Genetic Risk For Alzheimer's Disease Research Articles

Moving Beyond Depression: Mood Symptoms Across the Spectrum Relate to Tau Pathology in Older Women at Risk for Alzheimer's Disease.

We examined how symptoms across the mood spectrum relate to Alzheimer's disease (AD) biomarkers in older women at high risk for AD. Participants included 25 women aged 65+ with mild cognitive deficits and elevated AD genetic risk. The Profile of Mood States Questionnaire measured mood symptoms and a total mood disturbance (TMD) score. Tau burden in the meta-temporal region of interest was measured using MK-6240 Tau positron emission tomography (PET) imaging. A subset (n = 12) also had p-Tau181, and Aß40/42 levels measured in plasma. Higher TMD scores related to higher tau PET standardized uptake value ratio (SUVR). Greater negative mood symptoms correlated with higher tau PET SUVR, while greater vigor correlated with lower SUVR. Similar results were seen with plasma p-Tau181 levels, but not with Aβ40/42 levels. In conclusion, positive and negative mood symptoms related to tau pathology in older women at high risk for AD, highlighting a role of mental well-being in AD risk.

Peripheral GFAP and NfL as early biomarkers for dementia: longitudinal insights from the UK Biobank

BackgroundPeripheral glial fibrillary acidic protein (GFAP) and neurofilament light chain (NfL) are sensitive markers of neuroinflammation and neuronal damage. Previous studies with highly selected participants have shown that peripheral GFAP and NfL levels are elevated in the pre-clinical phase of Alzheimer’s disease (AD) and dementia. However, the predictive value of GFAP and NfL for dementia requires more evidence from population-based cohorts.MethodsThis was a prospective cohort study to evaluate UK Biobank participants enrolled from 2006 to 2010 using plasma GFAP and NfL measurements measured by Olink Target Platform and prospectively followed up for dementia diagnosis. Primary outcome was the risk of clinical diagnosed dementia. Secondary outcomes were cognition. Linear regression was used to assess the associations between peripheral GFAP and NfL with cognition. Cox proportional hazard models with cross-validations were used to estimate associations between elevated GFAP and NfL with risk of dementia. All models were adjusted for covariates.ResultsA subsample of 48,542 participants in the UK Biobank with peripheral GFAP and NfL measurements were evaluated. With an average follow-up of 13.18 ± 2.42 years, 1312 new all-cause dementia cases were identified. Peripheral GFAP and NfL increased up to 15 years before dementia diagnosis was made. After strictly adjusting for confounders, increment in NfL was found to be associated with decreased numeric memory and prolonged reaction time. A greater annualized rate of change in GFAP was significantly associated with faster global cognitive decline. Elevation of GFAP (hazard ratio (HR) ranges from 2.25 to 3.15) and NfL (HR ranges from 1.98 to 4.23) increased the risk for several types of dementia. GFAP and NfL significantly improved the predictive values for dementia using previous models (area under the curve (AUC) ranges from 0.80 to 0.89, C-index ranges from 0.86 to 0.91). The AD genetic risk score and number of APOE*E4 alleles strongly correlated with GFAP and NfL levels.ConclusionsThese results suggest that peripheral GFAP and NfL are potential biomarkers for the early diagnosis of dementia. In addition, anti-inflammatory therapies in the initial stages of dementia may have potential benefits.

Association of Rest-Activity Rhythm and Risk of Developing Dementia or Mild Cognitive Impairment in the Middle-Aged and Older Population: Prospective Cohort Study.

