Association of white matter hyperintensities and gray matter volume with cognition in older individuals without cognitive impairment

Both presence of white matter hyperintensities (WMH) and smaller total gray matter volume on brain magnetic resonance imaging (MRI) are common findings in old age, and contribute to impaired cognition. We tested whether total WMH volume and gray matter volume had independent associations with cognition in community-dwelling individuals without dementia or mild cognitive impairment (MCI). We used data from participants of the Rush Memory and Aging Project. Brain MRI was available in 209 subjects without dementia or MCI (mean age 80; education = 15 years; 74 % women). WMH and gray matter were automatically segmented, and the total WMH and gray matter volumes were measured. Both MRI-derived measures were normalized by the intracranial volume. Cognitive data included composite measures of five different cognitive domains, based on 19 individual tests. Linear regression analyses, adjusted for age, sex, and education, were used to examine the relationship of logarithmically-transformed total WMH volume and of total gray matter volume to cognition. Larger total WMH volumes were associated with lower levels of perceptual speed (p < 0.001), but not with episodic memory, semantic memory, working memory, or visuospatial abilities (all p > 0.10). Smaller total gray matter volumes were associated with lower levels of perceptual speed (p = 0.013) and episodic memory (p = 0.001), but not with the other three cognitive domains (all p > 0.14). Larger total WMH volume was correlated with smaller total gray matter volume (p < 0.001). In a model with both MRI-derived measures included, the relation of WMH to perceptual speed remained significant (p < 0.001), while gray matter volumes were no longer related (p = 0.14). This study of older community-dwelling individuals without overt cognitive impairment suggests that the association of larger total WMH volume with lower perceptual speed is independent of total gray matter volume. These results help elucidate the pathological processes leading to lower cognitive function in aging.     

Brain volume and white matter hyperintensities as determinants of cerebral blood flow in Alzheimer's disease

To better understand whether decreased cerebral blood flow (CBF) in patients with Alzheimer's disease (AD) reflects neurodegeneration or cerebral small vessel disease, we investigated the associations of normalized brain volume (NBV) and white matter hyperintensity (WMH) volume with CBF. We included 129 patients with AD (66 ± 7 years, 53% female) and 61 age-matched controls (64 ± 5 years, 43% female). CBF was measured with pseudocontinuous arterial spin labeling at 3T in the whole brain and in partial volume corrected cortical maps. When NBV and WMH were simultaneously entered in age and sex adjusted models, smaller NBV was associated with lower whole brain (Stβ: 0.29; p < 0.01) and cortical CBF (Stβ: 0.28; p < 0.01) in patients with AD. Larger WMH volume was also associated with lower whole brain (Stβ: −0.22; p < 0.05) and cortical CBF (Stβ: −0.24; p < 0.05) in AD. Additional adjustments did not change these results. In controls, neither NBV nor WMH was associated with CBF. Our results indicate that in AD, lower CBF as measured using pseudocontinuous arterial spin labeling, reflects the combined disease burden of both neurodegeneration and small vessel disease.     

White Matter Integrity in the Splenium of the Corpus Callosum is Related to Successful Cognitive Aging and Partly Mediates the Protective Effect of an Ancestral Polymorphism in <Emphasis Type="Italic">ADRB2</Emphasis>

It has recently been reported that the evolutionarily ancestral alleles of two functional polymorphisms in the β₂-adrenergic receptor gene (ADRB2) were related to higher cognitive ability in the 70 year old participants of the Lothian Birth Cohort 1936 (LBC1936). One emerging important factor in cognitive aging is the integrity of white matter tracts in the brain. Here, we used diffusion tensor MRI-based tractography to assess the integrity of eight white matter tracts in a subsample of the LBC1936. Higher integrity of the splenium of the corpus callosum predicted better cognitive ability in old age, even after controlling for IQ at age 11. Also, the ancestral allele of one ADRB2 SNP was associated with both splenium integrity and better cognitive aging. While the effects of the SNP and splenium integrity on cognitive aging were largely independent, there was some evidence for a partial mediation effect of ADRB2 status via splenium integrity.     

