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Biomedical subjects

Richard Mayeux

Publications and source records attributed to Richard Mayeux.

At least 19 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

Comprehensive adjudication identifies 111 high-confidence loci for Alzheimer's disease and related dementias.

BACKGROUND: The Alzheimer's Disease Sequencing Project Gene Verification Committee developed a systematic framework to adjudicate genetic evidence for AD and related dementias, addressing wide variation in association quality. METHODS: Phase 1 established tiered criteria by evaluating 23 nominated loci across study designs. Phase 2 applied this framework to 29 large-scale genome-wide studies published since 2015, tiering 163 unique loci. RESULTS: Phase 1 yielded 17 high-confidence loci (12 linked to specific genes), and Phase 2 identified 111 high-confidence loci/genes with replicated associations across ancestries and convergent single-variant/variant-set evidence. Prioritized loci highlight APP processing, microglial immunity, and lipid metabolism pathways, including genes not captured by existing resources like Agora or Open Targets. Summarized results can be viewed at https://topgenes.niagads.org/. CONCLUSION: This rigorously adjudicated catalog represents the most comprehensive AD/ADRD genetics resource to date, providing a foundation for functional validation and therapeutic discovery with broad applicability to complex diseases.

Journal Article↗
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↗
PubMed2012

Clinical and biomarker changes in dominantly inherited Alzheimer's disease.

BACKGROUND: The order and magnitude of pathologic processes in Alzheimer's disease are not well understood, partly because the disease develops over many years. Autosomal dominant Alzheimer's disease has a predictable age at onset and provides an opportunity to determine the sequence and magnitude of pathologic changes that culminate in symptomatic disease. METHODS: In this prospective, longitudinal study, we analyzed data from 128 participants who underwent baseline clinical and cognitive assessments, brain imaging, and cerebrospinal fluid (CSF) and blood tests. We used the participant's age at baseline assessment and the parent's age at the onset of symptoms of Alzheimer's disease to calculate the estimated years from expected symptom onset (age of the participant minus parent's age at symptom onset). We conducted cross-sectional analyses of baseline data in relation to estimated years from expected symptom onset in order to determine the relative order and magnitude of pathophysiological changes. RESULTS: Concentrations of amyloid-beta (Aβ)(42) in the CSF appeared to decline 25 years before expected symptom onset. Aβ deposition, as measured by positron-emission tomography with the use of Pittsburgh compound B, was detected 15 years before expected symptom onset. Increased concentrations of tau protein in the CSF and an increase in brain atrophy were detected 15 years before expected symptom onset. Cerebral hypometabolism and impaired episodic memory were observed 10 years before expected symptom onset. Global cognitive impairment, as measured by the Mini-Mental State Examination and the Clinical Dementia Rating scale, was detected 5 years before expected symptom onset, and patients met diagnostic criteria for dementia at an average of 3 years after expected symptom onset. CONCLUSIONS: We found that autosomal dominant Alzheimer's disease was associated with a series of pathophysiological changes over decades in CSF biochemical markers of Alzheimer's disease, brain amyloid deposition, and brain metabolism as well as progressive cognitive impairment. Our results require confirmation with the use of longitudinal data and may not apply to patients with sporadic Alzheimer's disease. (Funded by the National Institute on Aging and others; DIAN ClinicalTrials.gov number, NCT00869817.).

Age of Onset↗
PubMed2007

The neuronal sortilin-related receptor SORL1 is genetically associated with Alzheimer disease.

The recycling of the amyloid precursor protein (APP) from the cell surface via the endocytic pathways plays a key role in the generation of amyloid beta peptide (Abeta) in Alzheimer disease. We report here that inherited variants in the SORL1 neuronal sorting receptor are associated with late-onset Alzheimer disease. These variants, which occur in at least two different clusters of intronic sequences within the SORL1 gene (also known as LR11 or SORLA) may regulate tissue-specific expression of SORL1. We also show that SORL1 directs trafficking of APP into recycling pathways and that when SORL1 is underexpressed, APP is sorted into Abeta-generating compartments. These data suggest that inherited or acquired changes in SORL1 expression or function are mechanistically involved in causing Alzheimer disease.

Age of Onset↗
PubMed2007

Relation of higher folate intake to lower risk of Alzheimer disease in the elderly.

