Laure Rouch

Background: DNA methylation and systemic age‐related inflammation patterns have been employed to develop epigenetic and inflammatory aging clocks as a measure of biological aging. The extent to which it impacts cognition remains unclear, and the link with blood‐based biomarkers of Alzheimer’s disease (AD) has yet to be investigated. Methods: We included 586 participants (median age 51 [37‐61] years, women 66%) from the INSPIRE‐T cohort. At baseline, 5 measures of epigenetic age accelerations were considered from Horvath pan tissue, Horvath skin and blood, Hannum, PhenoAge and GrimAge epigenetic aging clocks. Inflammatory age acceleration was estimated from iAge clock. Biological age accelerations were calculated as the residuals from a linear regression of biological age on chronological age. Cognition was assessed at baseline and annually over 3 years. Global cognition was calculated as a composite measure using the average of Z scores for the MMSE orientation items (orientation), FCSRT (episodic memory), DSST (processing speed) and CNT (verbal fluency) tests. Each domain was also assessed separately. Blood NFL and p ‐tau217 were measured at baseline. Results: In cross‐sectional analyses and after adjustment for chronological age and sex, only GrimAge accelerated epigenetic aging was associated with lower global cognition (β = ‐0.18, 95% CI [‐0.33; ‐0.03], p =0.02). Further adjustment for education and ApoE4 genotype did not modify the results. Accelerated inflammatory aging was not associated with global cognition ( p =0.55). Longitudinal analyses did not reveal any significant interaction effect between GrimAge epigenetic aging and advancing chronological age. Skin and blood Horvath’s accelerated epigenetic aging was associated with lower processing speed (β = ‐ 1.49, 95% CI [‐2.70; ‐0.27], p =0.02) with advancing age. In fully adjusted models, neither epigenetic nor inflammatory accelerated aging were significantly associated with p ‐tau217 levels ( p >0.05 for all clocks). However, accelerated inflammatory aging was associated with higher NFL levels (β = 0.76, 95% CI [0.23; 1.30], p <0.01). Conclusions: Our findings showed that accelerated GrimAge epigenetic aging was associated with lower cognition. Accelerated inflammatory aging was linked to higher blood NFL levels. Our research could pave the way for an early molecular identification of at‐risk individuals, enabling personalized medicine interventions to promote brain health.

Background: Over the past decade, higher blood pressure (BP) variability and postural changes in BP have been associated with lower cognitive function. However, only one study has investigated the specific association between BP postural changes variability and brain health, showing a greater risk of dementia with higher systolic BP (SBP) postural changes variability. We aimed to investigate the association between BP postural changes variability and cognitive function in community‐dwelling older adults. Methods: Participants from the S.AGES (Sujets ÂGES) cohort underwent clinical examinations every 6 months during 3 years. At each clinical visit, an orthostatic SBP ratio was calculated: (seated SBP/standing SBP)×100. A similar method was used to compute an orthostatic diastolic BP ratio. Then, we assessed the visit‐to‐visit BP postural changes variability according to several indicators including coefficient of variation. Cognition was evaluated annually using the Mini‐Mental State Examination. Statistical analyses were performed with linear mixed models. Results: We included 2974 patients (mean age, 78 years). After adjustment for demographics, cardiovascular risk factors and disease, seated SBP/diastolic BP, and BP‐lowering treatment, visit‐to‐visit SBP postural changes variability was significantly associated with lower cognition (per 1‐SD increase in coefficient of variation: adjusted β=−0.15 [95% CI, −0.27 to −0.04], P =0.01). Similar results were found with visit‐to‐visit diastolic BP postural changes variability. Conclusions: Visit‐to‐visit SBP and diastolic BP postural changes variability were associated with lower cognition. Further studies are needed to assess whether controlling orthostatic BP instability over time could help preserve cognitive function. Registration: URL: https://clinicaltrials.gov ; Unique identifier: NCT01065909.

Understanding the relationship between blood nutrients and neurodegeneration could contribute to devising strategies for preventing Alzheimer’s disease. We investigated the associations between fatty acids, vitamins D, B6, B12, folate, homocysteine, and the cerebral load of amyloid β (Aβ). This cross-sectional study included 177 older adults (70–96 years, 65% female) with objective cognitive impairment, prefrail, or frail. Cerebral Aβ load was determined using positron emission tomography Standardized Uptake Value ratios. Fatty acids were assessed in erythrocytes, vitamins D and homocysteine in serum, and the other vitamins in plasma. Linear regression models corrected for multiple comparisons evaluated the associations between each nutrient and Aβ. The principal component factor followed by linear regression grouped the fatty acids strongly correlated (factor) and associated with Aβ. Higher concentrations of polyunsaturated fatty acids (PUFAs): clupanodonic acid (22:5n-3; β: −0.13; p = .001), mead acid (20:3n-9; β: −0.07; p = .036), and adrenic acid (22:4n-6; β: −0.05; p = .031) were associated with lower global Aβ load, whereas linoleic acid (18:2n-6) was associated with higher global Aβ load (β: 0.18; p = .042). Clupanodonic acid was inversely associated with Aβ in all cerebral regions except the thalamus. The factor composed of mead, clupanodonic, and arachidonic (20:4n-6) acids was associated with a lower global Aβ load (β: −0.02; p = .002). Some erythrocyte PUFAs were inversely associated with Aβ load in the brain, and most of them were metabolites of the essential fatty acids linoleic and α-linolenic. Given the cross-sectional design, these results must be carefully interpreted, and longitudinal studies are needed.

