Shea J. Andrews

Association of genetic risk factors with cognitive decline: the PATH through life project

We examined the association of 28 single nucleotide polymorphisms (SNPs), previously associated with dementia or cognitive performance, with tests assessing episodic memory, working memory, vocabulary, and perceptual speed in 1689 nondemented older Australians of European ancestry. In addition to testing each variant individually, we assessed the collective association of the 12-risk SNPs for late-onset Alzheimers disease using weighted and unweighted genetic risk scores. Significant associations with cognitive performance were observed for APOE ε4 allele, ABCA7-rs3764650, CR1-rs3818361, MS4A4E-rs6109332, BDNF-rs6265, COMT-rs4680, CTNNBL-rs6125962, FRMD4A-rs17314229, FRMD4A-rs17314229, intergenic SNP chrX-rs12007229, PDE7A-rs10808746, SORL1-rs668387, and ZNF224-rs3746319. In addition, the weighted genetic risk score was associated with worse performance on episodic memory. The identification of genetic risk factors, that act individually or collectively, may help in screening for people with elevated risk of cognitive decline and for understanding the biological pathways that underlie cognitive decline.

Late Onset Alzheimer's Disease Risk Variants in Cognitive Decline: The PATH Through Life Study.

Recent genome wide association studies have identified a number of single nucleotide polymorphisms associated with late onset Alzheimers disease (LOAD). We examined the associations of 24 LOAD risk loci, individually and collectively as a genetic risk score, with cognitive function. We used data from 1,626 non-demented older Australians of European ancestry who were examined up to four times over 12 years on tests assessing episodic memory, working memory, vocabulary, and information processing speed. Linear mixed models were generated to examine associations between genetic factors and cognitive performance. Twelve SNPs were significantly associated with baseline cognitive performance (ABCA7, MS4A4E, SORL1), linear rate of change (APOE, ABCA7, INPP5D, ZCWPW1, CELF1), or quadratic rate of change (APOE, CLU, EPHA1, HLA-DRB5, INPP5D, FERMT2). In addition, a weighted genetic risk score was associated with linear rate of change in episodic memory and information processing speed. Our results suggest that a minority of AD related SNPs may be associated with non-clinical cognitive decline. Further research is required to verify these results and to examine the effect of preclinical AD in genetic association studies of cognitive decline. The identification of LOAD risk loci associated with non-clinical cognitive performance may help in screening for individuals at greater risk of cognitive decline.

Validating the role of the Australian National University Alzheimer’s Disease Risk Index (ANU-ADRI) and a genetic risk score in progression to cognitive impairment in a population-based cohort of older adults followed for 12 years

BackgroundThe number of people living with dementia is expected to exceed 130 million by 2050, which will have serious personal, social and economic implications. Employing successful intervention and treatment strategies focused on disease prevention is currently the only available approach that can have an impact on the projected rates of dementia, with risk assessment being a key component of population-based risk reduction for identification of at-risk individuals. We evaluated a risk index comprising lifestyle, medical and demographic factors (the Australian National University Alzheimer’s Disease Risk Index [ANU-ADRI]), as well as a genetic risk score (GRS), for assessment of the risk of progression to mild cognitive impairment (MCI).MethodsThe ANU-ADRI was computed for the baseline assessment of 2078 participants in the Personality and Total Health (PATH) Through Life project. GRSs were constructed on the basis of 25 single-nucleotide polymorphisms previously associated with Alzheimer’s disease (AD). Participants were assessed for clinically diagnosed MCI and dementia as well as psychometric test-based MCI (MCI-TB) at 12 years of follow-up. Multi-state models were used to estimate the odds of transitioning from cognitively normal (CN) to MCI, dementia and MCI-TB over 12 years according to baseline ANU-ADRI and GRS.ResultsA higher ANU-ADRI score was associated with increased risk of progressing from CN to both MCI and MCI-TB (HR 1.07 [95% CI 1.04–1.11]; 1.07 [1.04–1.09]). The GRS was associated with transitions from CN to dementia (HR 4.19 [95% CI 1.72–10.20), but not to MCI or MCI-TB (HR 1.05 [95% CI 0.86–1.29]; 1.03 [0.87–1.21]). Limitations of our study include that the ethnicity of participants in the PATH project is predominately Caucasian, potentially limiting the generalisability of the results of this study to people of other ethnicities. Biomarkers of AD were not available to define MCI attributable to AD. Not all the predictive variables for the ANU-ADRI were available in the PATH project.ConclusionsIn the general population, the ANU-ADRI, comprising lifestyle, medical and demographic factors, is associated with the risk of progression from CN to MCI, whereas a GRS comprising the main AD risk genes was not associated with this risk. The ANU-ADRI may be used for population-level risk assessment and screening.

