Cognitive Decline In Normal Aging Research Articles

Pick a PACC: Comparing domain-specific and general cognitive composites in Alzheimer disease research.

We aimed to illustrate how complex cognitive data can be used to create domain-specific and general cognitive composites relevant to Alzheimer disease research. Using equipercentile equating, we combined data from the Charles F. and Joanne Knight Alzheimer Disease Research Center that spanned multiple iterations of the Uniform Data Set. Exploratory factor analyses revealed four domain-specific composites representing episodic memory, semantic memory, working memory, and attention/processing speed. The previously defined preclinical Alzheimer disease cognitive composite (PACC) and a novel alternative, the Knight-PACC, were also computed alongside a global composite comprising all available tests. These three composites allowed us to compare the usefulness of domain and general composites in the context of predicting common Alzheimer disease biomarkers. General composites slightly outperformed domain-specific metrics in predicting imaging-derived amyloid, tau, and neurodegeneration burden. Power analyses revealed that the global, Knight-PACC, and attention and processing speed composites would require the smallest sample sizes to detect cognitive change in a clinical trial, while the Alzheimer Disease Cooperative Study-PACC required two to three times as many participants. Analyses of cognition with the Knight-PACC and our domain-specific composites offer researchers flexibility by providing validated outcome assessments that can equate across test versions to answer a wide range of questions regarding cognitive decline in normal aging and neurodegenerative disease. (PsycInfo Database Record (c) 2024 APA, all rights reserved).

Atrophy of hippocampal subfields relates to memory decline during the pathological progression of Alzheimer's disease.

It has been well documented that atrophy of hippocampus and hippocampal subfields is closely linked to cognitive decline in normal aging and patients with mild cognitive impairment (MCI) and Alzheimer's disease (AD). However, evidence is still sparce regarding the atrophy of hippocampus and hippocampal subfields in normal aging adults who later developed MCI or AD. To examine whether atrophy of hippocampus and hippocampal subfields has occurred in normal aging before a diagnosis of MCI or AD. We analyzed structural magnetic resonance imaging (MRI) data of cognitively normal (CN, n = 144), MCI (n = 90), and AD (n = 145) participants obtained from the Alzheimer's Disease Neuroimaging Initiative. The CN participants were categorized into early dementia converters (CN-C) and non-converters (CN-NC) based on their scores of clinical dementia rating after an average of 36.2 months (range: 6-105 months). We extracted the whole hippocampus and hippocampal subfields for each participant using FreeSurfer, and analyzed the differences in volumes of hippocampus and hippocampal subfields between groups. We then examined the associations between volume of hippocampal subfields and delayed recall scores in each group separately. Hippocampus and most of the hippocampal subfields demonstrated significant atrophy during the progression of AD. The CN-C and CN-NC groups differed in the left hippocampus-amygdala transition area (HATA). Furthermore, the volume of presubiculum was significantly correlated with delayed recall scores in the CN-NC and AD groups, but not in the CN-C and MCI groups. Hippocampal subfield atrophy (i.e., left HATA) had occurred in cognitively normal elderly individuals before clinical symptoms were recognized. Significant associations of presubiculum with delayed recall scores in the CN-NC and AD groups highlight the essential role of the hippocampal subfields in both early dementia detection and AD progression.

Review articles (Meta-Analyses) effects of walking on cognitive function in individuals with mild cognitive impairment: a systematic review and meta-analysis

