Non-pathological Cognitive Ageing Research Articles

80 Processing Speed Mediates the Association between Executive Functioning and Adaptive Functioning Among Older Adults

Objective:Cognitive decline is expected in normative aging (Cabeza et al., 2018; Salthouse, 2019), which can lead to impairments in adaptive functioning (Yam et al., 2014). Several cognitive domains have been associated with adaptive functioning in older adult samples, including processing speed and executive functioning (e.g., Nguyen et al., 2019; Vaughn & Giovanello, 2010). A recent study examining a mixed clinical sample of older adults demonstrated that processing speed was more predictive of functional decline than other cognitive domains, including aspects of executive functioning (Roye et al., 2022). Therefore, this study attempts to build on previous findings by further examining the relationships between processing speed, adaptive functioning, and executive functioning. Specifically, it investigated the extent to which processing speed mediated the associations between executive functioning and adaptive functioning.Participants and Methods:Participants (N = 239) were selected from a clinical database of neuropsychological evaluations. Inclusion criteria were age 60+ (M = 74.0, SD = 6.9) and completion of relevant study measures. Participants were majority White (93%) women (53.1%). Three cognitive diagnosis groups were coded: No Diagnosis (N = 82), Mild Neurocognitive Disorder (NCD; N = 78), and Major NCD (N = 79). The Texas Functional Living Scale (TFLS) was used as a performance-based measure of adaptive functioning. Processing speed was measured using the Coding subtest from the Repeatable Battery for the Assessment of Neuropsychological Status. Executive functioning performance was quantified using part B of the Trail Making Test, Controlled Oral Word Association Test, and Similarities and Matrix Reasoning subtests from the WAIS-IV and WASI-II. Mediation models included age and years of education as covariates and indirect effects were assessed with bootstrapped confidence intervals (Hayes, 2020).Results:Processing speed mediated all measures of executive functioning. The pattern was consistent for all executive functioning measures such that poorer executive functioning was associated with poorer processing speed, which was subsequently associated with poorer adaptive functioning. Direct effects were significant for all models (ps < .03), suggesting that executive functioning maintained unique associations with adaptive functioning. Follow-up analyses indicated no evidence for moderation of the mediation models based on diagnostic group.Conclusions:These results highlight the importance of processing speed in understanding real-world implications of pathological and non-pathological cognitive aging. Processing speed mediated all relationships between executive functioning and adaptive functioning. There was no evidence for moderation of these effects, supporting generalizability regardless of neurocognitive disorder and etiologic subtype. Further investigation is warranted into the importance of processing speed in explaining associations of other cognitive domains with adaptive functioning.

Adaptive Functioning Among Older Adults: The Essence of Information Processing Speed in Executive Functioning.

The current study investigated the degree to which information processing speed mediates the association between executive functioning and adaptive functioning among older adults. Cases (N = 239) were selected from a clinical database of neuropsychological evaluations. Inclusion criteria were age 60+ (M = 74.0, standard deviation = 6.9) and completion of relevant study measures. Participants were majority White (93%) women (53.1%). The Texas Functional Living Scale was used as a performance-based measure of adaptive functioning. Information processing speed was measured using the Coding subtest from the Repeatable Battery for the Assessment of Neuropsychological Status. Executive functioning performance was quantified using part B of the Trail Making Test, Controlled Oral Word Association Test, and Similarities and Matrix Reasoning subtests from the Wechsler Abbreviated Scale of Intelligence, second edition. Mediation models were assessed with bootstrapped confidence intervals. Information processing speed mediated all measures of executive functioning. Direct effects were significant for all models (ps < 0.03), suggesting that executive functioning maintained unique associations with adaptive functioning. Follow-up analyses indicated no evidence for moderation of the mediation models based on diagnostic group. Additional models with executive functioning mediating information processing speed and adaptive functioning revealed inconsistent mediation, with smaller effects. Results highlight the importance of information processing speed in understanding real-world implications of pathological and non-pathological cognitive aging. Information processing speed mediated all relationships between executive functioning and adaptive functioning. Further investigation is warranted into the importance of processing speed in explaining associations of other cognitive domains with adaptive functioning.

