Family History Of Alzheimer's Disease Research Articles

Specification curve analysis to identify heterogeneity in risk factors for dementia: findings from the UK Biobank

BackgroundIn 2020, the Lancet Commission identified 12 risk factors as priorities for prevention of dementia, and other studies identified APOE e4/e4 genotype and family history of Alzheimer’s disease strongly associated with dementia outcomes; however, it is unclear how robust these relationships are across dementia subtypes and analytic scenarios. Specification curve analysis (SCA) is a new tool to probe how plausible analytical scenarios influence outcomes.MethodsWe evaluated the heterogeneity of odds ratios for 12 risk factors reported from the Lancet 2020 report and two additional strong associated non-modifiable factors (APOE e4/e4 genotype and family history of Alzheimer’s disease) with dementia outcomes across 450,707 UK Biobank participants using SCA with 5357 specifications across dementia subtypes (outcomes) and analytic models (e.g., standard demographic covariates such as age or sex and/or 14 correlated risk factors).ResultsSCA revealed variable dementia risks by subtype and age, with associations for TBI and APOE e4/e4 robust to model specification; in contrast, diabetes showed fluctuating links with dementia subtypes. We found that unattributed dementia participants had similar risk factor profiles to participants with defined subtypes.ConclusionsWe observed heterogeneity in the risk of dementia, and estimates of risk were influenced by the inclusion of a combination of other modifiable risk factors; non-modifiable demographic factors had a minimal role in analytic heterogeneity. Future studies should report multiple plausible analytic scenarios to test the robustness of their association. Considering these combinations of risk factors could be advantageous for the clinical development and evaluation of novel screening models for different types of dementia.

A.2 Understanding Grit in healthy older adults at-risk for Alzheimer’s disease

Background: Adherence to healthy lifestyle behaviours or to prescribed medication requires perseverance with stamina, and this is captured by Grit, a non-cognitive trait defined as perseverance and passion for long-term goals. Despite predicting cognitive decline and physical, emotional, and social functioning, Grit remains poorly understood and its neural substrates are unknown in cognitive aging. Methods: Ninety-five cognitively unimpaired older adults with a family history of Alzheimer’s disease were recruited through the PREVENT-AD longitudinal cohort. Participants completed tests that assess grit and conscientiousness and underwent resting-state functional magnetic resonance imaging (fMRI). Multivariate pattern analyses (MVPA), a rigorous data-driven whole-brain approach, were used to examine if resting-state functional connectivity of connectome-wide voxels were associated with grit scores, controlling for age, sex, APOE ε4 carriership, mean displacement, and conscientiousness. Results: Our analyses identified two large (≥54 voxels) and statistically significant (p<0.01 corrected for family-wise error) clusters in the right ventrolateral prefrontal cortex and the left orbitofrontal cortex underlying grit. Conclusions: Being the first to identify functional neural correlates supporting grit in the aging population while accounting for the variance of conscientiousness, our study provides unique insights into the construct which has important applications in adherence to clinical and empirical neurological interventions as well as in successful aging.

Burden of undiagnosed depression among older adults in India: a population based study.

The study explored the levels and associated factors of undiagnosed depression among community-dwelling older Indian adults. It also identified the socio-demographic predictors of undiagnosed depression among the study population at national and state levels. The study employed data from the Longitudinal Ageing Study in India wave-I, 2017-18. Based on the data on depression from interviewee's self-reporting and measurement on Composite International Diagnostic Interview- Short Form (CIDI-SF) and Centre for Epidemiological Studies- Depression scale (CES-D) scales, we estimated undiagnosed depression among older adults (age 60+). We estimated multivariable binary logistic regressions to examine the socio-demographic and health-related predictors of undiagnosed depression among older adults. 8% (95% CI: 7.8-8.4) of the total older adults had undiagnosed depression on CIDI-SF scale and 5% (95% CI: 4.8-5.3) on the combined CIDI-SF and CES-D. Undiagnosed depression was higher among those who were widowed, worked in the past and currently not working, scheduled castes, higher educated and the richest. Lack of health insurance coverage, presence of any other physical or mental impairment, family history of Alzheimer's/Parkinson's disease/ psychotic disorder, lower self-rated health and poor life satisfaction were significant predictors of undiagnosed depression on both CIDI-SF and combined scales. To improve the health of older adults in India, targeted policy efforts integrating mental health screening, awareness campaigns and decentralization of mental healthcare to primary level is needed. Further research could explore the causal factors behind different levels of undiagnosed depression.

