Exploring the Role of the NO-Detoxifying Enzyme HmpA in the Evolution of Domesticated Alfalfa Rhizobia.

We have previously shown the extensive loss of genes during the domestication of alfalfa rhizobia and the high nitrous oxide emission associated with the extreme genomic instability of commercial inoculants. In the present note, we describe the molecular mechanism involved in the evolution of alfalfa rhizobia. Genomic analysis showed that most of the gene losses in inoculants are due to large genomic deletions rather than to small deletions or point mutations, a fact consistent with recurrent DNA double-strand breaks (DSBs) at numerous locations throughout the microbial genome. Genetic analysis showed that the loss of the NO-detoxifying enzyme HmpA in inoculants results in growth inhibition and high DSB levels under nitrosative stress, and large genomic deletions in planta but not in the soil. Therefore, besides its known function in the effective establishment of the symbiosis, HmpA can play a critical role in the preservation of the genomic integrity of alfalfa rhizobia under host-derived nitrosative stress.

Adaptation of a social vulnerability index for measuring social frailty among East African women.

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.

Theoretical impact of the AT(N) framework on dementia using a community autopsy sample.

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.

Spontaneous Mutations in the Nitrate Reductase Gene napC Drive the Emergence of Eco-friendly Low-N2O-Emitting Alfalfa Rhizobia in Regions with Different Climates.

We have recently shown that commercial alfalfa inoculants (e.g., Sinorhizobium meliloti B399), which are closely related to the denitrifier model strain Sinorhizobium meliloti 1021, have conserved nitrate, nitrite, and nitric oxide reductases associated with the production of the greenhouse gas nitrous oxide (N2O) from nitrate but lost the N2O reductase related to the degradation of N2O to gas nitrogen. Here, we screened a library of nitrogen-fixing alfalfa symbionts originating from different ecoregions and containing N2O reductase genes and identified novel rhizobia (Sinorhizobium meliloti INTA1-6) exhibiting exceptionally low N2O emissions. To understand the genetic basis of this novel eco-friendly phenotype, we sequenced and analyzed the genomes of these strains, focusing on their denitrification genes, and found mutations only in the nitrate reductase structural gene napC. The evolutionary analysis supported that, in these natural strains, the denitrification genes were inherited by vertical transfer and that their defective nitrate reductase napC alleles emerged by independent spontaneous mutations. In silico analyses showed that mutations in this gene occurred in ssDNA loop structures with high negative free energy (-ΔG) and that the resulting mutated stem-loop structures exhibited increased stability, suggesting the occurrence of transcription-associated mutation events. In vivo assays supported that at least one of these ssDNA sites is a mutational hot spot under denitrification conditions. Similar benefits from nitrogen fixation were observed when plants were inoculated with the commercial inoculant B399 and strains INTA4-6, suggesting that the low-N2O-emitting rhizobia can be an ecological alternative to the current inoculants without resigning economic profitability.

Associations between recent and established ophthalmic conditions and risk of Alzheimer's disease.

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.

Impact of home visit capacity on genetic association studies of late-onset Alzheimer's disease.

INTRODUCTION: Findings for genetic correlates of late-onset Alzheimer's disease (LOAD) in studies that rely solely on clinic visits may differ from those with capacity to follow participants unable to attend clinic visits. METHODS: We evaluated previously identified LOAD-risk single nucleotide variants in the prospective Adult Changes in Thought study, comparing hazard ratios (HRs) estimated using the full data set of both in-home and clinic visits (n = 1697) to HRs estimated using only data that were obtained from clinic visits (n = 1308). Models were adjusted for age, sex, principal components to account for ancestry, and additional health indicators. RESULTS: LOAD associations nominally differed for 4 of 21 variants; CR1 and APOE variants were significant after Bonferroni correction. DISCUSSION: Estimates of genetic associations may differ for studies limited to clinic-only designs. Home visit capacity should be explored as a possible source of heterogeneity and potential bias in genetic studies.

Incidence of cognitively defined late-onset Alzheimer's dementia subgroups from a prospective cohort study.

INTRODUCTION: There may be biologically relevant heterogeneity within typical late-onset Alzheimer's dementia. METHODS: We analyzed cognitive data from people with incident late-onset Alzheimer's dementia from a prospective cohort study. We determined individual averages across memory, visuospatial functioning, language, and executive functioning. We identified domains with substantial impairments relative to that average. We compared demographic, neuropathology, and genetic findings across groups defined by relative impairments. RESULTS: During 32,286 person-years of follow-up, 869 people developed Alzheimer's dementia. There were 393 (48%) with no domain with substantial relative impairments. Some participants had isolated relative impairments in memory (148, 18%), visuospatial functioning (117, 14%), language (71, 9%), and executive functioning (66, 8%). The group with isolated relative memory impairments had higher proportions with ≥ APOE ε4 allele, more extensive Alzheimer's-related neuropathology, and higher proportions with other Alzheimer's dementia genetic risk variants. DISCUSSION: A cognitive subgrouping strategy may identify biologically distinct subsets of people with Alzheimer's dementia.

