Risk Of Incident Alzheimer's Disease Research Articles

Statin Initiation and Risk of Incident Alzheimer Disease and Cognitive Decline in Genetically Susceptible Older Adults.

The association of statin initiation with incident Alzheimer disease (AD) dementia and cognitive decline by the APOE ε4 allele is unknown. Our objective was to examine whether the association of statin initiation with incident AD dementia and cognitive decline differs by the APOE ε4 allele. This population-based longitudinal cohort study was conducted in 4 urban communities in Chicago, IL, United States, consisting of 4,807 participants. Statin initiation is based on the inspection of medications during home assessments. Clinical diagnosis for incident AD used the NINCDS-ADRDA criteria, and longitudinal measurements of global cognition consisted of episodic memory, perceptual speed, and the Mini-Mental State Examination tests. The study participants had a mean age of 72 years, consisting of 63% female individuals and 61% non-Hispanic Black individuals. During the study period, 1,470 (31%) participants reported statin initiation. In a covariate-adjusted competing risk model, statin initiation was associated with a reduced risk of incident clinical AD [hazard ratio (HR) 0.81 (95% CI 0.70-0.94)] compared with nonusers. This association was statistically significantly lower (p interaction = 0.015) among participants with the APOE ε4 allele [HR 0.60 (95% CI 0.49-0.74)] compared with those without the APOE ε4 allele [HR 0.96 (95% CI 0.82-1.12)]. The annual decline in global cognition (β = 0.021, 95% CI 0.007-0.034) and episodic memory (β = 0.020, 95% CI 0.007-0.033) was also substantially slower among participants with the APOE ε4 allele after statin initiation compared with nonusers. However, the association of statin initiation with cognitive decline was not significant among those without the APOE ε4 allele. Our findings suggest that statins might be associated with a lower risk of incident AD among individuals with the APOE ε4 allele. The benefits of statin therapy need further consideration in randomized clinical trials, especially among those with the APOE ε4 allele. This study provides Class II evidence that among those aged 65 years or older, statin initiation was associated with a reduced risk of Alzheimer disease, especially in the presence of an APOE-e4 allele.

Reproductive Markers in Alzheimer's Disease Progression: The Framingham Heart Study.

Reproductive status, such as the age of menarche or menopause, may be linked to cognitive abilities and risk for incident Alzheimer's disease (AD) but the evidence is conflicting. It is also not fully known if these factors interact with cortical beta-amyloid deposition. To study the relationship between reproductive risks, sex hormone markers and risk for decline in specific cognitive domains in women. We analyzed the association of reproductive markers (age at menarche, number of births, age at menopause, sex hormone-binding globulin, estradiol, estrone, total testosterone, free testosterone) with incident AD and annualized cognitive decline in the community-based longitudinal Framingham Heart Study (FHS) Offspring women 60 years and older (n=772, mean age 68 years, mean follow-up 10.7 ± 3 years). We used the Cox proportional hazards regression model and linear regression model, adjusting for covariates. Incident AD dementia as well as the annualized change in memory, language, attention and executive functions. Older age at menopause was associated with a lower risk of incident AD dementia (p = 0.047, 6% lower risk per older year) after adjusting for baseline age, education, hormone therapy status, and MMSE score. Older age at menopause was significantly associated with a slower annualized decline in memory (beta = 0.085, p = 0.00059). The lower level of plasma Aβ42 was also associated with a higher risk of incident AD (HR = 0.97, 95% CI = 0.95, 0.99; p = 0.0039) but there was no significant interaction effect with age at menarche, age at menopause or plasma sex hormone levels. Younger age at menopause is a risk factor for late-life memory decline and incident AD. This risk appears to be independent of Aβ42 pathology. Further studies to understand the biological and social mechanisms underlying the differential effects of reproductive risks are warranted.

Effect of antioxidant intake patterns on risks of dementia and cognitive decline.

