ABSTRACT
Approximately 30% of elderly adults are cognitively unimpaired at time of death despite the presence of Alzheimer's disease neuropathology at autopsy. Studying individuals who are resilient to the cognitive consequences of Alzheimer's disease neuropathology may uncover novel therapeutic targets to treat Alzheimer's disease. It is well established that there are sex differences in response to Alzheimer's disease pathology, and growing evidence suggests that genetic factors may contribute to these differences. Taken together, we sought to elucidate sex-specific genetic drivers of resilience. We extended our recent large scale genomic analysis of resilience in which we harmonized cognitive data across four cohorts of cognitive ageing, in vivo amyloid PET across two cohorts, and autopsy measures of amyloid neuritic plaque burden across two cohorts. These data were leveraged to build robust, continuous resilience phenotypes. With these phenotypes, we performed sex-stratified [n (males) = 2093, n (females) = 2931] and sex-interaction [n (both sexes) = 5024] genome-wide association studies (GWAS), gene and pathway-based tests, and genetic correlation analyses to clarify the variants, genes and molecular pathways that relate to resilience in a sex-specific manner. Estimated among cognitively normal individuals of both sexes, resilience was 20-25% heritable, and when estimated in either sex among cognitively normal individuals, resilience was 15-44% heritable. In our GWAS, we identified a female-specific locus on chromosome 10 [rs827389, ß (females) = 0.08, P (females) = 5.76 × 10-09, ß (males) = -0.01, P(males) = 0.70, ß (interaction) = 0.09, P (interaction) = 1.01 × 10-04] in which the minor allele was associated with higher resilience scores among females. This locus is located within chromatin loops that interact with promoters of genes involved in RNA processing, including GATA3. Finally, our genetic correlation analyses revealed shared genetic architecture between resilience phenotypes and other complex traits, including a female-specific association with frontotemporal dementia and male-specific associations with heart rate variability traits. We also observed opposing associations between sexes for multiple sclerosis, such that more resilient females had a lower genetic susceptibility to multiple sclerosis, and more resilient males had a higher genetic susceptibility to multiple sclerosis. Overall, we identified sex differences in the genetic architecture of resilience, identified a female-specific resilience locus and highlighted numerous sex-specific molecular pathways that may underly resilience to Alzheimer's disease pathology. This study illustrates the need to conduct sex-aware genomic analyses to identify novel targets that are unidentified in sex-agnostic models. Our findings support the theory that the most successful treatment for an individual with Alzheimer's disease may be personalized based on their biological sex and genetic context.
Subject(s)
Alzheimer Disease , Cognitive Dysfunction , Multiple Sclerosis , Alzheimer Disease/genetics , Alzheimer Disease/pathology , Cognition , Cognitive Dysfunction/genetics , Female , Genetic Predisposition to Disease , Genome-Wide Association Study , Humans , Male , Sex CharacteristicsABSTRACT
Mitochondrial dysfunction is an early and prominent feature of Alzheimer's disease (AD), with impaired energy metabolism preceding the onset of clinical symptoms. Here we propose an update to the mitochondrial dysfunction hypothesis of AD based on recent results examining the role of mitochondrial genome abundance in AD. In a large post mortem study, we show that lower brain mitochondrial genome abundance is associated with a greater odds of AD neuropathological change and worse cognitive performance. We hypothesize that lower mitochondrial genome abundance impairs mitochondrial function by reducing mitochondrial bioenergetics, thereby impacting neuronal and glial cell function. However, it remains to be determined if mitochondrial dysfunction causes, mediates, or is a by-product of AD pathogenesis. Additional support for this hypothesis will be generated by linking peripheral blood mitochondrial genome abundance to AD and establishing clinical trials of compounds that upregulate total mitochondrial genome abundance or boost mitochondrial mass.
Subject(s)
Alzheimer Disease , Genome, Mitochondrial , Humans , Alzheimer Disease/pathology , Mitochondria/genetics , Energy Metabolism , Brain/pathologyABSTRACT
INTRODUCTION: Genetic associations with Alzheimer's disease (AD) age at onset (AAO) could reveal genetic variants with therapeutic applications. We present a large Colombian kindred with autosomal dominant AD (ADAD) as a unique opportunity to discover AAO genetic associations. METHODS: A genetic association study was conducted to examine ADAD AAO in 340 individuals with the PSEN1 E280A mutation via TOPMed array imputation. Replication was assessed in two ADAD cohorts, one sporadic early-onset AD study and four late-onset AD studies. RESULTS: 13 variants had p<1×10-7 or p<1×10-5 with replication including three independent loci with candidate associations with clusterin including near CLU. Other suggestive associations were identified in or near HS3ST1, HSPG2, ACE, LRP1B, TSPAN10, and TSPAN14. DISCUSSION: Variants with suggestive associations with AAO were associated with biological processes including clusterin, heparin sulfate, and amyloid processing. The detection of these effects in the presence of a strong mutation for ADAD reinforces their potentially impactful role.