Resilience and Psychological Distress in Genetic Testing for Alzheimer's Disease

The relationship between resilience and psychological distress resulting from genetic testing for Alzheimer’s disease among non-cognitively impaired individuals is examined in this study. Preventative genetic testing determines the likelihood of developing or passing on genetic disorders. However, receiving genetic information, especially regarding incurable diseases like Alzheimer’s disease, can lead to significant psychological distress. Resilience, the ability to cope with adversity and recover quickly, is considered a protective factor against psychological distress. The purpose of this study is to investigate whether higher levels of resilience are associated with lower psychological distress from genetic testing for Alzheimer’s disease and to determine if having a familial history of Alzheimer’s disease influences this relationship. An online cross-sectional survey was conducted among 181 non-cognitively impaired participants (43.6% Male; 54.1% Female; Mage=38.1 [13.9]) using the Impact of Genetic Testing for Alzheimer’s Disease (IGT-AD) scale and the Brief Resilience Scale (BRS), along with a question about family history of Alzheimer’s disease. The results indicated a significant negative correlation between resilience and psychological distress, suggesting that individuals with higher resilience experienced lower distress related to genetic testing. However, family history did not mediate the relationship, meaning the protective effect of resilience was consistent regardless of familial risk. These findings have implications for developing targeted support services and resilience-based interventions to help individuals cope with the emotional impact of genetic testing for Alzheimer’s disease. Further research could explore other potential protective factors and examine the long-term impact of genetic testing results on psychological well-being and behavior.

Neurobehavioral mechanisms influencing the association between generativity, the desire to promote well-being of younger generations, and purpose in life in older adults at risk for Alzheimer's disease.

Generativity, the desire and action to improve the well-being of younger generations, is associated with purpose in life among older adults. However, the neurobehavioral factors supporting the relationship between generativity and purpose in life remain unknown. This study aims to identify the functional neuroanatomy of generativity and mechanisms linking generativity with purpose in life in at-risk older adults. Fifty-eight older adults (mean age = 70.8, SD = 5.03, 45 females) with a family history of Alzheimer's disease (AD) were recruited from the PREVENT-AD cohort. Participants underwent brain imaging and completed questionnaires assessing generativity, social support, and purpose in life. Mediation models examined whether social support mediated the association between generativity and purpose in life. Seed-to-voxel analyses investigated the association between generativity and resting-state functional connectivity (rsFC) to the ventromedial prefrontal cortex (vmPFC) and ventral striatum (VS), and whether this rsFC moderated the relationship between generativity and purpose in life. Affectionate social support mediated the association between generative desire and purpose in life. Generative desire was associated with rsFC between VS and precuneus, and, vmPFC and right dorsolateral prefrontal cortex (rdlPFC). The vmPFC-rdlPFC rsFC moderated the association between generative desire and purpose in life. These findings provide insight into how the brain supports complex social behavior and, separately, purpose in life in at-risk aging. Affectionate social support may be a putative target process to enhance purpose in life in older adults. This knowledge contributes to future developments of personalized interventions that promote healthy aging.

Generation of human induced pluripotent stem cell line (XWHNi004-A) from a male with APOE gene mutation

Genetic polymorphism of apolipoprotein E (APOE) confers differential susceptibility to Alzheimer's disease (AD), and APOE ɛ4 variants is the most powerful risk factor for this disease. Here, we report the generation of a human induced pluripotent stem cell (iPSC) line carrying the APOE ɛ4/ɛ4 genotype from peripheral blood mononuclear cells (PBMCs) isolated from a male with a family history of AD utilizing non-integrative Sendai virus vector. The iPSC maintains their original genotype, highly express endogenous pluripotency markers, displays a normal karyotype, and retains the ability to differentiate into cells representative of the three germ layers.