Previous studies have suggested that increased antioxidant intakes might reduce risk of cognitive disorders including Alzheimer's disease (AD). Which avenue of antioxidant intake (vitamin E/C) is more effective for decreasing risk, however, is largely unknown. To quantitatively investigate the relationships between the pattern of antioxidant intakes and risks of dementia and cognitive decline. We searched all related prospective cohort studies reporting antioxidant intakes (diet and/or supplement) from patients with cognitive disorders. We conducted dose-response meta-analyses to assess potential linear and non-linear dose-response relationships. Summary RRs and 95% CIs were calculated using a random- or fixed-effects model. 73 eligible cohort studies totaling > 28,257 participants were included in the meta-analysis; the pooled relative risks of AD were 0.75 (95% CI 0.57-0.99; I2 = 59.9%) for the dietary only intake of vitamin E, 0.73 (95% CI 0.54-1.00; I2 = 0%) for the dietary plus supplemental intake of vitamin E, and 0.70 (95% CI 0.51-0.95; I2 = 0%) for the dietary plus supplemental intake of vitamin C. Moreover, pooled RRs of AD and vitamin C intake per 20mg/day increase were 0.98 (95% CI 0.97-0.99) via dietary plus supplemental intake, 0.98 (95% CI 0.96-1.00) in the dietary only intake and 0.98 (95% CI 0.98-0.99) in the overall intake. There were no significant associations of all-cause dementia or cognitive impairment no dementia with the antioxidant intake. The risk of incident AD is significantly reduced by higher consumption of vitamin C by the intake avenue of diet plus supplement.

Diabetic Retinopathy Predicts Risk of Alzheimer's Disease: A Danish Registry-Based Nationwide Cohort Study.

Background:Retinal neurodegeneration is evident in early diabetic retinopathy (DR) which may be associated with other neurodegenerative diseases like Alzheimer's disease (AD).Objective:To investigate diabetes and DR as a risk marker of present and incident AD.Methods:A register-based cohort study was performed. We included 134,327 persons with diabetes above 60 years of age, who had attended DR screening, and 651,936 age- and gender-matched persons without diabetes.Results:At baseline, the prevalence of AD was 0.7% and 1.3% among patients with and without diabetes, respectively. In a multivariable regression model, patients with diabetes were less likely to have AD at baseline (adjusted OR 0.63, 95% CI 0.59–0.68). During follow-up, incident AD was registered for 1473 (0.35%) and 6,899 (0.34%) persons with and without diabetes, respectively. Compared to persons without diabetes, persons with diabetes and no DR had a lower risk to develop AD (adjusted HR 0.87, 95% CI 0.81–0.93), while persons with diabetes and DR had higher risk of AD (adjusted HR 1.24, 95% CI 1.08–1.43). When persons with diabetes and no DR were used as references, a higher risk of incident AD was observed in persons with DR (adjusted HR 1.34, 95% CI 1.18–1.53).Conclusion:Individuals with diabetes without DR were less likely to develop AD compared to persons without diabetes. However, individuals with DR had a 34% higher risk of incident AD, which raise the question whether screening for cognitive impairment should be done among individuals with DR.

Intravesical Bacillus Calmette-Guérin Treatment Is Inversely Associated With the Risk of Developing Alzheimer Disease or Other Dementia Among Patients With Non-muscle-invasive Bladder Cancer.

The immune system plays an important role in the pathogenesis of Alzheimer disease (AD), but it remains unclear whether bacillus Calmette-Guérin (BCG) may affect the risk of AD or not. Using retrospective chart review, we collected data regarding demographics, comorbidities, cancer diagnosis, BCG treatment, and subsequent diagnosis of AD or other dementia in a racially/ethnically diverse cohort of patients with non-muscle-invasive bladder cancer (NIMBC) receiving treatment between 1984 and 2020 in the Bronx, New York. We used Cox proportional hazard models to examine association between BCG treatment and risk of incident AD or other dementia, adjusting for age, gender, race/ethnicity, and major comorbidities. In our cohort of 1290 patients with NMIBC, a total of 99 (7.7%) patients developed AD or other dementia during follow-up. Patients who received BCG treatment (25%) had a 60% lowered incidence of AD or other dementia (adjusted hazard ratio [HR], 0.41; 95% confidence interval [CI], 0.21-0.80) in comparison to those who did not receive BCG. There was also suggestive evidence that the reduction in risk of AD or other dementia associated with BCG treatment was stronger in men (adjusted HR, 0.34; 95% CI, 0.15-0.81) but not in women (adjusted HR, 0.75; 95% CI 0.25-2.24). When we stratified the patients who received BCG by type of treatments, patients who received both induction and maintenance rounds of BCG had a further lowered incidence of AD or other dementia (HR, 0.23; 95% CI, 0.06-0.96) than patients who did not receive BCG. To our knowledge, our study is one of the first to suggest that BCG treatment is associated with a reduced risk of developing AD or other dementia in a multiethnic population, independent of significant comorbidities. Larger cohort studies are needed to corroborate our findings.