The relationship between 24-hour rest-activity rhythms (RARs) and risk for dementia or mild cognitive impairment (MCI) remains an area of growing interest. Previous studies were often limited by small sample sizes, short follow-ups, and older participants. More studies are required to fully explore the link between disrupted RARs and dementia or MCI in middle-aged and older adults. We leveraged the UK Biobank data to examine how RAR disturbances correlate with the risk of developing dementia and MCI in middle-aged and older adults. We analyzed the data of 91,517 UK Biobank participants aged between 43 and 79 years. Wrist actigraphy recordings were used to derive nonparametric RAR metrics, including the activity level of the most active 10-hour period (M10) and its midpoint, the activity level of the least active 5-hour period (L5) and its midpoint, relative amplitude (RA) of the 24-hour cycle [RA=(M10-L5)/(M10+L5)], interdaily stability, and intradaily variability, as well as the amplitude and acrophase of 24-hour rhythms (cosinor analysis). We used Cox proportional hazards models to examine the associations between baseline RAR and subsequent incidence of dementia or MCI, adjusting for demographic characteristics, comorbidities, lifestyle factors, shiftwork status, and genetic risk for Alzheimer's disease. During the follow-up of up to 7.5 years, 555 participants developed MCI or dementia. The dementia or MCI risk increased for those with lower M10 activity (hazard ratio [HR] 1.28, 95% CI 1.14-1.44, per 1-SD decrease), higher L5 activity (HR 1.15, 95% CI 1.10-1.21, per 1-SD increase), lower RA (HR 1.23, 95% CI 1.16-1.29, per 1-SD decrease), lower amplitude (HR 1.32, 95% CI 1.17-1.49, per 1-SD decrease), and higher intradaily variability (HR 1.14, 95% CI 1.05-1.24, per 1-SD increase) as well as advanced L5 midpoint (HR 0.92, 95% CI 0.85-0.99, per 1-SD advance). These associations were similar in people aged <70 and >70 years, and in non-shift workers, and they were independent of genetic and cardiovascular risk factors. No significant associations were observed for M10 midpoint, interdaily stability, or acrophase. Based on findings from a large sample of middle-to-older adults with objective RAR assessment and almost 8-years of follow-up, we suggest that suppressed and fragmented daily activity rhythms precede the onset of dementia or MCI and may serve as risk biomarkers for preclinical dementia in middle-aged and older adults.

Proteomic changes in the human cerebrovasculature in Alzheimer's disease and related tauopathies linked to peripheral biomarkers in plasma and cerebrospinal fluid.

Cerebrovascular dysfunction is a pathological hallmark of Alzheimer's disease (AD). Nevertheless, detecting cerebrovascular changes within bulk tissues has limited our ability to characterize proteomic alterations from less abundant cell types. We conducted quantitative proteomics on bulk brain tissues and isolated cerebrovasculature from the same individuals, encompassing control (N=28), progressive supranuclear palsy (PSP) (N=18), and AD (N=21) cases. Protein co-expression network analysis identified unique cerebrovascular modules significantly correlated with amyloid plaques, cerebrovascular amyloid angiopathy (CAA), and/or tau pathology. The protein products within AD genetic risk loci were concentrated within cerebrovascular modules. The overlap between differentially abundant proteins in AD cerebrospinal fluid (CSF) and plasma with cerebrovascular network highlighted a significant increase of matrisome proteins, SMOC1 and SMOC2, in CSF, plasma, and brain. These findings enhance our understanding of cerebrovascular deficits in AD, shedding light on potential biomarkers associated with CAA and vascular dysfunction in neurodegenerative diseases.

In vivo validation of late-onset Alzheimer's disease genetic risk factors.

Genome-wide association studies have identified over 70 genetic loci associated with late-onset Alzheimer's disease (LOAD), but few candidate polymorphisms have been functionally assessed for disease relevance and mechanism of action. Candidate genetic risk variants were informatically prioritized and individually engineered into a LOAD-sensitized mouse model that carries the AD risk variants APOE ε4/ε4 and Trem2*R47H. The potential disease relevance of each model was assessed by comparing brain transcriptomes measured with the Nanostring Mouse AD Panel at 4 and 12 months of age with human study cohorts. We created new models for 11 coding and loss-of-function risk variants. Transcriptomic effects from multiple genetic variants recapitulated a variety of human gene expression patterns observed in LOAD study cohorts. Specific models matched to emerging molecular LOAD subtypes. These results provide an initial functionalization of 11 candidate risk variants and identify potential preclinical models for testing targeted therapeutics. A novel approach to validate genetic risk factors for late-onset AD (LOAD) is presented. LOAD risk variants were knocked in to conserved mouse loci. Variant effects were assayed by transcriptional analysis. Risk variants in Abca7, Mthfr, Plcg2, and Sorl1 loci modeled molecular signatures of clinical disease. This approach should generate more translationally relevant animal models.