BackgroundMild cognitive impairment (MCI) is the stage between the expected cognitive decline of normal aging and the more serious decline of dementia. Previous studies have shown that regular exercise can improve cognition and physical performance in older adults. Walking is a low-technology and low-cost exercise that has been proven to improve cognition and mobility in healthy elderly individuals. However, no systematic review or meta-analysis has explored whether walking can improve cognitive function in older adults with MCI. This study aimed to explore the effects of walking interventions on cognitive functions in individuals with MCI.MethodsIn accordance with the PRISMA guidelines, MEDLINE, PubMed, SPORTDiscus, Cochrane Central Register of Controlled Trials, CINAHL, Web of Science, Airiti Library, and the National Digital Library of Theses and Dissertations in Taiwan were searched from inception to July 2023. Independent reviewers selected randomized clinical trials (RCT) that compared the effects of walking with no intervention or other exercises in individuals with MCI. The primary outcomes were cognitive functions, and the secondary outcome was walking endurance. Three reviewers independently conducted data extraction. The risk of bias was assessed using the Revised Cochrane Risk of Bias assessment tool.ResultsFourteen RCTs were included in this review. The quality of evidence in these studies was rated as good to excellent. The results of the meta-analysis showed that the individuals with MCI had no significant improvement in cognitive function but had significant improvement in the 6-min walk test (Mean Difference=23.70, p=0.008) after walking interventions compared to no intervention or other exercises.ConclusionWalking intervention has no significant improvement on cognitive functions in older adults with MCI. However, walking induces beneficial effects on aerobic capacity.Trial registrationThis systematic review has the registration number CRD42021283753 on PROSPERO.

Executive Functions and Episodic Memory are Associated with Extracellular White Matter Microstructure in Early Old Age

AbstractBackgroundCortical surface area, cortical thickness, and hippocampal volume are well‐studied in relation to later life cognitive impairments and AD. Fewer studies have investigated how white mater microstructure relates to cognition in late life. Existing work has focused on fractional anisotropy (FA) and mean diffusivity (MD) measures that are thought to capture demyelination and axonal degradation and relate to cognitive decline in normal aging and AD. However, these measures are susceptible to partial volume effects. Here, we evaluated whether executive function and memory are associated with FA and MD after deploying a free‐water (FW) elimination post‐processing method that separates fluid (FW) from tissue (FW‐corrected FA and MD).MethodWe examined 489 non‐demented men in the Vietnam Era Twin Study of Aging (VETSA) at mean age 68. Executive function was based on 6 tasks spanning inhibition, shifting, and working memory. Memory was based on 7 subtests from the Logical Memory, Visual Reproductions, and California Verbal Learning tests. Analyses focused on 11 cortical white matter tracts across three metrics: FW, FW‐corrected FA, and FW‐corrected MD. Analyses controlled for age, scanner, diabetes, hypertension, race, and ethnicity. We used false discovery rate to account for multiple testing.ResultBetter executive functioning was associated with lower FW across all 11 tracts. Better memory was associated with lower FW in 3 tracts: the superior longitudinal fasciculus (SLF) and two sections of the inferior frontal gyrus (opercularis and triangularis). Despite widespread differences with FW, there was only one significant association with intracellular metrics (executive function and FW‐corrected FA in the SLF). Finally, indicators of cognitive reserve (education or general cognitive ability assessed in early adulthood) did not moderate these associations between cognition and white matter microstructure.ConclusionOur findings leveraged a post‐processing method that separates extracellular fluid (FW) from intracellular tissue (FA, MD). We found that cognitive abilities in early old age are associated primarily with extracellular white matter microstructure (FW), which demonstrated global associations with executive function. Finally, there was no evidence that indicators of cognitive reserve influenced the strength of the association between cognition and white matter, at least in this sample of non‐demented men.

White matter hyperintensities are an early marker for cognitive decline in cognitively healthy older adults