Subject(s)
Alzheimer Disease , Clusterin , Humans , Clusterin/genetics , Colombia , Alzheimer Disease/diagnosis , Mutation/genetics , Amyloid , Presenilin-1/genetics , Age of OnsetABSTRACT
Alzheimer's disease (AD) is a growing global health crisis affecting millions and incurring substantial economic costs. However, clinical diagnosis remains challenging, with misdiagnoses and underdiagnoses being prevalent. There is an increased focus on putative, blood-based biomarkers that may be useful for the diagnosis as well as early detection of AD. In the present study, we used an unbiased combination of machine learning and functional network analyses to identify blood gene biomarker candidates in AD. Using supervised machine learning, we also determined whether these candidates were indeed unique to AD or whether they were indicative of other neurodegenerative diseases, such as Parkinson's disease (PD) and amyotrophic lateral sclerosis (ALS). Our analyses showed that genes involved in spliceosome assembly, RNA binding, transcription, protein synthesis, mitoribosomes, and NADH dehydrogenase were the best-performing genes for identifying AD patients relative to cognitively healthy controls. This transcriptomic signature, however, was not unique to AD, and subsequent machine learning showed that this signature could also predict PD and ALS relative to controls without neurodegenerative disease. Combined, our results suggest that mRNA from whole blood can indeed be used to screen for patients with neurodegeneration but may be less effective in diagnosing the specific neurodegenerative disease.
Subject(s)
Alzheimer Disease , Amyotrophic Lateral Sclerosis , Neurodegenerative Diseases , Parkinson Disease , Humans , Alzheimer Disease/diagnosis , Alzheimer Disease/genetics , Alzheimer Disease/metabolism , Amyotrophic Lateral Sclerosis/diagnosis , Amyotrophic Lateral Sclerosis/genetics , Amyotrophic Lateral Sclerosis/metabolism , Transcriptome , Parkinson Disease/diagnosis , Parkinson Disease/genetics , Parkinson Disease/metabolism , Biomarkers/metabolismABSTRACT
OBJECTIVE: The purpose of this study was to infer causal relationships between 22 previously reported risk factors for Alzheimer's disease (AD) and the "AD phenome": AD, AD age of onset (AAOS), hippocampal volume, cortical surface area and thickness, cerebrospinal fluid (CSF) levels of amyloid-ß (Aß42 ), tau, and ptau181 , and the neuropathological burden of neuritic plaques, neurofibrillary tangles (NFTs), and vascular brain injury (VBI). METHODS: Polygenic risk scores (PRS) for the 22 risk factors were computed in 26,431 AD cases/controls and the association with AD was evaluated using logistic regression. Two-sample Mendelian randomization (MR) was used to infer the causal effect of risk factors on the AD phenome. RESULTS: PRS for increased education and diastolic blood pressure were associated with reduced risk for AD. MR indicated that only education was causally associated with reduced risk of AD, delayed AAOS, and increased cortical surface area and thickness. Total- and LDL-cholesterol levels were causally associated with increased neuritic plaque burden, although the effects were driven by single nucleotide polymorphisms (SNPs) within the APOE locus. Diastolic blood pressure and pulse pressure are causally associated with increased risk of VBI. Furthermore, total cholesterol was associated with decreased hippocampal volume; smoking initiation with decreased cortical thickness; type 2 diabetes with an earlier AAOS; and sleep duration with increased cortical thickness. INTERPRETATION: Our comprehensive examination of the genetic evidence for the causal relationships between previously reported risk factors in AD using PRS and MR supports a causal role for education, blood pressure, cholesterol levels, smoking, and diabetes with the AD phenome. ANN NEUROL 2021;89:54-65.
