Age-Dependent and APOE-Modified Associations Between Vascular Risk Factor Patterns and Cognitive Function: A Latent Class Analysis of 44,879 NACC Participants.
Aug 2026· Alzheimer Disease and Associated Disorders· 0 citations· 39 references
Medicine
TL;DR
Attenuated associations in older-old adults may reflect survivor bias, while stronger associations in APOE ε4 carriers are consistent with gene-environment interactions, which are consistent with gene-environment interactions.
Abstract
INTRODUCTION
Vascular risk factors (VRFs) are established contributors to cognitive decline, yet they often co-occur in distinct patterns. Whether VRF pattern-cognition associations are modified by age or apolipoprotein E (APOE) genotype remains unclear.
Methods
We analyzed 44,879 participants aged 60 to 90 years from the National Alzheimer's Coordinating Center (NACC) with normal cognition or mild cognitive impairment (MCI). Latent class analysis (LCA) identified VRF patterns from 7 indicators: hypertension, diabetes, hypercholesterolemia, myocardial infarction, atrial fibrillation, heart failure, and stroke. Multivariable linear regression examined associations between VRF patterns and Mini-Mental State Examination (MMSE) scores, with stratification by age and APOE ε4 status.
Results
Five VRF patterns were identified: Low Risk (38.4%), Metabolic Predominant (40.5%), Hypertension Predominant (16.0%), Arrhythmia-Cardiac (2.7%), and High Multimorbidity (2.4%). Each additional VRF was associated with 0.056-point lower MMSE (β=-0.056, 95% CI: -0.072 to -0.039, P<0.001). Significant age × pattern (P=0.0015) and APOE × pattern (P=0.0016) interactions emerged. In younger-old adults (60 to 74 y), Metabolic Predominant was associated with lower MMSE (β=-0.171, P<0.001), but not in older-old adults (75 to 90 y; β=0.020, P=0.53). Among APOE ε4 carriers, the Metabolic Predominant association was substantially stronger (β=-0.228, P<0.001) compared with noncarriers (β=-0.053, P=0.025), a 4.3-fold difference in magnitude.
Conclusions
VRF-cognition associations show significant heterogeneity by age and APOE genotype. Attenuated associations in older-old adults may reflect survivor bias, while stronger associations in APOE ε4 carriers are consistent with gene-environment interactions.
BACKGROUND
Poor cognitive function is associated with increased mortality; however, whether these associations are consistent across different cognitive domains remains incompletely understood.
METHODS
We examined associations between cognitive function and all-cause mortality in a population-based cohort of Australian adults (N = 4561, median age = 60.0 years). In addition to global cognitive function (Mini-Mental State Examination [MMSE]) and premorbid verbal ability, participants underwent clinical assessments targeting the specific cognitive domains of processing speed and memory. Cox proportional hazards models with age as the time scale estimated hazard ratios (HR) for all-cause mortality per 1-standard deviation (SD) increase in cognitive scores. Analyses were adjusted for sociodemographic (including education), lifestyle, and clinical factors.
RESULTS
In this cohort with predominantly normal MMSE scores (98%), followed for a median of 11.3 years, 566 deaths occurred. Cognitive function was associated with lower mortality across most domains, as evidenced by 22% reduced mortality risk per 1-SD increase in global cognitive function (HR 0.78, 95% CI [0.67, 0.90]), 32% per 1-SD increase in processing speed (HR 0.68, [0.59, 0.78]) and 20% per 1-SD increase in memory (HR 0.80, [0.71, 0.91]), in fully adjusted models. Premorbid verbal ability was not associated with mortality (HR 0.92, [0.83, 1.02]). Associations were similar in men and women, and robust across sensitivity analyses.
CONCLUSIONS
Processing speed and memory were independently associated with mortality after covariate adjustment. The presence of these associations in a cohort with mostly preserved cognitive function underscores the potential of domain-specific cognitive measures to serve as indirect prognostic markers of mortality and to inform risk stratification.