BACKGROUND: Higher intake of folate and vitamins B6 (pyridoxine hydrochloride) and B12 (cyanocobalamin) may decrease the risk of Alzheimer disease (AD) through the lowering of homocysteine levels. OBJECTIVE: To relate intake of folate and vitamins B6 and B12 to AD risk. DESIGN AND PATIENTS: We followed up 965 persons 65 years or older without dementia at baseline for a mean +/- SD period of 6.1 +/- 3.3 person-years after the administration of a semiquantitative food frequency questionnaire. Total, dietary, and supplement intake of folate and vitamins B6 and B12 and kilocalorie intake were estimated from the questionnaire responses. We related energy-adjusted intake of folate and vitamins B6 and B12 to incident AD using the Cox proportional hazards regression model. MAIN OUTCOME MEASURE: Incident AD. RESULTS: We found 192 cases of incident AD. The highest quartile of total folate intake was related to a lower risk of AD (hazard ratio, 0.5; 95% confidence interval, 0.3-0.9; P=.02 for trend) after adjustment for age, sex, education, ethnic group, the epsilon4 allele of apolipoprotein E, diabetes mellitus, hypertension, current smoking, heart disease, stroke, and vitamin B6 and B12 levels. Vitamin B6 and B12 levels were not related to the risk of AD. CONCLUSIONS: Higher folate intake may decrease the risk of AD independent of other risk factors and levels of vitamins B6 and B12. These results require confirmation with clinical trials.

Aged↗
PubMed2006

Relation of plasma homocysteine to plasma amyloid beta levels.

BACKGROUND: Elevated plasma homocysteine and amyloid beta (Abeta) have been associated with Alzheimer's disease (AD). We investigated the cross-sectional association between these biomarkers. METHODS: We used linear regression to relate plasma homocysteine and Abeta adjusting for age, gender, creatinine, APOE-epsilon4, and ethnic group in 327 persons aged 78 +/- 6.6 years. RESULTS: Plasma homocysteine correlated with age, serum creatinine, plasma Abeta40 and Abeta42, and was inversely correlated with serum vitamin B12, and folate. Abeta42, but not Abeta40, was related to later development of dementia. Homocysteine was related to higher Abeta40 levels (coefficient = 2.0; P < 0.0001) and this association was attenuated after adjustment for creatinine (coefficient = 1.0; P < 0.0001). The crude association between homocysteine and Abeta42 was weaker (coefficient = 0.5; P = 0.01) and became non-significant after adjustment for creatinine (coefficient = 0.4; P = 0.06). These associations were unrelated to ethnicity, the presence of APOE-epsilon4 or dementia. Analyses by quartiles of homocysteine showed that these association were driven primarily by the fourth quartile. CONCLUSIONS: Plasma homocysteine is directly related to Abeta40. The association with Abeta42 is not significant. These results seem to indicate that homocysteine is related to aging but not specifically to AD.

Aged↗
PubMed2006

Mediterranean diet, Alzheimer disease, and vascular mediation.

OBJECTIVES: To examine the association between the Mediterranean diet (MeDi) and Alzheimer disease (AD) in a different AD population and to investigate possible mediation by vascular pathways. Design, Setting, Patients, and MAIN OUTCOME MEASURES: A case-control study nested within a community-based cohort in New York, NY. Adherence to the MeDi (0- to 9-point scale with higher scores indicating higher adherence) was the main predictor of AD status (194 patients with AD vs 1790 nondemented subjects) in logistic regression models that were adjusted for cohort, age, sex, ethnicity, education, apolipoprotein E genotype, caloric intake, smoking, medical comorbidity index, and body mass index (calculated as weight in kilograms divided by height in meters squared). We investigated whether there was attenuation of the association between MeDi and AD when vascular variables (stroke, diabetes mellitus, hypertension, heart disease, lipid levels) were simultaneously introduced in the models (which would constitute evidence of mediation). RESULTS: Higher adherence to the MeDi was associated with lower risk for AD (odds ratio, 0.76; 95% confidence interval, 0.67-0.87; P<.001). Compared with subjects in the lowest MeDi tertile, subjects in the middle MeDi tertile had an odds ratio of 0.47 (95% confidence interval, 0.29-0.76) and those at the highest tertile an odds ratio of 0.32 (95% confidence interval, 0.17-0.59) for AD (P for trend <.001). Introduction of the vascular variables in the model did not change the magnitude of the association. CONCLUSIONS: We note once more that higher adherence to the MeDi is associated with a reduced risk for AD. The association does not seem to be mediated by vascular comorbidity. This could be the result of either other biological mechanisms (oxidative or inflammatory) being implicated or measurement error of the vascular variables.