Subject(s)
Alzheimer Disease/genetics , Amyloid beta-Peptides/cerebrospinal fluid , Cholesterol/metabolism , Neurofibrillary Tangles/genetics , Peptide Fragments/cerebrospinal fluid , Aged , Aged, 80 and over , Alzheimer Disease/cerebrospinal fluid , Alzheimer Disease/complications , Brain/metabolism , Brain/physiopathology , Cognition/physiology , Diabetes Mellitus, Type 2/complications , Diabetes Mellitus, Type 2/genetics , Female , Humans , Male , Middle Aged , Risk Factors , Sleep/physiologyABSTRACT
Primary age-related tauopathy (PART) is a neurodegenerative pathology with features distinct from but also overlapping with Alzheimer disease (AD). While both exhibit Alzheimer-type temporal lobe neurofibrillary degeneration alongside amnestic cognitive impairment, PART develops independently of amyloid-ß (Aß) plaques. The pathogenesis of PART is not known, but evidence suggests an association with genes that promote tau pathology and others that protect from Aß toxicity. Here, we performed a genetic association study in an autopsy cohort of individuals with PART (n = 647) using Braak neurofibrillary tangle stage as a quantitative trait. We found some significant associations with candidate loci associated with AD (SLC24A4, MS4A6A, HS3ST1) and progressive supranuclear palsy (MAPT and EIF2AK3). Genome-wide association analysis revealed a novel significant association with a single nucleotide polymorphism on chromosome 4 (rs56405341) in a locus containing three genes, including JADE1 which was significantly upregulated in tangle-bearing neurons by single-soma RNA-seq. Immunohistochemical studies using antisera targeting JADE1 protein revealed localization within tau aggregates in autopsy brains with four microtubule-binding domain repeats (4R) isoforms and mixed 3R/4R, but not with 3R exclusively. Co-immunoprecipitation in post-mortem human PART brain tissue revealed a specific binding of JADE1 protein to four repeat tau lacking N-terminal inserts (0N4R). Finally, knockdown of the Drosophila JADE1 homolog rhinoceros (rno) enhanced tau-induced toxicity and apoptosis in vivo in a humanized 0N4R mutant tau knock-in model, as quantified by rough eye phenotype and terminal deoxynucleotidyl transferase dUTP nick end-labeling (TUNEL) in the fly brain. Together, these findings indicate that PART has a genetic architecture that partially overlaps with AD and other tauopathies and suggests a novel role for JADE1 as a modifier of neurofibrillary degeneration.
Subject(s)
Homeodomain Proteins/genetics , Tauopathies/genetics , Tauopathies/pathology , Tumor Suppressor Proteins/genetics , Aged , Aged, 80 and over , Aging/pathology , Animals , Cohort Studies , Drosophila , Female , Genome-Wide Association Study , Humans , Male , Middle Aged , Polymorphism, Single NucleotideABSTRACT
BACKGROUND: Variation in mitochondrial DNA (mtDNA) identified by genotyping microarrays or by sequencing only the hypervariable regions of the genome may be insufficient to reliably assign mitochondrial genomes to phylogenetic lineages or haplogroups. This lack of resolution can limit functional and clinical interpretation of a substantial body of existing mtDNA data. To address this limitation, we developed and evaluated a large, curated reference alignment of complete mtDNA sequences as part of a pipeline for imputing missing mtDNA single nucleotide variants (mtSNVs). We call our reference alignment and pipeline MitoImpute. RESULTS: We aligned the sequences of 36,960 complete human mitochondrial genomes downloaded from GenBank, filtered and controlled for quality. These sequences were reformatted for use in imputation software, IMPUTE2. We assessed the imputation accuracy of MitoImpute by measuring haplogroup and genotype concordance in data from the 1000 Genomes Project and the Alzheimer's Disease Neuroimaging Initiative (ADNI). The mean improvement of haplogroup assignment in the 1000 Genomes samples was 42.7% (Matthew's correlation coefficient = 0.64). In the ADNI cohort, we imputed missing single nucleotide variants. CONCLUSION: These results show that our reference alignment and panel can be used to impute missing mtSNVs in existing data obtained from using microarrays, thereby broadening the scope of functional and clinical investigation of mtDNA. This improvement may be particularly useful in studies where participants have been recruited over time and mtDNA data obtained using different methods, enabling better integration of early data collected using less accurate methods with more recent sequence data.
