.15, 2.82]) were not altered by adjustment for estimates of microalbuminuria, long-term glycemia, and renal function (dementia: 1.69 [1.14, 2.50]; AD: 1.73 [1.10, 2.74]).center dot CONCLUSIONS: Among people with type 2 diabetes, DR itself appears to be an important biomarker of demen-tia risk in addition to glycemia and renal complications. (Am J Ophthalmol 2023;249: 90-98. (c) 2022 Elsevier Inc. All rights reserved.)

ABSTRACTLimited ancestral diversity has impaired our ability to detect risk variants more prevalent in non-European ancestry groups in genome-wide association studies (GWAS). We constructed and analyzed a multi-ancestry GWAS dataset in the Alzheimer’s Disease (AD) Genetics Consortium (ADGC) to test for novel shared and ancestry-specific AD susceptibility loci and evaluate underlying genetic architecture in 37,382 non-Hispanic White (NHW), 6,728 African American, 8,899 Hispanic (HIS), and 3,232 East Asian individuals, performing within-ancestry fixed-effects meta-analysis followed by a cross-ancestry random-effects meta-analysis. We identified 13 loci with cross-ancestry associations including known loci at/nearCR1,BIN1,TREM2,CD2AP,PTK2B,CLU,SHARPIN,MS4A6A,PICALM,ABCA7,APOEand two novel loci not previously reported at 11p12 (LRRC4C) and 12q24.13 (LHX5-AS1). Reflecting the power of diverse ancestry in GWAS, we observed theSHARPINlocus using 7.1% the sample size of the original discovering single-ancestry GWAS (n=788,989). We additionally identified three GWS ancestry-specific loci at/near (PTPRK(P=2.4×10-8) andGRB14(P=1.7×10-8) in HIS), andKIAA0825(P=2.9×10-8in NHW). Pathway analysis implicated multiple amyloid regulation pathways (strongest withPadjusted=1.6×10-4) and the classical complement pathway (Padjusted=1.3×10-3). Genes at/near our novel loci have known roles in neuronal development (LRRC4C, LHX5-AS1, andPTPRK) and insulin receptor activity regulation (GRB14). These findings provide compelling support for using traditionally-underrepresented populations for gene discovery, even with smaller sample sizes.

Limited ancestral diversity has impaired our ability to detect risk variants more prevalent in non-European ancestry groups in genome-wide association studies (GWAS). We constructed and analyzed a multi-ancestry GWAS dataset in the Alzheimer Disease (AD) Genetics Consortium (ADGC) to test for novel shared and ancestry-specific AD susceptibility loci and evaluate underlying genetic architecture in 37,382 non-Hispanic White (NHW), 6,728 African American, 8,899 Hispanic (HIS), and 3,232 East Asian individuals, performing within-ancestry fixed-effects meta-analysis followed by a cross-ancestry random-effects meta-analysis. We identified 13 loci with cross-ancestry associations including known loci at/near CR1, BIN1, TREM2, CD2AP, PTK2B, CLU, SHARPIN, MS4A6A, PICALM, ABCA7, APOE and two novel loci not previously reported at 11p12 (LRRC4C) and 12q24.13 (LHX5-AS1). Reflecting the power of diverse ancestry in GWAS, we observed the SHARPIN locus using 7.1% the sample size of the original discovering single-ancestry GWAS (n=788,989). We additionally identified three GWS ancestry-specific loci at/near (PTPRK (P=2.4E10-8) and GRB14 (P=1.7E10-8) in HIS), and KIAA0825 (P=2.9E10-8 in NHW). Pathway analysis implicated multiple amyloid regulation pathways (strongest with Padjusted=1.6E10-4) and the classical complement pathway (Padjusted=1.3E10-3). Genes at/near our novel loci have known roles in neuronal development (LRRC4C, LHX5-AS1, and PTPRK) and insulin receptor activity regulation (GRB14). These findings provide compelling support for using traditionally-underrepresented populations for gene discovery, even with smaller sample sizes.

