Risk Factor For Alzheimer's Disease Research Articles

MUTUAL INFORMATION OF NEUROIMAGES AND GENETIC VARIANTS TO STUDY THE DETERMINANTS OF BRAIN AGING

Abstract Understanding the genetic determinants of brain aging is important because advanced biological age of the brain is a risk factor for Alzheimer’s disease (AD). Single-nucleotide polymorphisms (SNPs) are genetic variations with effects on brain aging; mapping their influence on brain structure can elucidate the genetic correlates of AD. We adopted an information theoretic approach to this by computing the mutual information (MI) between (A) 22 AD-risk SNPs and (B) the MRI intensities of the cortex in 6,000 UK Biobank participants (~50% females) aged 54 to 84 years. These cortex-wide calculations quantified how SNPs impact brain structure. As expected, the APOE-ε4 allele, the strongest genetic risk factor for AD, exhibited significantly (p < 0.025) higher MI with MRI intensity, when compared to the average MI expected for a null distribution model, in the medial parietal lobe, pars orbitalis, and left inferior occipital lobe, three brain structures responsible for memory recall, language processing, and visual perception. These findings reflect the memory loss, decreased speech, and reduced peripheral vision experienced by individuals with AD. The ABCA7 allele, a risk factor for late- onset AD, had significantly (p < 0.025) higher MI in the inferior temporal sulcus and angular gyrus. These structures are responsible for visual recognition and attention, two functions that are severely impaired by AD. Other findings reveal similar relationships between AD-risk SNPs and brain structure. Our findings illustrate how mapping the MI between MRI intensities and SNPs provides insight into genetic influences on brain structures linked to AD symptoms.

CHILDHOOD FAMILY ENVIRONMENT, GENETIC RISK FOR ALZHEIMER’S DISEASE, AND LATE-LIFE COGNITIVE DECLINE

Abstract How genetic risks for Alzheimer’s disease (AD) interact with environmental factors to shape individuals’ cognitive trajectories across the lifespan is a burgeoning area of research. However, relatively little is known about the role childhood family environment plays in the relationship between genetic risk factors for AD and cognitive decline in later life. This study examined whether and how early-life family environments may modify cognitive decline associated with genetic AD risks. Using longitudinal data from the Health and Retirement Study (HRS; 1998-2018), we followed over 9,000 individuals aged 51 and older during the observation period spanning nearly two decades. Cognitive functioning was assessed with the full cognitive battery from the HRS. Childhood family environment was evaluated separately with the relationship quality with one’s mother and the number of household adults before the age of 16. We estimated a series of multilevel models to assess the association between polygenic risk score for AD (PGS-AD) and changes in cognitive functioning, and whether the association was moderated by the two measures of childhood social capital. Findings indicated that childhood maternal relationship quality, but not the number of household adults, protected against cognitive decline accelerated by PGS-AD. That is, the associations between higher PGS-AD and accelerated cognitive decline were attenuated for individuals who reported a better childhood maternal relationship. Findings are in line with the biopsychosocial model of health and suggest that a better quality of maternal relationships in childhood may have a protective effect on cognitive functioning across the lifespan.

SOCIAL SUPPORT BUFFERS THE EFFECT OF APOE4 GENE ON COGNITION

Abstract APOE4 allele is one of the most robust genetic risks for Alzheimer’s Disease (AD). It is associated with an earlier onset and conversion from Mild Cognitive Impairment (MCI) to AD dementia. Several studies have shown epigenetic interactions between the social context and the APOE4 allele’s relationship with cognition. Still, explorations of social risk factors for AD in genetically vulnerable populations are limited. This study explored whether the positive effects of social support (SS) on cognition are affected by APOE status in a sample of 115 older adults (n = 72.25, SD = 8.29). SS was measured using the Multidimensional Scale of Perceived Social Support (MSPSS), the preclinical Alzheimer’s Cognitive Composite-5 (PACC5) score to assess concurrent cognition, and the APOE polymorphism was determined via genotyping. As hypothesized, SS buffered the effect of APOE4 gene on PACC5 score, F(1, 107)=5.18, p = .02, Δ R2=.02. Specifically, older individuals who were positive for the allele displayed a significant and positive association between SS and mPACC5 (b=.19, p = .03). This relationship was not found for those who were APOE4 negative (b = -.04, p =.49). These results support the need to consider the epigenetic influence of social factors on later-life cognition, especially for those at risk for developing AD.