Subject(s)
DNA, Mitochondrial , Polymorphism, Single Nucleotide , DNA, Mitochondrial/genetics , Gene Frequency , Genome, Human , Genome-Wide Association Study , Genotype , Humans , PhylogenyABSTRACT
Approximately 30% of older adults exhibit the neuropathological features of Alzheimer's disease without signs of cognitive impairment. Yet, little is known about the genetic factors that allow these potentially resilient individuals to remain cognitively unimpaired in the face of substantial neuropathology. We performed a large, genome-wide association study (GWAS) of two previously validated metrics of cognitive resilience quantified using a latent variable modelling approach and representing better-than-predicted cognitive performance for a given level of neuropathology. Data were harmonized across 5108 participants from a clinical trial of Alzheimer's disease and three longitudinal cohort studies of cognitive ageing. All analyses were run across all participants and repeated restricting the sample to individuals with unimpaired cognition to identify variants at the earliest stages of disease. As expected, all resilience metrics were genetically correlated with cognitive performance and education attainment traits (P-values < 2.5 × 10-20), and we observed novel correlations with neuropsychiatric conditions (P-values < 7.9 × 10-4). Notably, neither resilience metric was genetically correlated with clinical Alzheimer's disease (P-values > 0.42) nor associated with APOE (P-values > 0.13). In single variant analyses, we observed a genome-wide significant locus among participants with unimpaired cognition on chromosome 18 upstream of ATP8B1 (index single nucleotide polymorphism rs2571244, minor allele frequency = 0.08, P = 2.3 × 10-8). The top variant at this locus (rs2571244) was significantly associated with methylation in prefrontal cortex tissue at multiple CpG sites, including one just upstream of ATPB81 (cg19596477; P = 2 × 10-13). Overall, this comprehensive genetic analysis of resilience implicates a putative role of vascular risk, metabolism, and mental health in protection from the cognitive consequences of neuropathology, while also providing evidence for a novel resilience gene along the bile acid metabolism pathway. Furthermore, the genetic architecture of resilience appears to be distinct from that of clinical Alzheimer's disease, suggesting that a shift in focus to molecular contributors to resilience may identify novel pathways for therapeutic targets.
Subject(s)
Aging/genetics , Alzheimer Disease/pathology , Brain/pathology , Cognitive Dysfunction/genetics , Cognitive Reserve/physiology , Aged, 80 and over , Aging/pathology , Chromosomes, Human, Pair 18/genetics , Female , Genome-Wide Association Study , Genotype , Humans , Male , Polymorphism, Single NucleotideABSTRACT
Short open reading frames (sORFs) are a common feature of all genomes, but their coding potential has mostly been disregarded, partly because of the difficulty in determining whether these sequences are translated. Recent innovations in computing, proteomics and high-throughput analyses of translation start sites have begun to address this challenge and have identified hundreds of putative coding sORFs. The translation of some of these has been confirmed, although the contribution of their peptide products to cellular functions remains largely unknown. This Review examines this hitherto overlooked component of the proteome and considers potential roles for sORF-encoded peptides.
Subject(s)
Open Reading Frames , Peptides/chemistry , Animals , Humans , Protein Biosynthesis , RNA, Messenger/genetics , RNA, Untranslated/geneticsABSTRACT
INTRODUCTION: Observational studies have suggested that light-to-moderate alcohol consumption decreases the risk of Alzheimer's disease, but it is unclear if this association is causal. METHODS: Two-sample Mendelian randomization (MR) analysis was used to examine whether alcohol consumption, alcohol dependence, or Alcohol Use Disorder Identification Test (AUDIT) scores were causally associated with the risk of Late-Onset Alzheimer's disease (LOAD) or Alzheimer's disease age of onset survival (AAOS). Additionally, γ-glutamyltransferase levels were included as a positive control. RESULTS: There was no evidence of a causal association between alcohol consumption, alcohol dependence, or AUDIT, and LOAD. Alcohol consumption was associated with an earlier AAOS and increased γ-glutamyltransferase blood concentrations. Alcohol dependence was associated with a delayed AAOS. DISCUSSION: MR found robust evidence of a causal association between alcohol consumption and an earlier AAOS, but not alcohol intake and LOAD risk. The protective effect of alcohol dependence is potentially due to survivor bias.
Subject(s)
Alcohol Drinking/adverse effects , Alcoholism , Alzheimer Disease/diagnosis , Mendelian Randomization Analysis , Female , Genome-Wide Association Study , Humans , Male , Polymorphism, Single NucleotideABSTRACT
INTRODUCTION: Inherited mitochondrial DNA (mtDNA) variants may influence Alzheimer's disease (AD) risk. METHODS: We sequenced mtDNA from 146 AD and 265 cognitively normal (CN) subjects from the University of Kansas AD Center (KUADC) and assigned haplogroups. We further considered 244 AD and 242 CN AD Neuroimaging Initiative (ADNI) subjects with equivalent data. RESULTS: Without applying multiple comparisons corrections, KUADC haplogroup J AD and CN frequencies were 16.4% versus 7.6% (P = .007), and haplogroup K AD and CN frequencies were 4.8% versus 10.2% (P = .063). ADNI haplogroup J AD and CN frequencies were 10.7% versus 7.0% (P = .20), and haplogroup K frequencies were 4.9% versus 8.7% (P = .11). For the combined 390 AD and 507 CN cases haplogroup J frequencies were 12.8% versus 7.3% (P = .006), odds ratio (OR) = 1.87, and haplogroup K frequencies were 4.9% versus 9.5% (P = .010), OR = 0.49. Associations remained significant after adjusting for apolipoprotein E, age, and sex. CONCLUSION: This exploratory analysis suggests inherited mtDNA variants influence AD risk.