AbstractBackgroundPrevious research suggests that white matter hyperintensities, amyloid, and tau contribute to cognitive decline. It remains unknown as to how these factors relate to one another and how they jointly contribute to cognitive decline in normal aging. The goal of this study was to examine the association between these pathologies and their relationship to cognitive decline.MethodsCognitively normal older adult data from the Alzheimer’s Disease Neuroimaging Initiative were examined. Participants were included if they had no subjective cognitive decline, had baseline white matter hyperintensity measurements, CSF Aß42, CSF pTau181, and cognitive scores. WMHs were segmented using a previously validated automatic technique (Dadar et al., 2018). Of the 230 participants included, only 199 had follow‐up cognitive scores. Linear regressions examined the influence of white matter hyperintensities, amyloid, and tau on baseline and follow‐up cognitive scores. Linear regressions also examined the association of amyloid and tau on white matter hyperintensities and between tau and amyloid.ResultsIncreased baseline WMHs were associated with increased baseline ADAS‐13 scores (t=2.59, p=.01) and lower follow‐up executive functioning (t= ‐2.84, p=.005). Lower baseline Aß42 was associated with lower baseline (t=3.58, p<.004) but not follow‐up executive function. Baseline pTau was not associated with decline in cognition at baseline or follow‐up. At baseline, WMHs were not associated with pTau but were inversely related to lower baseline Aß42 (t=‐4.20, p<.001). Aß42 and pTau were not associated (t=0.51, p=.61).ConclusionWhite matter hyperintensities may be one of the earliest pathologies observed in healthy older adults that contribute to cognitive decline. The inclusion of white matter hyperintensities as an additional marker for early cognitive decline may improve our current understanding of age‐related changes in cognitively healthy older adults.

Remote Learning for Adults with Mild Cognitive Impairment in the New Landscape of COVID-19 Restrictions

Introduction: Mild Cognitive Impairment (MCI) is a transitional stage between the expected cognitive decline of normal aging and the more serious decline of dementia. Research interest focuses on the protection of this transition, through a combination of therapeutic interventions. Μaterials and Methods: 45 individuals with MCI who were followed up by the interdisciplinary team of our Memory School attended an online remote educational program that consisted of a series of cognitive and occupational therapy interventions designed to maintain their cognitive, executive, motor and emotional skills during the COVID-19 period. At baseline and at twelve-month follow-up all patients underwent several neuropsychological tests that included the Montreal Cognitive Assessment (MoCA), the Mini Mental State Examination (MMSE), the Functional Cognitive Assessment Scale (FUCAS), the Geriatric Depression Scale (GDS) and the Functional Rating Scale of Symptoms of Dementia (FRRSD). Also, the Barthel Index scale and the Timed Up and Go (TUG) test were utilized to assess functionality and mobility, respectively. Results: Within twelve months participants’ performance did not change significantly (MoCA; p=0.908, MMSE; p=0.625, FUCAS; p=0.782; GDS; p=0.218, FRSSD; p=0.18, Barthel Index; p=0.317, TUG; p=0.68). Results confirmed the hypothesis that cognitive, executive, motor and behavioral skills can be maintained through an online educational protocol during the COVID-19 lockdown period. Conclusions: It is proposed that similar educational protocols should be included in the design of strategic directions in the field of healthcare in MCI and dementia, especially in health crisis situations.

Elucidation of the mechanism of cognitive decline in mild cognitive impairment using causal discovery

Mild cognitive impairment (MCI) is the stage between the expected cognitive decline of normal aging and the more serious decline of dementia. Since MCI may increase risk of later developing dementia caused by Alzheimer's disease (AD) or other neurological conditions, it is important to detect and treat MCI early in order to prevent dementia. Causal discovery, which can visualize causal relationships (cause and effect) among data, has recently been attracting attention. One of its algorithms, the Linear Non-Gaussian Acyclic Model (LiNGAM), can extract causal relationships among variables from statistical data only, using probability distributions of variables that are generally non-Gaussian. In this study, we used LiNGAM to analyze gene expression data in the hippocampus of healthy subjects and of MCI patients, and also the Mini-Mental State Examination (MMSE) scores, which are used to assess cognitive decline. We found that cell adhesion molecule 4 (CADM4) gene regulates cognitive processes that are measured in terms of MMSE scores. Our results revealed a causal relationship between gene expression changes and MMSE scores, and allowed us to identify the genes responsible for cognitive decline..

Neuronal C/EBPβ/AEP pathway shortens life span via selective GABAnergic neuronal degeneration by FOXO repression.