PROTECTIVE EFFECT OF SHINGLES VACCINE ON ALZHEIMER’S DISEASE CAN BE MODULATED BY RISK VARIANT OF NECTIN2 GENE

Abstract The aging-related decline in immune surveillance was suggested to play a major role in Alzheimer’s disease (AD). Adult vaccinations may support the aging immune system beyond prevention of the target disease, and through this provide a protection against AD. Such off-target effects of vaccines may potentially be affected by genetic risk factors for AD. To explore this possibility, we estimated association of the vaccination against shingles (reactivated herpes zoster virus infection) received between ages 65-75 with AD onset at ages 75+ in the Health and Retirement Study (HRS) survey participants, comparing the carriers and non-carriers of rs6859 A allele of NECTIN2 gene (AD risk factor that is also involved in vulnerability to viral infections). We used logistic regression model with covariates including sex, race, education, and smoking status. We found that shingles vaccine was significantly associated with lower odds of AD onset later in life, in the total sample (p-value=0.021; OR=0.55 (0.33, 0.92)). After stratification by genotype, the protective effect of vaccine became stronger in rs6859 A carriers (p-value=0.016; OR=0.44 (0.22, 0.86)), but disappeared in the non-carriers, for both significance and size (p-value=0.81; OR=0.90). We conclude that adult shingles vaccine may reduce chances of AD at older ages, and this effect appears more beneficial for carriers of rs6859 A allele of NECTIN2 gene. Repurposing of existing vaccines may benefit the aging immune system, and be a promising approach to personalized genotype-tailored prevention of AD.

Prolactin-Releasing Peptide, a Peptide with an Improper Name, but Proper Biological Activity for Obesity, Type-2 Diabetes, and Alzheimer's Disease Treatment

Obesity is an escalating epidemic, but an effective non-invasive therapy is still scarce. For the obesity treatment, anorexigenic neuropeptides represent promising tools, but their delivery from the periphery to the brain is complicated because peptides have a low stability and limited ability to cross the blood-brain barrier. Recently discovered anorexigenic neuropeptides, such as prolactin-releasing peptide, represent new trends in development of anti-obesity agents. They are released and acting directly in brain areas regulating food intake, but generally do not cross the blood-brain barrier if administered peripherally. We succeeded to design stable palmitoylated analogs of this neuropeptide with a prolonged acute anorexigenic effect after peripheral administration as shown in mice and rats. Repeated peripheral administration of the lipidized prolactin-releasing peptide analogs resulted in long-lasting anti-obesity and antidiabetic effects in rodent models of diet-induced obesity and insulin resistance. We proved that lipidation might be an effective way to transmit the desired effect to the central nervous system after peripheral administration, for a potential treatment of obesity and related complications such as type-2 diabetes. Besides the advanced age, type-2 diabetes and obesity were shown to be risk factors for Alzheimer's disease; therefore, compounds with glucose-lowering and/or anorexigenic properties were proposed to be neuroprotective. In our group, we studied a possible crosstalk between obesity, type-2 diabetes and Alzheimer's-like pathology. We also investigated if our novel palmitoylated analogs of prolactin-releasing peptide could have beneficial effect on neurodegeneration in several mouse models of Alzheimer's-like pathology and their age-matched wild type controls. We demonstrated that these lipidized analogs are potentially neuroprotective substances improving spatial memory, neurogenesis, synaptogenesis and attenuating neuroinflammation and two hallmarks of Alzheimer's disease, i.e., tau hyper-phosphorylation and β-amyloid plaques in different mouse models of Alzheimer's-like neurodegeneration.

Association of Glycemic Variability With Imaging Markers of Vascular Burden, β-Amyloid, Brain Atrophy, and Cognitive Impairment.