Subject(s)
Alzheimer Disease/genetics , DNA, Mitochondrial/genetics , Genetic Predisposition to Disease/genetics , Aged , Cohort Studies , Female , Haplotypes , Humans , Longitudinal Studies , Male , Middle AgedABSTRACT
PURPOSE: We investigated the association of the Australian National University Alzheimer's Disease Risk Index (ANU-ADRI) and an Alzheimer disease (AD) genetic risk score (GRS) with cognitive performance. METHODS: The ANU-ADRI (composed of 12 risk factors for AD) and GRS (composed of 25 AD risk loci) were computed in 1061 community-dwelling older adults. Participants were assessed on 11 cognitive tests and activities of daily living. Structural equation modeling was used to evaluate the association of the ANU-ADRI and GRS with: (1) general cognitive ability (g), (2) dementia-related variance in cognitive performance (δ), and (3) verbal ability (VA), episodic memory (EM), executive function (EF), and processing speed (PS). RESULTS: A worse ANU-ADRI score was associated with poorer performance in "g" [ß (SE)=-0.40 (0.02), P<0.001], δ [-0.40 (0.04), P<0.001], and each cognitive domain [VA=-0.29 (0.04), P<0.001; EM=-0.34 (0.03), P<0.001; EF=-0.38 (0.03), P<0.001; and PS=-0.40 (0.03), P<0.001]. A worse GRS was associated with poorer performance in δ [-0.08 (0.03), P=0.041] and EM [-0.10 (0.03), P=0.035]. CONCLUSIONS: The ANU-ADRI was broadly associated with worse cognitive performance, including general ability and dementia severity, validating its further use in early dementia risk assessment.
Subject(s)
Alzheimer Disease/diagnosis , Alzheimer Disease/genetics , Cognition/physiology , Gene-Environment Interaction , Severity of Illness Index , Activities of Daily Living , Aged , Aged, 80 and over , Australia , Female , Humans , Longitudinal Studies , Male , Neuropsychological Tests/statistics & numerical data , Risk Assessment , Surveys and QuestionnairesABSTRACT
BACKGROUND: Physical activity may preserve cognitive function in older adults, but benefits vary by sex and genetic factors. OBJECTIVE: We tested the longitudinal association between physical activity and cognitive performance to de termine whether a common genetic polymorphism for brain-derived neurotrophic factor (BDNF Val66Met) moderated this effect. METHODS: In a 12-year longitudinal population-based sample of older adults (n = 2,218), we used growth curve modeling to investigate whether the benefits of physical activity on cognitive preservation differed by BDNF genotype and sex across multiple cognitive domains including processing speed, attention, working memory, and episodic verbal memory. RESULTS: The relationship between physical activity and cognitive performance was dependent on BDNF carrier status in males (Δχ2 [Δdf] = 12.94 [4], p = 0.01), but not in females (Δχ2 [Δdf] = 4.38 [4], p = 0.36). Cognition benefited from physical activity in male BDNF met noncarriers, but not met carriers, whereas cognition was not statistically significantly related to physical activity in females regardless of genotype. CONCLUSION: We observed longitudinal, but not cross-sectional, effects of physical activity on cognitive performance. Our study highlights the importance of longitudinal follow-up and consideration of sex differences in the relationships between physical activity, BDNF genotype, and cognitive decline. The findings contribute to understanding gene-lifestyle interactions in promoting cognitive health.
