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Jonathan L Haines

Publications and source records attributed to Jonathan L Haines.

7 recordsLinked to original sources
PubMed2026

A multiancestry polygenic risk score for Alzheimer's disease is associated with cognitive decline and neuropathological hallmarks in diverse populations.

Previously derived polygenic risk scores (PRSs) for Alzheimer's disease (AD) perform inconsistently across diverse ancestries. We developed an APOE-independent multiancestry AD PRS using genome-wide association study summary statistics applied to European ancestry, African American, Caribbean Hispanic and East Asian cohorts. PRS performance was evaluated in a large independent multiancestry dataset and validated in several additional multiancestry cohorts. The PRS was significantly associated with AD in European ancestry, African American, Caribbean Hispanic and Native American Hispanic groups with adjusted odds ratios between 1.14 and 1.52 per PRS standard deviation. PRS performance was validated in the replication cohorts (odds ratios: 1.21-1.65). The PRS was also associated with poorer memory, executive function and language performance, greater AD-related neuropathological burden, reduced hippocampal volume, lower cerebrospinal fluid amyloid-β42 and elevated total tau and phosphorylated tau, with stronger phosphorylated tau associations observed in women. Our findings support the value of ancestry-aware PRSs as a component of broader multimodal risk stratification frameworks.

Aged↗
PubMed2026

Can we identify people with Alzheimer's disease from examination of the eye? A bidirectional Mendelian randomization (MR) study.

BACKGROUND: Neurodegeneration in Alzheimer's disease (AD) is thought to be driven by amyloid-beta and tau deposition in the cerebral vasculature and brain. As the eye is an extension of the central nervous system, this study aimed to determine which neurovascular and neuroretinal changes in the eye are caused by AD rather than associations of the disease. METHODS: Bidirectional two-sample univariable and multivariable Mendelian randomization (MR) methods were applied. Instrumental variables were derived from genome-wide association studies (GWAS) of AD and the following ocular features: thickness measurements of central macula (MT), retinal nerve fibre layer (mRNFL), ganglion cell-inner plexiform layer (mGCIPL), outer nuclear layer (ONL), inner segment layer (IS), and outer segment (OS) from macular region OCT scans; arteriolar tortuosity (AT), venular tortuosity (VT), venular width (VW), fractal dimension (FD), vertical cup-to-disc ratio (VCDR), optic cup area (OCA), and optic disc area (ODA) derived from other imaging methods. RESULTS: There was strong evidence that genetic liability to AD affected the retinal vasculature by specifically increasing AT (β = 0.007;95%CI=0.002,0.011;p-value=0.005) in UK Biobank participants (n=52,798). AD may influence the mRNFL (β=-0.047,95%CI=-0.119,0.023,p-value=0.18) and mGCIPL (β=-0.061;95%CI=-0.14,0.025,p-value=0.16) of the inner retina and OS layer (β = 0.044;95%CI=-0.0001,0.08;p-value=0.05) but the evidence was weak. Multivariable MR analysis showed that a causal relationship between optic disc area and AD (OR=0.76;95%CI=0.62,0.93,p-value=0.009) was probably mediated by refractive error. CONCLUSION: Early cerebrovascular signs of AD may be detected by examination of the eye. Further investigation is required to determine the clinical utility of eye screening for dementia.

Humans↗
PubMed2026

Genetic modifiers of APOE-ε4-associated cognitive decline.

The APOE-ε4 allele is the strongest genetic risk factor for late-onset Alzheimer's disease. However, APOE-ε4 is not deterministic, highlighting the need to identify additional genetic and environmental factors. APOE-ε4 has been linked to accelerated cognitive decline, so we sought to investigate genetic factors that modify APOE-ε4-associated cognitive decline. We conduct cross-ancestry APOE-ε4-stratified and interaction GWAS using harmonized cognitive data from 32,778 participants, including 29,354 non-Hispanic White and 3,424 non-Hispanic Black individuals. Our primary outcome is late-life cognition, measured using harmonized composite scores for memory, executive function, and language, modeled as continuous traits reflecting both normative cognitive aging and disease-related decline. We identify two genome-wide significant loci in APOE-ε4 carriers, reaching genome-wide significance for executive function. These loci also demonstrate nominal associations across the other domains, suggesting broad effects on cognition. In non-carriers, we identify a genome-wide significant association at ITGB8 restricted to executive function, and another locus associated with language. We further link these loci to SEMA6D, GRIN3A, and ITGB8 through expression and methylation databases. Post-GWAS analyses implicate additional genes including SLCO1A2, and DNAH11. Genetic correlation analyses reveal differences by APOE-ε4 status for immune-related traits, suggesting immune-related predispositions may exacerbate cognitive risk in APOE-ε4 carriers.

