Age-associated Cognitive Decline Research Articles

Mouse Models for Studying Hippocampal Adult Neural Stem Cell Biology.

The mammalian hippocampus shows a remarkable capacity for continued neurogenesis throughout life. Newborn neurons, generated by the radial neural stem cells (NSCs), are important for learning and memory as well as mood control. During aging, the number and responses of NSCs to neurogenic stimuli diminish, leading to decreased neurogenesis and age-associated cognitive decline and psychiatric disorders. Thus, adult hippocampal neurogenesis has been the subject of intense investigation, generating both excitement and controversy. Identifying the core molecular machinery responsible for NSC preservation is of fundamental importance if we are to use neurogenesis to halt or reverse hippocampal age-related pathology. Here, we briefly overview themost frequently used mouse models to study hippocampal neurogenesis and then focus on a unique mouse model that allows NSC-specific studies based on their unique expression of lunatic fringe (Lfng). The Lfng-eGFP and Lfng(BAC)-CreERT2;RCL-tdT transgenic mice provide us with an excellent tool to resolve long-standing questions regarding the properties of NSCs, such as their specific molecular composition, potency, and plasticity, in isolation from any other cell in the hippocampal neurogenic niche.

Reversing cognitive-decline in older adults in an open-label clinical trial: novel mechanisms and the role of GlyNAC

Age-associated cognitive-decline is an important risk factor for Alzheimer’s disease, but interventions are lacking. We conducted an open-label trial to test our hypotheses on whether: (1) compared to 8 healthy young adults (25y), 8 ‘healthy’ older adults (74y) have cognitive decline, decreased glucose availability for the brain due to mitochondrial dysfunction, elevated insulin-resistance, oxidative-stress and elevated inflammation; (2) supplementing glycine and N-acetylcysteine (GlyNAC) for 24-weeks corrects deficiency of the endogenous-antioxidant Glutathione and improves these defects, and thereby cognition; (3) stopping GlyNAC supplementation for 12-weeks results in a decline in accrued benefits. Outcome measures included cognitive testing (Montreal cognitive assessment; trail-making tests; verbal-fluency tests; digital-symbol substitution-test), mitochondrial fuel-oxidation, RBC-Glutathione concentrations, plasma oxidative-stress, insulin-resistance and inflammation, and tracer-studies to measure glucose metabolism. Results validated our hypotheses and showed that GlyNAC-supplementation corrected these defects and improved cognition. This trial suggests that supplementing GlyNAC may be important for improving/preventing age-associated cognitive-decline in older adults.

Small molecule cognitive enhancer reverses age-related memory decline in mice.

With increased life expectancy, age-associated cognitive decline becomes a growing concern, even in the absence of recognizable neurodegenerative disease. The integrated stress response (ISR) is activated during aging and contributes to age-related brain phenotypes. We demonstrate that treatment with the drug-like small-molecule ISR inhibitor ISRIB reverses ISR activation in the brain, as indicated by decreased levels of activating transcription factor 4 (ATF4) and phosphorylated eukaryotic translation initiation factor eIF2. Furthermore, ISRIB treatment reverses spatial memory deficits and ameliorates working memory in old mice. At the cellular level in the hippocampus, ISR inhibition (i) rescues intrinsic neuronal electrophysiological properties, (ii) restores spine density and (iii) reduces immune profiles, specifically interferon and T cell-mediated responses. Thus, pharmacological interference with the ISR emerges as a promising intervention strategy for combating age-related cognitive decline in otherwise healthy individuals.

Predicting non-elective hospital readmission or death using a composite assessment of cognitive impairment and frailty in elderly inpatients with cardiovascular diseases