Subject(s)
Brain-Derived Neurotrophic Factor/genetics , Brain-Derived Neurotrophic Factor/physiology , Cognition/physiology , Exercise/physiology , Aging/genetics , Aging/physiology , Aging/psychology , Amino Acid Substitution , Attention/physiology , Female , Genotype , Humans , Longitudinal Studies , Male , Memory, Episodic , Memory, Short-Term/physiology , Middle Aged , Polymorphism, Single Nucleotide , Sex CharacteristicsABSTRACT
Mild behavioral impairment (MBI) describes the emergence of later-life neuropsychiatric symptoms (NPS) as an at-risk state for incident cognitive decline and dementia, and for some as a potential manifestation of prodromal dementia. How NPS mechanistically link to the development of mild cognitive impairment and Alzheimer's disease (AD) is not fully understood, with potential mechanisms including shared risk factors related to both NPS and cognitive impairment, or AD pathology promoting NPS. This is the first exploratory study to examine whether AD genetic loci as a genetic risk score (GRS), or individually, are a shared risk factor with MBI. Participants were 1,226 older adults (aged 72-79; 738 males; 763 normal cognition) from the Personality and Total Health Through Life project. MBI was approximated in accordance with Criterion 1 of the ISTAART-AA diagnostic criteria using a transformation algorithm for the neuropsychiatric inventory. A GRS was constructed from 25 AD risk loci. Binomial logistic regression adjusting for age, gender, and education examined the association between GRS and MBI. A higher GRS and APOE*ε4 were associated with increased likelihood of affective dysregulation. Nominally significant associations were observed between MS4A4A-rs4938933*C and MS4A6A-rs610932*G with a reduced likelihood of affective dysregulation; ZCWPW1-rs1476679*C with a reduced likelihood of social inappropriateness and abnormal perception/thought content; BIN1-rs744373*G and EPHA1-rs11767557*C with higher likelihood of abnormal perception/thought content; NME8-rs2718058*G with a reduced likelihood of decreased motivation. These preliminary findings suggest a common genetic etiology between MBI and traditionally recognized cognitive problems observed in AD and improve our understanding of the pathophysiological features underlying MBI.
Subject(s)
Alzheimer Disease/genetics , Cognitive Dysfunction/genetics , Adaptor Proteins, Signal Transducing/genetics , Aged , Cognition , Disease Progression , Female , Genetic Association Studies/methods , Genetic Loci , Genetic Predisposition to Disease , Humans , Male , Membrane Proteins/genetics , Neuropsychological Tests , Nuclear Proteins/genetics , Polymorphism, Single Nucleotide/genetics , Preliminary Data , Receptor, EphA1/genetics , Risk Factors , Tumor Suppressor Proteins/geneticsABSTRACT
Introduction: People with university degrees have a lower incidence of Alzheimer's Disease (AD). However, the relationship between education and AD could be due to selection, collider, and ascertainment biases, such as lower familiarity with cognitive testing or the fact that those with degrees are more likely to participate in research. Here, we use two-sample Mendelian randomization (MR) to investigate the causal relationships between education, participation, and AD. Method: We used genome-wide association study (GWAS) summary statistics for educational attainment, three different measures of participation, AD (clinically diagnosed AD), and AD/ADRD (clinical diagnosis and family history of AD and related dementias). Independent genome-wide significant single nucleotide polymorphisms (SNPs) were extracted from the exposure summary statistics and harmonized with the outcome SNPs. Fixed-effects inverse variance weighted meta-analysis was the primary MR method; Cochran's Q statistic and MR Egger intercept were used to test for heterogeneity and pleiotropy, and Radial-MR was used to identify outliers. Sensitivity analyses included MR Egger, Weighted Median, and Weighted mode. Bidirectional analyses were used to test if AD pathology affects participation and multivariable MR (MVMR) assessed independent exposure-outcome effects. Results: Educational attainment reduced the risk of AD (OR IVW 95% CI= 0.70 [0.63, 0.79], p = 8e-10), and the results were robust based on sensitivity analyses. However, education increased the risk of AD/ADRD, though the results were not robust to sensitivity analyses (OR IVW 95% CI= 1.09 [1.02, 1.15], p = 0.006). Participation in MHQ reduced the odds of AD (OR IVW 95% CI= 0.325 [0.128, 0.326], p = 0.01). When adjusting for participation in MVMR, education remained associated with a reduced risk of AD (OR IVW 95% CI= 0.76 [0.62, 0.92], p = 0.006). Conclusion: Univariate MR analyses indicated that education and participation reduced the risk of AD. However, MR also suggested that education increased the risk of AD/ADRD, highlighting the inconsistencies between clinical and proxy diagnoses of AD, as proxy-AD may be affected by selection, collider, or ascertainment bias. MVMR indicated that participation is unlikely to explain the effect of education on AD identified in MR, and the protective effect of educational attainment may be due to other biological mechanisms, such as cognitive reserve.