Background The number of older women living with HIV in Africa is growing, and their health outcomes may be adversely impacted by social frailty, which reflects deficits in social resources that accumulate over the lifespan. Our objective was to adapt a Social Vulnerability Index (SVI) originally developed in Canada for use in a study of older women living with or without HIV infection in Mombasa, Kenya. Methods We adapted the SVI using a five-step process: formative qualitative work, translation into Kiswahili, a Delphi procedure, exploration of potential SVI items in qualitative work, and a rating and ranking exercise. Four focus group discussions (FGD) were conducted (three with women living with HIV and one with HIV-negative women), and two expert panels were constituted for this process. Results Themes that emerged in the qualitative work were physical impairment with aging, decreased family support, a turn to religion and social groups, lack of a financial safety net, mixed support from healthcare providers, and stigma as an added burden for women living with HIV. Based on the formative FGD, the expert panel expanded the original 19-item SVI to include 34 items. The exploratory FGD and rating and ranking exercise led to a final 16-item Kenyan version of the SVI (SVI-Kenya) with six domains: physical safety, support from family, group participation, instrumental support, emotional support, and financial security. Conclusions The SVI-Kenya is a holistic index to measure social frailty among older women in Kenya, incorporating questions in multiple domains. Further research is needed to validate this adapted instrument.

IMPORTANCE Visual function is important for older adults. Interventions to preserve vision, such as cataract extraction, may modify dementia risk. OBJECTIVE To determine whether cataract extraction is associated with reduced risk of dementia among older adults. DESIGN, SETTING, AND PARTICIPANTS This prospective, longitudinal cohort study analyzed data from the Adult Changes in Thought study, an ongoing, population-based cohort of randomly selected, cognitively normal members of Kaiser Permanente Washington. Study participants were 65 years of age or older and dementia free at enrollment and were followed up biennially until incident dementia (all-cause, Alzheimer disease, or Alzheimer disease and related dementia). Only participants who had a diagnosis of cataract or glaucoma before enrollment or during follow-up were included in the analyses (ie, a total of 3038 participants). Data used in the analyses were collected from 1994 through September 30, 2018, and all data were analyzed from April 6, 2019, to September 15, 2021. EXPOSURES The primary exposure of interest was cataract extraction. Data on diagnosis of cataract or glaucoma and exposure to surgery were extracted from electronic medical records. Extensive lists of dementia-related risk factors and health-related variables were obtained from study visit data and electronic medical records. MAIN OUTCOMES AND MEASURES The primary outcome was dementia as defined by Diagnostic and Statistical Manual of Mental Disorders (Fourth Edition) criteria. Multivariate Cox proportional hazards regression analyses were conducted with the primary outcome. To address potential healthy patient bias, weighted marginal structural models incorporating the probability of surgery were used and the association of dementia with glaucoma surgery, which does not restore vision, was evaluated. RESULTS In total, 3038 participants were included (mean [SD] age at first cataract diagnosis, 74.4 (6.2) years; 1800 women (59%) and 1238 men (41%); and 2752 (91%) self-reported White race). Based on 23 554 person-years of follow-up, cataract extraction was associated with significantly reduced risk (hazard ratio, 0.71; 95% CI, 0.62-0.83; P < .001) of dementia compared with participants without surgery after controlling for years of education, self-reported White race, and smoking history and stratifying by apolipoprotein E genotype, sex, and age group at cataract diagnosis. Similar results were obtained in marginal structural models after adjusting for an extensive list of potential confounders. Glaucoma surgery did not have a significant association with dementia risk (hazard ratio, 1.08; 95% CI, 0.75-1.56; P = .68). Similar results were found with the development of Alzheimer disease dementia. CONCLUSIONS AND RELEVANCE This cohort study found that cataract extraction was significantly associated with lower risk of dementia development. If validated in future studies, cataract surgery may have clinical relevance in older adults at risk of developing dementia.