Kanika Mehta, D. Magliano, Ruth George et al.· Archives of gerontology and...· 0 citations
Dementia is a major public health challenge, and Apolipoprotein E (APOE) ε4 is strongly associated with all-cause dementia, particularly Alzheimer's disease (AD). We aim to quantify the overall contribution of modifiable lifestyle, adiposity, socioeconomic status (SES), and health conditions occurring before dementia, to the association between ε4 genotype and the development of all-cause dementia, with AD examined as a major subtype. A population cohort study of 181,006 white UK Biobank participants aged ≥ 55 years at baseline was conducted, to examine the associations between APOE ε4 and all-cause dementia, and specifically AD, including modification and mediation role of lifestyle factors, adiposity, SES, and health conditions occurring before dementia. All risk factors, except for high alcohol intake, low diet quality, and phenotypic obesity, were associated with higher risk of all-cause dementia. The interaction contributions of lifestyle, adiposity, SES, and health conditions occurring before dementia varied by sex and dementia type. Low educational attainment had the strongest interaction effects with the association of APOE ε4 carriers and AD/all-cause dementia (up to 32.1%). In women, high deprivation level, abnormal sleep duration, anxiety, and depression showed interaction effects with APOE genotype (5-11.6%) as well. Phenotypic adiposity was associated with an increased risk of dementia among APOE ε4 non-carriers, but with a reduced risk among APOE ε4 carriers. Educational attainment explained a meaningful proportion of the APOE ε4 association with dementia. The strength of the association between APOE ε4 and dementia differed by risk factors and sex.
Mengrong Zhang, Frederick K. Ho, Jill P. Pell et al.· GeroScience· 0 citations
Abstract INTRODUCTION The associations of modifiable daily lifestyle variables (e.g., smoking, diet, alcohol intake, sedentary behavior, and physical activity) with structural brain atrophy, and interaction with apolipoprotein E (APOE) ε4 genetic risk, remain unclear. METHODS Among 3265 UK Biobank participants with repeated magnetic resonance imaging (MRI) data (mean follow‐up 2.6 years), we assessed the relations between lifestyle, APOE ε4 genotype, and volumetric changes in 15 structural brain phenotypes, using linear regression. RESULTS APOE ε4 presence showed greater atrophy by 25.1 mm3 in the left hippocampus (β: −0.115 standard deviations, 95% confidence interval [CI] [−0.192, −0.039] and 187.7 mm3 in frontal pole gray matter (β: −0.112, 95% CI [–0.186, −0.039]) (q < 0.05). Unfavorable lifestyle accelerated left hippocampal atrophy, and smoking increased white matter hyperintensity volumes (q > 0.05). No interactions were observed. DISCUSSION Our study reinforces the independent effect of APOE ε4 on longitudinal brain atrophy. Lifestyle may help preserve structural brain health, and our findings provide no evidence this varies by APOE ε4 genotype.
Yating You, Laura M. Lyall, Frederick K. Ho et al.· Alzheimer's & Dementia· 0 citations
Background Alzheimer’s disease (AD) pathogenesis involves complex interactions between neuroinflammation and vascular dysfunction. While leukocyte-albumin ratio (LAR) and hypertension are independently linked to cognitive decline, their joint associations with multidimensional cognitive impairment and AD risk remain understudied. Methods We analyzed two cohorts: 1,300 adults (≥ 60 years) from NHANES 2011–2014, and a clinical cohort (50 AD patients + 125 age-/gender-matched controls). LAR was calculated, hypertension was defined as per JNC7 criteria, and cognitive function was assessed via AD-sensitive tests standardized to z-scores. Restricted cubic spline (RCS) regression, multivariable linear regression, subgroup analysis, and Cox regression were used to examine LAR, hypertension, and their combined associations with cognitive outcomes. Results In the NHANES cohort, LAR was significantly correlated with DSST performance; participants with co-occurring high LAR + hypertension had lower scores across three cognitive domains, with age- (65–74 years) and sex-specific patterns and a 2.17-fold higher all-cause mortality risk. In the validation cohort, AD patients had higher LAR, with the highest LAR quartile linked to a 3.92-fold increased AD risk (p = 0.015). Conclusion Our findings support an association between LAR, hypertension, and cognitive decline. Elevated LAR in conjunction with hypertension is associated with poorer cognitive performance across multiple domains in older adults, as observed in both the NHANES and a clinical AD cohort. As a low-cost, easily measurable biomarker, LAR may hold promise for early AD risk stratification in primary care, highlighting a potential target for combined anti-inflammatory and antihypertensive interventions. However, its modest discriminative ability (AUC = 0.61) indicates that LAR should not be used as a standalone diagnostic tool. Prospective longitudinal studies are warranted to validate these associations.