Resting heart rate and risk of dementia: a Mendelian randomization study in the international genomics of Alzheimer's Project and UK Biobank.

Observational studies have demonstrated that a higher resting heart rate (RHR) is associated with an increased risk of dementia. However, it is not clear whether the association is causal. This study aimed to determine the causal effects of higher genetically predicted RHR on the risk of dementia. We performed a two-sample Mendelian randomization analysis to investigate the causal effect of higher genetically predicted RHR on Alzheimer's disease (AD) using summary statistics from genome-wide association studies. The generalized summary Mendelian randomization (GSMR) analysis was used to analyze the corresponding effects of RHR on following different outcomes: 1) diagnosis of AD (International Genomics of Alzheimer's Project), 2) family history (maternal and paternal) of AD from UK Biobank, 3) combined meta-analysis including these three GWAS results. Further analyses were conducted to determine the possibility of reverse causal association by adjusting for RHR modifying medication. The results of GSMR showed no significant causal effect of higher genetically predicted RHR on the risk of AD (βGSMR = 0.12, P = 0.30). GSMR applied to the maternal family history of AD (βGSMR = -0.18, P = 0.13) and to the paternal family history of AD (βGSMR = -0.14, P = 0.39) showed the same results. Furthermore, the results were robust after adjusting for RHR modifying drugs (βGSMR = -0.03, P = 0.72). Our study did not find any evidence that supports a causal effect of RHR on dementia. Previous observational associations between RHR and dementia are likely attributed to the correlation between RHR and other cardiovascular diseases.

Subjective Cognitive Decline and Genetic Propensity for Dementia beyond Apolipoprotein ε4: A Systematic Review.

Subjective cognitive decline (SCD) has been described as a probable early stage of dementia, as it has consistently appeared to precede the onset of objective cognitive impairment. SCD is related to many risk factors, including genetic predisposition for dementia. The Apolipoprotein (APOE) ε4 allele, which has been thoroughly studied, seems to explain genetic risk for SCD only partially. Therefore, we aimed to summarize existing data regarding genetic factors related to SCD, beyond APOE ε4, in order to improve our current understanding of SCD. We conducted a PRISMA systematic search in PubMed/MEDLINE and Embase databases using the keywords "subjective cognitive decline" and "genetic predisposition" with specific inclusion and exclusion criteria. From the 270 articles identified, 16 were finally included for the qualitative analysis. Family history of Alzheimer's disease (AD) in regard to SCD was explored in eight studies, with conflicting results. Other genes implicated in SCD, beyond APOE ε4, were investigated in six studies, which were not strong enough to provide clear conclusions. Very few data have been published regarding the association of polygenic risk for AD and SCD. Thus, many more genes related to AD must be studied, with polygenic risk scores appearing to be really promising for future investigation.

Retinal imaging and Alzheimer's disease: a future powered by Artificial Intelligence.

Alzheimer's disease (AD) is a neurodegenerative condition that primarily affects brain tissue. Because the retina and brain share the same embryonic origin, visual deficits have been reported in AD patients. Artificial Intelligence (AI) has recently received a lot of attention due to its immense power to process and detect image hallmarks and make clinical decisions (like diagnosis) based onimages. Since retinal changes have been reported in AD patients, AI is being proposed to process images to predict, diagnose, and prognosis AD. As a result, the purpose of this review was to discuss the use of AI trained on retinal images of AD patients. According to previous research, AD patients experience retinal thickness and retinal vessel density changes, which can occasionally occur before the onset of the disease's clinical symptoms. AI and machine vision can detect and use these changes in the domains of disease prediction, diagnosis, and prognosis. As a result, not only have unique algorithms been developed for this condition, but also databases such as the Retinal OCTA Segmentation dataset (ROSE) have been constructed for this purpose. The achievement of high accuracy, sensitivity, and specificity in the classification of retinal images between AD and healthy groups is one of the major breakthroughs in using AI based on retinal images for AD. It is fascinating that researchers could pinpoint individuals with a positive family history of AD based on the properties of their eyes. In conclusion, the growing application of AI in medicine promises its future position in processing different aspects of patients with AD, but we need cohort studies to determine whether it can help to follow up with healthy persons at risk of AD for a quicker diagnosis or assess the prognosis of patients with AD.