Alzheimer's disease genetic risk score and neuroimaging in the FINGER lifestyle trial.

We assessed a genetic risk score for Alzheimer's disease (AD-GRS) and apolipoprotein E (APOE4) in an exploratory neuroimaging substudy of the FINGER trial. 1260 at-risk older individuals without dementia were randomized to multidomain lifestyle intervention or health advice. N=126 participants underwent magnetic resonance imaging (MRI), and N=47 positron emission tomography (PET) scans (Pittsburgh Compund B [PiB], Fluorodeoxyglucose) at baseline; N=107 and N=38 had repeated 2-year scans. The APOE4 allele, but not AD-GRS, was associated with baseline lower hippocampus volume (β=-0.27, p=0.001), greater amyloid deposition (β=0.48, p=0.001), 2-year decline in hippocampus (β=-0.27, p=0.01), total gray matter volume (β=-0.25, p=0.01), and cortical thickness (β=-0.28, p=0.003). In analyses stratified by AD-GRS (below vs above median), the PiB composite score increased less in intervention versus control in the higher AD-GRS group (β=-0.60, p=0.03). AD-GRS and APOE4 may have different impacts on potential intervention effects on amyloid, that is, less accumulation in the higher-risk group (AD-GRS) versus lower-risk group (APOE). First study of neuroimaging and AD genetics in a multidomain lifestyle intervention. Possible intervention effect on brain amyloid deposition may rely on genetic risk. AD-GRS and APOE4 allele may have different impacts on amyloid during intervention.

Impact of Short-Term Computerized Cognitive Training on Cognition in Older Adults With and Without Genetic Risk of Alzheimer's Disease: Outcomes From the START Randomized Controlled Trial

ObjectivesTo establish the impact of a 3-minute computerized cognitive training program (START) on cognition in older adults with and without genetic risk of Alzheimer's disease. DesignTwo-arm randomized controlled trial of the START program. Setting and ParticipantsRemote online trial in adults older than 50 taking part from home. MethodsThe trial compared the START program with placebo in 6544 people older than 50. Primary outcome was executive function measured through Trailmaking B, with other secondary cognitive measures. Genetic risk profile and ApoE4 status were determined by Illumina Array. ResultsSTART conferred benefit to executive function, attention, memory, and a composite measure, including in people with the ApoE4 genotype. Conclusions and ImplicationsThe 3-minute START task offers a means of supporting cognitive health in older adults and could be used at scale and within a precision medicine approach to reduce risk of cognitive decline in a targeted way.

Older adults with reduced cerebrovascular reactivity exhibit high white matter hyperintensity burden

Cerebrovascular reactivity (CVR) deficits may contribute to small vessel disease, such as white matter hyperintensities (WMH). Moreover, apolipoprotein-e4 (APOE4) carriers at genetic risk for Alzheimer’s disease exhibit cerebrovascular dysfunction relative to non-carriers. We examined whether older adults, and APOE4 carriers specifically, with diminished CVR would exhibit higher WMH burden. Independently living older adults (N = 125, mean age = 69.2 years; SD = 7.6; 31.2% male) free of dementia or clinical stroke underwent brain MRI to quantify cerebral perfusion during CVR to hypercapnia and hypocapnia and determine WMH volume. Adjusting for age, sex and intracranial volume, hierarchical regression analysis revealed a significant association between whole brain CVR to hypercapnia and WMH overall [B = −.02, 95% CI (-.04, −.008), p =.003] and in APOE4 carriers [B = −.03, 95% CI (-.06, −.009), p =.009]. Findings suggest deficits in cerebral vasodilatory capacity are associated with WMH burden in older adults and future studies are warranted to further delineate the effect of APOE4 on precipitating WMH.

