👤 Reisa A Sperling

Alzheimer disease (AD) biomarker and genetic testing results are increasingly disclosed to cognitively unimpaired adults in research and could in the future inform clinical treatment decisions in this population. To assess psychological outcomes after returning 3 categories of amyloid biomarker results as well as apolipoprotein E (APOE) genotypes. This cohort study was a secondary analysis of data collected as part of screening for the multisite AHEAD preclinical AD trial. Participants were individuals aged 55 to 80 years undergoing screening from July 14, 2020, to October 15, 2024. Participants were informed whether they had not-detected, intermediate, or elevated amyloid positron emission tomography levels, as well as their APOE genotype, which were categorized as noncarrier, ε4 heterozygote, or ε4 homozygote. Impact of Events Scale (IES; 15 items to assess intrusive thoughts and avoidance; each item is scored as not at all [0], rarely [1], sometimes [3], or often [5]; total range, 0-75), collected 24 to 72 hours after disclosure, and change in a scale measuring concerns about AD dementia (adapted scale using 6 items in which participants indicated their level of agreement with statements related to their perceived probability of developing AD dementia; items scored as strongly disagree [1] through strongly agree [5]; total range, 6-30), calculated by subtracting the score collected before biomarker testing from 1 collected after biomarker and genetic test results disclosure. Among 3414 included individuals, the mean (SD) age was 68.8 (6.0) years and 2116 (62%) were female. Group mean IES scores were below clinically significant thresholds. Nevertheless, across genetic groups, learning an elevated amyloid result (1184 participants) was associated with higher IES (mean [SD], 10.5 [10.9]) than intermediate amyloid (482 participants; mean [SD] IES, 8.8 [9.8]), and intermediate amyloid was associated with higher scores than not-detected amyloid (1748 participants; mean [SD] IES, 6.5 [8.4]). Across amyloid groups, learning APOE ε4 homozygosity (337 participants) was associated with higher mean (SD) IES (12.7 [11.6]) than heterozygosity (1609 participants; 9.1 [10.2]), and heterozygosity was associated with higher IES than noncarrier status (1468 participants; mean [SD] IES, 6.2 [8.1]). Both types of information were significant in an analysis of covariance model; no interaction effect was observed. In contrast, only biomarker disclosure was associated with differential change in concerns about AD dementia. Those with elevated amyloid showed a mean (SD) increase in concern (0.8 [3.5]), those with intermediate amyloid showed a smaller increase (0.4 [3.7]), and those with not-detected amyloid showed decreased concerns (-1.1 [4.2]). In this cohort study of cognitively unimpaired adults, associations with intrusive thoughts were observed to differ among genetic and biomarker subgroups; such associations were limited to biomarker subgroups for measures of perceived dementia risk. Show less

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. Show less

Women show higher levels of Alzheimer's disease (AD) pathology than men, but the implications for cognitive decline remain unclear. Determining the extent to which tau burden differentially accelerates cognitive decline in men and women will provide critical insights into sex-specific pathways of disease progression. We leveraged tau positron emission tomography (PET), amyloid beta (Aβ) PET, apolipoprotein E (APOE) ε4 genotyping, and longitudinal cognitive data over approximately 8.6 (standard deviation [SD] = 3.8) years from 1007 cognitively unimpaired adults across three cohorts. Cognitive trajectories were modeled with linear mixed-effects regression including sex × tau × time interactions, and results were synthesized using random-effects meta-analysis. Higher tau burden in medial and lateral temporal regions was associated with faster cognitive decline in women than in men. High tau burden carries a disproportionately greater cognitive cost for women, underscoring the need for sex-specific approaches to early detection and therapeutic intervention in AD. A meta-analysis across three independent cohorts shows that female cognitive advantage at low tau shifts to vulnerability at higher tau. Sex differences in tau-related cognitive decline were consistent after accounting for amyloid burden. Sex-specific rates of cognitive decline should be considered in clinical trial design. Show less