Background: Blood pressure (BP) postural changes, both orthostatic hypotension (OHYPO) and orthostatic hypertension (OHYPER) are common in older adults. Few studies have investigated their association with cognition, particularly for OHYPER, an emerging cardiovascular risk factor. We aimed to assess the association between OHYPO, OHYPER and cognition in non‐institutionalized older subjects. Methods: The S.AGES (Sujets ÂGES, Aged Subjects) cohort followed every 6 months for 3 years non‐institutionalized subjects aged ≥65 years without dementia at inclusion, in France. OHYPO and OHYPER were respectively defined as a fall or an increase of ≥20 mmHg in systolic BP and/or ≥10 mmHg in diastolic BP after standing from a sitting position. Cognition was assessed using the Mini‐Mental State Examination (MMSE). Linear mixed models were used for the analyses. Results: Among the 3170 subjects included (mean age 78 years, 56% women), 209 (6.5%) had OHYPO and 226 (7.1%) had OHYPER at baseline. After adjustment for demographics, cardiovascular risk factors and disease, seated SBP/DBP and BP lowering treatment, mean MMSE was 0.52 point lower in participants with OHYPER compared to those with normal BP postural changes ( β adjusted [95% CI] = −0.52 [−0.96; −0.09], p = 0.02) and 0.50 point lower in participants with OHYPO compared to those with normal BP postural changes ( β adjusted [95% CI] = −0.50 [−0.95; −0.06], p = 0.03). Sensitivity analyses showed a dose–response relationship between OHYPO and cognition. Conclusion: Although the absolute differences in MMSE were small, both OHYPO and OHYPER were associated with lower cognition. Orthostatic BP measurements could help identify patients with risk of cognitive impairment. Further studies are needed to assess whether controlling orthostatic BP could be a promising interventional target in preserving cognition among older adults.

The association between omega-3 (ω-3) PUFAs and cognition, brain imaging and biomarkers is still not fully established. The aim was to analyze the cross-sectional and retrospective longitudinal associations between erythrocyte ω-3 index and cognition, brain imaging, and biomarkers among older adults. A total of 832 Alzheimer's Disease Neuroimaging Initiative 3 (ADNI-3) participants, with a mean (SD) age of 74.0 (7.9) y, 50.8% female, 55.9% cognitively normal, 32.7% with mild cognitive impairment, and 11.4% with Alzheimer disease (AD) were included. A low ω-3 index (%EPA + %DHA) was defined as the lowest quartile (≤3.70%). Cognitive tests [composite score, AD Assessment Scale Cognitive (ADAS-Cog), Wechsler Memory Scale (WMS), Trail Making Test, Category Fluency, Mini-Mental State Examination, Montreal Cognitive Assessment] and brain variables [hippocampal volume, white matter hyperintensities (WMHs), positron emission tomography (PET) amyloid-β (Aβ) and tau] were considered as outcomes in regression models. Low ω-3 index was not associated with cognition, hippocampal, and WMH volume or brain Aβ and tau after adjustment for demographics, ApoEε4, cardiovascular disease, BMI, and total intracranial volume in the cross-sectional analysis. In the retrospective analysis, low ω-3 index was associated with greater Aβ accumulation (adjusted β = 0.02; 95% CI: 0.01, 0.03; P = 0.003). The composite cognitive score did not differ between groups; however, low ω-3 index was significantly associated with greater WMS-delayed recall cognitive decline (adjusted β = –1.18; 95% CI: –2.16, –0.19; P = 0.019), but unexpectedly lower total ADAS-Cog cognitive decline. Low ω-3 index was cross-sectionally associated with lower WMS performance (adjusted β = –1.81, SE = 0.73, P = 0.014) and higher tau accumulation among ApoE ε4 carriers. Longitudinally, low ω-3 index was associated with greater Aβ accumulation and WMS cognitive decline but unexpectedly with lower total ADAS-Cog cognitive decline. Although no associations were cross-sectionally found in the whole population, low ω-3 index was associated with lower WMS cognition and higher tau accumulation among ApoE ε4 carriers. The Alzheimer's Disease Neuroimaging Initiative (ADNI) is registered at clinicaltrials.gov as NCT00106899.