Glucose levels and risk of dementia.

BACKGROUND: Diabetes is a risk factor for dementia. It is unknown whether higher glucose levels increase the risk of dementia in people without diabetes. METHODS: We used 35,264 clinical measurements of glucose levels and 10,208 measurements of glycated hemoglobin levels from 2067 participants without dementia to examine the relationship between glucose levels and the risk of dementia. Participants were from the Adult Changes in Thought study and included 839 men and 1228 women whose mean age at baseline was 76 years; 232 participants had diabetes, and 1835 did not. We fit Cox regression models, stratified according to diabetes status and adjusted for age, sex, study cohort, educational level, level of exercise, blood pressure, and status with respect to coronary and cerebrovascular diseases, atrial fibrillation, smoking, and treatment for hypertension. RESULTS: During a median follow-up of 6.8 years, dementia developed in 524 participants (74 with diabetes and 450 without). Among participants without diabetes, higher average glucose levels within the preceding 5 years were related to an increased risk of dementia (P=0.01); with a glucose level of 115 mg per deciliter (6.4 mmol per liter) as compared with 100 mg per deciliter (5.5 mmol per liter), the adjusted hazard ratio for dementia was 1.18 (95% confidence interval [CI], 1.04 to 1.33). Among participants with diabetes, higher average glucose levels were also related to an increased risk of dementia (P=0.002); with a glucose level of 190 mg per deciliter (10.5 mmol per liter) as compared with 160 mg per deciliter (8.9 mmol per liter), the adjusted hazard ratio was 1.40 (95% CI, 1.12 to 1.76). CONCLUSIONS: Our results suggest that higher glucose levels may be a risk factor for dementia, even among persons without diabetes. (Funded by the National Institutes of Health.)

Importance of home study visit capacity in dementia studies.

INTRODUCTION: The importance of home research study visit capacity in Alzheimer's disease (AD) studies is unknown. METHODS: All evaluations are from the prospective Adult Changes in Thought study. Based on analyses of factors associated with volunteering for a new in-clinic initiative, we analyzed AD risk factors and the relevance of neuropathologic findings for dementia comparing all data including home visits, and in-clinic data only. We performed bootstrapping to determine whether differences were greater than expected by chance. RESULTS: Of the 1781 people enrolled during 1994-1996 with ≥1 follow-up, 1369 (77%) had in-clinic data, covering 61% of follow-up time. In-clinic data resulted in excluding 76% of incident dementia and AD cases. AD risk factors and the relevance of neuropathologic findings for dementia were both different with in-clinic data. DISCUSSION: Limiting data collection in AD studies to research clinics alone likely reduces power and also can lead to erroneous inferences.

Characterization of dementia and Alzheimer's disease in an older population: updated incidence and life expectancy with and without dementia.

OBJECTIVES: We estimated dementia incidence rates, life expectancies with and without dementia, and percentage of total life expectancy without dementia. METHODS: We studied 3605 members of Group Health (Seattle, WA) aged 65 years or older who did not have dementia at enrollment to the Adult Changes in Thought study between 1994 and 2008. We estimated incidence rates of Alzheimer's disease and dementia, as well as life expectancies with and without dementia, defined as the average number of years one is expected to live with and without dementia, and percentage of total life expectancy without dementia. RESULTS: Dementia incidence increased through ages 85 to 89 years (74.2 cases per 1000 person-years) and 90 years or older (105 cases per 1000 person-years). Life expectancy without dementia and percentage of total life expectancy without dementia decreased with age. Life expectancy with dementia was longer in women and people with at least a college degree. Percentage of total life expectancy without dementia was greater in younger age groups, men, and those with more education. CONCLUSIONS: Efforts to delay onset of dementia, if successful, would likely benefit older adults of all ages.

Incidence rates of dementia, Alzheimer disease, and vascular dementia in the Japanese American population in Seattle, WA: the Kame Project.