Pan Gao, Yi-Ming Chu, Ming-Jun Geng et al.· Frontiers in Aging Neuroscie...· 0 citations
AIM
The apolipoprotein E ε4 (APOE ε4) allele is a well-established genetic risk factor for Alzheimer's disease (AD), with a gene-dose effect, but its prevalence and clinical correlates in remain underexplored in South Asians. We examined APOE ε4 homozygosity and its clinical correlates in Indian cohort.
PATIENTS AND METHODS
We analyzed APOE genotype data from 393 patients with AD and 850 age-matched healthy controls from India. Variables included family history of dementia, age at onset, behavioral and psychological symptoms of dementia (BPSD), comorbidities (Diabetes and Hypertension), and severity on the Hindi Mental Status Examination (HMSE) and Clinical Dementia Rating (CDR) scale.
RESULTS
APOE ε4 allele frequency was higher in patients with AD (25%) than controls (9%); homozygosity was also more frequent among patients (5% vs 1%; X2 = 103.48, p < 0.001). Homozygosity was associated with family history of dementia, [Odds Ratio (OR) 4.03, 95% CI 1.46-11.10, p = 0.007], consistent on Firth analysis, but not with age at onset, duration, severity, BPSD, or comorbidities.
CONCLUSION
In this Indian cohort, APOE ε4 homozygosity reflects increased susceptibility and familial aggregation of AD but does not confer a more severe or distinct phenotype, suggesting ancestry- specific expression of APOE ε4 gene-dose effects.
Pratibha Vinod, C. Arampady, Somdatta Sen et al.· Neurodegenerative Disease Ma...· 0 citations
OBJECTIVE
Diabetes mellitus (DM) and cognitive impairment (CoI) are correlated, but the combined impact of depressive symptoms on CoI risk in older adults remains unclear.
METHODS
This study included 1,200 U.S. adults aged ≥60 years (National Health and Nutrition Examination Survey, NHANES) and 1,500 Chinese adults (China Health and Retirement Longitudinal Study, CHARLS). DM was defined by laboratory measures or self-report; depressive symptoms were assessed via the Patient Health Questionnaire-9 (PHQ-9) (NHANES) and CES-D-10 (CHARLS); CoI was measured using the CERAD battery (NHANES) and situational memory/mental integrity scores (CHARLS). Multivariate logistic regression estimated associations of DM and depressive symptoms with CoI. Additive interaction was evaluated by the relative excess risk due to interaction (RERI), attributable proportion (AP), and synergy index (S). Restricted cubic spline (RCS) analyses examined nonlinear DM-depressive symptoms interactions.
RESULTS
Both DM and depressive symptoms were independently and significantly associated with CoI. After multivariate adjustment, diabetic patients exhibited significantly increased CoI risk; depressive symptoms similarly elevated CoI risk. Interaction analysis revealed an additive effect when DM co-occurred with depressive symptoms in CHARLS but not in NHANES. Mediation analyses further suggest bidirectional associations: in CHARLS, diabetes and depressive symptoms appear to mediate each other's effects on CoI. Additionally, RCS analysis in NHANES indicated a nonlinear interaction between depressive symptom severity (PHQ-9) and DM on CoI (p<0.05).
CONCLUSION
The observed associations varied across cohorts, with a significant additive interaction between diabetes and depressive symptoms found only in the CHARLS cohort. Integrating metabolic and mental health screening and interventions may optimize cognitive outcomes in high-risk older adult populations.