Importance:Age-related hearing difficulties can include problems with signal audibility and central auditory processing. Studies have demonstrated associations between audibility and dementia risk. To our knowledge, limited data exist to determine whether audibility, central processing, or both drive these associations. Objective:To determine the associations between signal sensitivity, central auditory processing, and dementia and Alzheimer dementia (AD) risk. Design, Setting, and Participants:This follow-up observational study of a sample from the prospective Adult Changes in Thought study of dementia risk was conducted at Kaiser Permanente Washington, a western Washington health care delivery system, and included 280 volunteer participants without dementia who were evaluated from October 2003 to February 2006 with follow-up through September 2018. Analyses began in 2019 and continued through 2021. Exposures:Hearing tests included pure tone signal audibility, a monaural word recognition test, and 2 dichotic tests: the Dichotic Sentence Identification (DSI) test and the Dichotic Digits test (DDT). Main Outcomes and Measures:Cognition was assessed biennially with the Cognitive Abilities Screening Instrument (range, 1-100; higher scores are better), and scores of less than 86 prompted clinical and neuropsychological evaluations. All data were reviewed at multidisciplinary consensus conferences, and standardized criteria were used to define incident cases of dementia and probable or possible AD. Cox proportional hazard models were used to determine associations with hearing test performance. Results:A total of 280 participants (177 women [63%]; mean [SD] age, 79.5 [5.2] years). As of September 2018, there were 2196 person-years of follow-up (mean, 7.8 years) and 89 incident cases of dementia (66 not previously analyzed), of which 84 (94.4%) were AD (63 not previously analyzed). Compared with people with DSI scores of more than 80, the dementia adjusted hazard ratio (aHR) for DSI scores of less than 50 was 4.18 (95% CI, 2.37-7.38; P < .001); for a DSI score of 50 to 80, it was 1.82 (95% CI, 1.10-3.04; P = .02). Compared with people with DDT scores of more than 80, the dementia aHR for DDT scores of less than 50 was 2.66 (95% CI, 1.31-5.42; P = .01); for a DDT score of 50 to 80, it was 2.40 (95% CI, 1.45-3.98; P = .001). The AD results were similar. Pure tone averages were weakly and insignificantly associated with dementia and AD, and associations were null when controlling for DSI scores. Conclusions and Relevance:In this cohort study, abnormal central auditory processing as measured by dichotic tests was independently associated with dementia and AD risk.

The AT(N) research framework categorizes eight biomarker profiles using amyloid (A), tauopathy (T), and neurodegeneration (N), regardless of dementia status. We evaluated associations with dementia risk in a community-based cohort by approximating AT(N) profiles using autopsy-based neuropathology correlates, and considered cost implications for clinical trials for secondary prevention of dementia based on AT(N) profiles. We used Consortium to Establish a Registry for Alzheimer's Disease (moderate/frequent) to approximate A+, Braak stage (IV-VI) for T+, and temporal pole lateral ventricular dilation for (N)+. Outcomes included dementia prevalence at death and incidence in the last 5 years of life. A+T+(N)+ was the most common profile (31%). Dementia prevalence ranged from 14% (A-T-[N]-) to 79% (A+T+[N]+). Between 8% (A+T-[N]-) and 68% (A+T+[N]-) of decedents developed incident dementia in the last 5 years of life. Clinical trials would incur substantial expense to characterize AT(N). Many people with biomarker-defined preclinical Alzheimer's disease will never develop clinical dementia during life, highlighting resilience to clinical expression of AD neuropathologic changes and the need for improved tools for prediction beyond current AT(N) biomarkers.

BACKGROUND:Vascular disease is a risk factor for Alzheimer's disease (AD) and related dementia in older adults. Retinal artery/vein occlusion (RAVO) is an ophthalmic complication of systemic vascular pathology. Whether there are associations between RAVO and dementia risk is unknown.OBJECTIVE:To determine whether RAVOs are associated with an increased risk of developing vascular dementia or AD.METHODS:Data from Adult Changes in Thought (ACT) study participants were analyzed. This prospective, population-based cohort study followed older adults (age ≥65 years) who were dementia-free at enrollment for development of vascular dementia or AD based on research criteria. RAVO diagnoses were extracted from electronic medical records. Cox-regression survival analyses were stratified by APOEɛ4 genotype and adjusted for demographic and clinical factors.RESULTS:On review of 41,216 person-years (4,743 participants), 266 (5.6%) experienced RAVO. APOEɛ4 carriers who developed RAVO had greater than four-fold higher risk for developing vascular dementia (Hazard Ratio [HR] 4.54, 95% Confidence Interval [CI] 1.86, 11.10, p = 0.001). When including other cerebrovascular disease (history of carotid endarterectomy or transient ischemic attack) in the model, the risk was three-fold higher (HR 3.06, 95% CI 1.23, 7.62). No other conditions evaluated in the secondary analyses were found to confound this relationship. There was no effect in non-APOEɛ4 carriers (HR 1.03, 95% CI 0.37, 2.80). There were no significant associations between RAVO and AD in either APOE group.CONCLUSION:Older dementia-free patients who present with RAVO and carry the APOEɛ4 allele appear to be at higher risk for vascular dementia.