Cytomegalovirus infection and cognitive abilities in old age

Cytomegalovirus infection has been implicated in cognitive impairment in studies using brief clinical assessments though findings are inconsistent. The association between cytomegalovirus infection, measured as serostatus or a semiquantitative assessment of antibody level, and cognitive abilities in a sample of older adults was examined. Cytomegalovirus status was assessed at a mean age of 70 years in 1061 participants of the Lothian Birth Cohort 1936. Cognitive ability scores were available for general cognitive ability, processing speed, memory, and vocabulary. Background demographic and environmental factors included father's social class, years of education, childhood cognitive ability, overcrowding in childhood, and access to indoor toilet facilities. Cytomegalovirus seropositive individuals had lower cognitive ability at age 70: mean IQ was 99.1 (SD, 15.1) versus 102.4 (SD, 13.1) in seronegative individuals (t = 3.65; p < 0.001). The likelihood of contracting cytomegalovirus infection by age 70 was predicted by a number of demographic and environmental factors and, after accounting for these, cytomegalovirus infection (considered as serostatus) was not cognitively detrimental. Within cytomegalovirus seropositive individuals, however, higher cytomegalovirus antibody levels were associated with lower general cognitive ability.     

Estimated maximal and current brain volume predict cognitive ability in old age

Brain tissue deterioration is a significant contributor to lower cognitive ability in later life; however, few studies have appropriate data to establish how much influence prior brain volume and prior cognitive performance have on this association. We investigated the associations between structural brain imaging biomarkers, including an estimate of maximal brain volume, and detailed measures of cognitive ability at age 73 years in a large (N = 620), generally healthy, community-dwelling population. Cognitive ability data were available from age 11 years. We found positive associations (r) between general cognitive ability and estimated brain volume in youth (male, 0.28; females, 0.12), and in measured brain volume in later life (males, 0.27; females, 0.26). Our findings show that cognitive ability in youth is a strong predictor of estimated prior and measured current brain volume in old age but that these effects were the same for both white and gray matter. As 1 of the largest studies of associations between brain volume and cognitive ability with normal aging, this work contributes to the wider understanding of how some early-life factors influence cognitive aging.     

Evaluating brain white matter hyperintensity,IQ scores,and plasma neurofilament light chain concentration in early-treated patients with infantile-onset Pompe disease

PurposeThe study aimed to describe central nervous system (CNS) progression in patients with infantile-onset Pompe disease (IOPD) and explore the potential clinical impact and predictors.MethodsPatients with IOPD treated with enzyme replacement therapy were longitudinally followed with brain magnetic resonance imaging (MRI) and evaluation for IQ scores from 2004 to 2021. Investigation of CNS involvement focused on white matter (WM) abnormalities and was quantified using a scoring system for metachromatic leukodystrophy. MRI scores were correlated with plasma neurofilament light chain (NfL) concentration and IQ scores.ResultsA total of 19 patients who started enzyme replacement therapy at a mean age of 26 days were analyzed; the median age at last examination was 12.1 (range = 1.7-19) years. MRI abnormalities were found in all patients, from supratentorial central WM to U-fibers, then to infratentorial WM, and eventually to gray matter. MRI scores progressed (n = 16) at variable rates (range = 0.8-2.7/y) and were positively correlated with age (n = 16) and negatively correlated with IQ scores (n = 8). Plasma NfL concentration was positively correlated with MRI scores (r² = 0.8569; P < .001; n = 13).ConclusionOur results suggest that the progression of CNS involvement in IOPD may be associated with neuroaxonal injury and decreased IQ scores. NfL could serve as a biomarker for CNS involvement in IOPD.     

Specific risk factors for microbleeds and white matter hyperintensities in Alzheimer's disease

We investigated whether microbleeds and white matter hyperintensities (WMH) in Alzheimer's disease (AD) associate more with conventional vascular risk factors or with risk factors that reflect amyloid burden. A total of 371 patients with probable AD were included. WMH (Fazekas 2 or 3) were present in 107 (29%) patients and microbleeds were seen in 98 (26%). Patients with both microbleeds and WMH were older and presented more frequently with lacunes and multiple microbleeds than patients with microbleeds in isolation (all p < 0.05). Using multivariate regression models, we found that WMH presence showed independent associations with age, hypertension, current smoking, and lacune presence. Microbleeds were independently associated with male gender, higher blood pressure, lower cerebrospinal fluid Aβ42, and apolipoprotein E ε4 homozygosity. Separate analyses for microbleeds according to their location showed that these associations were driven by microbleeds in lobar locations. Our results suggest that, unlike WMH, microbleeds in AD are particularly associated with additional amyloid burden, and as such, may relate to cerebral amyloid angiopathy.     