Lipoprotein(a) [Lp(a)] and LDL cholesterol (LDL-C) are causally linked to aortic valve calcium (AVC) and aortic stenosis (AS). Lipoprotein(a) has anti-fibrinolytic properties; therefore, aspirin may reduce cardiovascular disease risk among individuals with high Lp(a). This analysis sought to determine the association of aspirin with incident AVC and AS across Lp(a) and LDL-C levels. This observational study included up to 6598 participants in the Multi-Ethnic Study of Atherosclerosis. Aortic valve calcium was measured on non-contrast cardiac computed tomography. Multivariable Cox hazards regression assessed the association of self-reported regular aspirin use (≥3 days/week) with incident AVC and severe AS, stratified by Lp(a) and LDL-C. Aortic valve calcium and Lp(a) values were not reported to participants. Mean age was 62 years, 53% were women, 23% reported regular aspirin use, 8% developed AVC (median 8.9 years), and 1% developed severe AS (median 16.7 years). Among individuals with elevated Lp(a), regular aspirin use was associated with a lower risk of incident AVC (Lp(a) ≥75 mg/dL: hazard ratio (HR) .42, 95% confidence interval (CI) .19-.93; Lp(a) ≥100 mg/dL: HR .17, 95% CI .04-.67) and severe AS (Lp(a) ≥50 mg/dL: HR .13, 95% CI: .04-.47; Lp(a) ≥75 mg/dL: HR .02, 95% CI .001-.29). For participants with elevated LDL-C, there was no association of regular aspirin use with incident AVC (LDL-C ≥130 mg/dL: HR 1.02, 95% CI .66-1.58; LDL-C ≥160 mg/dL: HR 1.51, 95% CI .53-4.28) or severe AS (LDL-C ≥100 mg/dL: HR .70, 95% CI .39-1.26; LDL-C ≥130 mg/dL: HR .46, 95% CI .14-1.47). In this exploratory analysis of prospective observational cohort data, regular aspirin use was associated with a lower risk of AVC and severe AS in persons with high Lp(a), but not high LDL-C. Confirmatory studies are required to determine the role of aspirin in the prevention of AVC and AS for persons with high Lp(a). Show less

In anticipation of updates to cholesterol guidelines globally, evidence since the most recent iteration of recommendations across US and Europe for risk assessment and lipid management are reviewed. ASCVD risk estimation is at the core of determining lipid lowering goals and consideration for therapies. In primary prevention, incorporation of the PREVENT equations will be featured in updated guidelines, which will likely demarcate new, lower risk thresholds compared to the prior Pooled Cohort Equations. Additionally, the use of coronary artery calcium (CAC) improves risk estimation to inform medication allocation and LDL-C goals beyond traditional risk factor risk estimation. To achieve lower LDL-C, many adults will need multiple lipid-lowering medications. For high-risk individuals, combination therapy with low/moderate intensity statin and ezetimibe or bempedoic acid should be considered. Additionally, proprotein convertase subtilisin/kexin type 9 inhibitor (PCSK9i) therapies can be used to attain lower LDL-C in high-risk individuals, including those with clinical ASCVD or a high CAC burden. In very-high risk patients, treatment to LDL-C values as low as <30 mg/dL further reduces ASCVD risk without significant adverse events. Among individuals treated with PSCK9i therapy, those with elevated Lp(a) may have greater ASCVD risk reduction and may be a patient population that is prioritized for PCSK9i until therapies directly targeting Lp(a) are available. An ASCVD risk-based approach should be the foundation for determining LDL-C goals with consideration that multiple lipid-lowering therapies are often necessary for high and very-high risk patients who were treated to very low LDL-C in more recent randomized controlled trials. Show less

In the era of the Predicting Risk of Cardiovascular Disease (CVD) EVENTs (PREVENT) equations, recalibrating definitions for low, borderline, intermediate, and high risk will be of primary importance. Similarly, the cardiovascular-kidney-metabolic construct calls for more robust assessment of residual risk among individuals with clinical CVD. Recent observational studies demonstrate long-term prognostic value of LDL-cholesterol, lipoprotein(a) [Lp(a)], and high-sensitivity C-reactive protein (hsCRP) for the prediction of CVD. These findings support prior randomized clinical trial data demonstrating a benefit of primary prevention statin therapy for individuals with elevated hsCRP, and that elevated Lp(a) and hsCRP are associated with residual CVD risk in those with clinical CVD and well-controlled LDL-C. Overall, such evidence supports universal measurement of LDL-C, Lp(a), and, for most patients, hsCRP across the spectrum of CVD to facilitate earlier lifestyle guidance and more precise allocation of preventive pharmacotherapies. Show less

Lipoprotein(a) (Lp[a]), is a significant risk factor for cardiovascular disease, yet is infrequently measured. A qualitative investigation was designed to better understand the barriers and facilitators to Lp(a) testing. Focus groups were held with clinicians (n = 26) and at-risk individuals (n = 24). Transcripts were thematically analyzed, guided by the Integrated Screening Action Model (I-SAM). Consistent with the I-SAM, barriers and facilitators of Lp(a) measurement were categorized as motivational, capability, and opportunity factors. Facilitators identified included perceived clinical utility, emotional reassurance associated with a newfound understanding of prior events, the ability to use Lp(a) knowledge to better prepare for the future, as well as active requests for testing. Barriers identified included a lack of perceived clinical utility and the potential to cause emotional distress with results, uncertainty and knowledge limitations around Lp(a), cost-related concerns, low expectations for testing, and clinician reluctance to test. This analysis highlights that Lp(a) testing decisions are multifactorial, providing multiple opportunities for intervention and improvement. Strategies to convey how Lp(a) measurement can inform risk assessment and treatment approaches may be foundational to encouraging more widespread testing. Show less