Operationalizations of mild cognitive impairment (MCI) are inconsistent. Actuarial criteria have been proposed to improve accuracy. We investigated dementia and Alzheimer’s disease (AD) conversion for conventional versus actuarial MCI criteria in a community-based prospective cohort study. 1413 non-demented participants were administered measures from memory, language, and attention/executive function domains. We used published norms to generate demographically-adjusted z-scores. Conventional MCI criteria were met for scores >1.5sd below the mean on any measure. Actuarial MCI criteria were met for 2 scores >1.0sd below the mean in one domain or a score >1.0sd below the mean in all three domains. Participants were followed biennially to capture dementia incidence. A consensus conference used DSM-IV dementia criteria and NINDS-ADRDA AD criteria for diagnosis. We focused on 6-year outcomes following MCI categorization. At baseline, n=875 (62%) met neither conventional nor actuarial MCI criteria, n=16 (1%) met only actuarial MCI criteria, n=383 (27%) met only conventional MCI criteria, and n=139 (10%) met both. Demographic characteristics are in Table 1. Education differed across criteria (p<0.0001); more people with lower education met only conventional MCI criteria. During follow up (7090 person-years, mean=5 years), there were 175 incident dementia cases, of whom 110 (63%) met conventional and 53 (30%) met actuarial MCI criteria at their baseline neuropsychological evaluation. In a Cox model adjusting for age, sex, education, and race/ethnicity, the conventional MCI dementia hazard ratio (HR) was 2.93 (95% CI 2.15, 4.01, p<0.001), and the actuarial MCI HR was 3.62 (95% CI 2.60, 5.03; p<0.001). There were 154 incident AD cases; 101 (66%) met conventional and 49 (32%) met actuarial criteria. The adjusted conventional MCI AD HR was 3.25 (95% CI 2.32, 4.56, p<0.001), and the actuarial MCI AD HR was 3.81 (95% CI 2.69, 5.38, p<0.001). Both conventional and actuarial MCI criteria identified individuals at higher risk of developing dementia and AD over 6 years of follow-up. Conventional criteria flag a higher proportion of those who ultimately developed dementia and AD compared to actuarial criteria. However, hazard ratios for progression to dementia and AD were slightly higher for the actuarial criteria.

BACKGROUND:Higher glucose levels are associated with dementia risk in people with and without diabetes. However, little is known about how this association might vary by hypertension status and antihypertensive treatment. Most studies on modifiable dementia risk factors consider each factor in isolation. OBJECTIVE:To test the hypothesis that hypertension and antihypertensive treatments may modify associations between glucose levels and dementia. METHODS:Analyses of data generated from a research study and clinical care of participants from a prospective cohort of dementia-free older adults, including glucose measures, diabetes and antihypertensive treatments, and blood pressure data. We defined groups based on blood pressure (hypertensive versus not, ≥140/90 mmHg versus <140/90 mmHg) and antihypertensive treatment intensity (0, 1, or ≥2 classes of antihypertensives). We used Bayesian joint models to jointly model longitudinal exposure and time to event data. RESULTS:A total of 3,056 participants without diabetes treatment and 480 with diabetes treatment were included (mean age at baseline, 75.1 years; mean 7.5 years of follow-up). Higher glucose levels were associated with greater dementia risk among people without and with treated diabetes. Hazard ratios for dementia were similar across all blood pressure/antihypertensive treatment groups (omnibus p = 0.82 for people without and p = 0.59 for people with treated diabetes). CONCLUSION:Hypertension and antihypertensive treatments do not appear to affect the association between glucose and dementia risk in this population-based longitudinal cohort study of community-dwelling older adults. Future studies are needed to examine this question in midlife and by specific antihypertensive treatments.