We aimed to investigate the association between glycemic variability (GV) and neuroimaging markers of white matter hyperintensities (WMH), beta-amyloid (Aβ), brain atrophy, and cognitive impairment. This was a retrospective cohort study that included participants without dementia from a memory clinic. They all had Aβ PET, brain MRI, and standardized neuropsychological tests and had fasting glucose (FG) levels tested more than twice during the study period. We defined GV as the intraindividual visit-to-visit variability in FG levels. Multivariable linear regression and logistic regression were used to identify whether GV was associated with the presence of severe WMH and Aβ uptake with DM, mean FG levels, age, sex, hypertension, and presence of APOE4 allele as covariates. Mediation analyses were used to investigate the mediating effect of WMH and Aβ uptake on the relationship between GV and brain atrophy and cognition. Among the 688 participants, the mean age was 72.2 years, and the proportion of female participants was 51.9%. Increase in GV was predictive of the presence of severe WMH (coefficient [95% CI] 1.032 [1.012-1.054]; p = 0.002) and increased Aβ uptake (1.005 [1.001-1.008]; p = 0.007). Both WMH and increased Aβ uptake partially mediated the relationship between GV and frontal-executive dysfunction (GV → WMH → frontal-executive; direct effect, -0.319 [-0.557 to -0.080]; indirect effect, -0.050 [-0.091 to -0.008]) and memory dysfunction (GV → Aβ → memory; direct effect, -0.182 [-0.338 to -0.026]; indirect effect, -0.067 [-0.119 to -0.015]), respectively. In addition, increased Aβ uptake completely mediated the relationship between GV and hippocampal volume (indirect effect, -1.091 [-2.078 to -0.103]) and partially mediated the relationship between GV and parietal thickness (direct effect, -0.00101 [-0.00185 to -0.00016]; indirect effect, -0.00016 [-0.00032 to -0.000002]). Our findings suggest that increased GV is related to vascular and Alzheimer risk factors and neurodegenerative markers, which in turn leads to subsequent cognitive impairment. Furthermore, GV can be considered a potentially modifiable risk factor for dementia prevention.

Towards A Cell Biology of Alzheimer’s Disease

In many neurodegenerative disorders, including Alzheimer's Disease (AD), the dysfunction of multiple cell types causes neuronal cell death, but the precise cellular processes involved remain incompletely understood for any neurodegenerative disease. Strikingly, synapses are often affected early during pathogenesis, probably because presynaptic terminals are distant outstations of neurons that are the most vulnerable part of a neuron. In AD, multiple mutations in APP and presenilin genes cause rare familial cases, while the ApoE4 variant of the ApoE gene represents the strongest genetic risk factor for sporadic AD in the general population. APP and presenilin gene mutations are thought to induce AD pathogenesis by overproducing pathogenic Abeta variants, and ApoE4 is thought to influence Abeta clearance, but how Abeta might incite AD pathogenesis and how ApoE4 might predispose to AD pathogenesis remains incompletely understood. Moreover, compelling evidence implicates microglial and possibly astrocytic dysfunction in AD pathogenesis. In my lab, we have taken a cell-biological approach to these questions with a focus on synapses because of their prominent role in AD, recognizing that synapse impairments in AD may also be secondary to microglial dysfunction. We have examined how pathogenic APP mutations, chronic impairments of presenilin function, or ApoE4 may act on synapses, using human neurons trans-differentiated from ES and iPS cells as a model. In my presentation, I will discuss the current status of this project which is far from providing a definitive account of AD pathogenesis but may offer a basis for understanding the most basic processes underlying such pathogenesis.

The Role of Periodontitis as Modifiable Risk Factor for Alzheimer’s Disease- A Recent Update

Alzheimer’s disease (AD) is among the most common form of dementia affecting geriatric population. Various studies have been carried out to understand the etiopathogenesis of the disease. However, no definite cause has been established and thereby, there is no definite treatment/cure available for eradication of same. The solution for managing the disease is to control the risk factors or triggering factors related to progression or worsening of the condition. Among various risk factors of AD, invasion of the oral pathogens in the brain tissue due to periodontitis (PD) has been associated as risk factor. Various studies had been carried out to state an association between PD and AD. Thereby, this article will discuss most recent evidences available to claim the role of PD as modifiable risk factor in mechanism of AD.

Elevated Homocysteine Level and Brain Atrophy Changes as Markers to Screen the Alzheimer Disease: Case Series.