Dietary sugar intake and risk of Alzheimer's disease in older women

ABSTRACT Background Despite some reports of cardiometabolic disorders associated with the risk of Alzheimer's disease (AD), limited studies have been conducted to examine the association between excessive sugar intake (a risk factor for cardiometabolic disorders) and AD risk. Aim The purpose of our study was to evaluate if excessive sugar intake has a significant long-term effect on the risk of AD. Methods A population sample of 37,689 participants, who enrolled in the United States (US) Women's Health Initiative – Dietary Modification Trial (WHI-DM) in 1993–2005 and its extended observational follow-up study through 1 March 2019, were analyzed. Dietary sugar intake was measured using food frequency questionnaires. AD was classified by reports using a standard questionnaire. A dietary pattern that explained the maxima variations in sugar intake was constructed using reduced rank regression (RRR) technique. Associations of RRR dietary pattern scores and sugar intake (g/day) by quartiles (Q1 through Q4) with AD risk were examined using Cox proportional hazards regression analysis with adjusting for key covariates. Results During a mean follow-up of 18.7 years, 4586 participants reported having incident AD. The total incidence rate (95% confidence interval [CI]) of AD was 6.5 (6.3–6.7) per 1000 person-years (PYs). The incidence rates (95% CI) of AD by total sugar intake were 6.2 (5.8–6.6), 6.4 (6.0–6.8), 6.6 (6.3–7.0), and 6.9 (6.5–7.3) per 1000 PYs among those in quartiles (Q) 1 to Q4 (toward higher sugar consumption) of total sugar intake, respectively (test for trend of AD incident rates, p < 0.001). Individuals in Q4 of total sugar intake had a 1.19 higher risk of incident AD than those in Q1 (hazard ratio [HR] = 1.19, 95% CI: 1.05–1.34, p = 0.01). An estimated increase of 10 g/day in total sugar intake (about 2.4 teaspoons) was associated with an increased AD risk by 1.3–1.4%. Of six subtypes of sugar intake, lactose was significantly associated with AD risk. Conclusions Our study indicates that excessive total sugar intake was significantly associated with AD risk in women. Of six subtypes of sugar intake, lactose had a stronger impact on AD risk.

The Association between Dietary Inflammatory Index and Sex Hormones among Men in the United States.

This study investigated the association between Dietary Inflammatory Index and sex hormones in a large, nationally representative adult male sample. We utilized data from the 2013-2014 and 2015-2016 National Health and Nutrition Examination Survey. Males aged ≥20 years who provided a 24-hour dietary intake history and underwent serum sex hormone testing were included in analysis. Weighted proportions and multivariable analysis controlling for age, race, energy, smoking status, education level, body mass index and time of venipuncture were used to evaluate the associations between Dietary Inflammatory Index and sex hormones. For 4,151 participants, Dietary Inflammatory Index ranged from -5.05 to 5.48. Mean±SD total testosterone was 419.30±176.27 ng/dl. Mean±SD total testosterone was lower among men in the highest tertile compared with men in the lowest tertile group (410.42±171.97 vs 422.71±175.69, p <0.001). A per unit increase in Dietary Inflammatory Index was related to 4.0% (95% CI 0.5-7.6) higher odds of testosterone deficiency. In the fully adjusted multivariable model, males in Dietary Inflammatory Index tertile 3 (the most pro-inflammatory) had 29.6% (3.1-63.0) higher odds of testosterone deficiency than those in tertile 1 (p trend=0.025). Interaction tests revealed no significant effect of body mass index on the association of Dietary Inflammatory Index with testosterone deficiency and all sex hormone parameters. Men adhering to a more pro-inflammatory diet appear to have a higher risk of testosterone deficiency, indicating the important role of diet in male reproductive health.

Impact of diabetes mellitus and cardiometabolic syndrome on the risk of Alzheimer's disease among postmenopausal women.