Frontal-temporal regional differences in brain energy metabolism and mitochondrial function using 31P MRS in older adults.

Aging is a major risk for cognitive decline and transition to dementia. One well-known age-related change involves decreased brain efficiency and energy production, mediated in part by changes in mitochondrial function. Damaged or dysfunctional mitochondria have been implicated in the pathogenesis of age-related neurodegenerative conditions like Alzheimer's disease (AD). The aim of the current study was to investigate mitochondrial function over frontal and temporal regions in a sample of 70 cognitively normal older adults with subjective memory complaints and a first-degree family history of AD. We hypothesized cerebral mitochondrial function and energy metabolism would be greater in temporal as compared to frontal regions based on the high energy consumption in the temporal lobes (i.e., hippocampus). To test this hypothesis, we used phosphorous (31P) magnetic resonance spectroscopy (MRS) which is a non-invasive and powerful method for investigating in vivo mitochondrial function via high energy phosphates and phospholipid metabolism ratios. We used a single voxel method (left temporal and bilateral prefrontal) to achieve optimal sensitivity. Results of separate repeated measures analyses of variance showed 31P MRS ratios of static energy, energy reserve, energy consumption, energy demand, and phospholipid membrane metabolism were greater in the left temporal than bilateral prefrontal voxels. Our findings that all 31P MRS ratios were greater in temporal than bifrontal regions support our hypothesis. Future studies are needed to determine whether findings are related to cognition in older adults.

Longitudinal changes in the functional connectivity of individuals at risk of Alzheimer's disease.

First-degree relatives of Alzheimer's disease patients constitute a key population in the search for early markers. Our group identified functional connectivity differences between cognitively unimpaired individuals with and without a family history. In this unprecedented follow-up study, we examine whether family history is associated with a longitudinal increase in the functional connectivity of those regions. Moreover, this is the first work to correlate electrophysiological measures with plasma p-tau231 levels, a known pathology marker, to interpret the nature of the change. We evaluated 69 cognitively unimpaired individuals with a family history of Alzheimer's disease and 28 without, at two different time points, approximately 3years apart, including resting state magnetoencephalography recordings and plasma p-tau231 determinations. Functional connectivity changes in both precunei and left anterior cingulate cortex in the high-alpha band were studied using non-parametric cluster-based permutation tests. Connectivity values were correlated with p-tau231 levels. Three clusters emerged in individuals with family history, exhibiting a longitudinal increase of connectivity. Notably, the clusters for both precunei bore a striking resemblance to those found in previous cross-sectional studies. The connectivity values at follow-up and the change in connectivity in the left precuneus cluster showed significant positive correlations with p-tau231. This study consolidates the use of electrophysiology, in combination with plasma biomarkers, to monitor healthy individuals at risk of Alzheimer's disease and emphasizes the value of combining noninvasive markers to understand the underlying mechanisms and track disease progression. This could facilitate the design of more effective intervention strategies and accurate progression assessment tools.

Attitudes of Family Members and Caregivers Regarding Alzheimer's Disease Pre-Symptomatic Screening.