Abstract Background Cardiovascular disease (CVD) and related complications are significant healthcare problems in the growing elderly population. Metabolic factors are the predominant risk factors for CVD, sedentary behaviour and physical inactivity are major modifiable risk factors for CVD. Age-associated cognitive decline and impairment are associated with an increased mortality. Cognitive and physical components of frailty have pathophysiologic rationale as risk factors for CVD. There is a clinical need to identify more practical screens that can assist us to definite cognitive impairment and physical frailty, then to determine which patients with CVD are at high risk of adverse outcomes, early management of these high-risk patients can reduce readmission rates, healthcare spending, and improve quality of care. Purpose We aimed to assess the utility of a combination developed using the mini-mental state examination + clock drawing test and the Fried phenotype for predicting non-elective hospital readmission or death within 6-month in elderly inpatients with CVD. Methods A single center prospective cohort was conducted between September 2018 and February 2019. Inpatients aged 65 years or older were recruited. All enrolled patients received a comprehensive geriatric assessment during hospitalization. The Kaplan-Meier curves were used to estimate the cumulative incidence of events. The multivariate Cox regression model was used to analyze the association between frailty and cognitive status and the non-elective hospital readmission or death. Results A total of 542 patients were included; and a total of 113 patients (20.9%) died or were readmitted at 6-month. Overall 20% screened positive for cognitive impairment, including 8% were cognitive impairment combined with physical frailty, which were more older, more common in women and non-married group, had a lower education and a higher risk of malnutrition. Frail participants with normal (hazard ratio [HR]: 1.73, 95% confidence intervals [CI]: 1.06–2.82, P=0.028) and impaired cognition (HR: 2.50, 95% CI: 1.27–4.91, P=0.008) had a higher risk of non-elective hospital readmission or death than robust patients, after adjustment for age, sex, education level, marital status, the presence of diabetes mellitus, heart failure, and previous stroke. Conclusions The presence of physical frailty and cognitive frailty were powerful predictors of non-elective hospital readmission or death in elderly inpatients with CVD, and taking cognitive impairment into account in the frailty model may allow better prediction of adverse outcomes of frailty in the short time. Kaplan-Meier survival curves Funding Acknowledgement Type of funding source: Public Institution(s). Main funding source(s): Beijing Municipal Science & Technology Commission, Chinese Academy of Medical Sciences

Pattern Recognition to Objectively Differentiate the Etiology of Cognitive Decline: Analysis of the Impact of Stroke and Alzheimer’s Disease

Background: Undetected Alzheimer’s disease (AD) and stroke neuropathology is believed to account for a large proportion of decline in cognitive performance that is attributed to normal aging. This study examined the amount of variance in age-related cognitive change that is accounted for by AD and stroke using a novel pattern recognition protocol. Method: Secondary analyses of data collected for the Health and Retirement Study (N = 17,579) were used to objectively characterize patterns of cognitive decline associated with AD and stroke. The rate of decline in episodic memory and orientation was the outcome of interest, while algorithms indicative of AD and stroke pathology were the predictors of interest. Results: The average age of the sample was 67.54 ± 10.45 years at baseline, and they completed, on average, 14.20 ± 3.56 years of follow-up. After adjusting for demographics, AD and stroke accounted for approximately half of age-associated decline in cognition (51.07–55.6% for orientation and episodic memory, respectively) and explained variance attributed to random slopes in longitudinal multilevel models. Discussion: The results of this study suggested that approximately half of the cognitive decline usually attributed to normal aging are more characteristic of AD and stroke.

Capacity-limited resources are used for managing sensory degradation and cognitive demands: Implications for age-related cognitive decline and dementia

Older adults with sensory deficits are at higher risk for developing cognitive impairment and dementia. It remains uncertain if the link between sensory and cognitive functioning reflects a common underlying factor or whether sensory deficits directly undermine cognitive processing. This issue was addressed by comparing behavioral and event-related potential responses of 16 older and 16 young adults during a working memory paradigm that parametrically varied visual contrast level (100%, 69%, 22%) and cognitive task load (1–4 face pairs to remember). The groups were well-matched on demographic and neuropsychological variables; however, older adults had worse corrected visual acuity and contrast sensitivity. The study's major finding was an interaction between visual contrast level and task load on performance accuracy (percent of correct responses) and the allocation of resources for decision making/updating (as indexed by the P3b amplitude). The negative impact of degraded visual processing was greater at higher levels of task demand. This result suggests that a shared pool of processing resources is used to mediate cognitive operations and manage the processing of degraded images. The study also demonstrated that older adults reach the limits of their processing capacity at lower levels of task load. The interaction between visual degradation and task demand, accompanied by the age-related reduction in available processing resources highlight the increased vulnerability of older adults. Specifically, an age-associated decline in visual acuity and contrast sensitivity puts older adults at risk for depleting their limited resources in the service of processing degraded visual images. The results of this study underscore the potential importance of optimizing vision in older adults to help mitigate age-associated cognitive decline.