Genetic Risk for Alzheimer's Disease Alters Perceived Executive Dysfunction in Cognitively Healthy Middle-Aged and Older Adults.

Subjective cognitive complaints (SCC) may be an early indicator of future cognitive decline. However, findings comparing SCC and objective cognitive performance have varied, particularly in the memory domain. Even less well established is the relationship between subjective and objective complaints in non-amnestic domains, such as in executive functioning, despite evidence indicating very early changes in these domains. Moreover, particularly early changes in both amnestic and non-amnestic domains are apparent in those carrying the Apolipoprotein-E ɛ4 allele, a primary genetic risk for Alzheimer's disease (AD). This study investigated the role of the ɛ4 allele in the consistency between subjective and objective executive functioning in 54 healthy, cognitively intact, middle-aged and older adults. Participants (Mage = 64.07, SD = 9.27, range = 48-84; ɛ4+ = 18) completed the Frontal Systems Behavior Scale (FrSBe) Executive Dysfunction Scale (EXECDYS) to measure subjective executive functioning (SEF) and multiple executive functioning tasks, which were condensed into a single factor. After accounting for age, depression, and anxiety, objective executive functioning performance significantly predicted SEF. Importantly, ɛ4 moderated this effect. Specifically, those carrying the ɛ4 allele had significantly less accurate self-awareness of their executive functioning compared to ɛ4 non-carriers. Utilizing an approach that integrates self-evaluation of executive functioning with objective neurocognitive assessment may help identify the earliest signs of impending cognitive decline, particularly in those with genetic risk for AD. Such an approach could sensitively determine those most prone to future cognitive decline prior to symptom onset, when interventions could be most effective.

Naturalistic assessment of reaction time variability in older adults at risk for Alzheimer's disease.

Maintaining attention underlies many aspects of cognition and becomes compromised early in neurodegenerative diseases like Alzheimer's disease (AD). The consistency of maintaining attention can be measured with reaction time (RT) variability. Previous work has focused on measuring such fluctuations during in-clinic testing, but recent developments in remote, smartphone-based cognitive assessments can allow one to test if these fluctuations in attention are evident in naturalistic settings and if they are sensitive to traditional clinical and cognitive markers of AD. Three hundred and seventy older adults (aged 75.8 +/- 5.8 years) completed a week of remote daily testing on the Ambulatory Research in Cognition (ARC) smartphone platform and also completed clinical, genetic, and conventional in-clinic cognitive assessments. RT variability was assessed in a brief (20-40 seconds) processing speed task using two different measures of variability, the Coefficient of Variation (CoV) and the Root Mean Squared Successive Difference (RMSSD) of RTs on correct trials. Symptomatic participants showed greater variability compared to cognitively normal participants. When restricted to cognitively normal participants, APOE ε4 carriers exhibited greater variability than noncarriers. Both CoV and RMSSD showed significant, and similar, correlations with several in-clinic cognitive composites. Finally, both RT variability measures significantly mediated the relationship between APOE ε4 status and several in-clinic cognition composites. Attentional fluctuations over 20-40 seconds assessed in daily life, are sensitive to clinical status and genetic risk for AD. RT variability appears to be an important predictor of cognitive deficits during the preclinical disease stage.

Interest in genetic susceptibility testing and disclosure of AD dementia risk in cognitively normal adults: a survey study