BACKGROUNDIn spite of an increase in the incidence and prevalence of diabetes mellitus (DM) and Alzheimer’s disease (AD) in the aging population worldwide, limited attention has been paid to their potential association.AIMTo investigate the association of DM and cardiometabolic syndrome (CMS, a precursor to DM) with risk of incident AD among postmenopausal women.METHODSPostmenopausal women aged 50-79 (n = 63117) who participated in the U.S. Women’s Health Initiative Observational Study (WHIOS), recruited in 1993-1998, without baseline AD and followed up through March 1, 2019, were analyzed. AD was classified by participant-reported history of doctor-diagnosis of incident AD in the WHIOS. DM was defined by participant-report or treated because of diabetes or serum glucose concentrations ≥ 126 mg/dL. CMS was defined as having ≥ 3 of five CMS components: large waist circumference, high blood pressure, elevated triglycerides, elevated glucose, and low high-density lipoprotein cholesterol. The associations of DM and CMS with AD were analyzed using Cox’s proportional hazards regression analysis.RESULTSDuring a median follow-up of 20 years (range: 3.36 to 23.36 years), of 63117 participants, 8340 developed incident AD. Women with DM had significantly higher incidence of AD [8.5, 95% confidence interval (CI): 8.0-9.0 per 1000 person-years (PY)] than those without DM (7.1, 95%CI: 6.9-7.2 per 1000 PY). Multivariate Cox’s regression analysis indicated that women with DM or CMS had a significantly higher risk of AD than those without DM or CMS. The corresponding hazard ratios [HR (95%CI)] were 1.22 (1.13-1.31, P < 0.001) in subjects with DM, and 1.18 (1.09-1.27, P < 0.001) in subjects with CMS. The HRs diminished with age and became non-significant in the oldest age group.CONCLUSIONDuring a median follow-up of 20 years, DM and CMS were significantly associated with the risk of AD among postmenopausal women. More specifically, women aged 50-69 with DM or CMS vs those without these conditions had significantly higher relative risks of AD than the relative risks of AD in those aged 70-79 with DM or CMS vs those without DM or CMS.

Interaction between Apolipoprotein E and Butyrylcholinesterase Genes on Risk of Alzheimer's Disease in a Prospective Cohort Study.

An epistatic interaction between the ɛ4 allele of apolipoprotein E (APOEɛ4) gene and the K-variant of butyrylcholinesterase (BCHE-K) genes has been previously reported to increase risk of Alzheimer's disease (AD). However, these observations were largely from case-control studies with small sample sizes. To examine the interaction between APOEɛ4 and BCHE-K on: 1) the risk of incident AD and 2) rates of change in brain volumes and cognitive performance during the preclinical stages of AD in a prospective cohort study. The study sample for survival analysis included 691 Caucasian participants (age at baseline, 58.4±9.9 years; follow-up time,16.9±9.7 years) from the Baltimore Longitudinal Study of Aging. The neuroimaging sample included 302 participants with 1,388 magnetic resonance imaging (MRI) scans. Cognitive performance was assessed in 703 participants over 4,908 visits. A total of 122 diagnoses (79 AD, 43 mild cognitive impairment [MCI]) were identified. Participants with both APOEɛ4 and BCHE-K variants had a 3.7-fold greater risk of AD (Hazard ratio [HR] 95% CI=1.99-6.89, p < 0.001) compared to non-carriers of both genes (APOE ɛ4 x BCHE-K interaction p = 0.025). There was no APOE ɛ4-BCHE-K interaction effect on rate of cognitive decline and brain atrophy. The APOE and BCHE genes interact to influence risk of incident AD/MCI but not rates of brain atrophy and decline in cognitive performance before onset of cognitive impairment. This may suggest the epistatic interaction between APOE ɛ4 and BCHE-K on AD risk is disease stage-dependent.

Joint Effect of ABCA7 rs4147929 and Body Mass Index on Progression from Mild Cognitive Impairment to Alzheimer's Disease: The Shanghai Aging Study.