Regional white matter hyperintensities: aging,Alzheimer's disease risk,and cognitive function

White matter hyperintensities (WMH) of presumed vascular origin, as seen on T2-weighted fluid attenuated inversion recovery magnetic resonance imaging, are known to increase with age and are elevated in Alzheimer's disease (AD). The cognitive implications of these common markers are not well understood. Previous research has primarily focused on global measures of WMH burden and broad localizations that contain multiple white matter tracts. The aims of this study were to determine the pattern of WMH accumulation with age, risk for AD, and the relationship with cognitive function utilizing a voxel-wise analysis capable of identifying specific white matter regions. A total of 349 participants underwent T1-weighted and high-resolution T2-weighted fluid attenuated inversion recovery magnetic resonance imaging and neuropsychological testing. Increasing age and lower cognitive speed and flexibility (a component of executive function), were both significantly associated with regional WMH throughout the brain. When age was controlled, lower cognitive speed and flexibility was independently associated with WMH in the superior corona radiata. Apolipoprotein E ε4 and parental family history of AD were not associated with higher burden of WMH. The results contribute to a larger body of literature suggesting that white matter measures are linked with processing speed, and illustrate the utility of voxel-wise analysis in understanding the effect of lesion location on cognitive function.     

A brief report: The National Adult Reading Test (NART) is a stable assessment of premorbid intelligence across disease severity in obstructive sleep apnea (OSA)

Obstructive sleep apnea (OSA) is a widely prevalent disorder that can affect cognitive function. The relationship between cognitive function and OSA is known to be affected by an individual's premorbid cognitive ability. Tools to measure premorbid intelligence across OSA disease severity have not been validated. This brief report aims to establish if the National Adult Reading Test (NART) provides a stable estimate of premorbid intelligence across levels of OSA disease severity. We examined if NART scores varied systematically across levels of untreated OSA severity (defined according to the apnea–hypopnea index [AHI]) and mean oxygen saturation in sleep clinic (n = 121) and community samples (n = 398) using regression analysis. Simple linear regression was used to predict NART scores based on the AHI. NART‐estimated premorbid IQ scores without demographics did not vary systematically with AHI (F < 1; β = 0.01) or mean SpO₂ (F < 1; β = 0.12). NART‐estimated premorbid IQ scores with added demographic information also did not vary systematically with AHI (F < 1; β = ?0.01) or mean SpO₂ (F < 1; β = 0.15). This preliminary examination shows that the NART provides a stable estimate of premorbid intelligence across untreated OSA disease severity, as demarcated by AHI or mean nocturnal SpO₂.     

Neurobehavioral Profiles in Individuals with Hyperimmunoglobulin E Syndrome (HIES) and Brain White Matter Hyperintensities

Purpose

Individuals with hyperimmunoglobulin E Syndrome (HIES) have central nervous system abnormalities, including focal white matter hyperintensities (WMH), or unidentified bright objects. This cross-sectional study aimed to describe the cognitive and emotional functioning and quality of life of people with HIES. We also sought to explore the relationship between cognitive functioning and WMHs in this population.

Methods

Twenty-nine individuals (13 males) with autosomal-dominant HIES (mean age?=?35.1 years, range 16–55) were administered a comprehensive psychological assessment as part of a natural history protocol. The assessment included measures of global cognitive functioning (Wechsler Adult Intelligence Scale-III), memory (California Verbal Learning Test-II, Wechsler Memory Scale-III), executive skills (Delis Kaplan Executive Function System), and attention (Test of Everyday Attention). Emotional symptoms and quality of life also were assessed.

Results

All mean cognitive scores were within normal limits. Mean scores on memory and executive functioning measures were significantly lower than Full Scale IQ scores (ps?<?.05). Substantial percentages of patients self-reported executive skills to be in the clinical range. Patients with fewer (1–20) versus more (21+) WMHs scored significantly better on measures of global cognitive skills, visual-perceptual skills, and working memory. Mean scores on emotional symptom and quality of life measures were in the average range and unrelated to WMHs.

Conclusions

Global cognitive functioning was average to high average in our sample of individuals with HIES. However, focal brain lesions were associated with lower scores in specific domains. Emotional functioning and quality of life are within normal limits in this sample.     