Memory Resilience to Alzheimer's Genetic Risk: Sex Effects in Predictor Profiles.

Objectives Apolipoprotein E (APOE) ɛ4 and Clusterin (CLU) C alleles are risk factors for Alzheimers disease (AD) and episodic memory (EM) decline. Memory resilience occurs when genetically at-risk adults perform at high and sustained levels. We investigated whether (a) memory resilience to AD genetic risk is predicted by biological and other risk markers and (b) the prediction profiles vary by sex and AD risk variant. Method Using a longitudinal sample of nondemented adults (n = 642, aged 53-95) we focused on memory resilience (over 9 years) to 2 AD risk variants (APOE, CLU). Growth mixture models classified resilience. Random forest analysis, stratified by sex, tested the predictive importance of 22 nongenetic risk factors from 5 domains (n = 24-112). Results For both sexes, younger age, higher education, stronger grip, and everyday novel cognitive activity predicted memory resilience. For women, 9 factors from functional, health, mobility, and lifestyle domains were also predictive. For men, only fewer depressive symptoms was an additional important predictor. The prediction profiles were similar for APOE and CLU. Discussion Although several factors predicted resilience in both sexes, a greater number applied only to women. Sex-specific mechanisms and intervention targets are implied.

Sex Differences in the Impact of BDNF Genotype on the Longitudinal Relationship between Physical Activity and Cognitive Performance

Background: Physical activity may preserve cognitive function in older adults, but benefits vary by sex and genetic factors. Objective: We tested the longitudinal association between physical activity and cognitive performance to de termine whether a common genetic polymorphism for brain-derived neurotrophic factor (BDNF Val66Met) moderated this effect. Methods: In a 12-year longitudinal population-based sample of older adults (n = 2,218), we used growth curve modeling to investigate whether the benefits of physical activity on cognitive preservation differed by BDNF genotype and sex across multiple cognitive domains including processing speed, attention, working memory, and episodic verbal memory. Results: The relationship between physical activity and cognitive performance was dependent on BDNF carrier status in males (Δχ2 [Δdf] = 12.94 [4], p = 0.01), but not in females (Δχ2 [Δdf] = 4.38 [4], p = 0.36). Cognition benefited from physical activity in male BDNF met noncarriers, but not met carriers, whereas cognition was not statistically significantly related to physical activity in females regardless of genotype. Conclusion: We observed longitudinal, but not cross-sectional, effects of physical activity on cognitive performance. Our study highlights the importance of longitudinal follow-up and consideration of sex differences in the relationships between physical activity, BDNF genotype, and cognitive decline. The findings contribute to understanding gene-lifestyle interactions in promoting cognitive health.