Neurophysiological mechanisms and perspective for the use of dual tasks inrecovering cognitive function after cardiac surgery

This review encompasses current trends regarding the use of dual tasks in recovering of cognitive functions in patients with ageassociated cognitive decline, traumatic brain injury and brain ischemia. The dual task represents a cognitive rehabilitation approach which implies the simultaneous execution of physical activity (walking, running or postural training) and cognitive tasks (internal counting, short-term memory and attention tasks, divergent tasks). Dual tasks with the simultaneous involvement of motor and cognitive functions are associated with specific features of brain activity and permit evaluation of the brain compensatory resources both in the normal state and in ageassociated cognitive decline or ischemic/ traumatic injury. The review also describes the basic neurophysiological mechanisms of the dual task-associated action on cognitive functions including transfer and interference. Performing of complex, multidirectional tasks provides a more efficient coordination of cognitive processes and improves the opportunities for successful cognitive functioning. The work underlines the high prevalence of cognitive impairment in cardiac surgery patients and shows the prospects of using dual tasks for the postoperative cognitive recovery. We assume that the rehabilitation using dual tasks involving brain areas providing executive control, working memory, attention and motor control can result in a pronounced cognitive recovery in cardiac surgery patients with cognitive impairment.

Extracellular vesicle biomarkers of Alzheimer's disease associated with sub-clinical cognitive decline in late middle age.

IntroductionNeuronal extracellular vesicle (nEV) tau and insulin signaling biomarkers may detect preclinical Alzheimer's disease and age‐associated cognitive decline.MethodsThis case‐control study used repeated serum samples from 73 cognitively declining and 73 stable Wisconsin Registry for Alzheimer's Prevention participants (62.4 ± 6.3 years old). We immunocaptured nEVs; measured tau and insulin signaling biomarkers; and examined biomarker differences by group, their performance in group classification in training and test datasets (97, 49 individuals, respectively), and whether they predict cognitive performance change.ResultsDeclining compared to stable individuals showed higher baseline total, p231‐, and p181‐tau with older age and higher annualized change for p‐IR and p‐IGF‐1R. Combining biomarkers classified decliners with 94% area under the curve (AUC), 86.0% sensitivity and 86.7% specificity, in training data, and 75% AUC, 71.4% sensitivity, and 77.3% specificity, in test data. Insulin biomarkers predicted cognitive performance change prospectively.DiscussionCombining nEV biomarkers can identify individuals with age‐associated cognitive decline.

Comparison of Amyloid Positivity Rate and Accumulation Pattern between Amnestic and Non-Amnestic Type Mild Cognitive Impairment.

ObjectiveWe aimed to compare cerebral beta-amyloid protein (Aβ) positivity rate and amyloid accumulation pattern on amyloid positron emission tomography (PET) between mild cognitive impairment (MCI) subtypes, i.e. amnestic mild cognitive impairment (aMCI) and non-amnestic mild cognitive impairment (naMCI). MethodsThe study participants were 34 naMCI patients and age-, sex- and education-matched 68 aMCI patients (1:2 ratio) who visited the Dementia and Age-Associated Cognitive Decline Clinic of the Seoul National University Hospital. All participants received comprehensive clinical and neuropsychological assessments and [18F] florbetaben PET. ResultsAβ positivity rate of naMCI group (26.5%) was significantly lower than that of aMCI group (64.7%). Among Aβ positive individuals, there was no difference in Aβ accumulation pattern between naMCI and aMCI. ConclusionThe findings suggest that MCI subtypes based on impaired cognitive domains have a differential association with brain Aβ deposition, a core pathology of AD. Amnestic subtype of MCI are more closely associated with cerebral Aβ deposition compared to non-amnestic subtype. In contrast, the pattern of amyloid deposition does not appear to have any difference between the subtypes.

Sources, Production, and Clinical Treatments of Milk Fat Globule Membrane for Infant Nutrition and Well-Being.

Research on milk fat globule membrane (MFGM) is gaining traction. The interest is two-fold; on the one hand, it is a unique trilayer structure with specific secretory function. On the other hand, it is the basis for ingredients with the presence of phospho- and sphingolipids and glycoproteins, which are being used as food ingredients with valuable functionality, in particular, for use as a supplement in infant nutrition. This last application is at the center of this Review, which aims to contribute to understanding MFGM’s function in the proper development of immunity, cognition, and intestinal trophism, in addition to other potential effects such as prevention of diseases including cardiovascular disease, impaired bone turnover and inflammation, skin conditions, and infections as well as age-associated cognitive decline and muscle loss. The phospholipid composition of MFGM from bovine milk is quite like human milk and, although there are some differences due to dairy processing, these do not result in a chemical change. The MFGM ingredients, as used to improve the formulation in different clinical studies, have indeed increased the presence of phospholipids, sphingolipids, glycolipids, and glycoproteins with the resulting benefits of different outcomes (especially immune and cognitive outcomes) with no reported adverse effects. Nevertheless, the precise mechanism(s) of action of MFGM remain to be elucidated and further basic investigation is warranted.