Genetic Covariation Between Brain Volumes and IQ,Reading Performance,and Processing Speed

Although there has been much interest in the relation between brain size and cognition, few studies have investigated this relation within a genetic framework and fewer still in non-adult samples. We analyzed the genetic and environmental covariance between structural MRI data from four brain regions (total brain volume, neocortex, white matter, and prefrontal cortex), and four cognitive measures (verbal IQ (VIQ), performance IQ (PIQ), reading ability, and processing speed), in a sample of 41 MZ twin pairs and 30 same-sex DZ twin pairs (mean age at cognitive test = 11.4 years; mean age at scan = 15.4 years). Multivariate Cholesky decompositions were performed with each brain volume measure entered first, followed by the four cognitive measures. Consistent with previous research, each brain and cognitive measure was found to be significantly heritable. The novel finding was the significant genetic but not environmental covariance between brain volumes and cognitive measures. Specifically, PIQ shared significant common genetic variance with all four measures of brain volume (r _g = .58–.82). In contrast, VIQ shared significant genetic influence with neocortex volume only (r _g = .58). Processing speed was significant with total brain volume (r _g = .79), neocortex (r _g = .64), and white matter (r _g = .89), but not prefrontal cortex. The only brain measure to share genetic influence with reading was total brain volume (r _g = .32), which also shared genetic influences with processing speed.     

Understanding the relationship between alcohol outlet density and life expectancy in Baltimore City: The role of community violence and community disadvantage

This research investigated the relationship between alcohol outlet density (AOD) and life expectancy, as mediated by community violence and community disadvantage. We used linear regression models to assess bivariate and multivariate relationships. There was a negative bivariate association between liquor store density and average life expectancy (β = ?7.3370, p < 0.001). This relationship was partially attenuated when controlling for community disadvantage and fully attenuated when controlling for community violence. Bars/taverns (i.e., on‐premise) were not associated with average life expectancy (β = ?0.589, p = 0.220). Liquor store density is associated with higher levels of community disadvantage and higher rates of violence, both of which are associated with lower life expectancies. Future research, potential intervention, and current related policies are discussed.     

Abdominal obesity and lower gray matter volume: a Mendelian randomization study

We investigated the relationship of anthropometric markers of obesity with quantitative magnetic resonance imaging markers of brain aging, including measures of total brain volume (TBV), gray matter volume (GMV), hippocampal volume, white matter hyperintensity volume (WMHV), and brain infarcts, and examined causality using Mendelian randomization (MR). Analyses were performed in 1779 individuals (60.4% women, 72.8 ± 4.1 years of age) from the 3C-Dijon population-based cohort study (N = 1555 for the MR). Larger waist-to-hip-ratio (WHR) and waist circumference (WC) were associated with lower TBV (p = 0.0001 and p = 0.005), and lower GMV (p = 0.0008 and p = 0.003), independently of age, gender, body mass index (BMI), and vascular risk factors. Higher BMI, WC, and WHR were associated with larger WMHV and WC with brain infarcts, before adjusting for vascular risk factors only. We used MR to investigate the inverse relationship between WHR and GMV. One valid instrumental variable was available in women only (rs6905288), which was associated with GMV (p = 0.015). Age and BMI-adjusted effect estimates from the MR analysis confirmed the inverse association between GMV and WHR and are in favor of a causal association.     

White matter integrity of motor connections related to training gains in healthy aging

Impaired motor skill acquisition is a feature of older age. Acquisition of new motor skills requires the interplay between different cortical motor areas. Using diffusion tensor imaging we reconstructed cortico-cortical connections between the primary motor cortex (M1) and secondary motor areas in 11 older and 11 young participants who took part in a motor skill acquisition paradigm with the nondominant left hand. Examining the extent to which tract-related integrity correlated with training gains we found that white matter integrity of fibers connecting contralateral M1 with both contralateral (r = 0.85) and ipsilateral supplementary motor areas (r = 0.92) were positively associated in old participants. Also, fibers connecting contralateral M1 with ipsilateral dorsal premotor (r = 0.82) and fibers connecting ipsilateral dorsal premotor and supplementary motor area (r = 0.88) were positively related to skill acquisition (all p < 0.05). A similar structure-behavior relationship was not present in the young control subjects suggesting a critical role of brain structural integrity for motor learning in healthy aging.     