Background: There is considerable heterogeneity in clinical presentation among people with late-onset Alzheimer's disease (LOAD). We have categorized people with LOAD into subgroups based on relative impairments across cognitive domains. These 6 groups are people with no relatively impaired domains (AD-No Domains), 4 groups with one relatively impaired domain (AD-Memory, AD-Executive, AD-Language, and AD-Visuospatial), and a group with multiple relatively impaired domains (AD-Multiple Domains). Our previous analysis demonstrated that genetic factors vary across cognitively-defined LOAD groups. Objective: To determine whether risks associated with depression and traumatic brain injury with loss of consciousness (TBI) for cognitively defined LOAD subgroups are similar. Methods: We used cognitive data at LOAD diagnosis from three prospective cohort studies to determine cognitively-defined subgroups. We compared subgroups in endorsement of items from the Centers for Epidemiological Studies Depression (CES-D) scale and history of TBI. Results: Among 1,505 people with LOAD from the three studies, there were substantial differences across subgroups in total CES-D score, with lower scores (less depression) for people with AD with relative impairments in memory (AD-Memory) compared to those in other groups. Differences were noteworthy for the sleep-related item of the CES-D, as people with AD-Memory were less likely to report restless sleep than people in other groups. There were no differences in TBI history across groups. Conclusions: Differences in risk factor associations across subgroups such as differences in endorsement of depression symptoms and restless sleep provide support for the hypothesis that there are biologically coherent subgroups of AD.

Lack of a unitary operational definition of mild cognitive impairment (MCI) has resulted in mixed prevalence rates and unclear predictive validity regarding conversion to dementia and likelihood of reversion. We examined 1,721 nondemented participants aged 65 and older from the Adult Changes in Thought (ACT) community-based cohort. Participants were followed longitudinally through biennial visits (average years assessed = 5.38). Categorization of MCI was based on: 1) deviation of neuropsychological test scores from a benchmark based on either standard or individualized expectations of a participant's mean premorbid cognitive ability, and 2) cutoff for impairment (1.0 versus 1.5 standard deviations [sd] below benchmark). MCI prevalence ranged from 56-92%; using individualized benchmarks and less stringent cutoffs produced higher rates. During follow-up, 17% of the cohort developed dementia. Examination of sensitivity, specificity, and predictive validity revealed that the criterion of 1.5 sd from the standardized benchmark was optimal, but still had limited predictive validity. Participants meeting this criterion at their first visit were three times more likely to develop dementia and this increased to seven times if participants had this diagnosis at the second timepoint as well. Those who did not have an MCI diagnosis at their first visit, but did at their second, had a significant increase of risk (but to a lesser extent than those diagnosed at both visits), while those who had an MCI diagnosis at their first visit, but not their second, did not have a significantly increased risk. These results highlight how assessing MCI stability greatly improves prediction of risk.

Studies have separately shown associations between dementia risk and glucose levels and blood pressure (BP) and antihypertensives. We sought to determine whether glucose-dementia relationships differed across BP and antihypertensive-defined groups. We used Adult Changes in Thought (ACT) study data through September 30, 2016. We obtained blood pressure measures from ACT study visits, and glucose/hemoglobin A1c (HbA1c) results and diabetes and antihypertensive medications from clinical databases. Cognition was evaluated every 2 years with the Cognitive Abilities Screening Instrument (CASI). People with low scores had additional clinical and cognitive evaluations, with dementia (DSM-IV criteria) identified in a consensus conference. We estimated associations between glucose and dementia onset in 6 groups defined by time-varying BP (controlled, defined as <140/90 mmHg, vs. uncontrolled) and extent of antihypertensive treatment (0, 1, or ≥2 drugs). We used a Bayesian joint model framework with age as the time scale. We included main effects for each of the 6 groups, current glucose values, the glucose rate of change (slope), and interactions between groups and the glucose level and slope. We adjusted for enrollment cohort, sex, education, exercise, coronary artery and cerebrovascular disease, atrial fibrillation, and smoking status. Of the included 3056 participants, 670 developed dementia over 23,680 person-years of follow-up (mean 7.7 years per person). In models that included current glucose and slope, the slope was associated with higher dementia risk. The hazard ratio (HR) associated with each 10mg/dL/year greater slope was 1.030 (95% CI 1.017-1.044). We did not detect interactions between group membership and glucose-dementia associations for level or slope. We found lower dementia risk in the group with uncontrolled blood pressure with ≥2 medications. The HR for that group compared to those with controlled blood pressure and ≥2 medications was 0.69 (95% CI 0.53, 0.92). Other groups did not differ in AD risk. Associations between blood pressure, antihypertensive medications, and glucose levels and dementia risk are complicated. Our data suggest the glucose/dementia relationship is independent of the blood pressure / antihypertensives / dementia relationship. These risk factors may impact dementia risk through independent mechanisms, which should be explored in future research.