Aging with Toxoplasma gondii results in pathogen clearance, resolution of inflammation, and minimal consequences to learning and memory

Persistent inflammation has been identified as a contributor to aging-related neurodegenerative disorders such as Alzheimer’s disease. Normal aging, in the absence of dementia, also results in gradual cognitive decline and is thought to arise, in part, because of a chronic pro-inflammatory state in the brain. Toxoplasma gondii is an obligate intracellular parasite that establishes a persistent, asymptomatic infection of the central nervous system (CNS) accompanied by a pro-inflammatory immune response in many of its hosts, including humans and rodents. Several studies have suggested that the inflammation generated by certain strains of T. gondii infection can be neuroprotective in the context of a secondary insult like beta-amyloid accumulation or stroke. Given these neuroprotective studies, we hypothesized that a prolonged infection with T. gondii may protect against age-associated decline in cognition. To test this hypothesis, we infected young adult mice with either of two genetically distinct, persistent T. gondii strains (Prugniaud/type II/haplogroup 2 and CEP/type III/haplogroup 3) and monitored mouse weight, survival, and learning and memory over the ensuing 20 months. At the end of the study, we evaluated CNS inflammation and parasite burden in the surviving mice. We found that parasite infection had no impact on age-associated decline in learning and memory and that by 20 months post infection, in the surviving mice, we found no evidence of parasite DNA, cysts, or inflammation in the CNS. In addition, we found that mice infected with type III parasites, which are supposed to be less virulent than the type II parasites, had a lower rate of long-term survival. Collectively, these data indicate that T. gondii may not cause a life-long CNS infection. Rather, parasites are likely slowly cleared from the CNS and infection and parasite clearance neither positively nor negatively impacts learning and memory in aging.

Accumulation and activation of group 2 innate lymphoid cells in the aged brain alleviate aging associated cognitive decline

Abstract Increasing evidence has challenged the traditional view about the immune privilege of the brain, but the precise roles of immune cells in regulating brain physiology and function remain poorly understood. Here we report that tissue-resident group 2 innate lymphoid cells (ILC2) accumulate in the choroid plexus of aged brains. ILC2 in the aged brain are long-lived, relatively resistant to cellular senescence and exhaustion, and are capable of switching between cell cycle dormancy and proliferation. They are functionally quiescent at homeostasis but can be activated by IL-33 to produce large amounts of type-2 cytokines and other effector molecules in vitro and in vivo. Intracerebroventricular transfer of activated ILC2 revitalized the aged brain and enhanced the cognitive function of aged mice. Administration of IL-5, a major ILC2 product, was sufficient to repress aging-associated neuroinflammation and alleviate aging-associated cognitive decline. Targeting ILC2 in the aged brain may provide new avenues to combat aging-associated neurodegenerative disorders.

Oxidative Stress in Cognitive and Epigenetic Aging: A Retrospective Glance.

Brain aging is the critical and common factor among several neurodegenerative disorders and dementia. Cellular, biochemical and molecular studies have shown intimate links between oxidative stress and cognitive dysfunction during aging and age-associated neuronal diseases. Brain aging is accompanied by oxidative damage of nuclear as well as mitochondrial DNA, and diminished repair. Recent studies have reported epigenetic alterations during aging of the brain which involves reactive oxygen species (ROS) that regulates various systems through distinct mechanisms. However, there are studies which depict differing roles of reactive oxidant species as a major factor during aging. In this review, we describe the evidence to show how oxidative stress is intricately linked to age-associated cognitive decline. The review will primarily focus on implications of age-associated oxidative damage on learning and memory, and the cellular events, with special emphasis on associated epigenetic machinery. A comprehensive understanding of these mechanisms may provide a perspective on the development of potential therapeutic targets within the oxidative system.

Healthy Lifestyle and Cognition: Interaction between Diet and Physical Activity.

This review discusses current research on the impact of specific dietary patterns and exercise, both individually and combined, on cognitive function in older adults. Observational evidence generally supports a relationship between diet adherence and positive cognitive outcomes related to memory, executive function, and risk for cognitive impairment; however, randomized controlled trials (RCTs) are limited. Exercise research is more extensive, showing improvements in cognitive performance after exercise interventions regardless of baseline cognitive status and noting lower incidences of cognitive impairment in people who engage in regular physical activity. Evidence supports adherence to specific dietary patterns and a combination of aerobic and resistance exercise as an effective approach to mitigate age-associated cognitive decline. Further research on older adults at various stages of cognitive decline, as well as longer-term RCTs, will help determine the best clinical markers of early cognitive dysfunction, and the effectiveness of early lifestyle intervention on cognitive function.