Neuroprotective pathways: lifestyle activity,brain pathology,and cognition in cognitively normal older adults

This study used path analysis to examine effects of cognitive activity and physical activity on cognitive functioning in older adults, through pathways involving beta-amyloid (Aβ) burden, cerebrovascular lesions, and neural injury within the brain regions affected in Alzheimer's disease (AD). Ninety-two cognitively normal older adults (75.2 ± 5.6 years) reported lifetime cognitive activity and current physical activity using validated questionnaires. For each participant, we evaluated cortical Aβ burden (using [¹¹C] labeled Pittsburgh-Compound-B positron emission tomography), cerebrovascular lesions (using magnetic resonance imaging-defined white matter lesion [WML]), and neural integrity within AD regions (using a multimodal neuroimaging biomarker). Path models (adjusted for age, gender, and education) indicated that higher lifetime cognitive activity and higher current physical activity was associated with fewer WMLs. Lower WML volumes were in turn related to higher neural integrity and higher global cognitive functioning. As shown previously, higher lifetime cognitive activity was associated with lower [¹¹C] labeled Pittsburgh-Compound-B retention, which itself moderated the impact of neural integrity on cognitive functioning. Lifestyle activity may thus promote cognitive health in aging by protecting against cerebrovascular pathology and Aβ pathology thought to be relevant to AD development.     

Cognitive ability and decline after early life stress exposure

We examined the effects of early life stress on cognitive ability and decline among men of the Helsinki Birth Cohort Study, 10% of whom were separated temporarily (mean age at separation = 4.1 years) from their parent(s) during World War II. The men underwent the Finnish Defense Forces Basic Intellectual Ability Test twice, at 20 years and retest at 70 years. Compared with the men without childhood separation and matched for year of birth (n = 186), men separated from their parents (n = 93) scored lower by 5.5 (95% confidence interval [CI], −9.2 to −1.7), 4.2 (95% CI, −8.1 to −0.3), 3.1 (95% CI, −7.0 to 0.8), and 4.5 (95% CI, −10.5 to −1.4) standardized points (SD = 15) on verbal, visuospatial, arithmetic, and general cognitive ability, respectively, at 70 years. Longer duration of separation was associated with lower test scores. Though early life stress was also associated significantly with weaker cognitive performance at the ages 20 and 70 years, it was not associated with cognitive decline over the 50-year period within this sample.     

Atlas-derived perfusion correlates of white matter hyperintensities in patients with reduced cardiac output

Reduced cardiac output is associated with increased white matter hyperintensities (WMH) and executive dysfunction in older adults, which may be secondary to relations between systemic and cerebral perfusion. This study preliminarily describes the regional distribution of cerebral WMH in the context of a normal cerebral perfusion atlas and aims to determine if these variables are associated with reduced cardiac output. Thirty-two participants (72 ± 8 years old, 38% female) with cardiovascular risk factors or disease underwent structural MRI acquisition at 1.5 T using a standard imaging protocol that included FLAIR sequences. WMH distribution was examined in common anatomical space using voxel-based morphometry and as a function of normal cerebral perfusion patterns by overlaying a single photon emission computed tomography (SPECT) atlas. Doppler echocardiogram data was used to dichotomize the participants on the basis of low (n = 9) and normal (n = 23) cardiac output. Global WMH count and volume did not differ between the low and normal cardiac output groups; however, atlas-derived SPECT perfusion values in regions of hyperintensities were reduced in the low versus normal cardiac output group (p < 0.001). Our preliminary data suggest that participants with low cardiac output have WMH in regions of relatively reduced perfusion, while normal cardiac output participants have WMH in regions with relatively higher regional perfusion. This spatial perfusion distribution difference for areas of WMH may occur in the context of reduced systemic perfusion, which subsequently impacts cerebral perfusion and contributes to subclinical or clinical microvascular damage.     

BOLD‐based cerebrovascular reactivity vascular transfer function isolates amplitude and timing responses to better characterize cerebral small vessel disease