Background and Objective The goal of this work was to determine whether midlife cardiac structure and function and their 25-year change from early to middle adulthood are associated with lower midlife cognition. Methods We studied 2,653 participants from the Coronary Artery Risk Development in Young Adults (CARDIA) study (57% women, 46% Black). Echocardiograms were obtained at year 5, 25, and 30 visits (participant mean age 30, 50, and 55 years) to assess left ventricular (LV) mass (LVM), LV systolic function with LV ejection fraction (LVEF), and LV diastolic function with left atrial volume (LAV) and early peak mitral velocity (E)/early peak mitral annular velocity (e’) ratio. LVM and LAV were indexed to body surface area (LVMi and LAVi). At year 30, 5 cognitive domains were measured: global cognition, processing speed, executive function, delayed verbal memory, and verbal fluency. We investigated the association between midlife (year 30) and 25-year change in cardiac structure and function on midlife cognition using linear regressions. Results Over 25 years, LVMi and LAVi increased with mean change (SD) per year of 0.27 (0.28) g/m² and 0.42 (0.15) mL/m², while LVEF decreased by 0.11% (0.02%). After adjustment for demographics and education, 25-year increase (≥1 SD) in LVMi was associated with lower cognition on most tests (p ≤ 0.02); 25-year increase in LAVi was associated with lower global cognition (p = 0.04), but 25-year decrease in LVEF was not associated with cognition. Further adjustment for cardiovascular risk factors led to similar results. In addition, unlike year 30 E/e’ ratio and LVEF, higher year 30 LVMi and LAVi were significantly associated with worse cognition on most cognitive tests. Discussion Midlife cardiac structure and its change from early to middle adulthood are associated with lower midlife cognition even after accounting for confounders. Unlike systolic function, midlife LV diastolic function and its 25-year change were also linked to cognition. Our results provide information linking early to midlife cardiac structure and function to cognition.

Background: Orthostatic hypertension (OHYPER), an emerging hemodynamic cardiovascular risk factor, is associated with cardiovascular events and mortality. Recent findings indicated that it could be an important risk factor for cognitive decline and dementia, including Alzheimer’s disease (AD). We aimed to assess the association between OHYPER and low plasma Aβ₄₂/Aβ₄₀ ratio, a surrogate biomarker for brain amyloidosis, associated with greater risk of mild cognitive impairment (MCI) and AD.Method: We included 483 non‐demented community‐dwelling participants aged ≥ 70 years from the Multidomain Alzheimer Preventive Trial (MAPT). OHYPER was assessed at baseline and defined as an increase of at least 20 mmHg in systolic blood pressure (BP) and/or 10 mmHg in diastolic BP after standing. Plasma Aβ₄₂ and Aβ₄₀ were measured at 12 months, using an immunoprecipitation and liquid chromatography‐mass spectrometry assay. Low plasma Aβ₄₂/Aβ₄₀ ratio was defined as ≤ 0.107. Logistic regression models were used to assess the association between OHYPER and low plasma Aβ₄₂/Aβ₄₀ ratio.Result: Of 483 participants (mean age 76 years, 59% female), 113 (23.6%) had OHYPER and 161 (33.3%) low plasma Aβ₄₂/Aβ₄₀ ratio. OHYPER was associated with low plasma Aβ₄₂/Aβ₄₀ ratio (OR = 1.58, 95% CI [1.02‐2.44]) in unadjusted models. Adjustment for age, sex, education, MAPT randomization group, lying BP, antihypertensive drug use, MCI, and presence of 1 or 2 ApoE ε4 alleles did not change the results (OR = 1.67, 95% CI [1.02‐2.72]). Sensitivity analyses using the 25^th percentile of plasma Aβ₄₂/Aβ₄₀ ratio (≤ 0.103) as an alternative cutoff and long‐term OHYPER (at least two‐thirds of visits over 12 months) reported consistent findings.Conclusion: OHYPER was associated with lower plasma Aβ₄₂/Aβ₄₀ ratio in community‐dwelling older adults, even after accounting for potential confounders. Monitoring OHYPER may have clinical utility for identifying patients who are at risk for cognitive decline, AD or in the preclinical stages of the disease.

(1) Background: Some medications may be dangerous for older patients. Potentially inappropriate medication prescribing (PIP) among older patients represents a significant cause of morbidity. The aim of this study was to create an algorithm to detect PIP in a geriatric database (Multidomain Alzheimer Preventive Trial (MAPT) study), and then to assess the algorithm construct validity by comparing the prevalence of PIP and associated factors with literature data. (2) Methods: An algorithm was constructed to detect PIP and was based on different explicit criteria among which the European list of potentially inappropriate medications (EU(7)-PIM), the STOPP and START version 2 tools. For construct validity assessment, logistic mixed-effects model repeated measures analyses were used to identify factors associated with PIP. (3) Results: Prevalence of PIP was 59.0% with the EU(7)-PIM list criteria, 43.2% with the STOPP criteria and 51.3% with the START criteria. Age, polypharmacy, and higher Charlson comorbidity index were associated with PIP. (4) Conclusions: Prevalence of PIP and associated factors are consistent with literature data, supporting the construct validity of our algorithm. This algorithm opens up interesting perspectives both in terms of analysis of very large databases and integration into e-prescribing or pharmaceutical validation software.