In recent years, studies have examined the acceptability and attitudes that influence the intention to early screen for Alzheimer's disease (AD) in the general population, older people, carers, and asymptomatic individuals who report a family history of AD. However, it remains unclear what specific factors promote or reduce the acceptability of pre-symptomatic screening. The aim of this study is to explore the attitudes of family and non-family members as well as caregivers and non-caregivers toward the pre-symptomatic screening of AD. A total of 213 participants completed the Perceptions regarding pRE-symptomatic Alzheimer's Disease Screening (PRE-ADS) Questionnaire. Group comparisons using t-test and one-way ANOVA were used to examine differences in attitudes toward pre-symptomatic screening regarding age, family history, knowing someone with AD, influence of depression, and feelings of anxiety. The subscale "Acceptability of Screening" was developed to investigate the willingness to undergo pre-symptomatic screening. Participants with a family history showed greater acceptance of pre-symptomatic screening while both caregivers and non-caregivers had similar attitudes. People with a family history as well as those with personal connections to dementia indicate a greater need for knowledge. The findings suggest that younger adults appear to perceive less harm from testing, whereas those who experience higher levels of anxiety and depression seem to perceive more testing harms. Comparing the attitudes of people with and without a family history as well as caregivers and non-caregivers toward pre-symptomatic screening of AD is critical to understand the differences between these groups and develop comprehensive screening programs.

Changes in colour perception in Alzheimer's disease continuum

Aims/Purpose: The progression of Alzheimer's disease (AD) manifests from a preclinical stage, characterized by asymptomatic pathological alterations, to an advanced stage of AD accompanied by cognitive impairment. The aim of this study was to explore visual function along the entire AD continuum, from individuals with a high genetic predisposition to those in the moderate phase of the disease.Methods: All participants underwent a visual examination and had to be visually healthy to be included. The study contained five groups: controls (n = 53), individuals with a positive family history of AD (HF+) (n = 13), mild cognitive impairment (MCI) (n = 23), mild AD (n = 25) and moderate AD (n = 21). The study analysed the results of errors in colour perception.Results: A significant increase in the total number of errors was observed between the control group and the moderate AD group. And also when comparing the FH+ group with the MCI group, the mild AD group and the moderate AD group. Significant differences were found on the tritan axis between the control group and the mild AD group, as well as in the moderate AD group. Significant differences were observed between the FH+ group and the mild AD group, as well as in the moderate AD group. A significant increase in the number of errors on the deutan axis was observed between the control group and both the mild and moderate AD groups. In addition, a statistically significant increase was observed when comparing the FH+ group with the moderate AD group. The test correlated with the MMSE score and also showed good predictive value when memory impairment was present.Conclusions: Understanding the importance of changes in colour perception in AD continuum can aid in the early detection and treatment of AD, potentially improving patient outcomes and facilitating targeted interventions.

Visual function changes along the continuum of Alzheimer's disease

Aims/Purpose: The progression of Alzheimer's disease (AD) is manifested by a gradual transition from a preclinical phase, characterized by asymptomatic pathological alterations, to an advanced phase of AD accompanied by cognitive impairment. The aim of this study was to explore visual function along the entire AD continuum.Methods: Each participant underwent a comprehensive visual examination, with only visually healthy individuals being selected for the study. The study comprised the following groups: controls (n = 53), positive family history of AD (FH+) (n = 13), mild cognitive impairment (MCI) (n = 23), mild AD (n = 25), and moderate AD (n = 21). The study analysed the results of visual acuity (VA) and contrast sensitivity (CS).Results: A significant reduction in VA was identified between the control group and the MCI, mild AD and moderate AD groups. CS showed significant changes in all cognitive impairment groups compared to the control group and the FH+ group at spatial frequencies of 12 and 18 cpd. In contrast, significant differences were only observed at spatial frequencies of 3 and 6 cpd between the cognitively impaired groups, starting from moderate AD, with no detectable decrease in CS during the MCI phase. No differences were detected between the control group and the FH+ group. The tests showed a positive correlation with the Mini Mental State Examination score and exhibited a favourable predictive ability in the presence of memory impairment, with higher predictive performance observed in the advance stages of AD.Conclusions: The presence of alterations in VA and CS can be observed as early as the MCI stage in individuals with AD. Recognizing the continuum of AD holds significant significance in early detection, with visual examination offering a straightforward and cost‐effective diagnostic tool for AD. Healthcare professionals can leverage this knowledge to gain a better understanding of the progressive nature of the disease.