Are you more impulsive with age? Examining age, marital status, and gender on cognitive ageing

Understanding non-pathological cognitive aging processes remains a public health goal and research priority. Age-associated cognitive aging is a normal human process, however, individual differences may aid in the mitigation of cognitive aging. Assessing the role of certain protective factors (i.e., age, marital status, and gender) that influence age-related cognitive aging is imperative to slow down the progression of unwarranted cognitive aging. Participants aged over 18 (N = 123; 97 females and 26 males) recruited from Sydney, New South Wales, and Gold Coast, Queensland, completed an online neuropsychological test battery with computer-administered tasks, assessing impulsivity and working memory, which were entered as dependent variables. A 3(Age Group: 18–27 years; 28–61 years; 62+ years) x2(Marital Status: married; single) x2(Gender: male; female) Multivariate Analysis of Covariance (MANCOVA) design was used to examine the relationship between age, marital status, and gender (entered as independent variables) on cognitive aging. Participants’ total scores from psychometrically sound measures assessing depressive symptomology, personal wellbeing, resilience, and social network engagement, were entered as covariates. No significant effects were found from the independent variables included in the MANCOVA. A significant covariate effect for resilience and depressive symptomology on impulsivity was found. A multiple regression analysis was performed on the significant covariates, and revealed increased resilience and depressive symptomology to significantly predict greater impulsivity.

The Role of Resting-State Network Functional Connectivity in Cognitive Aging.

Aging is associated with disruptions in the resting-state functional architecture of the brain. Previous studies have primarily focused on age-related declines in the default mode network (DMN) and its implications in Alzheimer’s disease. However, due to mixed findings, it is unclear if changes in resting-state network functional connectivity are linked to cognitive decline in healthy older adults. In the present study, we evaluated the influence of intra-network coherence for four higher-order cognitive resting-state networks on a sensitive measure of cognitive aging (i.e., NIH Toolbox Fluid Cognition Battery) in 154 healthy older adults with a mean age of 71 and education ranging between 12 years and 21 years (mean = 16). Only coherence within the cingulo-opercular network (CON) was significantly related to Fluid Cognition Composite scores, explaining more variance in scores than age and education. Furthermore, we mapped CON connectivity onto fluid cognitive subdomains that typically decline in advanced age. Greater CON connectivity was associated with better performance on episodic memory, attention, and executive function tasks. Overall, the present study provides evidence to propose CON coherence as a potential novel neural marker for nonpathological cognitive aging.

Underappreciated Roles of the Translocase of the Outer and Inner Mitochondrial Membrane Protein Complexes in Human Disease

Mitochondria are critical for cellular survival, and for their proper functioning, translocation of ∼1500 proteins across the mitochondrial membranes is required. The translocase of the outer (TOMM) and inner mitochondrial membrane (TIMM) complexes are major components of this translocation machinery. Through specific processes, preproteins and other molecules are imported, translocated, and directed to specific mitochondrial compartments for their function. In this study, we review the association of subunits of these complexes with human disease. Pathogenic mutations have been identified in the TIMM8A (DDP) and DNAJC19 (TIMM14) genes and are linked to Mohr-Tranebjærg syndrome and dilated cardiomyopathy syndrome (with and without ataxia), respectively. Polymorphisms in TOMM40 have been associated with Alzheimer's disease, frontotemporal lobar degeneration, Parkinson's disease with dementia, dementia with Lewy bodies, nonpathological cognitive aging, and various cardiovascular-related traits. Furthermore, reduced protein expression levels of several complex subunits have been associated with Parkinson's disease, Meniere's disease, and cardiovascular disorders. However, increased mRNA and protein levels of complex subunits are found in cancers. This review highlights the importance of the mitochondrial import machinery in human disease and stresses the need for further studies. Ultimately, this knowledge may prove to be critical for the development of therapeutic modalities for these conditions.

APOE ɛ4, rs405509, and rs440446 promoter and intron-1 polymorphisms and dementia risk in a cohort of elderly Finns-Helsinki Birth Cohort Study.