Alzheimer disease (AD) is the most common cause of dementia worldwide. Its clinical manifestations include a progressive loss of memory and other cognitive domains, as well as brain atrophy. An elevated homocysteine level (>15 µmol/L), known as hyperhomocysteinemia, is also an attributing risk factor for AD, vascular pathologies, and brain atrophy. Neuroimaging studies including T2-weighted magnetic resonance imaging scans revealed white matter hyperintensities in the periventricular and deep white matter, enlarged ventricles, widened sulci, and decreased white matter mass, which are features of aging, as well as cerebrovascular changes. This case series investigated changes in biochemical marker levels including serum homocysteine, folate, and vitamin B12, and the degree of atrophic variations in cortical-subcortical white matter in AD. The present study hypothesized that serum homocysteine levels might be used as a surrogate marker to screen for AD at an earlier stage.

Mortality Trends in Alzheimer's Disease in Mississippi, 2011-2021.

This paper reviews the risk factors, mortality trends, etiology, and prognosis of Alzheimer's in Mississippi with a focus on prevention. The southern diet with foods high in sugar and sodium, along with sedentary and poor lifestyle choices, increases mortality risk from Alzheimer's disease for women in Mississippi, specifically due to women over 65 having higher rates of obesity and hypertension. Understanding the epidemiology and risk factors of Alzheimer's in Mississippi will help inform communities, policies, and programs to prevent disease occurrence.

Interplay between microglia and environmental risk factors in Alzheimer's disease.

Alzheimer's disease, among the most common neurodegenerative disorders, is characterized by progressive cognitive impairment. At present, the Alzheimer's disease main risk remains genetic risks, but major environmental factors are increasingly shown to impact Alzheimer's disease development and progression. Microglia, the most important brain immune cells, play a central role in Alzheimer's disease pathogenesis and are considered environmental and lifestyle "sensors." Factors like environmental pollution and modern lifestyles (e.g., chronic stress, poor dietary habits, sleep, and circadian rhythm disorders) can cause neuroinflammatory responses that lead to cognitive impairment via microglial functioning and phenotypic regulation. However, the specific mechanisms underlying interactions among these factors and microglia in Alzheimer's disease are unclear. Herein, we: discuss the biological effects of air pollution, chronic stress, gut microbiota, sleep patterns, physical exercise, cigarette smoking, and caffeine consumption on microglia; consider how unhealthy lifestyle factors influence individual susceptibility to Alzheimer's disease; and present the neuroprotective effects of a healthy lifestyle. Toward intervening and controlling these environmental risk factors at an early Alzheimer's disease stage, understanding the role of microglia in Alzheimer's disease development, and targeting strategies to target microglia, could be essential to future Alzheimer's disease treatments.

In Silico Design of Natural Inhibitors of ApoE4 from the Plant Moringa oleifera: Molecular Docking and Ab Initio Fragment Molecular Orbital Calculations.

Alzheimer's disease (AD) is a neurological disease, and its signs and symptoms appear slowly over time. Although current Alzheimer's disease treatments can alleviate symptoms, they cannot prevent the disease from progressing. To accurately diagnose and treat Alzheimer's disease, it is therefore necessary to establish effective methods for diagnosis. Apolipoprotein E4 (ApoE4), the most frequent genetic risk factor for AD, is expressed in more than half of patients with AD, making it an attractive target for AD therapy. We used molecular docking simulations, classical molecular mechanics optimizations, and ab initio fragment molecular orbital (FMO) calculations to investigate the specific interactions between ApoE4 and the naturally occurring compounds found in the plant Moringa Oleifera. According to the FMO calculations, quercetin had the highest binding affinity to ApoE4 among the sixteen compounds because its hydroxyl groups generated strong hydrogen bonds with the ApoE4 residues Trp11, Asp12, Arg15, and Asp130. As a result, we proposed various quercetin derivatives by introducing a hydroxyl group into quercetin and studied their ApoE4 binding properties. The FMO data clearly showed that adding a hydroxyl group to quercetin improved its binding capacity to ApoE4. Furthermore, ApoE4 Trp11, Asp12, Arg15, and Asp130 residues were discovered to be required for significant interactions between ApoE4 and quercetin derivatives. They had a higher ApoE4 binding affinity than our previously proposed epicatechin derivatives. Accordingly, the current results evaluated using the ab initio FMO method will be useful for designing potent ApoE4 inhibitors that can be used as a candidate agent for AD treatment.