ABSTRACT
Importance: By integrating genetic and clinical risk factors into genomic-informed dementia risk reports, healthcare providers can offer patients detailed risk profiles to facilitate understanding of individual risk and support the implementation of personalized strategies for promoting brain health. Objective: To develop a genomic-informed risk assessment composed of family history, genetic, and clinical risk factors and, in turn, evaluate how the risk assessment predicted incident dementia. Design: This longitudinal study included data from two clinical case-control cohorts with an average of 6.6 visits. Secondary analyses were conducted from July 2023 - March 2024. Setting: Data were previously collected across multiple US locations from 1994 to 2023. Participants: Older adults aged 55+ with whole-genome sequencing and dementia-free at baseline. Exposures: An additive score comprising the modified Cardiovascular Risk Factors, Aging, and Incidence of Dementia Risk Score (mCAIDE), family history of dementia, APOE genotype, and an AD polygenic risk score. Main Outcomes and Measures: The risk of progression to all-cause dementia was evaluated using Cox-proportional hazard models (hazard ratios with 95% confidence intervals [OR 9%CI]). Results: A total of 3,429 older adults were included (aged 75 ± 7 years; 59% female; 75% non-Latino White, 15% Black, 5.2% Latino, 3.6% other, and 0.4% Asian; 27% MCI), with 751 participants progressing to dementia. The most common high-risk indicator was a family history of dementia (56%), followed by APOE*ε4 genotype (36%), high mCAIDE score (34%), and high AD-PRS (11%). Most participants had at least one high-risk indicator, with 39% having one, 32% two, 9.8% three, and 1% four. The presence of 1, 2, 3, or 4 risk indicators was associated with a doubling (HR = 1.72, CI: 1.34-2.22, p = 2.5e-05), tripling (HR = 3.09, CI: 2.41-3.95, p = 4.4e-19), quadrupling (HR = 4.46, CI: 3.34-5.94, p = 2.2e-24), and a twelvefold increase (HR = 12.15, CI: 7.33-20.14, p = 3.2e-22) in dementia risk. Conclusion & Relevance: We found that most participants in memory and aging clinics had at least one high-risk indicator for dementia. Furthermore, we observed a dose-response relationship where a greater number of risk indicators was associated with an increased risk of incident dementia.
ABSTRACT
Introduction: Evaluating the generalizability of dementia risk scores, primarily developed in non-Latinx White (NLW) participants, and interactions with genetic risk factors in diverse populations is crucial for addressing health disparities. Methods: We analyzed the association of the Cardiovascular Risk Factors, Aging, and Incidence of Dementia (CAIDE) and modified CAIDE (mCAIDE) scores with dementia risk using logistic regression models stratified by race/ethnicity in NACC and ADNI, and assessed their interaction with APOE . Results: Higher CAIDE scores were associated with an increased risk of dementia in Asian, Latinx, and NLW participants but not in Black participants. In contrast, higher mCAIDE scores were also associated with an increased risk of dementia in Black participants. Unfavorable mCAIDE risk profiles exacerbated the APOE *ε4 risk effect and attenuated the APOE *ε2 protective effect. Discussion: Our findings underscore the importance of evaluating the validity of dementia risk scores in diverse populations for their use in personalized medicine approaches to promote brain health.
ABSTRACT
Importance: Vision and eye conditions are associated with increased risk for Alzheimer disease and related dementias (ADRDs), but the nature of the association and the underlying biological pathways remain unclear. If causal, vision would be an important modifiable risk factor with viable population-level interventions. Objective: To evaluate potentially causal associations between visual acuity, eye conditions (specifically cataracts and myopia), neuroimaging outcomes, and ADRDs. Design, Setting, and Participants: A cohort and 2-sample bidirectional mendelian randomization (MR) study was conducted using UK Biobank participants and summary statistics from previously published genome-wide association studies on cataract, myopia, and AD. The participants included in the analysis were aged 55 to 70 years without dementia at baseline (calendar years 2006 to 2010), underwent genotyping, and reported on eye conditions; a subset completed visual acuity examinations (n = 69 852-71 429) or brain imaging (n = 36â¯591-36 855). Data were analyzed from August 15, 2022, through November 28, 2023. Exposure: Self-reported cataracts, visual acuity, and myopia measured by refraction error. Main Outcomes and Measures: ADRD, AD, and vascular dementia were identified from electronic medical records. Total and regional brain volumes were determined using magnetic resonance imaging. Results: The sample included 304â¯953 participants (mean [SD] age, 62.1 (4.1) years; 163â¯825 women [53.72%]); 14â¯295 (4.69%) had cataracts and 2754 (3.86%) had worse than 20/40 vision. Cataracts (hazard ratio [HR], 1.18; 95% CI, 1.07-1.29) and myopia (HR, 1.35; 95% CI, 1.06-1.70) were associated with a higher hazard of ADRD. In MR analyses to estimate potential causal effects, cataracts were associated with increased risk of vascular dementia (inverse variance-weighted odds ratio [OR], 1.92; 95% CI, 1.26-2.92) but were not associated with increased dementia (OR, 1.21; 95% CI, 0.98-1.50). There were no associations between myopia and dementia. In MR for potential reverse causality, AD was not associated with cataracts (inverse variance-weighted OR, 0.99; 95% CI, 0.96-1.01). Genetic risk for cataracts was associated with smaller total brain (ß = -597.43 mm3; 95% CI, -1077.87 to -117.00 mm3) and gray matter (ß = -375.17 mm3; 95% CI, -680.10 to -70.24 mm3) volumes, but not other brain regions. Conclusions and Relevance: In this cohort and MR study of UK Biobank participants, cataracts were associated with increased risk of dementia, especially vascular dementia, and reduced total brain volumes. These findings lend further support to the hypothesis that cataract extraction may reduce the risk for dementia.