Humans↗
PubMed2025

Domain mapping of disease mutations reveals pathogenic SORL1 variants in Alzheimer's disease.

BACKGROUND: Protein truncating variants (PTVs) in SORL1 are observed almost exclusively in Alzheimer’s Disease (AD) cases, but the effect of rare SORL1 missense variants is unclear. METHODS: To identify high-priority missense variants (HPVs), we applied ‘domain mapping of disease mutations’ for the 637 unique coding SORL1 variants detected in 18,959 AD-cases and 21,893 non-demented controls. RESULTS: In this sample, PTVs and HPVs associated with respectively a 35- and 10-fold increased risk of early onset AD and 17- and 6-fold increased risk of overall AD. The median age at onset (AAO) of PTV- and HPV-carriers was 62 and 64 years, and APOE-genotype contributed to AAO-variability. The median AAO of PTV- and HPV-carriers is ~8–10 years earlier than wild-type SORL1 carriers, matched for APOE-genotype. Specific HPVs are highly penetrant and lead to earlier AAOs than PTVs, suggesting possible dominant negative effects. CONCLUSION: Our results justify a debate on whether HPV carriers should be considered for clinical counseling.

Humans↗
PubMed2025

A multi-ancestry polygenic risk score for Alzheimer disease is associated with cognitive decline, hippocampal atrophy and neuropathological hallmarks in diverse populations.

Alzheimer disease (AD) has a strong genetic basis, yet previously derived polygenic risk scores (PRS) are heavily weighted by the APOE locus and perform inconsistently across diverse ancestries. We developed an APOE-independent multi-ancestry AD PRS using genome-wide association study summary statistics from cohorts in the United States, Europe and East Asia that were applied to European ancestry (EA), African American (AA), Caribbean Hispanic (CH), and East Asian cohorts from the Alzheimer's Disease Genetics Consortium. PRS performance was evaluated in the multi-ancestry Alzheimer's Disease Sequencing Project (ADSP) dataset and validated in several additional multi-ancestry cohorts. The PRS was significantly associated with AD in the ADSP EA, AA, CH, and Native American Hispanic groups with adjusted odds ratios (ORs) between 1.14 and 1.52 per standard deviation of the PRS. PRS performance was validated in the replication cohorts (ORs 1.21-1.65). The PRS was also associated with poorer memory, executive function, and language performance; greater AD-related neuropathological burden (including CERAD, Braak stage, and Thal phase scores); reduced hippocampal volume; lower CSF Aβ42; and elevated total tau and phosphorylated tau (p-tau), with stronger p-tau associations observed in women. Longitudinal analyses revealed that individuals in the highest PRS decile exhibited the steepest cognitive decline, particularly among those who progressed to AD. Our findings demonstrate the utility of an ancestry-aware and APOE-independent PRS for advancing understanding of the genetic basis of AD across diverse populations. Associations observed with early biological and cognitive changes and potential sex-specific differences support the incorporation of a PRS in clinical trials and personalized intervention and prevention strategies.

Journal Article↗
PubMed2024

Association of common and rare variants with Alzheimer's disease in more than 13,000 diverse individuals with whole-genome sequencing from the Alzheimer's Disease Sequencing Project.