OBJECTIVES:To evaluate associations between high-density lipoprotein cholesterol (HDL) and non-HDL-C levels at specific ages and subsequent Alzheimer's disease (AD) risk.DESIGN:Prospective population-based cohort study.SETTING:Adult Changes in Thought (ACT) Study.PARTICIPANTS:Individuals aged 65 and older with no dementia at ACT Study entry. We identified separate, partially overlapping subcohorts of ACT participants who were eligible for each age band-specific analysis (50-59, n = 1,088; 60-69, n = 2,852; 70-79, n = 2,344; 80-89, n = 537).MEASUREMENTS:Exposure consisted of clinical measures of total cholesterol (TC) and HDL-C from laboratory data during a given age band. Outcomes of incident AD were assessed post-age band using standard research diagnostic criteria. Statistical analyses used adjusted Cox proportional hazards regression models for each exposure and outcome pair within an age band. Cholesterol exposures were modeled using cubic splines.RESULTS:For non-HDL-C, we found a statistically significant association with AD risk in the 60 to 69 (omnibus p = .005) and 70 to 79 (omnibus p = .04) age bands, suggesting a potential U-shaped relationship (greater risk at low and high levels). For example, in people aged 60 to 69, those with an average non-HDL-C level of 120 mg/DL had a 29% greater AD hazard (hazard ratio (HR)=1.29, 95% confidence interval (CI)=1.04-1.61) than those with an average non-HDL-C level of 160 mg/dL, whereas those with an average non-HDL-C level of 210 mg/dL had a 16% greater hazard (HR=1.16, 95% CI=1.01-1.33). We did not find a statistically significant association between HDL-C and AD risk.CONCLUSION:People with low (120 mg/dL) and high (210 mg/dL) non-HDL-C levels during their 60s and 70s had modestly higher risk of AD than those with intermediate (160 mg/dL) levels. The extreme age bands (50s and 80s) had small sample sizes. J Am Geriatr Soc 66:2344-2352, 2018.

An amendment to this paper has been published and can be accessed via a link at the top of the paper.

Introduction: Identifying ophthalmic diseases associated with increased risk of Alzheimer's disease (AD) may enable better screening and understanding of those at risk of AD. Methods: Diagnoses of glaucoma, age-related macular degeneration (AMD), and diabetic retinopathy (DR) were based on International Classification of Diseases, 9th revision, codes for 3877 participants from the Adult Changes in Thought study. The adjusted hazard ratio for developing probable or possible AD for recent (within 5 years) and established (>5 years) diagnoses were assessed. Results: Over 31,142 person-years of follow-up, 792 AD cases occurred. The recent and established hazard ratio were 1.46 (P = .01) and 0.87 (P = .19) for glaucoma, 1.20 (P = .12) and 1.50 (P < .001) for AMD, and 1.50 (P = .045) and 1.50 (P = .03) for DR. Discussion: Increased AD risk was found for recent glaucoma diagnoses, established AMD diagnoses, and both recent and established DR. People with certain ophthalmic conditions may have increased AD risk. (C) 2018 the Alzheimer's Association. Published by Elsevier Inc. All rights reserved.

INTRODUCTION:Identifying ophthalmic diseases associated with increased risk of Alzheimer's disease (AD) may enable better screening and understanding of those at risk of AD. METHODS:Diagnoses of glaucoma, age-related macular degeneration (AMD), and diabetic retinopathy (DR) were based on International Classification of Diseases, 9th revision, codes for 3877 participants from the Adult Changes in Thought study. The adjusted hazard ratio for developing probable or possible AD for recent (within 5 years) and established (>5 years) diagnoses were assessed. RESULTS:Over 31,142 person-years of follow-up, 792 AD cases occurred. The recent and established hazard ratio were 1.46 (P = .01) and 0.87 (P = .19) for glaucoma, 1.20 (P = .12) and 1.50 (P < .001) for AMD, and 1.50 (P = .045) and 1.50 (P = .03) for DR. DISCUSSION:Increased AD risk was found for recent glaucoma diagnoses, established AMD diagnoses, and both recent and established DR. People with certain ophthalmic conditions may have increased AD risk.