Cerebrovascular reactivity (CVR) is a dynamic measure of the cerebral blood vessel response to vasoactive stimulus. Conventional CVR measures amplitude changes in the blood‐oxygenation‐level‐dependent (BOLD) signal per unit change in end‐tidal CO₂ (P_ETCO₂), effectively discarding potential timing information. This study proposes a deconvolution procedure to characterize CVR responses based on a vascular transfer function (VTF) that separates amplitude and timing CVR effects. We implemented the CVR‐VTF to primarily evaluate normal‐appearing white matter (WM) responses in those with a range of small vessel disease. Comparisons between simulations of P_ETCO₂ input models revealed that boxcar and ramp hypercapnia paradigms had the lowest relative deconvolution error. We used a T₂* BOLD‐MRI sequence on a 3 T MRI scanner, with a boxcar delivery model of CO₂, to test the CVR‐VTF approach in 18 healthy adults and three white matter hyperintensity (WMH) groups: 20 adults with moderate WMH, 12 adults with severe WMH, and 10 adults with genetic WMH (CADASIL). A subset of participants performed a second CVR session at a one‐year follow‐up. Conventional CVR, area under the curve of VTF (VTF‐AUC), and VTF time‐to‐peak (VTF‐TTP) were assessed in WM and grey matter (GM) at baseline and one‐year follow‐up. WMH groups had lower WM VTF‐AUC compared with the healthy group (p < 0.0001), whereas GM CVR did not differ between groups (p > 0.1). WM VTF‐TTP of the healthy group was less than that in the moderate WMH group (p = 0.016). Baseline VTF‐AUC was lower than follow‐up VTF‐AUC in WM (p = 0.013) and GM (p = 0.026). The intraclass correlation for VTF‐AUC in WM was 0.39 and coefficient of repeatability was 0.08 [%BOLD/mm Hg]. This study assessed CVR timing and amplitude information without applying model assumptions to the CVR response; this approach may be useful in the development of robust clinical biomarkers of CSVD.     

Associations between objective afternoon and evening physical activity and objective sleep in patients with fibromyalgia and insomnia

Patients with fibromyalgia (FM) suffer from chronic pain, which limits physical activity and is associated with disturbed sleep. However, the relationship between physical activity, pain and sleep is unclear in these patients. This study examined whether actigraphic (Actiwatch‐2, Philips Respironics) afternoon and evening activity and pain are associated with actigraphic sleep. Adults with FM and insomnia complaints (n = 160, mean age [M_age] = 52, SD = 12, 94% female) completed 14 days of actigraphy. Activity levels (i.e., activity counts per minute) were recorded, and average afternoon/evening activity for intervals 12:00–3:00 PM, 3:00–6:00 PM and 6:00–9:00 PM was computed. Multiple linear regressions examined whether afternoon/evening activity, pain (daily evening diaries from 0 [no pain sensation] to 100 [most intense pain imaginable]), or their interaction, predicted sleep onset latency (SOL), wake time after sleep onset (WASO), total sleep time (TST) and sleep efficiency (SE). Greater afternoon activity was independently associated with lower SE (B = ?0.08, p < .001), lower TST (β = ?0.36, standard error [SE] = 0.06, p < .001) and longer WASO (B = 0.34, p < .001). Greater early evening activity was independently associated with lower SE (B = ?0.06, p < .001), lower TST (β = ?0.26, SE = 0.06, p < .001) and longer WASO (B = 0.23, p < .001). Self‐reported pain intensity interacted with afternoon and early evening physical activity, such that associations between higher activity and lower SE were stronger for individuals reporting higher pain. Late evening activity was not associated with sleep outcomes. Results suggest that in FM, increased afternoon and early evening physical activity is associated with sleep disturbance, and this relationship is stronger in individuals with higher pain.     

Age differences in the association of obstructive sleep apnea risk with cognition and quality of life

Using a sample of 2925 stroke‐free participants drawn from a national population‐based study, we examined cross‐sectional associations of obstructive sleep apnea (OSA) risk with cognition and quality of life and whether these vary with age, while controlling for demographics and comorbidities. Included participants from the REasons for Geographic And Racial Differences in Stroke (REGARDS) study were aged 47–93 years. OSA risk was categorized as high or low based on responses to the Berlin Sleep Questionnaire. Cognitive function was assessed with standardized fluency and recall measures. Depressive symptoms were assessed with the four‐item Center for Epidemiologic Studies Depression Scale. Health‐related quality of life (HRQoL) was assessed with the Medical Outcomes Study Short Form‐12 (SF‐12). Multivariate analyses of covariance (mancova ) statistics were applied separately to the cognitive and quality of life dependent variables while accounting for potential confounders (demographics, comorbidities). In fully adjusted models, those at high risk for OSA had significantly lower cognitive scores (Wilks’ lambda = 0.996, F_3,2786 = 3.31, P < 0.05) and lower quality of life [depressive symptoms and HRQoL] (Wilks’ lambda = 0.989, F_3,2786 = 10.02, P < 0.0001). However, some of the associations were age‐dependent. Differences in cognition and quality of life between those at high and low obstructive sleep apnea risk were most pronounced during middle age, with attenuated effects after age 70 years.