Age Factors↗
PubMed2006

Bioavailable estradiol and age at onset of Alzheimer's disease in postmenopausal women with Down syndrome.

Several lines of evidence suggest that loss of estrogen after menopause may play a role in the cognitive declines associated with Alzheimer's disease (AD). Women with Down syndrome (DS) experience early onset of both menopause and AD. This timing provides a model to examine the influence of endogenous estrogen deficiency on risk of AD. We hypothesized that low serum levels of bioavailable estradiol (E2) would be associated with increased risk of AD. One hundred and nineteen postmenopausal women with DS, 42-59 years of age, were ascertained through the New York State developmental disability service system and followed at 18-month intervals. Information from cognitive assessments, caregiver interviews, medical record review and neurological examination was used to establish the diagnosis of dementia. Women with DS who developed AD had lower levels of bioavailable E2, lower levels of total estradiol, higher levels of sex-hormone binding globulin, and lower levels of dehydroepiandrosterone sulfate at baseline than women who remained dementia free over the course of follow-up. Women who had low levels of bioavailable E2 at baseline were four times as likely to develop AD (HR=4.1, 95% CI: 1.2-13.9) and developed AD, on average, 3 years earlier, than those with high levels of bioavailable E2, after adjustment for age, level of mental retardation, ethnicity, body mass index, history of hypothyroidism or depression and the presence of the apolipoprotein varepsilon4 allele. Our findings support the hypothesis that reductions in estrogen following menopause can contribute to the cascade of pathological processes leading to AD.

Adult↗
PubMed2006

Association studies between the plasmin genes and late-onset Alzheimer's disease.

The plasmin system is involved in the degradation of Abeta peptides, the accumulation of which in brain is a hallmark of Alzheimer's disease (AD). In a North European case-control AD dataset we studied 14 common variations in the PLG, PAI-1, PLAT and PLI genes encoding components of the plasmin system. Among the four polymorphisms in the PLAT, PAI-1 and PLI genes showing nominally significant evidence for an association with AD (allele p-value=0.01-0.00003) the strongest association was detected for the deletion allele in the Alu-repeat region of the PLAT gene. However, none of these positive results were confirmed in follow-up studies using an independent Canadian case-control cohort and two familial AD datasets of North European and Caribbean Hispanic origin. Thus, the current survey does not support the notion that common polymorphisms in the plasmin genes influence the development of AD.

Aged↗
PubMed2006

Apolipoprotein E epsilon4 and age at onset of sporadic and familial Alzheimer disease in Caribbean Hispanics.

BACKGROUND: The primary effect of the apolipoprotein E epsilon4 (APOE epsilon4) allele is on the age at onset of Alzheimer disease (AD). OBJECTIVE: To investigate whether the presence of the APOE epsilon4 allele can account for the earlier age at onset of familial AD (FAD) compared with sporadic AD (SAD). DESIGN: Population-based, case series ascertained in a prospective study of aging and dementia in Medicare recipients aged 65 years or older. SETTING: Clinics in northern Manhattan and in the Dominican Republic and Puerto Rico. PARTICIPANTS: There were 680 Caribbean Hispanic subjects: 111 patients with FAD, with at least 1 family member with dementia; 163 patients with SAD; and 406 elderly persons without dementia or other illnesses. Main Outcome Measure Age at onset of dementia was examined in relation to frequency of APOE epsilon4. Sex, education, and medical risk factors for stroke, hypertension, diabetes, and heart disease were examined as effect modifiers. RESULTS: The mean age at onset of AD was significantly lower in FAD than in SAD, and a statistically significant dose effect of the APOE epsilon4 allele was present for age at onset in FAD (P = .001) but not in SAD. The age at onset in patients homozygous for the APOE epsilon4 allele with FAD and SAD was similar. Compared with SAD, the major difference was younger age at onset in patients with FAD who were heterozygous for the APOE epsilon4 allele and those without an APOE epsilon4 allele. CONCLUSIONS: Apolipoprotein E epsilon4 had a consistent lowering effect on age at onset of FAD, but this was attenuated in SAD. This suggests that among individuals with a family history of AD and the APOE epsilon4 allele, additional genetic or environmental factors may accelerate the onset of dementia.