RESILIENCE AND PSYCHOLOGICAL DISTRESS IN GENETIC TESTING FOR ALZHEIMER’S DISEASE

Abstract This research project examines the relationship between resilience and psychological distress resulting from genetic testing for Alzheimer’s disease among individuals who are non-cognitively impaired. Preventative genetic testing is increasingly important to determine the likelihood of developing or passing on genetic disorders. However, receiving genetic information, especially regarding incurable diseases like Alzheimer’s disease, can lead to significant psychological distress. Resilience, the ability to cope with adversity and recover quickly, is considered a protective factor against psychological distress. The purpose of this study is to investigate whether higher levels of resilience are associated with lower psychological distress from genetic testing for Alzheimer’s disease. A cross-sectional survey was conducted online using the Impact of Genetic Testing for Alzheimer’s Disease (IGT-AD) scale and the Brief Resilience Scale (BRS), along with a question about family history of Alzheimer’s disease. The results indicated a significant negative correlation between resilience and psychological distress, suggesting that individuals with higher resilience experienced lower distress related to genetic testing. However, family history did not moderate the relationship, meaning the protective effect of resilience was consistent regardless of familial risk. These findings have implications for developing targeted support services and resilience-based interventions to help individuals cope with the emotional impact of genetic testing for Alzheimer’s disease. Further research could explore other potential protective factors and examine the long-term impact of genetic testing results on psychological well-being and behavior.

Caregivers and non‐caregivers attitudes regarding pre‐symptomatic Alzheimer’s disease testing

AbstractBackgroundOver the past decade there has been increasing testing of biomarkers and new methods of presymptomatic screening for Alzheimer disease (AD). But still, there is little known about the beliefs of patients and family caregivers regarding testing in Greece. The aim of this study is to assess the attitudes, barriers and motivations to pre‐symptomatic AD testing, among older adults with and without an experience of AD caregiving.MethodA total sample of 213 participants (Caregivers, N = 96 and Non‐Caregivers, N = 117) answered the ‘’Perceptions regarding pre‐symptomatic dementia testing” (Pre‐dem) questionnaire. Most participants were females (N = 179) and were 41‐50 (N = 56) and 51‐60 (N = 55) years old.ResultA two‐sample t‐test was performed to compare the four domains in caregivers and non‐caregivers and there was no significant difference, and also compare with and without a family history of AD and there was not a significant difference in perceived harms of testing, perceived benefits of testing, and need of knowledge. There was a significant difference in acceptance of testing between participants with a history of AD (M = 4.67, SD = 3.86) and non‐history (M = 6.83, SD = 4.33); t(211) = ‐3.75, p = 0.00. A one‐way ANOVA was conducted to compare the four domains with the years of care (1‐3, 3‐5, and more than 5 years). There were no significant differences between the domains and the years of care. Finally, a one‐way ANOVA was conducted to compare the four domains with the age of the first diagnosis of the relative or friend of the caregiver (51‐55, 56‐60, 61‐65, 66‐70 and 70+). There were no significant differences between the domains and the age that the relative/friend was diagnosed.ConclusionThis is the first study that assessed the attitudes towards dementia and genetic screening of Greek older adults with and without an experience of dementia caregiving. Both participants had similar beliefs regarding the pre‐symptomatic dementia testing, except for the acceptance of testing in participants with and without a family history of AD. There is a need for more information, education and empowerment of the caregivers regarding dementia screening but also the general public.