Meta-analysis of human prefrontal cortex reveals activation of GFAP and decline of synaptic transmission in the aging brain

Despite ongoing research efforts, mechanisms of brain aging are still enigmatic and need to be elucidated for a better understanding of age-associated cognitive decline. The aim of this study is to investigate aging in the prefrontal cortex region of human brain in a meta-analysis of transcriptome datasets. We analyzed 591 gene expression datasets pertaining to female and male human prefrontal cortex biopsies of distinct ages. We used hierarchical clustering and principal component analysis (PCA) to determine the influence of sex and age on global transcriptome levels. In sex-specific analysis we identified genes correlating with age and differentially expressed between groups of young, middle-aged and aged. Pathways and gene ontologies (GOs) over-represented in the resulting gene sets were calculated. Potential causal relationships between genes and between GOs were explored employing the Granger test of gene expression time series over the range of ages. The most outstanding results were the age-related decline of synaptic transmission and activated expression of glial fibrillary acidic protein (GFAP) in both sexes. We found an antagonistic relationship between calcium/calmodulin dependent protein kinase IV (CAMK4) and GFAP which may include regulatory mechanisms involving cAMP responsive element binding protein (CREB) and mitogen-activated protein kinase (MAPK, alias ERK). Common to both sexes was a decline in synaptic transmission, neurogenesis and an increased base-level of inflammatory and immune-related processes. Furthermore, we detected differences in dendritic spine morphogenesis, catecholamine signaling and cellular responses to external stimuli, particularly to metal (Zinc and cadmium) ions which were higher in female brains.

Functional dedifferentiation of the brain during healthy aging.

Nonpathological aging is associated with significant cognitive deficits. Thus, the underlying neurobiology of aging-associated cognitive decline warrants investigation. In a recent study, Chong et al. (Chong JSX, Ng KK, Tandi J, Wang C, Poh J-H, Lo JC, Chee MWL, Zhou JH. J Neurosci 39: 5534-5550, 2019) provided insights into the association between cognitive decline and the loss of functional specialization in the brains of older adults. Here, we introduce the novel graph theoretical approach utilized and discuss the significance of their findings and broader implications on aging. We also provide alternate perspectives of their findings and suggest directions for future work.

Activation of group 2 innate lymphoid cells alleviates aging-associated cognitive decline.

Increasing evidence has challenged the traditional view about the immune privilege of the brain, but the precise roles of immune cells in regulating brain physiology and function remain poorly understood. Here, we report that tissue-resident group 2 innate lymphoid cells (ILC2) accumulate in the choroid plexus of aged brains. ILC2 in the aged brain are long-lived, are relatively resistant to cellular senescence and exhaustion, and are capable of switching between cell cycle dormancy and proliferation. They are functionally quiescent at homeostasis but can be activated by IL-33 to produce large amounts of type 2 cytokines and other effector molecules in vitro and in vivo. Intracerebroventricular transfer of activated ILC2 revitalized the aged brain and enhanced the cognitive function of aged mice. Administration of IL-5, a major ILC2 product, was sufficient to repress aging-associated neuroinflammation and alleviate aging-associated cognitive decline. Targeting ILC2 in the aged brain may provide new avenues to combat aging-associated neurodegenerative disorders.

Abstract 109: Depletion of Microglia Does Not Improve Functional Outcomes in Aged Mice After Transient Focal Ischemia