Association between alcohol consumption and Alzheimer's disease: A Mendelian Randomization Study

Observational studies have suggested that a U-shaped relationship exists between alcohol consumption and Alzheimer’s disease, with light-moderate drinkers at lower risk of developing Alzheimer’s disease. A two-sample Mendelian randomization approach was used to examine whether alcohol consumption causally effects the risk of developing Alzheimer’s disease. We used summary level genome-wide association data for alcohol consumption from the UK biobank, alcohol dependence from the Netherlands Twin Register (NTR) and the Netherlands Study of Depression and Anxiety, and Alzheimer’s disease from the International Genomics of Alzheimer’s Project. Variants associated with alcohol consumption were combined using an inverse variance weighted fixed-effects approach. We found no evidence of a causal association between genetically predicted alcohol consumption (β = 0.078; SE = 0.354; 95% CI = -0.617, 0.772; p = 0.826) or alcohol dependence (β = -0.011; SE = 0.026; 95% CI = -0.062, 0.039; p = 0.666) with Alzheimer’s disease. A causal relationship was observed between genetically predicted alcohol consumption and γ-glutamyltransferase levels (β = 0.159; SE = 0.062; 95% CI = 0.037, 0.282; p = 0.011), which was used as a positive control. The findings from this Mendelian randomization study do not find evidence of a causal association between alcohol consumption and Alzheimer’s disease. These findings contrast with those of recent systematic reviews of observational studies.

Association of AKAP6 and MIR2113 with cognitive performance in a population-based sample of older adults

Genetic factors make a substantial contribution to inter‐individual variability in cognitive function. A recent meta‐analysis of genome‐wide association studies identified two loci, AKAP6 and MIR2113, that are associated with general cognitive function. Here, we extend this previous research by investigating the association of MIR2113 and AKAP6 with baseline and longitudinal non‐linear change across a broad spectrum of cognitive domains in a community‐based cohort of older adults without dementia. Two single nucleotide polymorphisms (SNPs), MIR211‐rs10457441 and AKAP6‐rs17522122 were genotyped in 1570 non‐demented older Australians of European ancestry, who were examined up to 4 times over 12 years. Linear mixed effects models were used to examine the association between AKAP6 and MIR2113 with cognitive performance in episodic memory, working memory, vocabulary, perceptual speed and reaction time at baseline and with linear and quadratic rates of change. AKAP6‐rs17522122*T was associated with worse baseline performance in episodic memory, working memory, vocabulary and perceptual speed, but it was not associated with cognitive change in any domain. MIR2113‐rs10457441*T was associated with accelerated decline in episodic memory. No other associations with baseline cognitive performance or with linear or quadratic rate or cognitive changes were observed for this SNP. These results confirm the previous finding that AKAP6 is associated with performance across multiple cognitive domains at baseline but not with cognitive decline, while MIR2113 primarily affects the rate at which memory declines over time.

MITOCHONDRIAL HAPLOGROUPS AND A NUCLEAR ENCODED MITOCHONDRIAL POLYGENIC RISK SCORE INTERACT TO INFLUENCE DEMENTIA RISK

P4-244 MITOCHONDRIAL HAPLOGROUPS AND A NUCLEAR ENCODED MITOCHONDRIAL POLYGENIC RISK SCORE INTERACT TO INFLUENCE DEMENTIA RISK Shea J. Andrews, Russell H. Swerdlow, Timothy McInerney, Brian Fulton-Howard, Alden L. Gross, G. Peggy McFall, Chris Patterson, Alison M. Goate, Elias K. Michaelis, Judy Pa and Alzheimer’s Disease Neuroimaging Initiative, Ronald M. Loeb Center for Alzheimer’s Disease, Department of Neuroscience, Icahn School of Medicine at Mount Sinai, New York, NY, USA; University of Kansas Alzheimer’s Disease Center, Fairway, KS, USA; John Curtin School of Medicine, Australian National University, Canberra, Australia; Johns Hopkins Bloomberg School of Public Health, Baltimore, MD, USA; University of Alberta, Edmonton, AB, Canada; Mark and Mary Stevens Neuroimaging and Informatics Institute, Keck School of Medicine, University of Southern California, Los Angeles, CA, USA; Icahn School of Medicine at Mount Sinai, New York, NY, USA; University of Kansas, Lawrence, KS, USA; Stevens Neuroimaging and Informatics Institute, University of Southern California, Los Angeles, CA, USA; Department of Neurology, Alzheimer’s Disease Research Center, Keck School of Medicine, University of Southern California, Los Angeles, CA, USA. Contact e-mail: shea.andrews@mssm.edu