INTRODUCTION: Alzheimer's disease (AD) is a common disorder of the elderly that is both highly heritable and genetically heterogeneous. METHODS: We investigated the association of AD with both common variants and aggregates of rare coding and non-coding variants in 13,371 individuals of diverse ancestry with whole genome sequencing (WGS) data. RESULTS: Pooled-population analyses of all individuals identified genetic variants at apolipoprotein E (APOE) and BIN1 associated with AD (p&#xa0;<&#xa0;5&#xa0;&#xd7;&#xa0;10-8). Subgroup-specific analyses identified a haplotype on chromosome 14 including PSEN1 associated with AD in Hispanics, further supported by aggregate testing of rare coding and non-coding variants in the region. Common variants in LINC00320 were observed associated with AD in Black individuals (p&#xa0;=&#xa0;1.9&#xa0;&#xd7;&#xa0;10-9). Finally, we observed rare non-coding variants in the promoter of TOMM40 distinct of APOE in pooled-population analyses (p&#xa0;=&#xa0;7.2&#xa0;&#xd7;&#xa0;10-8). DISCUSSION: We observed that complementary pooled-population and subgroup-specific analyses offered unique insights into the genetic architecture of AD. HIGHLIGHTS: We determine the association of genetic variants with Alzheimer's disease (AD) using 13,371 individuals of diverse ancestry with whole genome sequencing (WGS) data. We identified genetic variants at apolipoprotein E (APOE), BIN1, PSEN1, and LINC00320 associated with AD. We observed rare non-coding variants in the promoter of TOMM40 distinct of APOE.

Humans↗
PubMed2018

Sex-specific genetic predictors of Alzheimer's disease biomarkers.

Cerebrospinal fluid (CSF) levels of amyloid-&#x3b2; 42 (A&#x3b2;42) and tau have been evaluated as endophenotypes in Alzheimer's disease (AD) genetic studies. Although there are sex differences in AD risk, sex differences have not been evaluated in genetic studies of AD endophenotypes. We performed sex-stratified and sex interaction genetic analyses of CSF biomarkers to identify sex-specific associations. Data came from a previous genome-wide association study (GWAS) of CSF A&#x3b2;42 and tau (1527 males, 1509 females). We evaluated sex interactions at previous loci, performed sex-stratified GWAS to identify sex-specific associations, and evaluated sex interactions at sex-specific GWAS loci. We then evaluated sex-specific associations between prefrontal cortex (PFC) gene expression at relevant loci and autopsy measures of plaques and tangles using data from the Religious Orders Study and Rush Memory and Aging Project. In A&#x3b2;42, we observed sex interactions at one previous and one novel locus: rs316341 within SERPINB1 (p&#x2009;=&#x2009;0.04) and rs13115400 near LINC00290 (p&#x2009;=&#x2009;0.002). These loci showed stronger associations among females (&#x3b2;&#x2009;=&#x2009;-&#x2009;0.03, p&#x2009;=&#x2009;4.25&#x2009;&#xd7;&#x2009;10-8; &#x3b2;&#x2009;=&#x2009;0.03, p&#x2009;=&#x2009;3.97&#x2009;&#xd7;&#x2009;10-8) than males (&#x3b2;&#x2009;=&#x2009;-&#xa0;0.02, p&#x2009;=&#x2009;0.009; &#x3b2;&#x2009;=&#x2009;0.01, p&#x2009;=&#x2009;0.20). Higher levels of expression of SERPINB1, SERPINB6, and SERPINB9 in PFC was associated with higher levels of amyloidosis among females (corrected p values&#x2009;<&#x2009;0.02) but not males (p&#x2009;>&#x2009;0.38). In total tau, we observed a sex interaction at a previous locus, rs1393060 proximal to GMNC (p&#x2009;=&#x2009;0.004), driven by a stronger association among females (&#x3b2;&#x2009;=&#x2009;0.05, p&#x2009;=&#x2009;4.57&#x2009;&#xd7;&#x2009;10-10) compared to males (&#x3b2;&#x2009;=&#x2009;0.02, p&#x2009;=&#x2009;0.03). There was also a sex-specific association between rs1393060 and tangle density at autopsy (pfemale&#x2009;=&#x2009;0.047; pmale&#x2009;=&#x2009;0.96), and higher levels of expression of two genes within this locus were associated with lower tangle density among females (OSTN p&#x2009;=&#x2009;0.006; CLDN16 p&#x2009;=&#x2009;0.002) but not males (p&#x2009;&#x2265;&#x2009;0.32). Results suggest a female-specific role for SERPINB1 in amyloidosis and for OSTN and CLDN16 in tau pathology. Sex-specific genetic analyses may improve understanding of AD's genetic architecture.

Aged, 80 and over↗