A deep learning model for Alzheimer’s disease diagnosis based on patient clinical records

Background:Dementia, with Alzheimer’s disease (AD) being the most common type of this neurodegenerative disease, is an under-diagnosed health problem in older people. The creation of classification models based on AD risk factors using Deep Learning is a promising tool to minimize the impact of under-diagnosis. Objective:To develop a Deep Learning model that uses clinical data from patients with dementia to classify whether they have AD. Methods:A Deep Learning model to identify AD in clinical records is proposed. In addition, several rebalancing methods have been used to preprocess the dataset and several studies have been carried out to tune up the model. Results:Model has been tested against other well-established machine learning techniques, having better results than these in terms of AUC with alpha less than 0.05. Conclusions:The developed Neural Network Model has a good performance and can be an accurate assisting tool for AD diagnosis.

Hypertension linked to Alzheimer’s disease via stroke: Mendelian randomization

This study aimed to investigate the relationship between hypertension and Alzheimer’s disease (AD) and demonstrate the key role of stroke in this relationship using mediating Mendelian randomization. AD, a neurodegenerative disease characterized by memory loss, cognitive impairment, and behavioral abnormalities, severely affects the quality of life of patients. Hypertension is an important risk factor for AD. However, the precise mechanism underlying this relationship is unclear. To investigate the relationship between hypertension and AD, we used a mediated Mendelian randomization method and screened for mediating variables between hypertension and AD by setting instrumental variables. The results of the mediated analysis showed that stroke, as a mediating variable, plays an important role in the causal relationship between hypertension and AD. Specifically, the mediated indirect effect value for stroke obtained using multivariate mediated MR analysis was 54.9%. This implies that approximately 55% of the risk of AD owing to hypertension can be attributed to stroke. The results suggest that the increased risk of AD owing to hypertension is mediated through stroke. The finding not only sheds light on the relationship between hypertension and AD but also indicates novel methods for the prevention and treatment of AD. By identifying the critical role of stroke in the link between hypertension and AD, this study provides insights into potential interventions that could mitigate the impact of hypertension on AD. This could help develop personalized treatments and help improve the quality of life of patients with AD who suffer from hypertension.

Diet's Role in Modifying Risk of Alzheimer's Disease: History and Present Understanding.

Diet is an important nonpharmacological risk-modifying factor for Alzheimer's disease (AD). The approaches used here to assess diet's role in the risk of AD include multi-country ecological studies, prospective and cross-sectional observational studies, and laboratory studies. Ecological studies have identified fat, meat, and obesity from high-energy diets as important risk factors for AD and reported that AD rates peak about 15-20 years after national dietary changes. Observational studies have compared the Western dietary pattern with those of the Dietary Approaches to Stop Hypertension (DASH), Mediterranean (MedDi), and Mediterranean-DASH Intervention for Neurodegenerative Delay (MIND) diets. Those studies identified AD risk factors including higher consumption of saturated and total fats, meat, and ultraprocessed foods and a lower risk of AD with higher consumption of fruits, legumes, nuts, omega-3 fatty acids, vegetables, and whole grains. Diet-induced factors associated with a significant risk of AD include inflammation, insulin resistance, oxidative stress, elevated homocysteine, dietary advanced glycation end products, and trimethylamine N-oxide. The molecular mechanisms by which dietary bioactive components and specific foods affect risk of AD are discussed. Given most countries' entrenched food supply systems, the upward trends of AD rates would be hard to reverse. However, for people willing and able, a low-animal product diet with plenty of anti-inflammatory, low-glycemic load foods may be helpful.

Biochemical Markers and Genetic Risk Factors in Alzheimer's Disease

Biochemical Markers and Genetic Risk Factors in Alzheimer's Disease

Aging gene signature of memory CD8+ T cells is associated with neurocognitive functioning in Alzheimer’s disease