BackgroundApolipoprotein-E (APOE) genetic testing for Alzheimer’s disease is becoming more important as clinical trials are increasingly targeting individuals carrying APOE-ε4 alleles. Little is known about the interest in finding out one’s genetic risk for Alzheimer’s disease in the general population. Our objective was to examine this in a sample of cognitively normal (CN) adults within a population-based online research registry with the goal to implement APOE-ε4 status for trial recruitment.MethodsAn online survey was completed by 442 CN participants between the age of 49 and 75 years (56% female) from the Dutch Brain Research Registry. The survey assessed interest in participation in research into, and disclosure of, genetic risk for dementia. The survey assessed interest in participation in research into, and disclosure of, genetic risk for dementia and knowing their genetic risk in different hypothetical risk scenarios (10%, 30%, and 50% genetic risk for dementia at age 85, corresponding to APOEε2/ε2 or ε2/ε3, APOEε3/ε4 or ε2ε4, and APOE-ε4/ε4 genotypes). Cochran’s Q and post hoc McNemar tests were used to analyse differences in frequencies across scenarios.ResultsMost participants were interested in participating in research into and disclosure of their genetic risk (81%). The most reported reason was to contribute to scientific research (94%). Interest was higher in males, whilst lower-educated participants were more often undecided. When provided with different risk scenarios, interest in knowing their risk was somewhat higher in the scenarios with higher risk, i.e. in the 50% (79%) compared to the 10% scenario (73%;χ2(2) = 7.98; p = .005). Most individuals expected they would share their genetic risk with close relatives (77–89%), would participate in medication trials (79–88%), and would make long-term arrangements, e.g. retirement, health care, will (69–82%), with larger proportions for scenarios with higher hypothetical genetic risk.ConclusionsOur findings indicate that the vast majority of CN adults participating in a research registry expresses interest in AD genetic risk research and disclosure. Interest in genetic risk disclosure is higher in scenarios corresponding to the APOE-ε4 genotype. This suggests APOE-ε4 screening within an online research registry is potentially a well-received method to accelerate inclusion for trials.

Relationships between hourly cognitive variability and risk of Alzheimer's disease revealed with mixed-effects location scale models.

Observational studies on aging and Alzheimer's disease (AD) typically focus on mean-level changes in cognitive performance over relatively long periods of time (years or decades). Additionally, some studies have examined how trial-level fluctuations in speeded reaction time are related to both age and AD. The aim of the current project was to describe patterns of variability across repeated days of testing as a function of AD risk in cognitively normal older adults. The current project examined the performance of the Ambulatory Research in Cognition (ARC) smartphone application, a high-frequency remote cognitive assessment paradigm, that administers brief tests of episodic memory, spatial working memory, and processing speed. Bayesian mixed-effects location scale models were used to explore differences in mean cognitive performance and intraindividual variability across 28 repeated sessions over a 1-week assessment interval as function of age and genetic risk of AD, specifically the presence of at least one apolipoprotein E (APOE) ε4 allele. Mean performance on processing speed and working memory was negatively related to age and APOE status. More importantly, e4 carriers exhibited increased session-level variability on a test of processing speed compared to noncarriers. Age and education did not consistently relate to cognitive variability, contrary to expectations. Preclinical AD risk, defined as possessing at least one APOE ε4 allele, is not only associated with mean-level performance differences, but also with increases in variability across repeated testing occasions particularly on a test of processing speed. Thus, cognitive variability may serve as an additional and important indicator of AD risk. (PsycInfo Database Record (c) 2023 APA, all rights reserved).

Abnormal dynamics of functional brain network in Apolipoprotein E ε4 carriers with mild cognitive impairment

&lt;abstract&gt; &lt;p&gt;As is well known, the Apolipoprotein E (APOE) ε4 allele is the most pertinent genetic hazardous element for Alzheimer's disease (AD). Mild cognitive impairment (MCI) is considered a prodromal stage of AD. How the APOE ε4 allele modulates functional connectivity of brain network in MCI group is a question worth exploring. At present, some studies have evaluated the relationship between APOE ε4 allele and static functional network connectivity (sFNC) for MCI individuals, while the relationship of dynamic FNC (dFNC) with APOE ε4 allele still remained puzzled. Thus, we aim to detect aberrant dFNC for APOE ε4 carriers in the MCI group. On the basis of the resting-state functional magnetic resonance imaging (rs-fMRI) data, seven intrinsic brain functional networks were first recognized by the group independent component analysis. Then, the technique of sliding window was employed to determine the dFNC, and two dFNC states were detected by the k-means clustering algorithm. Finally, three temporal properties of fraction time, mean dwell time as well as transition numbers in the dFNC states were investigated. The results found that the dFNC and temporal properties in APOE ε4 carriers were abnormal compared with those in APOE ε4 noncarriers. In detail, in the MCI group, compared with APOE ε4 noncarriers, carriers had 9 pairs of abnormal dFNC and had significant differences in all the three temporal properties of the two dFNC states. In addition, two pairs of dFNC were found significantly correlated with clinical measure. This detected abnormal dynamics of temporal properties and dFNC in APOE ε4 carriers were similar with that reported for AD patients in previous studies. These results may suggest that in the MCI group, APOE carriers are more at risk for AD compared to noncarriers. Our findings may offer novel insights into the mechanisms of abnormal brain reconfiguration for individuals at genetic risk for AD, which could also be regarded as biomarkers for the early identification of AD.&lt;/p&gt; &lt;/abstract&gt;