The age-related cognitive decline of normal aging is exacerbated in neurodegenerative diseases including Alzheimer’s disease (AD). However, it remains unclear whether age-related cognitive regulators in AD pathologies contribute to life span. Here, we show that C/EBPβ, an Aβ and inflammatory cytokine–activated transcription factor that promotes AD pathologies via activating asparagine endopeptidase (AEP), mediates longevity in a gene dose–dependent manner in neuronal C/EBPβ transgenic mice. C/EBPβ selectively triggers inhibitory GABAnergic neuronal degeneration by repressing FOXOs and up-regulating AEP, leading to aberrant neural excitation and cognitive dysfunction. Overexpression of CEBP-2 or LGMN-1 (AEP) in Caenorhabditis elegans neurons but not muscle stimulates neural excitation and shortens life span. CEBP-2 or LGMN-1 reduces daf-2 mutant–elongated life span and diminishes daf-16–induced longevity. C/EBPβ and AEP are lower in humans with extended longevity and inversely correlated with REST/FOXO1. These findings demonstrate a conserved mechanism of aging that couples pathological cognitive decline to life span by the neuronal C/EBPβ/AEP pathway.

White matter lesions may be an early marker for age-related cognitive decline

BackgroundResearch suggests that cerebral small vessel disease (CSVD), amyloid, and pTau contribute to age-related cognitive decline. It remains unknown how these factors relate to one another and how they jointly contribute to cognitive decline in normal aging. This project examines the association between these factors and their relationship to cognitive decline in cognitively unimpaired older adults without subjective cognitive decline. MethodsA total of 230 subjects with cerebrospinal fluid (CSF) Aß42, CSF pTau181, white matter lesions (WMLs) used as a proxy of CSVD, and cognitive scores from the Alzheimer’s Disease Neuroimaging Initiative were included. Associations between each factor and cognitive score were investigated using regression models. Furthermore, relationships between the three pathologies were also examined using regression models. ResultsAt baseline, there was an inverse association between WML load and Aß42 (t = −4.20, p <.001). There was no association between WML load and pTau (t = 0.32, p = 0.75), nor with Aß42 and pTau (t = 0.51, p =.61). Correcting for age, sex and education, baseline WML load was associated with baseline ADAS-13 scores (t = 2.59, p =.01) and lower follow-up executive functioning (t = −2.84, p =.005). Baseline Aß42 was associated with executive function at baseline (t = 3.58, p<.004) but not at follow-up (t = 1.05, p = 0.30), nor with ADAS-13 at baseline (t = −0.24, p = 0.81) or follow-up (t = 0.09, p = 0.93). Finally, baseline pTau was not associated with any cognitive measure at baseline or follow-up. ConclusionBoth baseline Aß42 and WML load are associated with some baseline cognition scores, but only baseline WML load is associated with follow-up executive functioning. This finding suggests that WMLs may be one of the earliest clinical manifestations that contributes to future cognitive decline in cognitively healthy older adults. Given that healthy older adults with WMLs exhibit declines in cognitive functioning, they may be less resilient to future pathology increasing their risk for cognitive impairment due to dementia than those without WMLs.

How Can Cognitive Reserve Promote Cognitive and Neurobehavioral Health?

This review is aimed at understanding how cognitive reserve and related concepts contribute to promoting neurobehavioral and cognitive health, consistent with goal of the 2020 national academy of neuropsychology (NAN) Annual Meeting.Research indicates that lifestyle factors such as achieving educational and work milestones, participating in leisure and social activities and IQ are all associated with reduced risk of cognitive decline in normal aging and of developing dementia. Many of these lifestyle factors have also been associated with better cognition in other psychiatric and neurological conditions. The cognitive reserve hypothesis posits that these lifestyle factors result in individual differences in the flexibility and adaptability of brain networks that may allow some people to cope better than others with age- or dementia-related brain changes. Recent evidence also supports the idea that specific genetic and lifestyle factors may help preserve a healthy brain or enhance brain reserve, a process that has been called brain maintenance. The complementary concept of brain reserve posits that structural brain features can guard against dementia and related conditions. This review defines these theoretical concepts, their research basis, how they are studied and their clinical applications. Evidence supports the concept of reserve, which can be influenced by experiences in every stage of life. Focused research in this area can maximize the chance for successful intervention.