Alzheimer's Genetic Risk Score linked to Incident Mild Behavioral Impairment

Mild Behavioral Impairment (MBI) describes the emergence of later-life Neuropsychiatric Symptoms (NPS) as an at-risk state for cognitive decline and dementia and as a potential manifestation of prodromal dementia. How NPS mechanistically link to the development of Mild Cognitive Impairment (MCI) and Alzheimer’s disease (AD) is not fully understood. Potential mechanisms include either shared risk factors that are related to both NPS and cognitive impairment, or AD pathology promoting NPS. This is the first study to examine whether AD genetic loci, individually and as a genetic risk score, are a shared risk factor with MBI. 1377 older adults (aged 72-79; 738 males; 763 normal cognition) from the PATH Through Life project. MBI was assessed in accordance with Criterion 1 of the ISTAART-AA diagnostic criteria using the Neuropsychiatric Inventory. 25 LOAD risk loci were genotyped and a weighted genetic risk score (GRS) was constructed. Binomial logistic regression adjusting for age, gender, and education examined the association between LOAD GRS and MBI domains. An increase in the LOAD GRS and APOE*ε4 were associated with higher likelihood of Affective Dysregulation; MS4A4A-rs4938933*C and MS4A6A-rs610932*G were associated with a reduced likelihood of Affective Dysregulation; ZCWPW1-rs1476679*C was associated with a reduced likelihood of Social Inappropriateness and Abnormal Perception; BIN1-rs744373*G and EPHA1-rs11767557*C were associated with higher likelihood of Abnormal Perception; NME8-rs2718058*G was associated with a reduced likelihood Decreased Motivation. These findings suggest a common genetic etiology between MBI and traditionally recognized memory problems observed in AD and improve our understanding of the pathophysiological features underlying MBI.

ALZHEIMER’S GENETIC RISK SCORE LINKED TO MILD BEHAVIORAL IMPAIRMENT

Rotterdam Study. Methods:The Rotterdam Study is a populationbased follow-up study including 14926 participants who have been characterized in depth genetically. We constructed weighted genetic risk scores (GRS), first based on 20 genome-wide significant AD risk variants from the IGAP GWAS, second clustering these variants within the seven genetic pathways. GRS were constructed with and without apolipoprotein E (APOE). We used the Rotterdam Study to investigate the association of the pathway-specific GRS with AD (N1⁄4 1231 cases, 5118 controls), MCI (N1⁄4 360 cases, 3254 controls) and brain MRI phenotypes including white matter lesions, hippocampal volume and brain volume (N 1⁄4 4527 cognitively normal subjects). This was done via regression analyses adjusting for age and sex. Results:AD was significantly associated to overall GRS both with (P1⁄4 1.58*10) and without APOE (P1⁄4 2.23*10). Using pathway-specific GRS, AD was significantly associated with risk scores capturing specifically immune response (P 1⁄4 3.60*10), endocytosis (P 1⁄4 1.2*10) and nominally associated with clathrin/AP2 adaptor complex (P1⁄4 0.04). Studying early pathology, the GRS capturing Immune response (P 1⁄4 0.016) and clathrin/AP2 adaptor complex pathway (P 1⁄4 3.5*10; excluding APOE) were associated to white matter pathology. The endocytosis pathway was associated to MCI (P 1⁄4 1.44*10). Conclusions:Our study suggests that the clinical spectrum of early AD pathology is explained by different genetically driven pathways that are independent of APOE. In particular, the immune response, endocytosis and clathrin/AP2 adaptor complex pathways appear to play a role in the association of vascular pathology and AD.