Background: A recent Alzheimer's disease research diagnosis framework groups amyloid (A), tauopathy (T), and neurodegeneration (N) biomarkers into eight AT(N) profiles. We determined prevalence at death of each profile in the Adult Changes in Thought (ACT) community-based cohort. Within each profile, we determined dementia prevalence at death and incident dementia among those dementia free 5-7 years antemortem. Methods: Setting: prospective study of individuals ≥65 years; 25-30% consented to autopsy. Cognition was prospectively evaluated every 2 years and dementia determined using research criteria. At autopsy, A used CERAD levels (none/sparse vs. moderate/frequent), T used Braak staging (0-III vs. IV-VI), and N used absence vs. presence of lateral ventricular dilation at the temporal tip. We compared prevalent and incident dementia for each AT(N) profile. We used inverse-probability weighting to address potential selection bias, and considered the relevance of seven additional autopsy findings in predicting dementia status. Findings: Of 5,236 ACT participants, 2,870 died, and 603 had known dementia status and autopsy. The two most common profiles were A+T+(N)+ (31%) and A-T-(N)+ (22%). Dementia prevalence ranged from 14% (A-T-(N)-) to 79% (A+T+(N)+). Dementia incidence ranged from 8% (A+T-(N)-) to 67% (A+T+(N)+) and 68% (A+T+(N)-). Each additional neuropathological finding was associated with 7% (prevalence) to 9% (incidence) higher dementia risk independent of A,T and (N) (prevalence RR 1·07 (95% CI: 1·05-1·10); incidence RR 1·09 (95% CI: 1·05-1·14)). Interpretation: Dementia rates varied across AT(N) categories. Costs of determining AT(N) status may be considerable. That >30% of dementia-free people with the highest risk AT(N) categories did not develop incident dementia before death suggests restraint in population-based settings for treatments with more than trivial toxicity. Funding Statement: National Institute on Aging (US National Institutes of Health). (AG006781)Declaration of Interests: PKC reports grants from the US National Institutes of Health (NIH) and prior funding from the Alzheimer’s Association.Ethics Approval Statement: Study procedures were approved by KPW and UW institutional review boards. Participants provided written informed consent.

Sven van der Lee, Julie Williams, Gerard Schellenberg and colleagues identify rare coding variants in PLCG2, ABI3 and TREM2 associated with Alzheimer's disease. These genes are highly expressed in microglia and provide additional evidence that the microglia-mediated immune response contributes to the development of Alzheimer's disease. We identified rare coding variants associated with Alzheimer's disease in a three-stage case–control study of 85,133 subjects. In stage 1, we genotyped 34,174 samples using a whole-exome microarray. In stage 2, we tested associated variants (P < 1 × 10−4) in 35,962 independent samples using de novo genotyping and imputed genotypes. In stage 3, we used an additional 14,997 samples to test the most significant stage 2 associations (P < 5 × 10−8) using imputed genotypes. We observed three new genome-wide significant nonsynonymous variants associated with Alzheimer's disease: a protective variant in PLCG2 (rs72824905: p.Pro522Arg, P = 5.38 × 10−10, odds ratio (OR) = 0.68, minor allele frequency (MAF)cases = 0.0059, MAFcontrols = 0.0093), a risk variant in ABI3 (rs616338: p.Ser209Phe, P = 4.56 × 10−10, OR = 1.43, MAFcases = 0.011, MAFcontrols = 0.008), and a new genome-wide significant variant in TREM2 (rs143332484: p.Arg62His, P = 1.55 × 10−14, OR = 1.67, MAFcases = 0.0143, MAFcontrols = 0.0089), a known susceptibility gene for Alzheimer's disease. These protein-altering changes are in genes highly expressed in microglia and highlight an immune-related protein–protein interaction network enriched for previously identified risk genes in Alzheimer's disease. These genetic findings provide additional evidence that the microglia-mediated innate immune response contributes directly to the development of Alzheimer's disease.