Approximately 40 independent Single Nucleotide Polymorphisms (SNPs) have been associated with Alzheimer's Disease (AD) or cognitive decline in genome-wide association studies. We aimed to evaluate the joint effect of genetic polymorphisms and environmental factors on the progression from Mild Cognitive Impairment (MCI) to AD (MCI-AD progression) in a Chinese community cohort. Demographic, DNA and incident AD diagnosis data were derived from the follow-up of 316 participants with MCI at baseline of the Shanghai Aging Study. The associations of 40 SNPs and environmental predictors with MCI-AD progression were assessed using the Kaplan-Meier method with the log-rank test and Cox regression model. Rs4147929 at ATP-binding cassette family A member 7 (ABCA7) (AG/AA vs. GG, hazard ratio [HR] = 2.43, 95% confidence interval [CI] 1.24-4.76) and body mass index (BMI) (overweight vs. non-overweight, HR = 0.41, 95% CI 0.22-0.78) were independent predictors of MCI-AD progression. In the combined analyses, MCI participants with the copresence of non-overweight BMI and the ABCA7 rs4147929 (AG/AA) risk genotype had an approximately 6-fold higher risk of MCI-AD progression than those with an overweight BMI and a non-risk genotype (HR = 6.77, 95% CI 2.60-17.63). However, a nonsignificant result was found when participants carried only one of these two risk factors (nonoverweight BMI and AG/AA of ABCA7 rs4147929). ABCA7 rs4147929 and BMI jointly affect MCI-AD progression. MCI participants with the rs4147929 risk genotype may benefit from maintaining an overweight BMI level with regard to their risk for incident AD.

The Effect of the APOE ε2ε4 Genotype on the Development of Alzheimer's Disease (AD) and Mild Cognitive Impairment (MCI) in Non-Latino Whites.

To examine the associations of APOE ε2ε4 with the development of Alzheimer's disease (AD) and mild cognitive impairment (MCI) in non-Latino whites. Prospective longitudinal cohort study. Uniform Data Set from the National Alzheimer's Coordinating Center (NACC) between 2005 and August 2018 (data freeze in September 2018). Participants who were non-Latino white, had an APOE genotype available, first visit with dementia free for AD cohort and both dementia and MCI free for MCI cohort, and had a minimum of one follow-up visit (n = 11 871 for AD cohort, and n = 8305 for MCI cohort). The incidences of AD and MCI were determined based on consensus meetings at each Alzheimer's disease center. We used NACC-derived variables to define individuals experiencing incidents of AD and MCI at the initial visit as well as the follow-up visits. Among participants in the AD cohort (N = 11 871), ε2ε4 accounted for 2.5%, ε2ε2 accounted for 0.4%, ε2ε3 accounted for 11.0%, ε4ε4 accounted for 4.4%, ε3ε4 accounted for 27.3%, and ε3ε3 accounted for 54.4%. Over an average of 4.6 years follow-up, 1857 (15.6%) developed AD dementia, with the range from 6.0% to 35.2% across the six groups. Compared to ε3ε3 carriers, ε2ε4 carriers exhibited an increased risk of incident AD (18.4% vs 11.7%; adjusted hazard ratio [aHR] = 1.74; 95% confidence interval [CI] = 1.32-2.30; P < .0001). Among participants in the MCI cohort (N = 8305), the average follow-up was 4.7 years, and 1912 (23.0%) developed MCI, with the range from 20.4% to 33.9% across the six groups. Compared to ε3ε3 carriers, ε2ε4 carriers exhibited an increased risk of incident MCI (27.5% vs 21.5%; aHR = 1.52; 95% CI = 1.15-1.99; P = .003). The APOE ε2ε4 genotype is associated with the increased risk of AD and MCI in non-Latino whites. J Am Geriatr Soc 68:1044-1049, 2020.

Angiotensin-Receptor Blockers and the Risk of Alzheimer´s Disease: A Meta-analysis.

Anti-hypertensive medications may reduce the incidence of cognitive disorders. This may be due to reasons beyond their pure hypotensive effect. This study aimed to systematically review the association between the use of Angiotensin-Receptor Blockers (ARBs) and the incidence of Alzheimer's disease (AD). We systematically searched studies reporting the association between ARB use and the incidence of AD. Ten studies (1 RCT, 2 case-control and 7 cohort studies) met the inclusion criteria. When all observational studies (9) were analyzed, ARB use was associated with a reduced risk of incident AD (HR 0.72, 95% CI: 0.58-0.88, p<0.001). In the only RCT, decrease in the incidence of AD was also significant (HR= 0.31, 95% CI: 0.14-0.68). ARB use may reduce the risk of incident AD. This association does not imply causation and further research is required to clarify potential mechanisms.