Multivariate white matter differences links to cognition in individuals with family history of Alzheimer’s disease and APOE4 genetic risk

AbstractBackgroundGrowing evidence suggests Alzheimer’s disease (AD) develops from a complex cascade of events that vary between individuals. Multivariate approaches have the potential to capture the complexity and heterogeneity of pathologies underlying AD in a more holistic manner compared to univariate approaches.MethodThe MRI data of 105 older adults with a family history of AD from the PREVENT‐AD dataset were analysed. Forty six of these individuals had the APOE4‐3 genotype (greater risk of developing AD), while 59 subjects had the APOE3‐3 genotype (normal risk). Diffusion‐weighted imaging and multi‐echo magnetization transfer, proton density and T1‐weighted data were used to compute several WM metrics (Fig1 b‐c). We computed the voxel‐wise Mahalanobis distance (D2) in WM between APOE4‐3 individuals and a reference group (APOE3‐3) (Fig1). D2 is a multivariate measure that combines several MRI metrics, accounting for their covariance, and yielding a score indicative of the degree of abnormality at each WM voxel (Fig2). Associations between WM D2 and cognitive performance were then investigated (Fig3). Independent component analysis (ICA) was performed on spatial dimensions and linear regression analyses were conducted between D2 in ICA components and scores on items of the Repeatable Battery for the Assessment of Neuropsychological Status (RBANS). We then extracted the contribution of each MRI feature to D2 in the regions where significant associations were found.ResultA significant negative association (R = ‐0.36, p = 0.014) was found between D2 in a component corresponding to the splenium of the corpus callosum (CC) and scores on RBANS‐immediate memory (Fig3), indicating a link between a greater degree of WM abnormality and poorer performance. Proton density (MPM_PD) and longitudinal relaxation rate (MPM_R1), potentially indicative of WM loss, contributed most to D2 in this region.ConclusionOur findings suggest that microstructural alterations in the posterior part of the CC may play a role in memory deficit in older adults who are at greater risk of developing AD. This is in line with other studies that showed a link between CC degeneration and memory impairments in early AD stages.1 1. Qiu et al. (2016). Inter‐hemispheric dysconnectivity in AD and aMCI. Sci.Rep.

Pervasive biases in GWAS using family history of Alzheimer’s disease as proxy phenotypes

AbstractBackgroundUsing family health history as proxy phenotype has become a common approach in genome‐wide association studies (GWAS) of Alzheimer’s disease (AD). This approach leverages large samples in population biobanks where most mid‐aged participants do not have any AD diagnosis. However, methodological issues in GWAS‐by‐proxy (GWAX) and quality of its association results have not been carefully investigated.MethodWe performed GWAX on parental AD history in UK Biobank (N = 48,031 proxy cases and 315,286 controls). We then applied GWAS‐by‐subtraction to obtain the non‐AD component underlying AD GWAX. We computed genetic correlations of AD case‐control GWAS, AD GWAX, and the non‐AD component underlying GWAX with a suite of complex traits. We also explored the impact of various quality control procedures and additional covariates in AD GWAX analysis.ResultAD GWAS and GWAX showed drastically different genetic correlations with several other complex traits especially cognitive abilities (Figure 1). AD GWAX had a surprising genetic correlation with higher education (rg = 0.167, p = 1.7e‐11) as opposed to the negative AD‐education correlation observed for GWAS (rg = ‐0.133, p = 2.4e‐5). The positive genetic correlation between AD and cognition is explained by the non‐AD component in AD GWAX (rg = 0.260 with education, p = 5.2e‐11). The non‐AD component in GWAX also showed correlations with lower risks of health outcomes such as coronary artery disease (rg = ‐0.136, p = 2.8e‐3) and diabetes (rg = ‐0.206, p = 2.8e‐3), indicating substantial survival bias in samples reporting parental AD history. Adjusting for parental age in GWAX substantially reduced but did not fully remove the genetic correlation of AD and higher education (rg = 0.013, p = 0.67), hinting at additional unaccounted factors in the current GWAX practice. We also provide evidence that genetic correlation between family health history awareness and education (rg = 0.285, p = 1.4e‐10) leads to these biases in GWAX associations.ConclusionGWAX based on parental health history introduces substantial and systematic biases in AD genetic associations due to the non‐representativeness of the biobank health history survey. Naively combining GWAX with regular case‐control GWAS will lead to misleading results both at the single variant level and in genome‐wide analyses such as genetic correlation estimation and polygenic risk score applications.