BackgroundMemory CD8+ T cells expand with age. We previously demonstrated an age-associated expansion of effector memory (EM) CD8+ T cells expressing low levels of IL-7 receptor alpha (IL-7Rαlow) and the presence of its gene signature (i.e., IL-7Rαlow aging genes) in peripheral blood of older adults without Alzheimer’s disease (AD). Considering age as the strongest risk factor for AD and the recent finding of EM CD8+ T cell expansion, mostly IL-7Rαlow cells, in AD, we investigated whether subjects with AD have alterations in IL-7Rαlow aging gene signature, especially in relation to genes possibly associated with AD and disease severity.ResultsWe identified a set of 29 candidate genes (i.e., putative AD genes) which could be differentially expressed in peripheral blood of patients with AD through the systematic search of publicly available datasets. Of the 29 putative AD genes, 9 genes (31%) were IL-7Rαlow aging genes (P < 0.001), suggesting the possible implication of IL-7Rαlow aging genes in AD. These findings were validated by RT-qPCR analysis of 40 genes, including 29 putative AD genes, additional 9 top IL-7R⍺low aging but not the putative AD genes, and 2 inflammatory control genes in peripheral blood of cognitively normal persons (CN, 38 subjects) and patients with AD (40 mild cognitive impairment and 43 dementia subjects). The RT-qPCR results showed 8 differentially expressed genes between AD and CN groups; five (62.5%) of which were top IL-7Rαlow aging genes (FGFBP2, GZMH, NUAK1, PRSS23, TGFBR3) not previously reported to be altered in AD. Unbiased clustering analysis revealed 3 clusters of dementia patients with distinct expression levels of the 40 analyzed genes, including IL-7Rαlow aging genes, which were associated with neurocognitive function as determined by MoCA, CDRsob and neuropsychological testing.ConclusionsWe report differential expression of “normal” aging genes associated with IL‐7Rαlow EM CD8+ T cells in peripheral blood of patients with AD, and the significance of such gene expression in clustering subjects with dementia due to AD into groups with different levels of cognitive functioning. These results provide a platform for studies investigating the possible implications of age-related immune changes, including those associated with CD8+ T cells, in AD.

Recruitment data of the HAPPCAP‐AD (Human‐APPlication Combined Approach for Prevention of Alzheimer’s Disease): a feasibility study

AbstractBackgroundPhysical inactivity, obesity, type 2 diabetes [T2D], hypertension, smoking, and depression, are six major modifiable risk factors for Alzheimer’s disease (AD). While several multi‐domain intervention studies have been completed, mostly in older adults, targeting one or more modifiable risk factor, results have been inconsistent. We designed novel, “real‐life”, feasibility study of a personalized 18‐months intervention for prevention of cognitive decline in middle‐aged individuals at very high AD risk due the presence of at least two modifiable risk factors plus parental family history of AD. Our aims are to explore: 1) The feasibility of our novel approach; 2) Whether our intervention improves AD risk factors and whether greater adherence is associated with larger improvement; and 3) Whether our intervention improves cognition.MethodStudy’s participants are 40‐65 years old cognitively normal offspring of individuals with AD. Participants must have at least two of the six major modifiable AD risk factors. Recruitment goal was 100 participants. Participants were randomized at a 2:1 ratio to the intervention:control arms of the study. The 18‐months intervention combines a smartphone application (app) with study team guidance through phone‐calls, which include advice for risk factors improvement, interactive follow‐up using an app, and feedback on risk factors management for its modification.ResultSince study was launch in 2019, 500 individuals have completed an online eligibility questionnaire. We have achieved the recruitment goal, and 100 participants have been enrolled, with 67 in the intervention group and 33 in the control group. Groups are well‐matched for baseline demographics and AD risk factors (intervention vs control: age‐ 57.3[SE = 0.64]vs.57.0[SE = 0.99]; sex ‐ [% males]30%vs.33%; years of education‐ 17.7[SE = 0.77] vs.17.0[SE = 0.64]; BMI‐ 30.5[SE = 0.63]vs.29.6[SE = 0.59]; % physical inactivity ‐84vs.82; % T2D‐ 15vs.12; % hypertension‐ 27vs.30; % depression‐ 16vs.15; and MMSE‐ 29[SE = 0.17]vs. 29.2[SE = 0.16]; all p&gt;0.05), except for percentage of smokers which was significantly higher in the intervention arm (12vs.3). Additional analyses will be ready by AAIC 2023.ConclusionResults of this study will provide feasibility data on the adherence to the human‐app approach, characteristics of those who adhere, on whether the approach improves risk factors, and will provide initial data on intervention efficacy for cognition.