Subject(s)
Cataract , Dementia , Humans , Female , Male , Aged , Middle Aged , Cataract/epidemiology , Dementia/epidemiology , Dementia/genetics , Myopia/epidemiology , Myopia/genetics , Risk Factors , Alzheimer Disease/genetics , Alzheimer Disease/epidemiology , Vision Disorders/epidemiology , Mendelian Randomization Analysis , United Kingdom/epidemiology , Cohort Studies , Visual Acuity , Genome-Wide Association Study , Neurodegenerative Diseases/epidemiology , Neurodegenerative Diseases/geneticsABSTRACT
Infections have been associated with the incidence of Alzheimer disease and related dementias, but the mechanisms responsible for these associations remain unclear. Using a multicohort approach, we found that influenza, viral, respiratory, and skin and subcutaneous infections were associated with increased long-term dementia risk. These infections were also associated with region-specific brain volume loss, most commonly in the temporal lobe. We identified 260 out of 942 immunologically relevant proteins in plasma that were differentially expressed in individuals with an infection history. Of the infection-related proteins, 35 predicted volumetric changes in brain regions vulnerable to infection-specific atrophy. Several of these proteins, including PIK3CG, PACSIN2, and PRKCB, were related to cognitive decline and plasma biomarkers of dementia (Aß42/40, GFAP, NfL, pTau-181). Genetic variants that influenced expression of immunologically relevant infection-related proteins, including ITGB6 and TLR5, predicted brain volume loss. Our findings support the role of infections in dementia risk and identify molecular mediators by which infections may contribute to neurodegeneration.
ABSTRACT
BACKGROUND: Genome-wide association studies (GWAS) have indicated moderate genetic overlap between Alzheimer's disease (AD) and related dementias (ADRD), Parkinson's disease (PD) and amyotrophic lateral sclerosis (ALS), neurodegenerative disorders traditionally considered etiologically distinct. However, the specific genetic variants and loci underlying this overlap remain almost entirely unknown. METHODS: We leveraged state-of-the-art GWAS for ADRD, PD, and ALS. For each pair of disorders, we examined each of the GWAS hits for one disorder and tested whether they were also significant for the other disorder, applying Bonferroni correction for the number of variants tested. This approach rigorously controls the family-wise error rate for both disorders, analogously to genome-wide significance. RESULTS: Eleven loci with GWAS hits for one disorder were also associated with one or both of the other disorders: one with all three disorders (the MAPT/KANSL1 locus), five with ADRD and PD (near LCORL, CLU, SETD1A/KAT8, WWOX, and GRN), three with ADRD and ALS (near GPX3, HS3ST5/HDAC2/MARCKS, and TSPOAP1), and two with PD and ALS (near GAK/TMEM175 and NEK1). Two of these loci (LCORL and NEK1) were associated with an increased risk of one disorder but decreased risk of another. Colocalization analysis supported a shared causal variant between ADRD and PD at the CLU, WWOX, and LCORL loci, between ADRD and ALS at the TSPOAP1 locus, and between PD and ALS at the NEK1 and GAK/TMEM175 loci. To address the concern that ADRD is an imperfect proxy for AD and that the ADRD and PD GWAS have overlapping participants (nearly all of which are from the UK Biobank), we confirmed that all our ADRD associations had nearly identical odds ratios in an AD GWAS that excluded the UK Biobank, and all but one remained nominally significant (p < 0.05) for AD. CONCLUSIONS: In one of the most comprehensive investigations to date of pleiotropy between neurodegenerative disorders, we identify eleven genetic risk loci shared among ADRD, PD, and ALS. These loci support lysosomal/autophagic dysfunction (GAK/TMEM175, GRN, KANSL1), neuroinflammation/immunity (TSPOAP1), oxidative stress (GPX3, KANSL1), and the DNA damage response (NEK1) as transdiagnostic processes underlying multiple neurodegenerative disorders.