We tested if the ε4 major isoform of the APOE gene and rs405509 and rs440446 promoter and intron-1 polymorphisms predicted risk of any dementia or Alzheimer's disease with diagnoses derived from the Hospital Discharge and Causes of Death Registers in 1453 participants of the Helsinki Birth Cohort Study. We used Cox proportional hazard models adjusted for sex, year of birth, maximum lifetime occupational status and education, and diagnoses of stroke, coronary heart disease, mood disorders, and depressive symptoms. APOE ε4 predicted higher risk of any dementia (hazard ratios >3.68; 95% confidence interval [CI] 1.76, 7.70) across all statistical models, and when adjusted for rs405509 and rs440446. The number of minor alleles in rs405509 or rs440446 was not associated with dementia risk (hazard ratios<1.43; 95% CI 0.87, 2.36). As rs405509 or rs440446 has been associated with nonpathological cognitive aging in this and other cohorts independent of the APOE major isoforms, these findings lend credence that APOE locus may be linked with dementia risk and nonpathological cognitive aging via separate mechanisms.

Retinal microvascular network geometry and cognitive abilities in community-dwelling older people: The Lothian Birth Cohort 1936 study

AimTo examine the relationship between retinal vascular morphology and cognitive abilities in a narrow-age cohort of community-dwelling older people.MethodsDigital retinal images taken at age ∼73 years from 683 participants of...

Retinal vascular fractal dimension, childhood IQ, and cognitive ability in old age: the Lothian Birth Cohort Study 1936.

PurposeCerebral microvascular disease is associated with dementia. Differences in the topography of the retinal vascular network may be a marker for cerebrovascular disease. The association between cerebral microvascular state and non-pathological cognitive ageing is less clear, particularly because studies are rarely able to adjust for pre-morbid cognitive ability level. We measured retinal vascular fractal dimension (D f) as a potential marker of cerebral microvascular disease. We examined the extent to which it contributes to differences in non-pathological cognitive ability in old age, after adjusting for childhood mental ability.MethodsParticipants from the Lothian Birth Cohort 1936 Study (LBC1936) had cognitive ability assessments and retinal photographs taken of both eyes aged around 73 years (n = 648). IQ scores were available from childhood. Retinal vascular D f was calculated with monofractal and multifractal analysis, performed on custom-written software. Multiple regression models were applied to determine associations between retinal vascular D f and general cognitive ability (g), processing speed, and memory.ResultsOnly three out of 24 comparisons (two eyes × four D f parameters × three cognitive measures) were found to be significant. This is little more than would be expected by chance. No single association was verified by an equivalent association in the contralateral eye.ConclusionsThe results show little evidence that fractal measures of retinal vascular differences are associated with non-pathological cognitive ageing.

Polygenic Risk for Alzheimer's Disease is not Associated with Cognitive Ability or Cognitive Aging in Non-Demented Older People

Alzheimer's disease (AD) and non-pathological cognitive aging have phenotypic similarities which may be influenced by an overlapping set of genetic variants. Genome-wide complex trait analysis estimates that common genetic variants account for about 24% of the variation contributing to liability for AD. It is also estimated that 24% of the variance of non-pathological cognitive aging is accounted for by common single nucleotide polymorphisms. However, although the APOE locus is associated with both AD and cognitive aging, it is not known to what extent other common genetic variants, with smaller effect sizes that influence both, overlap. We test the hypothesis that polygenic risk for AD is associated with cognitive ability and cognitive change in about 3,000 non-demented older people (Cognitive Ageing Genetics England and Scotland-CAGES-consortium). We found no significant association of polygenic risk for AD with cognitive ability or cognitive change in CAGES, indicating that the genetic etiologies of AD and non-pathological cognitive decline differ.

A genome-wide association study implicates the APOE locus in nonpathological cognitive ageing