Age of Onset↗
PubMed2006

Expanded genomewide scan implicates a novel locus at 3q28 among Caribbean hispanics with familial Alzheimer disease.

OBJECTIVES: To identify novel candidate regions for late-onset Alzheimer disease (LOAD) and to confirm linkage in previously identified chromosomal regions. DESIGN: Family-based linkage analysis. SETTING: Probands with familial LOAD identified in clinics in the Dominican Republic, Puerto Rico, and the United States. Patients We conducted a genome scan in 1161 members primarily clinically diagnosed as having LOAD; these members were from 209 families of Caribbean Hispanic ancestry. MAIN OUTCOME MEASURES: We analyzed 376 microsatellite markers with an average intermarker distance of 9.3 centimorgan. We conducted linkage analysis using possible and probable LOAD, and we performed affecteds-only 2-point linkage analyses assuming either an autosomal dominant or a recessive model. Subsequently, we conducted a multipoint affected sibling pair linkage analysis. RESULTS: Two-point parametric linkage analysis identified a locus at 3q28 with a genomewide empirical P value of .03 (logarithm of odds [LOD], 3.09) in a dominant model for probable and possible LOAD. Other regions suggestive of linkage included 2p25.3 (LOD, 1.77), 7p21.1 (LOD, 1.82), and 9q32 (LOD, 1.94). Under a recessive model, we also identified loci at 5p15.33 (LOD, 1.86), 12q24.21 (LOD, 2.43), 14q22.3 (LOD, 2.53), and 14q23.1 (LOD, 2.16) as suggestive for linkage. Restricted to probable LOAD, many of these loci continued to meet criteria suggestive for linkage, as did loci at 2p25.3 (LOD, 2.72), 3q28 (LOD, 2.28), 6p21.31 (LOD, 2.19), and 7p21.1 (LOD, 2.05). APOE conditional analysis indicated that the observed linkage at 3q28 was independent of the APOE epsilon4 allele. Multipoint nonparametric affected sibling pair linkage analysis provided confirmation of suggestive linkage for most, but not all, loci. CONCLUSIONS: Seven loci with LOD scores greater than 2.0 were identified among multiple affected Caribbean Hispanic families with LOAD. The highest LOD score was found at chromosome 3q28. At least 2 other independent studies have observed support for significant linkage at chromosome 3q28, highlighting this region as a locus for further genetic exploration.

Age of Onset↗
PubMed2006

Stroke and memory performance in elderly persons without dementia.

BACKGROUND: There are conflicting data showing that stroke is associated with a higher risk of dementia and a more severe decline in persons with cognitive impairment. However, it remains unclear if cerebrovascular disease is directly related to cognitive decline in the absence of cognitive impairment or dementia. OBJECTIVE: To examine the association between stroke and changes in cognitive function over time in elderly persons without dementia at baseline. DESIGN: The results of neuropsychological tests from several intervals over a 5-year period were clustered into domains of memory, abstract/visuospatial, and language in 1271 elderly persons without dementia or cognitive decline. Stroke was related to the slope of performance in each cognitive domain using generalized estimating equations. RESULTS: Memory performance declined over time, while abstract/visuospatial and language performance remained stable during the study period. Stroke was associated with a more rapid decline in memory performance, while there was no association between stroke and decline in abstract/visuospatial or language performance. The association between stroke and decline in memory performance was strongest for men and for persons without an APOEepsilon4 allele. A significant association between stroke and decline in abstract/visuospatial performance was also observed for persons without the APOEepsilon4 allele. CONCLUSION: A history of stroke is related to a progressive decline in memory and abstract/visuospatial performance, especially among men and those without an APOEepsilon4 allele.

Aged↗
PubMed2006

Mediterranean diet and risk for Alzheimer's disease.