Current and past leisure time physical activity in relation to risk of Alzheimer's disease in older adults

IntroductionThe associations between self-reported current and past leisure time physical activity (LTPA) and Alzheimer's disease (AD) incidence were determined using data from the multiethnic Washington/Hamilton Heights-Inwood Columbia Aging Project (WHICAP) study. MethodsThe metabolic equivalent of LTPA energy expenditure was calculated for self-reported current and past LTPA for 1345 older adults. A Cox proportional hazard model was conducted to estimate the association between LTPA (low, middle, and high) and incident AD risk. ResultsComparing high to low level, current and past LTPA were both associated with reduced AD risk, with hazard ratio (95% confidence interval) = 0.39 (0.20–0.75) and 0.37 (0.18–0.75), respectively. Compared with “always low,” “increased” and “always high” LTPA throughout life were associated with reduced AD risk, with hazard ratio (95% confidence interval) = 0.60 (0.36–0.99) and 0.28 (0.08–0.94), respectively. Light- and moderate-intensity LTPA were associated with lower AD risk. DiscussionLTPA both throughout life and later in life are associated with lower risk of AD.

The new neurobiology of dementia

The repeated failures of clinical trials of disease-modifying treatments for Alzheimer's disease (AD) have highlighted the urgent need to better understand molecular mechanisms underlying AD pathogenesis in order to identify targets for effective treatments. Accumulating evidence suggests that metabolic abnormalities are important risk factors for AD and may play a key role in disease progression. We have combined deep molecular phenotyping of brain and blood tissue samples with analyses of longitudinal epidemiological data from well characterized cohorts of older individuals to identify distinct metabolic abnormalities associated with severity of AD pathology and the eventual expression of clinical symptoms. Using targeted and quantitative metabolomics analyses, we have identified perturbations in several metabolic pathways that underlie AD pathogenesis. These pathways include abnormalities in brain glucose utilization, phospholipid and fatty acid metabolism, cholesterol/oxysterol biosynthesis as well as polyamine metabolism and transmethylation reactions. Together, our studies suggest that AD is a pervasive metabolic disorder with dysregulation in multiple interacting biochemical pathways that may trigger accumulation of pathology in vulnerable brain regions leading to neurodegeneration and cognitive impairment. Strikingly, many of these biochemical reactions are targeted by commonly used medications for non-AD indications, raising the possibility that some of these drugs may protect against development of AD. We have combined insights from deep molecular phenotyping of brain and blood tissue samples with analyses of real-world prescription datasets to test the hypothesis that drugs targeting abnormal metabolism may alter the risk of incident AD. These studies suggest that metabolic perturbations are key players underlying the neurobiology of dementia and may offer novel targets for effective treatments

Interacting influences of aging and Alzheimer's disease on circadian rhythms.

Aging leads to changes in circadian rhythms, including decreased amplitude or robustness, altered synchrony with the environment, and reduced coordination of rhythms within body. These circadian rhythm alterations are more pronounced in age-associated neurodegenerative disorders such as Alzheimer's disease (AD), in which they often precede the onset of other symptoms by many years. As well as their early onset, the findings that fragmentation of daily rest-activity rhythms in non-demented older subjects is associated earlier cognitive decline, increased risk of incident AD, and preclinical AD neuropathology, suggest that circadian rhythm disruption may contribute to the development and progression of the neuropathological changes occurring in AD. Conversely, other studies have implicated amyloid-beta, a prominent neurotoxin that accumulates in AD, in the impairment of circadian rhythms. Thus, circadian rhythm disruption and AD-associated neurodegeneration may interact to form a deleterious cycle. This article reviews the neural and molecular mechanisms underlying the age- and AD-related changes in circadian rhythms. It also explores therapeutic strategies proposed to ameliorate circadian rhythm deficits in elderly and demented individuals.

Genetic Interaction with Plasma Lipids on Alzheimer's Disease in the Framingham Heart Study.

Epidemiological and genetic studies have pointed to the role of cholesterol in Alzheimer's disease (AD). We explored the interaction of a genetic risk score (GRS) of AD risk alleles with mid-life plasma lipid levels (LDL-C, HDL-C, and triglycerides) on risk for AD in the Framingham Heart Study (FHS). Mid-life (between the ages of 40-60 years old) lipid levels were obtained from individuals in the FHS Original and Offspring cohorts (157 cases and 2,882 controls) with genetic data and AD status available. Cox proportional hazards regression was performed to test the interaction between mid-life lipid levels and an AD GRS, as well as the individual contributing SNPs, on risk of incident AD adjusting for age, sex, and cohort. We found a significant interaction between a GRS of AD loci and log triglyceride levels on risk of clinical AD (p = 0.006), but no interaction of the GRS with HDL-C (p = 0.458) or LDL-C (p = 0.366). We then tested the interaction between the individual SNPs contributing to the GRS and log triglycerides. We found two SNPs that had interactions with triglycerides on AD risk that reached a p-value < 0.05 (rs11218343 and APOEɛ4). The association between some AD SNPs and risk of AD may be modified by triglyceride levels. Furthermore, sequential testing of a GRS with a set of traits on disease followed by testing individual SNPs for interaction provides a framework for narrowing the associations that need to be tested for interaction analyses. Replication is needed to confirm these findings.

