Publications by authors named "Brian Fulton‐Howard"
Due to the importance of 4R tau (with four microtubule-binding-repeat domains) in the pathogenicity of primary tauopathies, it has been challenging to model these diseases in induced pluripotent stem cell (iPSC)-derived neurons, which express very low levels of 4R tau. To address this, we have developed a panel of isogenic iPSC lines carrying MAPT splice-site mutations, S305S, S305I, or S305N, derived from four different donors. All mutations significantly increase 4R tau expression in iPSC neurons and astrocytes.
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- The study evaluates dementia risk scores developed primarily for non-Latinx White populations, focusing on their applicability in diverse racial and ethnic groups to tackle health disparities.* -
- Results indicate that while higher CAIDE scores increase dementia risk among Asian, Latinx, and NLW participants, mCAIDE scores reveal an increased risk for Black participants, showcasing varying effects based on race/ethnicity.* -
- The research emphasizes the necessity of validating dementia risk assessments across different populations to enhance personalized medicine and improve brain health outcomes.*
Article Synopsis
- The study highlights the value of combining genetic and clinical risk factors to create more personalized dementia risk assessments for older adults, enhancing their understanding of individual risk.
- Conducted with older adults aged 55+, the research evaluated how well these risk assessments predicted the onset of dementia using data from multiple US locations over nearly three decades.
- Among 3,429 participants, a family history of dementia was the strongest risk factor, with an increase in risk correlating to the number of high-risk indicators present, demonstrating the complex interplay of genetics and personal health in dementia risk.
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 .
Results: Higher CAIDE scores were associated with an increased risk of dementia in Asian, Latinx, and NLW participants but not in Black participants.
Article Synopsis
- The study investigates why some older individuals (70+) remain healthy despite having high predicted risks for atherosclerotic cardiovascular disease (ASCVD), suggesting they may possess protective genetic variants.
- Researchers conducted a genome-wide association study on over 12,000 asymptomatic older adults, identifying two significant genetic variants linked to better heart health and cholesterol profiles.
- The findings, which were confirmed in a separate population, highlight the role of these genetic variants in promoting cardiovascular resilience and could point towards new therapeutic targets for preventing ASCVD.
Article Synopsis
- - The study addresses the issue of limited ancestral diversity in genome-wide association studies (GWAS), which makes it hard to find genetic risk variants in non-European ancestry groups, focusing on Alzheimer's Disease (AD).
- - Researchers analyzed a multi-ancestry GWAS dataset within the Alzheimer's Disease Genetics Consortium (ADGC) involving individuals from various ancestries, identifying 13 shared risk loci and 3 ancestry-specific loci, highlighting the benefits of diverse samples.
- - The findings underscore the importance of including underrepresented populations in genetic research, suggesting that even smaller sample sizes can lead to the discovery of novel genetic variants related to AD and implicating specific biological pathways like amyloid regulation and neuronal development.
Article Synopsis
- - The study focuses on a Colombian family with a specific genetic mutation related to early-onset Alzheimer's disease, aiming to find genetic factors that affect the age at which the disease manifests.
- - Researchers analyzed genetic data from 340 individuals carrying the PSEN1 E280A mutation and found 13 genetic variants linked to Alzheimer's onset, with three significant variants associated with the gene clusterin.
- - The identified genetic variants are suggested to influence biological processes related to Alzheimer’s, highlighting their possible importance in developing future therapies, especially given the strong existing mutation linked to the disease.
Background: Alzheimer's disease (AD) is a complex multifactorial neurodegenerative disorder and the most common form of dementia. AD is highly heritable, with heritability estimates of ∼70% from twin studies. Progressively larger genome-wide association studies (GWAS) have continued to expand our knowledge of AD/dementia genetic architecture.
View Article and Find Full Text PDFCharacterization of the genetic landscape of Alzheimer's disease (AD) and related dementias (ADD) provides a unique opportunity for a better understanding of the associated pathophysiological processes. We performed a two-stage genome-wide association study totaling 111,326 clinically diagnosed/'proxy' AD cases and 677,663 controls. We found 75 risk loci, of which 42 were new at the time of analysis.
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- Primary age-related tauopathy (PART) is a neurodegenerative disease distinguished from Alzheimer’s disease (AD) by the absence of amyloid-β plaques, while still exhibiting similar neurofibrillary degeneration and cognitive impairment.
- A genetic study involving 647 individuals with PART identified significant genetic associations with known loci related to AD and other tauopathies, particularly highlighting a new link to the JADE1 gene located on chromosome 4.
- Experimental findings showed that JADE1 is associated with tau aggregates in the brain and its knockdown in a fruit fly model resulted in increased tau-induced toxicity, suggesting that JADE1 may play a crucial role in the progression of PART.
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).
View Article and Find Full Text PDFPolygenic score modifies risk for Alzheimer's disease in ε4 homozygotes at phenotypic extremes.
Alzheimers Dement (Amst)
August 2021
Introduction: Diversity in cognition among apolipoprotein E () ε4 homozygotes can range from early-onset Alzheimer's disease (AD) to a lifetime with no symptoms.
Methods: We evaluated a phenotypic extreme polygenic risk score (PRS) for AD between cognitively healthy ε4 homozygotes aged ≥75 years (n = 213) and early-onset ε4 homozygote AD cases aged ≤65 years (n = 223) as an explanation for this diversity.
Results: The PRS for AD was significantly higher in ε4 homozygote AD cases compared to older cognitively healthy ε4/ε4 controls (odds ratio [OR] 8.
To evaluate how age and apolipoprotein E-ε4 (APOE4) status interact with APOE-independent polygenic risk score (PRS), we estimated PRS in superagers (age ≥ 90 years, N = 346), 89- controls (age 60-89, N = 2930), and Alzheimer's disease (AD) cases (N = 1760). Using superagers, we see a nearly 5 times greater odds ratio (OR) for AD comparing the top PRS decile to the lowest decile (OR = 4.82, p = 2.
View Article and Find Full Text PDFObjective: 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-β (Aβ ), tau, and ptau , 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.
Background: Alzheimer's disease is a debilitating and highly heritable neurological condition. As such, genetic studies have sought to understand the genetic architecture of Alzheimer's disease since the 1990s, with successively larger genome-wide association studies (GWAS) and meta-analyses. These studies started with a small sample size of 1086 individuals in 2007, which was able to identify only the APOE locus.
View Article and Find Full Text PDFWe examined the associations between mitochondrial DNA haplogroups (MT-hgs; mitochondrial haplotype groups defined by a specific combination of single nucleotide polymorphisms labeled as letters running from A to Z) and their interactions with a polygenic risk score composed of nuclear-encoded mitochondrial genes (nMT-PRS) with risk of dementia and age of onset (AOO) of dementia. MT-hg K (Odds ratio [OR]: 2.03 [95% CI: 1.
View Article and Find Full Text PDFPurpose Of Review: Over the last decade over 40 loci have been associated with risk of Alzheimer's disease (AD). However, most studies have either focused on identifying risk loci or performing unbiased screens without a focus on protective variation in AD. Here, we provide a review of known protective variants in AD and their putative mechanisms of action.
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