Cerebrospinal fluid proteomics in patients with Alzheimer’s disease reveals five molecular subtypes with distinct genetic risk profiles

Alzheimer’s disease (AD) is heterogenous at the molecular level. Understanding this heterogeneity is critical for AD drug development. Here we define AD molecular subtypes using mass spectrometry proteomics in cerebrospinal fluid, based on 1,058 proteins, with different levels in individuals with AD (n = 419) compared to controls (n = 187). These AD subtypes had alterations in protein levels that were associated with distinct molecular processes: subtype 1 was characterized by proteins related to neuronal hyperplasticity; subtype 2 by innate immune activation; subtype 3 by RNA dysregulation; subtype 4 by choroid plexus dysfunction; and subtype 5 by blood–brain barrier impairment. Each subtype was related to specific AD genetic risk variants, for example, subtype 1 was enriched with TREM2 R47H. Subtypes also differed in clinical outcomes, survival times and anatomical patterns of brain atrophy. These results indicate molecular heterogeneity in AD and highlight the need for personalized medicine.

Effects of the active amyloid beta immunotherapy CAD106 on PET measurements of amyloid plaque deposition in cognitively unimpaired APOE ε4 homozygotes.

Alzheimer's Prevention Initiative Generation Study 1 evaluated amyloid beta (Aβ) active immunotherapy (vaccine) CAD106 and BACE-1 inhibitor umibecestat in cognitively unimpaired 60- to 75-year-old participants at genetic risk for Alzheimer's disease (AD). The study was reduced in size and terminated early. Results from the CAD106 cohort are presented. Sixty-five apolipoprotein E ε4 homozygotes with/without amyloid deposition received intramuscular CAD106 450μg (n=42) or placebo (n=23) at baseline; Weeks 1, 7, 13; and quarterly; 51 of them had follow-up Aβ positron emission tomography (PET) scans at 18 to 24 months. CAD106 induced measurable serum Aβ immunoglobulin G titers in 41/42 participants, slower rates of Aβ plaque accumulation (mean [standard deviation] annualized change from baseline in amyloid PET Centiloid: -0.91[5.65] for CAD106 versus 8.36 [6.68] for placebo; P<0.001), and three amyloid-related imaging abnormality cases (one symptomatic). Despite early termination, these findings support the potential value of conducting larger prevention trials of Aβ active immunotherapies in individuals at risk for AD. This was the first amyloid-lowering prevention trial in persons at genetic risk of late-onset Alzheimer's disease (AD). Active immunotherapy targeting amyloid (CAD106) was tested in this prevention trial. CAD106 significantly slowed down amyloid plaque deposition in apolipoprotein E homozygotes. CAD106 was generally safe and well tolerated, with only three amyloid-related imaging abnormality cases (one symptomatic). Such an approach deserves further evaluation in larger AD prevention trials.