Cognitive Variability Predicts Incident Alzheimer's Disease and Mild Cognitive Impairment Comparable to a Cerebrospinal Fluid Biomarker.

Alzheimer's disease (AD) biomarkers are emerging as critically important for disease detection and monitoring. Most biomarkers are obtained through invasive, resource-intense procedures. A cognitive marker, intra-individual cognitive variability (IICV) may provide an alternative or adjunct marker of disease risk for individuals unable or disinclined to undergo lumbar puncture. To contrast risk of incident AD and mild cognitive impairment (MCI) associated with IICV to risk associated with well-established biomarkers: cerebrospinal fluid (CSF) phosphorylated tau protein (p-tau181) and amyloid-β 42 (Aβ42) peptide. Dispersion in cognitive performance, IICV, was estimated with a published algorithm, and included Trail Making Test A and B, Rey Auditory Verbal Learning Test (RAVLT), and the American National Adult Reading Test (ANART). CSF biomarkers were expressed as a ratio: p-tau181/Aβ42, wherein high values signified pathognomonic profiles. Logistic regression models included longitudinal data from 349 Alzheimer's Disease Neuroimaging Initiative (ADNI) participants who completed lumbar puncture. All subjects were cognitively healthy (n = 105) or diagnosed with MCI (n = 244) at baseline. We examined odds of conversion associated with baseline elevations in IICV and/or ratio of CSF p-tau181/Aβ42. When included in models alone or in combination with CSF p-tau181/Aβ42, one standard IICV unit higher was associated with an estimated odds ratio for incident AD or MCI of 2.81 (95% CI: 1.83-4.33) in the most inclusive sample, and an odds ratio of 3.41 (95% CI: 2.03-5.73) when restricted to participants with MCI. Iterative analyses suggested that IICV independently improved model fit even when individual index components were included in comparative models. These analyses provide preliminary support for IICV as a marker of incident AD and MCI. This easily-disseminated, non-invasive marker compared favorably to well-established CSF biomarkers.

Midlife anticholinergic drug use, risk of Alzheimer's disease, and brain atrophy in community-dwelling older adults

IntroductionWe examined how long-term anticholinergic (AC) drug use beginning at midlife affects risk of Alzheimer's disease (AD) and rates of brain atrophy in cognitively normal older adults. MethodsWe followed 723 individuals (mean baseline age 52.3 years; mean follow-up interval 20.1 years) in the Baltimore Longitudinal Study of Aging. The AC drug exposure was defined using the Anticholinergic Cognitive Burden Scale: Nonusers (n = 404), as well as participants exposed to medications with AC activity but without known clinically relevant negative cognitive effects (i.e., “possible AC users”; n = 185) and those exposed to AC drugs with established and clinically relevant negative cognitive effects (i.e., “definite AC users”; n = 134). The neuroimaging sample included 93 participants who remained cognitively normal through follow-up and underwent serial magnetic resonance imaging (n = 93, 724 brain scans, mean follow-up interval 8.2 years, and baseline age 68.6 years). ResultsPossible AC users, but not definite AC users, showed increased risk of incident AD compared with nonusers (hazard ratio, 1.63; 95% confidence interval, 1.02–2.61; P = .04) and greater rates of atrophy in total cortical gray matter volume compared with nonusers (β = −0.74, P = .018). Faster rates of brain atrophy were also observed among possible AC users in the right posterior cingulate, as well as right middle frontal and left superior temporal gyri. Data on frequency and duration of medication use were available in only approximately half of the sample. Among these participants, definite AC users had both shorter duration and lower frequency of medication use relative to possible AC users. DiscussionLong-term exposure to medications with mild AC activity during midlife is associated with increased risk of AD and accelerated brain atrophy.