Cataracts are associated with smaller gray matter brain volume among participants in the UK Biobank

AbstractBackgroundVisual impairments, including reduced visual acuity and cataracts, are emerging as novel and modifiable risk factors for Alzheimer disease (AD) and related dementias (ADRD). However, it is unclear whether vision impairments or cataracts are associated with structural integrity of brain regions linked to ADRD or other brain regions. We investigate associations between visual acuity, cataracts, genetic risk for cataract, and brain volumes.MethodWe analyzed 33,923 UK Biobank participants aged 55‐82 without dementia at enrollment who underwent brain MRI. Subsets had usable genetic data (n = 29,963) and visual acuity exams (n = 7,837). Participants self‐reported history of cataracts. The following imaging volumes were generated from FreeSurfer segmentations: hippocampal volume, total brain volume, and total gray matter volume. We additionally included an AD signature region defined as the cortical thickness averaged across six relevant brain regions. We calculated a genetic risk score (GRS) for cataract using 43 previously‐reported genetic variants. Linear regressions estimated the associations between brain volumes and visual acuity or self‐reported cataract, separately with adjustment for demographic and clinical confounders, intracranial volume, and imaging center. Linear regressions for brain volume using cataract GRS adjusted for ancestry principal components, sex, age, intracranial volume, and imaging center.ResultThe sample was an average of 66.0 years (SD = 6.26) at imaging, with a cataract prevalence of 2.5% (n = 863). History of cataract was associated with significantly smaller total gray matter volume (β = ‐2483 mm3, 95% CI: ‐4225 to ‐741). Increased genetic risk for cataract was significantly associated with smaller total gray matter (β = ‐485 mm3, 95% CI: ‐732 to ‐138) and total brain volume (β = ‐707 mm3, 95% CI: ‐1192 to ‐221). Neither cataract nor cataract GRS was associated with hippocampal volume or the AD signature region. Poor visual acuity (worse than 20/40 vision) was not significantly associated with any brain volumes.ConclusionHistory of and genetic risk for cataract is associated with smaller total gray matter volume, but not hippocampal volume. Our results suggest that cataract may increase risk of neurodegeneration independent of typical AD, but more investigation is needed.

Moderation effects of APOE‐ε4 on marine omega‐3 fatty acids and its relation to change in cognitive function among community‐dwelling older adults

AbstractBackgroundIn a recent trial, we observed no effect of omega‐3 fatty acids (omega‐3s) supplementation on cognitive decline. However, brain concentrations and metabolism of lipid molecules in response to omega‐3s may be regulated by apolipoprotein E (APOE)‐ε4 allele status. Further, while APOE‐ε4 is an established risk factor for Alzheimer disease, its association with cognitive decline is uncertain, especially in more diverse samples. The few randomized clinical trials (RCTs) addressing the moderation of effects of omega‐3s on cognitive decline by APOE‐ε4 have yielded inconsistent findings. Thus, we examined moderation by APOE‐ε4 on effects of omega‐3s vs. placebo for global and domain‐specific cognitive change over 2 years in a well‐characterized, diverse sample of older adults.MethodsVITamin D and OmegA‐3 TriaL (VITAL) is a 2×2 factorial RCT of vitamin D3 (2000 IU/day) and/or omega‐3s (1 g/day including 460 mg of eicosapentaenoic acid and 380 mg of docosahexaenoic acid) for cardiovascular disease and cancer prevention. We included 743 VITAL in‐clinic sub‐cohort participants who completed all cognitive tests at baseline and had APOE genotype data. The primary outcome was change in global cognition (averaging z‐scores of 9 tests) over 2 years; episodic memory and executive function/attention were examined separately. We used multiplicative interaction terms in general linear models of response profiles to examine moderation by APOE‐ε4 carrier status on effects of omega‐3s vs. placebo for cognitive change outcomes over 2 years.ResultsThe mean age (standard deviation) of participants was 67.1 (5.3) years; 50.6% were females; 13.5% were from racial and/or ethnic minority backgrounds; and 24.9% were APOE‐ε4 allele carriers. Over 2 years, compared with APOE‐ε4 non‐carriers, APOE‐ε4 carriers had faster declines in global cognition and episodic memory but not in executive function/attention; e.g., the mean difference in change (95% confidence interval) for episodic memory comparing APOE‐ε4 carriers vs. non‐carriers was ‐0.18 (‐0.33 to ‐0.03). There were no significant interactions between APOE‐ε4 carrier status and randomization status (omega‐3s vs. placebo) on change in global, episodic memory, or executive function/attention scores.ConclusionAPOE‐ε4 significantly predicted cognitive decline but did not modify the effect of omega‐3s on global and domain‐specific cognitive change over 2 years.