THE ASSOCIATION BETWEEN APOE Ε4 AND EPISODIC MEMORY IN MIDLIFE: TESTING THE COGNITIVE PHENOTYPE HYPOTHESIS

Abstract Carrying at least one ε4 allele of Apolipoprotein E (APOE ε4) is a strong genetic risk factor for Alzheimer’s disease (AD). It is contentious whether the effect of APOE ε4 on memory decline is because of cognitive phenotype or prodromal AD cases. Inconsistent findings on this topic could be due to the presence of AD pathology in older ages and the lack of sensitivity of memory measures. To exclude potential prodromal AD cases, we tested the association between APOE ε4 and episodic memory among cognitively unimpaired adults in midlife. Data from a subset of 103 participants (Mage=57±6 years; 87.4% females) from an ongoing clinical trial (NIH R01AG058919) were analyzed. APOE genotype was assessed from passive drool saliva samples, and participants completed memory assessments. Analyses of covariance compared 39 carriers of APOE ε4 versus 64 non-carriers of APOE ε4 for their performance of mnemonic discrimination, auditory-verbal and visuospatial short- and long-term memory, paired associative memory, and verbal logical memory, while controlling relevant covariates (e.g., age, education, sex, and physical activity level). After covariate adjustments, significant negative relationships between APOE ε4 and mnemonic discrimination were observed while nearly significant negative relationships were observed for auditory-verbal long-term memory. These findings imply that APOE ε4 could be associated with a cognitive phenotype of decline in mnemonic discrimination and auditory-verbal long-term memory, and the phenotype effects on memory decline could start in midlife. This suggests the importance of early lifestyle interventions for cognitive health in midlife, especially in people at genetic risk for AD.

Genetic characterization of the ALFA study: Uncovering genetic profiles in the Alzheimer's continuum.

In 2013, the ALzheimer's and FAmilies (ALFA) project was established to investigate pathophysiological changes in preclinical Alzheimer's disease (AD), and to foster research on early detection and preventive interventions. We conducted a comprehensive genetic characterization of ALFA participants with respect to neurodegenerative/cerebrovascular diseases, AD biomarkers, brain endophenotypes, risk factors and aging biomarkers. We placed particular emphasis on amyloid/tau status and assessed gender differences. Multiple polygenic risk scores were computed to capture different aspects of genetic predisposition. We additionally compared AD risk in ALFA to that across the full disease spectrum from the Alzheimer's Disease Neuroimaging Initiative (ADNI). Results show that the ALFA project has been successful at establishing a cohort of cognitively unimpaired individuals at high genetic predisposition of AD. It is, therefore, well-suited to study early pathophysiological changes in the preclinical ADcontinuum. Highlights Prevalence of ε4 carriers in ALzheimer and FAmilies (ALFA) is higher than in the general European population The ALFA study is highly enriched in Alzheimer's disease (AD) genetic risk factors beyond APOE AD genetic profiles in ALFA are similar to clinical groups along the continuum ALFA has succeeded in establishing a cohort of cognitively unimpaired individuals at high genetic AD risk ALFA is well suited to study pathogenic events/early pathophysiological changes in AD.

Proof-of-concept recall-by-genotype study of extremely low and high Alzheimer’s polygenic risk reveals autobiographical deficits and cingulate cortex correlates

BackgroundGenome-wide association studies demonstrate that Alzheimer’s disease (AD) has a highly polygenic architecture, where thousands of independent genetic variants explain risk with high classification accuracy. This AD polygenic risk score (AD-PRS) has been previously linked to preclinical cognitive and neuroimaging features observed in asymptomatic individuals. However, shared variance between AD-PRS and neurocognitive features are small, suggesting limited preclinical utility.MethodsHere, we recruited sixteen clinically asymptomatic individuals (mean age 67; range 58–76) with either extremely low / high AD-PRS (defined as at least 2 standard deviations from the wider sample mean (N = 4504; NEFFECTIVE = 90)) with comparable age sex and education level. We assessed group differences in autobiographical memory and T1-weighted structural neuroimaging features.ResultsWe observed marked reductions in autobiographical recollection (Cohen’s d = − 1.66; PFDR = 0.014) and midline structure (cingulate) thickness (Cohen’s d = − 1.55, PFDR = 0.05), with no difference in hippocampal volume (P > 0.3). We further confirm the negative association between AD-PRS and cingulate thickness in a larger study with a comparable age (N = 31,966, β = − 0.002, P = 0.011), supporting the validity of our approach.ConclusionsThese observations conform with multiple streams of prior evidence suggesting alterations in cingulate structures may occur in individuals with higher AD genetic risk. We were able to use a genetically informed research design strategy that significantly improved the efficiency and power of the study. Thus, we further demonstrate that the recall-by-genotype of AD-PRS from wider samples is a promising approach for the detection, assessment, and intervention in specific individuals with increased AD genetic risk.