Conversion and Reversion Rates in Japanese Older People With Mild Cognitive Impairment

ObjectivesApproximately 25% of individuals who are diagnosed with amnestic mild cognitive impairment (aMCI) revert to normal cognition (NC) rather than progressing to Alzheimer disease (AD). However, the prevalence of progression and reversion among older people in Asia remains unclear. DesignA prospective cohort study. SettingA community in Japan. ParticipantsA total of 4153 individuals without dementia aged ≥65 years were classified as having NC, aMCI single domain (aMCIs), non-aMCI single domain (naMCIs), aMCI multiple domain (aMCIm), non-aMCI multiple domain (naMCIm), or global cognitive impairment (GCI). MeasurementsThe National Center for Geriatrics and Gerontology-Functional Assessment Tool and the Mini-Mental State Examination were used to conduct cognitive screening. The participants completed baseline (August 2011 to June 2012) and follow-up (August 2015 to June 2016) assessments. We followed up monthly for newly incident AD, as recorded by the Japanese National Health Insurance and Later-Stage Medical Care systems. Multiple imputation was used to adjust for selection bias and loss of information. ResultsAt 4-year follow-up, the reversion rates to NC in aMCIs, naMCIs, aMCIm, naMCIm, and GCI were 38.7%, 57.0%, 25.7%, 20.9%, and 43.7%, respectively. Of the participants with NC, aMCIs, naMCIs, aMCIm, naMCIm, and GCI at baseline, 4.7%, 4.5%, 13.1%, 20.6%, 21.6%, and 14.3%, respectively, were subsequently diagnosed with AD. We found significant associations between incident AD and naMCIs [hazard ratio (HR) compared to NC: 2.18, 95% confidence interval (CI): 1.45-3.26], and between AD and aMCIm (HR: 4.39, 95% CI: 2.06-9.39) and between AD and naMCIm (HR: 3.60, 95% CI: 2.13-6.08). However, the association between incident AD and aMCIs and between AD and GCI did not reach significance. ConclusionReversion to NC from MCI and GCI was frequent, and individuals with aMCIs and GCI did not show higher risk of incident AD than those with NC. Older adults with multiple cognitive impairments may be potential targets for preventing dementia.

THE APOE AND BCHE GENES INTERACT TO INCREASE RISK OF INCIDENT ALZHEIMER’S DISEASE IN THE BALTIMORE LONGITUDINAL STUDY OF AGING

An epistatic interaction between the ApolipoproteinE (APOE) and Butyrylcholinesterase (BCHE) genes has been previously reported to increase risk of Alzheimer's disease (AD). However, these observations were largely from case-control studies with small sample sizes and have not been consistently replicated, Few studies have examined the role of APOE X BCHE interactions on risk of incident AD/mild cognitive impairment (MCI) prospectively. The Baltimore Longitudinal Study of Aging (BLSA) is a prospective cohort study of community-dwelling participants since1958. Six hundred and ninety-one cognitively normal participants (age at baseline, 58.4 ± 9.9 years) with available APOE and BCHE (rs1803274) genotype data were included in this study. The rs1803274(A) allele encodes a version of the butyrylcholinesterase enzyme known as the K variant (BCHE-K) that produces a 30% reduction in serum butyrylcholinesterase activity and has been previously associated with AD risk. The mean follow-up time was 16.9 ± 9.7 years. Participants who developed AD or mild cognitive impairment (MCI) were captured as having an event at the estimated age of onset. Cox proportional hazards models were used to examine the association between APOE4, BCHE-K and their interaction on the risk of incident AD or MCI controlling for gender, years of education and birth year. A total of 122 participants were diagnosed as MCI (n=43) or AD (n=79) during follow-up. In two separate models, APOE4 was significantly associated with increased risk of AD (adjusted hazard ratio [aHR]=1.77; 95% confidence interval [CI]=1.19- 2.63; p=0.005) whereas BCHE-K did not show a significant association (aHR=1.20; 95%CI=0.82–1.76; p=0.339). The model including both APOE4 and BCHE-K showed a strong and significant effect of APOE4xBCHE-K interaction on the risk of AD (t=2.24, p=0.025). Compared to APOE4 and BCHE-K non-carriers, participants with both APOE4 and BCHE-K variants had a 3.36 fold greater risk of AD (95%CI=1.94–6.77, p < 0.001) (Fig 1).