OBJECTIVE: Previous research in Alzheimer's disease (AD) has focused on individual dietary components. There is converging evidence that composite dietary patterns such as the Mediterranean diet (MeDi) is related to lower risk for cardiovascular disease, several forms of cancer, and overall mortality. We sought to investigate the association between MeDi and risk for AD. METHODS: A total of 2,258 community-based nondemented individuals in New York were prospectively evaluated every 1.5 years. Adherence to the MeDi (zero- to nine-point scale with higher scores indicating higher adherence) was the main predictor in models that were adjusted for cohort, age, sex, ethnicity, education, apolipoprotein E genotype, caloric intake, smoking, medical comorbidity index, and body mass index. RESULTS: There were 262 incident AD cases during the course of 4 (+/-3.0; range, 0.2-13.9) years of follow-up. Higher adherence to the MeDi was associated with lower risk for AD (hazard ratio, 0.91; 95% confidence interval, 0.83-0.98; p=0.015). Compared with subjects in the lowest MeDi tertile, subjects in the middle MeDi tertile had a hazard ratio of 0.85 (95% confidence interval, 0.63-1.16) and those at the highest tertile had a hazard ratio of 0.60 (95% confidence interval, 0.42-0.87) for AD (p for trend=0.007). INTERPRETATION: We conclude that higher adherence to the MeDi is associated with a reduction in risk for AD.

Aged↗
PubMed2006

Shorter telomeres are associated with mortality in those with APOE epsilon4 and dementia.

OBJECTIVE: Reduced telomere length may be a marker of biological aging. We hypothesized that telomere length might thus relate to increased risk for dementia and mortality. METHODS: This nested case-control study used stored leukocyte DNA from 257 individuals (mean age, 81.4 +/- 7.9 years; 64.6% female; 44.7% Hispanic, 33.5% non-Hispanic black, and 21.8% non-Hispanic white). Our assay used real-time polymerase chain reaction, with two separate reactions amplifying telomere sequence and reference single copy gene (ribosomal-protein-P0), providing a calculated telomere-to-single copy gene (T/S) ratio. RESULTS: Mean telomere length was shorter among subjects dying during follow-up than in those surviving (0.453 +/- 0.211 vs 0.525 +/- 0.226 [+/- standard deviation]; p < 0.009). It was also shorter in those with Alzheimer's disease compared with control subjects (0.458 +/- 0.207 vs 0.516 +/- 0.229; p < 0.03). For participants with Alzheimer's disease, compared with those with the longest telomeres, the mortality odds ratio (OR) was 4.8 (95% confidence interval [CI], 1.7-13.8) in those with intermediate-length telomeres and 7.3 (95% CI, 2.4-22.0) in those with the shortest telomeres. The presence of an epsilon4 allele also increased the mortality OR, with an OR of 5.8 (95% CI, 1.3-26.4) for intermediate-length telomeres and an OR of 9.0 (95% CI, 1.9-41) for the shortest telomeres. INTERPRETATION: Our findings suggest that leukocyte telomere length is related to both dementia and mortality and may be a marker of biological aging.

Aged↗
PubMed2005

Effect of smoking and time on cognitive function in the elderly without dementia.

OBJECTIVE: To examine the association between smoking and changes in cognitive function over time in elderly persons without dementia. METHODS: The results of neuropsychological tests grouped into domains of memory, abstract-visuospatial, and language, from several intervals over a 5-year period in 791 elderly patients without dementia or cognitive impairment. Smoking history was categorized as never, current, or past smokers and related to the slope of performance in each cognitive domain using generalized estimating equations. RESULTS: Performance in all cognitive domains declined over time. Memory performance declined more rapidly among current smokers aged >75 years than in nonsmokers similar in age, including those who never smoked or had quit smoking. The effect was stronger among those without an APOE-epsilon4 allele. There was no association between smoking and performance in any cognitive domain in persons aged <75 years, and there was no association between past smoking and performance on any of the three cognitive factors at any time interval in either age group. CONCLUSION: Current smokers aged >75 years perform more poorly on cognitive tests and appear to decline in memory more rapidly than their peers who do not smoke, especially if they lack the APOE-epsilon4 allele. Smoking does not affect cognitive performance in those persons aged <75 years.

Age Factors↗