There are few studies on the incidence of dementia in representative minority populations in the United States; however, no population-based study has been conducted on Japanese American women. We identified 3045 individuals aged 65+ with at least 1 parent of Japanese descent living in King County, WA in the period 1992 to 1994, of whom 1836 were dementia-free and were examined every 2 years (1994 to 2001) to identify incident cases of all dementias, Alzheimer disease (AD), vascular dementia (VaD), and other dementias. Cox regression was used to examine associations with age, sex, years of education, and apolipoprotein (APOE)-ε4. Among 173 incident cases of dementia, the overall rate was 14.4/1000/y, with rates being slightly higher among women (15.9/1000) than men (12.5/1000). Rates roughly doubled every 5 years for dementia and AD; the age trend for VaD and other dementias was less consistent. Sex was not significantly related to incidence of dementia or its subtypes in adjusted models. There was a trend for an inverse association with increasing years of education. APOE-ε4 was a strong risk factor for all dementias [hazard ratio (HR)=2.89; 95% confidence interval (CI), 1.88-4.46], AD (HR=3.27; 95% CI, 2.03-5.28), and VaD (HR=3.33; 95% CI, 1.34-8.27). This study is the first to report population-based incidence rates for both Japanese American men and women.

Diabetic Retinopathy and Dementia Association, Beyond Diabetes Severity.

PURPOSE: To investigate whether associations between diabetic retinopathy (DR) and dementia and Alzheimer's disease (AD) remain significant after controlling for several measures of diabetes severity. DESIGN: Retrospective cohort study. METHODS: Adult Changes in Thought (ACT) is a prospective cohort study of adults aged ≥65 years, randomly selected and recruited from the membership rolls of Kaiser Permanente Washington, who are dementia free at enrollment and followed biennially until incident dementia. The ACT participants were included in this study if they had type 2 diabetes mellitus at enrollment or developed it during follow-up, and data were collected through September, 2018 (3516 person-years of follow-up). Diabetes was defined by ≥ 2 diabetes medication fills in 1 year. Diagnosis of DR was based on International Classification 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 disease and dementia were diagnosed using research criteria at expert consensus meetings. RESULTS: A total of 536 participants (median baseline age 75 [interquartile range 71-80], 54% women) met inclusion 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]). CONCLUSIONS: Among people with type 2 diabetes, DR itself appears to be an important biomarker of dementia risk in addition to glycemia and renal complications.

Multiple ways to evade the bacteriostatic action of glyphosate in rhizobia include the mutation of the conserved serine 90 of the nitrogenase subunit NifH to alanine.

The genome resequencing of spontaneous glyphosate-resistant mutants derived from the soybean inoculant E109 allowed identifying genes most likely associated with the uptake (gltL and cya) and metabolism (zigA and betA) of glyphosate, as well as with nitrogen fixation (nifH). Mutations in these genes reduce the lag phase and improve nodulation under glyphosate stress. In addition to providing glyphosate resistance, the amino acid exchange Ser90Ala in NifH increased the citrate synthase activity, growth rate and plant growth-promoting efficiency of E109 in the absence of glyphosate stress, suggesting roles for this site during both the free-living and symbiotic growth stages.

Association Between Cataract Extraction and Development of Dementia.

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.

Association of Performance on Dichotic Auditory Tests With Risk for Incident Dementia and Alzheimer 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.

Interdisciplinary collaboration in geriatrics: advancing health for older adults.

The call for interdisciplinary research, education, and practice is heightened by the recognition of the potential it holds in generating creative solutions to complex problems in health care and to improving quality and effectiveness of care. With the aging of the population and the complex issues in caring for older adults, interdisciplinary collaboration is particularly salient to the field of geriatrics. However, despite interest in this approach for several decades, adoption has been slow and dissemination is not widespread. This article provides examples of recent initiatives and presents driving and restraining forces involved in adoption of interdisciplinary approaches.

Development and evaluation of a target enrichment bait set for phylogenetic analysis of oomycetes.

Target enrichment is a term that encompasses multiple related approaches where desired genomic regions are captured by molecular baits, leaving behind redundant or non-target regions in the genome, followed by amplification and next-generation sequencing of those captured regions. A molecular bait set was developed based on 426 single-copy, oomycete-specific orthologs and 3 barcoding genes. The bait set was tested on 27 oomycete samples (belonging to the Saprolegniales, Albuginales, and Peronosporales) derived from live and herbarium specimens, as well as control samples of true fungi and plants. Results show that (i) our method greatly enriches for the targeted orthologs on oomycete samples, but insignificantly on fungal and plant samples; (ii) an average of 263 out of 429 orthologs (61%) were recovered from oomycete live and herbarium specimens; (iii) sequencing roughly 100 000 read pairs per sample is sufficient for optimal ortholog recovery while maintaining low sequencing costs; and (iv) the expected relationships were recovered by phylogenetic analysis from the data generated. This is the first report of an oomycete-specific target enrichment method with broad potential applications for evolutionary and taxonomic studies. A key benefit of our target enrichment method is that it allows researchers to easily unlock the vast and unexplored oomycete genomic diversity stored in natural history collections.

Glucose-Dementia Association Is Consistent Over Blood Pressure/Antihypertensive Groups.

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.

Associations Between Retinal Artery/Vein Occlusions and Risk of Vascular Dementia.

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.