Introduction: With aging, microglia acquire a dysfunctional phenotype characterized by dystrophic morphology, impaired phagocytosis, reduced motility, and an exaggerated response to injury. Microglia become pathologically activated with aging and play a detrimental role in age-associated cognitive decline and neurodegenerative diseases. Older mice exhibit a differential response to stroke and have worse outcomes despite smaller infarcts compared to young mice. Microglia from aged mice produce higher levels of reactive oxidative species and have an exaggerated inflammatory response after ischemic stroke. Hypothesis: We hypothesized that ablation of microglia would reduce the exaggerated neuroinflammatory responses in aged mice and loss of microglia would improve early recovery after ischemic stroke. Aged (18-19 months) male mice were fed a control chow diet (CD) or PLX5622 chow diet (PLXD) for 21 days. On day 22, 60-minute middle cerebral artery occlusion (MCAo) or sham surgery was performed. Twenty-four hours after MCAo, neurological deficit scores (NDS) and immunohistochemistry assessments, as well as flow cytometry, were performed. Results: There was a significant reduction in Iba1 + cells in striatum and cortex of the aged mice with PLX treatment: day 7 (p<0.05), day 14 (p<0.001), and day 21 (p<0.001) vs day 0. Twenty-four hours after MCAo, the NDS were not different between CD (3.0±0.18) and PLXD (2.92±0.21). However, an increase in infarct size was seen in the aged PLXD group compared to the aged CD group (p<0.05). After MCAo, there was an increase in infiltrating monocytes and neutrophils in both diet groups compared to their respective shams (p<0.05). However, an increase in infiltrating monocytes was observed in the PLXD MCAo vs. CD MCAo (p<0.0001) reflecting a differential monocyte response in animals without microglia. Additionally, a decrease in NeuN immunoreactivity was seen in the PLXD MCAo group compared to PLXD sham (p<0.01). GFAP + cells increased in PLXD sham group as compared to CD sham (p<0.05). Conclusions: Our results suggest that microglia are essential immune cells that surprisingly limit immune cell infiltration, decrease neuronal degeneration, and reduce neuroinflammation after ischemic stroke in aged mice.

Lifestyle Modifications and Nutritional Interventions in Aging-Associated Cognitive Decline and Alzheimer's Disease.

Alzheimer’s disease (AD) is a type of incurable neurodegenerative disease that is characterized by the accumulation of amyloid-β (Aβ; plaques) and tau hyperphosphorylation as neurofibrillary tangles (NFTs) in the brain followed by neuronal death, cognitive decline, and memory loss. The high prevalence of AD in the developed world has become a major public health challenge associated with social and economic burdens on individuals and society. Due to there being limited options for early diagnosis and determining the exact pathophysiology of AD, finding effective therapeutic strategies has become a great challenge. Several possible risk factors associated with AD pathology have been identified; however, their roles are still inconclusive. Recent clinical trials of the drugs targeting Aβ and tau have failed to find a cure for the AD pathology. Therefore, effective preventive strategies should be followed to reduce the exponential increase in the prevalence of cognitive decline and dementia, especially AD. Although the search for new therapeutic targets is a great challenge for the scientific community, the roles of lifestyle interventions and nutraceuticals in the prevention of many metabolic and neurodegenerative diseases are highly appreciated in the literature. In this article, we summarize the molecular mechanisms involved in AD pathology and the possible ameliorative action of lifestyle and nutritional interventions including diet, exercise, Calorie restriction (CR), and various bioactive compounds on cognitive decline and dementia. This article will provide insights into the role of non-pharmacologic interventions in the modulation of AD pathology, which may offer the benefit of improving quality of life by reducing cognitive decline and incident AD.

The Impact of Age, Gender, and Marital Status on Age-Associated Cognitive Decline

Age-associated cognitive decline is a normal, non-pathological and inevitable human occurrence. Therefore, it remains a research priority to assess the role of certain protective factors, such as age, gender, and marital status, that influence age-associated cognitive decline to intervene in the stemming of its progress and guide theory, policy, and practice. The study used a dissociative paradigm, using two measures to assess both short-term and visuo-spatial memory, to clarify the unestablished results of whether cognitive ageing occurs in one subsystem (i.e., modular) or across the whole brain (i.e., generalised). Participants (N = 126; 79 females and 46 males) from Sydney, New South Wales were recruited and divided into three age groups: 18 - 27, 27 - 62, and 62+. Participants completed an online questionnaire, with computer administered tasks, assessing visuo-spatial and short-term memory. A Multivariate Analysis of Covariance (MANCOVA) revealed no significant covariate effects; covariates entered included participants’ total scores from psychometrically established measures addressing engagement with social networks, depressive symptomology, personal wellbeing, and resilience. Consistent with previous findings, results from a Multivariate Analysis of Variance (MANOVA) supported the notion that being married is a protective factor in slowing down the progression of age-associated cognitive decline (i.e., visuo-spatial memory), in comparison to being single or in a de facto relationship. Older adults who were married performed lower on visuo-spatial memory tasks than younger adults. Support for the generalised model of ageing was revealed. Future directions and implications of the study’s findings indicate the need to maximise protective interventions for those who are single or in a de facto relationship, and the brain as a whole system, to prevent unwarranted cognitive decline.