Hypertriglyceridemia has been proposed as a risk factor for atherosclerotic cardiovascular disease (ASCVD). Triglycerides (TG) are viewed as a marker for remnant cholesterol in triglyceride-rich lipoproteins, as this remnant cholesterol has been identified as a causal risk factor for ASCVD. The limited number of effective treatments for elevated TG has fueled the search for novel pharmacotherapy options, and multiple medication classes are being explored. Apolipoprotein C3 (APOC3) and angiopoietin-like protein 3 (ANGPTL3) are among the most promising targets. Several novel agents utilizing these pathways, including olezarsen, plozasiran, and zodasiran, are currently under development for the management of elevated TG, with olezarsen approved in 2024 for the management of familial chylomicronemia syndrome. This comprehensive review provides updated insights into the development of novel hypertriglyceridemia treatments. Show less

Amyloid deposition occurs decades before symptoms emerge in Alzheimer's disease (AD). We leveraged blood transcriptomics and positron emission tomography (PET) measures of amyloidosis to identify gene networks in the blood that relate to amyloid burden in the brain. Whole-blood RNA sequencing and amyloid PET were leveraged from 1739 cognitively unimpaired participants in the Anti-Amyloid Treatment in Asymptomatic Alzheimer's Disease (A4) study. Linear regression related gene module expression to amyloid covarying for age, sex, education, and apolipoprotein E (APOE) ε2 and ε4 genotypes. Of the 18 gene modules, one histone gene cluster module was associated with amyloid (β = -0.55, false discovery rate-adjusted p value = 0.029). We also observed nominal associations for the predicted proportion of activated natural killer (NK) cells (β = -0.454, p = 0.02) and CD4+ activated memory T cells (β = -0.169, p = 0.03) with amyloid deposition. Our results implicate the histone gene cluster on chromosome 6 and immune cell proportions as blood correlates of brain amyloid deposition in preclinical AD. Higher expression of network module with histone gene cluster on chromosome 6 associated with lower amyloid levels. Four histone genes, H1-5, H3C3, H2BC3, H2AC14, and RRM2, emerged as key genes driving this association, where H1-5 emerged as a hub gene for this module. Pathways, including nucleosome assembly and DNA damage, were enriched in the histone module. A higher fraction of activated NK and activated CD4+ T cells was related to lower amyloid burden. Show less

New methods estimate amyloid positivity onset age (EAOA) from amyloid positron emission tomography (PET). We explore the genetics of EAOA to identify molecular factors underlying the earliest Alzheimer's disease (AD) changes. Harmonized amyloid PET data from 4216 participants were used in genome-wide survival, tissue-specific gene expression, and genetic covariance analyses of EAOA. Variants in apolipoprotein E (APOE), ABCA7, and RASGEF1C associated with earlier EAOA. APOE ε4/ε4 and ε3/ε4 converted 6.3 and 5 years earlier than ε3/ε3, respectively. ε2 was protective against earlier EAOA. rs4147929, an expression quantitative trait locus for ABCA7, associated with a 4 year earlier EAOA. This variant was associated with lower brain expression of ABCA7, which was associated with increased amyloid pathology at autopsy. Multiple immune-related diseases shared genetic covariance with EAOA. APOE, ABCA7, and RASGEF1C associated with earlier EAOA, with supporting evidence from tissue-specific expression analyses, offering insights into intervenable targets at early stages of AD. Novel methods estimate how long ago a patient converted to amyloid positivity. Estimating this amyloid clock allows us to determine the onset of the earliest Alzheimer's disease changes. We evaluated what genes influence when someone converts to amyloid positivity. Apolipoprotein E (APOE), ABCA7, and RASGEF1C associated with earlier age of amyloid positivity. Genetic results were supported by tissue-specific expression analyses. Show less