Cognitive decline is a feared aspect of growing old. It is a major contributor to lower quality of life and loss of independence in old age. We investigated the genetic contribution to individual differences in nonpathological cognitive ageing in five cohorts of older adults. We undertook a genome-wide association analysis using 549 692 single-nucleotide polymorphisms (SNPs) in 3511 unrelated adults in the Cognitive Ageing Genetics in England and Scotland (CAGES) project. These individuals have detailed longitudinal cognitive data from which phenotypes measuring each individual's cognitive changes were constructed. One SNP--rs2075650, located in TOMM40 (translocase of the outer mitochondrial membrane 40 homolog)--had a genome-wide significant association with cognitive ageing (P=2.5 × 10(-8)). This result was replicated in a meta-analysis of three independent Swedish cohorts (P=2.41 × 10(-6)). An Apolipoprotein E (APOE) haplotype (adjacent to TOMM40), previously associated with cognitive ageing, had a significant effect on cognitive ageing in the CAGES sample (P=2.18 × 10(-8); females, P=1.66 × 10(-11); males, P=0.01). Fine SNP mapping of the TOMM40/APOE region identified both APOE (rs429358; P=3.66 × 10(-11)) and TOMM40 (rs11556505; P=2.45 × 10(-8)) as loci that were associated with cognitive ageing. Imputation and conditional analyses in the discovery and replication cohorts strongly suggest that this effect is due to APOE (rs429358). Functional genomic analysis indicated that SNPs in the TOMM40/APOE region have a functional, regulatory non-protein-coding effect. The APOE region is significantly associated with nonpathological cognitive ageing. The identity and mechanism of one or multiple causal variants remain unclear.

From cell to cognition: can changes in telomere length indicate patterns of cognitive aging?

The review by Zhu et al. [1] appearing in Clinical Science earlier this year is one of several excellent recent review papers on telomeres and aging that, taken together, point to the importance of bridging the gap between research on cellular and cognitive aging. Researchers who study trends in aging across societies have shown that some factors can affect longevity. For instance, Fraser and Shavlik [2] have shown that optimal choices regarding diet, physical exercise, cigarette smoking, body weight and hormone replacement therapy in women had a significant influence on longevity in Californian Adventists. They followed up 34192 California Adventists from 1976 to 1988 and found higher life expectancy in this group compared with other white Californians by 7.28 years in men and 4.42 years in women. Other large cohort studies conducted in different countries have also reported that life expectancy can be extended by up to 18 years when associated, for instance, with physical exercise and refraining from smoking [3]. These clearly substantial gains in life expectancy are probably worthwhile only if the extended life span also matches the brain span. This is becoming a prominent issue as the population worldwide rapidly ages.The issue of how to study the impact of biological age on non-pathological cognitive aging is tightly related to the question of when cognitive decline begins. Theories on cognitive decline typically assume that deterioration occurs at older age. However, not all researchers agree with this assumption, presenting evidence that indicates that declines in speed processing, reasoning, memory, executive function, language and so on actually begin in our 20s and 30s (for example, see [4]). Although cognitive decline is part of normal aging, individual differences in how we age may reveal how genetics, general health, diet, lifestyle and other factors affect cognitive aging.When it comes to the role of biological age in cognitive aging, one particularly interesting question is whether telomere shortening is a marker for cognitive aging. Telomeres and their associated proteins have in particular been linked with cancer, cardiovascular disease and neurodegenerative diseases, but apart from a broad conclusion that telomere shortening is a marker of cellular aging and its association with the risk of Alzheimer's disease, chronic stress exposure and depression, little is known about how exactly changes in telomere length affect cognition and emotion in the course of aging. Studies that have been conducted on this topic so far typically report that telomere shortening is a distal correlate of cognitive decline [5]. However, some researchers have reported different findings, indicating that telomere length is not a reliable predictor of decline or mortality (for example, see [6]). These controversial findings on the impact of telomere length on cognitive aging clearly indicate a need for studying this issue in more detail. For instance, one could investigate whether different patterns of cognitive aging are associated with different patterns of telomere shortening. Ideally, examining the relationship between telomere length and cognition should be based on measuring telomeres in neural tissue. Although telomere length in leucocytes may act as a surrogate marker for telomere length in other tissues, it may not be applicable to all cell types. However, Takubo et al. [7] measured telomere lengths in five organs (cerebral cortex, myocardium, liver, renal cortex and spleen) in a large number of autopsy cases and found “a robust correlation of telomere length among these organs in any given individual”. Their data also suggest a specific telomere length in each person. Given these findings, it seems appropriate to investigate the relationship between the peripheral blood leucocyte telomere length and cognitive functions.If the hypothesis on the impact of telomere shortening on cognitive performance holds, we can expect to find different patterns of non-pathological cognitive decline associated with differences in telomere shortening. Finding out exactly what types of telomere length–cognitive decline patterns exist across different age groups would represent an important step in bridging the gap between the research on cellular and cognitive aging.