Association of Technology Use with Subjective Cognitive Decline among Older Adults

AbstractBackgroundOlder adults with a family history of Alzheimer’s disease (AD) have elevated rates of subjective cognitive decline (SCD). SCD is distressing for older adults and is a risk factor for future objective cognitive impairment, AD pathology, and AD diagnosis. Hence, it is important to understand whether lifestyle factors can mitigate SCD. One potentially protective factor is the use of technology‐based behavioral strategies for completing daily tasks. For example, in the face of subjective memory difficulties, an older adult may move from relying on memory to remember to pay bills to utilizing an automatic bill pay system. The current study examined whether greater use of technology for daily task completion was associated with fewer self‐reported cognitive symptoms, especially in individuals with family history of AD.MethodIndividuals over the age of 50 (range: 50‐85) completed surveys about their digital and analog approaches for completing daily tasks, as well as measures of physical activity and SCD. Participants with and without family histories of AD were matched on age, education, and sex. Multiple linear regression was used to assess main effects of family history and technology‐based behavioral strategy use on SCD. In addition, we examined whether family history of AD moderated this association.ResultThere was no main effect of technology‐based behavioral strategies on SCD (p = 0.259). However, there was an interaction effect between technology use and family history of AD on SCD. Specifically, in individuals with a family history of AD, more reliance on technology‐based behavioral strategies was associated with less SCD (t = ‐2.45, p = 0.018), but this relationship was not significant in individuals without family history of AD (t = 0.66, p = 0.511). This interaction remained significant even when controlling for another important protective lifestyle factor for SCD, physical activity.ConclusionOur findings suggest that technology‐based behavioral strategies are associated with less SCD in individuals with a family history of AD, independent of other protective lifestyle factors. Future recommendations provided by healthcare providers in the community to address subjective cognitive decline in cognitively unimpaired older adults might include focusing on technological assistance.

Multivariate white matter differences links to cognition in individuals with family history of Alzheimer’s disease and APOE4 genetic risk

AbstractBackgroundGrowing evidence suggests Alzheimer’s disease (AD) develops from a complex cascade of events that vary between individuals. Multivariate approaches have the potential to capture the complexity and heterogeneity of pathologies underlying AD in a more holistic manner compared to univariate approaches.MethodThe MRI data of 105 older adults with a family history of AD from the PREVENT‐AD dataset were analysed. Forty six of these individuals had the APOE4‐3 genotype (greater risk of developing AD), while 59 subjects had the APOE3‐3 genotype (normal risk). Diffusion‐weighted imaging and multi‐echo magnetization transfer, proton density and T1‐weighted data were used to compute several WM metrics (Fig1 b‐c). We computed the voxel‐wise Mahalanobis distance (D2) in WM between APOE4‐3 individuals and a reference group (APOE3‐3) (Fig1). D2 is a multivariate measure that combines several MRI metrics, accounting for their covariance, and yielding a score indicative of the degree of abnormality at each WM voxel (Fig2). Associations between WM D2 and cognitive performance were then investigated (Fig3). Independent component analysis (ICA) was performed on spatial dimensions and linear regression analyses were conducted between D2 in ICA components and scores on items of the Repeatable Battery for the Assessment of Neuropsychological Status (RBANS). We then extracted the contribution of each MRI feature to D2 in the regions where significant associations were found.ResultA significant negative association (R = ‐0.36, p = 0.014) was found between D2 in a component corresponding to the splenium of the corpus callosum (CC) and scores on RBANS‐immediate memory (Fig3), indicating a link between a greater degree of WM abnormality and poorer performance. Proton density (MPM_PD) and longitudinal relaxation rate (MPM_R1), potentially indicative of WM loss, contributed most to D2 in this region.ConclusionOur findings suggest that microstructural alterations in the posterior part of the CC may play a role in memory deficit in older adults who are at greater risk of developing AD. This is in line with other studies that showed a link between CC degeneration and memory impairments in early AD stages.1 1. Qiu et al. (2016). Inter‐hemispheric dysconnectivity in AD and aMCI. Sci.Rep.