Evaluating prognostic performance of Alzheimer's biomarkers, multi-modal physiological measures, and clinical history in asymptomatic individuals versus established risk factors in asymptomatic individuals is can inform efficient screening strategies. To determine and compare the prognostic performance of amyloid biomarkers, multi-modal physiological measures, and clinical/modifiable risk factors We used clinical trials (A4/LEARN), longitudinal cohorts (ADNI, AIBL, HABS, NACC, OASIS), and the UK Biobank spanning 2004-2025 (median follow-up time range: 1.8-13.72 years) in time-varying survival and binary classification analyses. Settings included a United States clinical trial, longitudinal cohort studies spread across medical centers in the United States and Australia, and the volunteer-based UK Biobank. Patients were cognitively asymptomatic and age 65+ at baseline, and potentially progressed to either clinical impairment, clinical AD diagnosis, or incurred AD ICD-codes. Patients were volunteer or convenience samples. PTau-217, amyloid-PET, CSF markers (AB1-42, pTau-181, total-Tau), plasma proteomics, multi-modal brain-imaging, and cognitive tests were evaluated as predictors, along with demographics (age, sex, education), APOE genotype, and modifiable risk factors in the 2024 Lancet report PTau-217 and amyloid-PET from A4/LEARN were used to predict clinical impairment (CDR score of 0.5+ on two consecutive visits). PTau-217, amyloid-PET imaging across five cohorts, and CSF markers were used to predict clinical AD diagnosis. Plasma proteomics, multimodal neuroimaging, and cognitive assessments from the UK Biobank were used to predict AD ICD-codes. Sample-sizes ranged from 356-28,533 (31-519 cases; female percentages: 48.45-67.39). Models of demographics, APOE genotype, and risk-factors as predictors did not show statistically significant differences in time-dependent area under the receiver operating characteristic curve (AUROC) compared to separate models using amyloid biomarkers. Predicting cognitive impairment in A4/LEARN, pTau-217 improved AUROC by 0.045-0.084 (best: 0.616 (CI: 0.51-0.723) vs. 0.7 (CI: 0.609-0.793)). Amyloid-PET improved AD prediction (maximum AUROC increase 0.074; 0.561 (CI: 0.468-0.653) vs. 0.635 (CI: 0.537-0.733)), and CSF biomarkers showed slightly larger gains (maximum AUROC increase 0.127; 0.627 (CI: 0.438-0.816) vs. 0.754 (CI: 0.577-0.931)). In UK Biobank analyses, mean AUROC improvements were minor across proteomics (0.044), neuroimaging (0.143, with 99.8%/0.2% class-balance), and cognitive tests (0.064). In cognitively asymptomatic populations, biomarkers offer limited advantage over demographics, APOE genotype, and modifiable risk factors, supporting their importance in early AD screening strategies. Show less

Cardiovascular (CV)- and lifestyle-associated risk factors (RFs) are increasingly recognized as important for Alzheimer's disease (AD) pathogenesis. Beyond the ε4 allele of apolipoprotein E (APOE), comparatively little is known about whether CV-associated genes also increase risk for AD. Using large genome-wide association studies and validated tools to quantify genetic overlap, we systematically identified single nucleotide polymorphisms (SNPs) jointly associated with AD and one or more CV-associated RFs, namely body mass index (BMI), type 2 diabetes (T2D), coronary artery disease (CAD), waist hip ratio (WHR), total cholesterol (TC), triglycerides (TG), low-density (LDL) and high-density lipoprotein (HDL). In fold enrichment plots, we observed robust genetic enrichment in AD as a function of plasma lipids (TG, TC, LDL, and HDL); we found minimal AD genetic enrichment conditional on BMI, T2D, CAD, and WHR. Beyond APOE, at conjunction FDR < 0.05 we identified 90 SNPs on 19 different chromosomes that were jointly associated with AD and CV-associated outcomes. In meta-analyses across three independent cohorts, we found four novel loci within MBLAC1 (chromosome 7, meta-p = 1.44 × 10 Show less

Hereditary multiple exostosis (HME) is an autosomal dominant bone disorder, characterized by short stature and the presence of multiple benign tumors mainly at the ends of long bones. HME is genetically heterogeneous with two known genes on 8q24 (EXT1) and 11p11 (EXT2), and a third minor locus mapped to 19p (EXT3). The majority of EXT1 and EXT2 mutations result in premature protein truncation and loss of function. We analyzed two autosomal dominant HME families of Indian origin. Linkage analysis using fluorescently labeled microsatellite markers at the candidate gene regions was performed. Mutation analysis was carried out by bidirectional sequencing of purified PCR products. We found linkage in one family to EXT1 and in the other family to EXT2. Mutation screening in the EXT1 gene revealed a novel frameshift mutation, a single base deletion in exon 1 (c.142delC). This mutation segregated in all affected members and was absent in the unaffected family members and 60 unrelated controls. In the second family, a previously unreported stop mutation, the substitution c.817C>T, was observed in the EXT2 gene in all affected members and in none of the unaffected family members and 90 unrelated controls. Our findings expand the mutation spectrum of EXT1 and EXT2 and highlight the genetic and phenotypic heterogeneity of HME. Show less