Poorer online cognitive performance is associated with genetic risk for Alzheimer’s disease and brain phenotypes in healthy mid‐life and older adults.

AbstractBackgroundSelf‐administered online cognitive testing offers a cost‐effective and flexible alternative to in‐person neuropsychological assessments. We used the Creyos platform (previously named Cambridge Brain Sciences) to assess cognitive function in a large sample (N = 1673) of middle aged and older adults participating in the PISA (Prospective Imaging Study of Aging) study. PISA aims to characterise the early symptoms and progression of Alzheimer’s disease at its prodromal phase.MethodWe have utilised our Australia‐wide population based sample recruitment pool of research participants with genome wide genotyping. Participants completed a comprehensive online survey and online cognitive assessments, including Creyos, consisting of 12 self‐administered tasks covering memory, executive function, language, and visuo‐spatial domains. Using genetic profile scores in a sample size of 1,673 (70% female, aged 42‐75 years, mean 60.8). We tested the association between cognitive test results and genetic risk for Alzheimer’s disease and related phenotypes including structural neuroimaging measures.ResultsOur findings indicate a significant association of Alzheimer’s polygenic risk scores (PRS) with cognitive test results in healthy individuals within memory and executive function domains. The results of analyses with additional genetic profile scores including psychiatric traits and structural neuroimaging measures will also be presented.ConclusionThose who are at high genetic risk for Alzheimer’s disease have reduced cognitive function prior to dementia diagnosis from middle age. Our results highlight the utility of online cognitive testing as a cost‐effective alternative to in person testing for large scale studies and the potential for it’s used as a pre‐screening approach to identify those at high risk of Alzheimer’s disease.

Investigating epigenetic regulation of microglia in a human‐mouse chimera model of Alzheimer’s disease

AbstractBackgroundMicroglia, the resident macrophages of the brain, are implicated in Alzheimer’s disease (AD). The genetic risk for AD is significantly enriched near microglial genes and enhancers. In the human brain, APOE is the strongest genetic risk factor for late onset AD and is primarily expressed in microglia and astrocytes. The “disease associated microglia” (DAM) state, in which inflammatory pathways are upregulated in amyloid plaque‐associated microglia, is a characteristic pathological response in AD.MethodHere, we studied how amyloid pathology interacts with genetic risk for AD to regulate the DAM state.We profiled gene regulation in human iPS‐derived microglia. We xenotransplanted the microglia into the APPNL‐G‐F mouse model of AD using isogenic APOE2/3/4 and APOE knockout (KO) microglia (n = 5 animals per microglial APOE genotype). We characterized dissociated iPS‐derived microglia from each animal by RNA‐seq, CUT&amp;Tag for H3K27ac, and ATAC‐seq. We performed quantitative analyses of the epigenetic landscapes of microglial populations across heterogeneous activation states. This allowed us to infer the regulatory pathways that are responsible for the differential microglia response to amyloid aggregation, depending on APOE.ResultWe observed widespread differences in gene regulation across microglia related to APOE genotype. While we observed upregulation of chemokine and interferon response signalling in AD‐risk variant e4, we observed corresponding downregulation in the AD‐protective variant e2. Additional analyses identified increased chromatin accessibility at vitamin D receptor binding motifs in e2 through motif analysis. Finally, we identified gene expression networks and modules underlying differential microglial activation states.ConclusionOur findings are important for understanding microglia and their activation in AD and neurodegenerative diseases. Here, we profiled comprehensive epigenetic landscapes in a human‐mouse chimera in the context of APOE genotype. This enabled us to leverage the realistic biological environment for the microglia offered by this model, and dissect genetic effects underlying microglial responses for the first time.