APOE E4 status predicts age-related cognitive decline in the ninth decade: longitudinal follow-up of the Lothian Birth Cohort 1921

Carriers of the APOE E4 allele have an increased risk of developing Alzheimer's disease. However, it is less clear whether APOE E4 status may also be involved in non-pathological cognitive ageing. The present study investigated the associations between APOE genotypes and cognitive change over 8 years in older community-dwelling individuals. APOE genotype was determined in 501 participants of the Lothian Birth Cohort 1921, whose intelligence had been measured in childhood in the Scottish Mental Survey 1932. A polymorphic variant of TOMM40 (rs10524523) was included to differentiate between the effects of the APOE E3 and E4 allelic variants. Cognitive performance on the domains of verbal memory, abstract reasoning and verbal fluency was assessed at mean age 79 years (n=501), and again at mean ages of 83 (n=284) and 87 (n=187). Using linear mixed models adjusted for demographic variables, vascular risk factors and IQ at age 11 years, possession of the APOE E4 allele was associated with a higher relative rate of cognitive decline over the subsequent 8 years for verbal memory and abstract reasoning. Individuals with the long allelic variant of TOMM40, which is linked to APOE E4, showed similar results. Verbal fluency was not affected by APOE E4 status. APOE E2 status was not associated with change in cognitive performance over 8 years. In non-demented older individuals, possession of the APOE E4 allele predicted a higher rate of cognitive decline on tests of verbal memory and abstract reasoning between 79 and 87 years. Thus, possession of the APOE E4 allele may not only predispose to Alzheimer's disease, but also appears to be a risk factor for non-pathological decline in verbal memory and abstract reasoning in the ninth decade of life.

A General Factor of Brain White Matter Integrity Predicts Information Processing Speed in Healthy Older People

Human white matter integrity has been related to information processing speed, but it is unknown whether impaired integrity results from localized processes or is a general property shared across white matter tracts. Based on diffusion MRI scans of 132 healthy individuals with a narrow age range around 72 years, the integrity of eight major white matter tracts was quantified using probabilistic neighborhood tractography. Principal component analyses (PCAs) were conducted on the correlations between the eight tracts, separately for four tract-averaged integrity parameters: fractional anisotropy, mean diffusivity, and radial and axial diffusivity. For all four parameters, the PCAs revealed a single general factor explaining approximately 45% of the individual differences across all eight tracts. Individuals' scores on a general factor that captures the common variance in white matter integrity had significant associations with a general factor of information processing speed for fractional anisotropy (r = -0.24, p = 0.007) and radial diffusivity (r = 0.21, p = 0.016), but not with general intelligence or memory factors. Individual tracts showed no associations beyond what the common integrity factor explained. Just as different types of cognitive ability tests share much of their variance, these novel findings show that a substantial amount of variance in white matter integrity is shared between different tracts. Therefore, impaired cortical connection is substantially a global process affecting various major tracts simultaneously. Further studies should investigate whether these findings relate more to the role of tract integrity and information processing speed in nonpathological cognitive aging or in lifelong-stable processes.

Apolipoprotein e gene variability and cognitive functions at age 79: a follow-up of the Scottish mental survey of 1932.

Apolipoprotein E (APOE) genotype is a possible influence on nonpathological cognitive aging. The authors studied 462 community-dwelling, 79-year-old people born in 1921, whose childhood IQ had been assessed in the Scottish Mental Survey of 1932 (Scottish Council for Research in Education, 1933). Adjusting for sex, childhood IQ, and self-reported illnesses, the authors found that those with an APOE e4 allele had significantly lower Wechsler Logical Memory (D. Wechsler, 1987) scores than those without an e4 allele. Those people with APOE s2/e3 genotypes had significantly higher Wechsler Logical Memory scores than e3/s3, who were significantly higher than e3/e4. Neither nonverbal reasoning nor verbal fluency were affected. In this sample, APOE genotype contributed to verbal memory in old age.