Prediction of Subtle Cognitive Decline in Normal Aging: Added Value of Quantitative MRI and PET Imaging.

Quantitative imaging processing tools have been proposed to improve clinic-radiological correlations but their added value at the initial stages of cognitive decline is still a matter of debate. We performed a longitudinal study in 90 community-dwelling elders with three neuropsychological assessments during a 4.5 year follow-up period, and visual assessment of medial temporal atrophy (MTA), white matter hyperintensities, cortical microbleeds (CMB) as well as amyloid positivity, and presence of abnormal FDG-PET patterns. Quantitative imaging data concerned ROI analysis of MRI volume, amyloid burden, and FDG-PET metabolism in several AD-signature areas. Multiple regression models, likelihood-ratio tests, and areas under the receiver operating characteristic curve (AUC) were used to compare quantitative imaging markers to visual inspection. The presence of more or equal to four CMB at inclusion and slight atrophy of the right MTL at follow-up were the only parameters to be independently related to the worst cognitive score explaining 6% of its variance. This percentage increased to 24.5% when the ROI-defined volume loss in the posterior cingulate cortex, baseline hippocampus volume, and MTL metabolism were also considered. When binary classification of cognition was made, the area under the ROC curve increased from 0.69 for the qualitative to 0.79 for the mixed imaging model. Our data reveal that the inclusion of quantitative imaging data significantly increases the prediction of cognitive changes in elderly controls compared to the single consideration of visual inspection.

Factors influencing the deterioration from cognitive decline of normal aging to dementia among nursing home residents

BackgroundA dearth of differential research exists regarding the determinants of mild cognitive impairment (MCI) and moderate cognitive impairment or dementia among nursing home residents. This study aimed to identify and examine the association between medical factors (number of comorbidities, hospitalization, disability, depression, frailty and quality of life) and moderate cognitive impairment or dementia in nursing homes residents.MethodsA cross-sectional design was used in this study. Convenience sampling of 182 participants was conducted in nursing homes located in the central part of Jordan. Montreal cognitive assessment (MoCA) was used to screen both MCI and moderate cognitive impairment or dementia. Bivariate analysis, including t-test and ANOVA test, and logistic and linear regression models were used to examine and identify the medical factors associated with moderate cognitive impairment or dementia compared to mild cognitive impairment.ResultsMost nursing home residents had MCI (87.4%) compared to a few with moderate cognitive impairment or dementia. Age (t = − 2.773), number of comorbidities (t = − 4.045), depression (t = − 4.809), frailty (t = − 4.038), and quality of life physical (t = 3.282) and mental component summaries (t = 2.469) were significantly different between the stages of cognitive impairment. Marital status (t = − 4.050, p < 0.001), higher-income (t = 3.755, p < 0.001), recent hospitalization (t = 2.622,p = 0.01), depression (t = − 2.737, p = 0.007), and frailty (t = 2.852, p = 0.005) were significantly associated with mental ability scores among nursing home residents.ConclusionThe coexistence of comorbidities and depression among nursing home residents with MCI necessitates prompt management by healthcare providers to combat depressive symptoms in order to delay the dementia trajectory among at-risk residents.Trail registrationClinicalTrials.gov NCT04589637, October 15,2020, Retrospectively registered.

Effects of polygenic risk for Alzheimer\u2019s disease on rate of cognitive decline in normal aging

Most people’s cognitive abilities decline with age, with significant and partly genetically driven, individual differences in rate of change. Although APOE ɛ4 and genetic scores for late-onset Alzheimer’s disease (LOAD) have been related to cognitive decline during preclinical stages of dementia, there is limited knowledge concerning genetic factors implied in normal cognitive aging. In the present study, we examined three potential genetic predictors of age-related cognitive decline as follows: (1) the APOE ɛ4 allele, (2) a polygenic score for general cognitive ability (PGS-cog), and (3) a polygenic risk score for late-onset AD (PRS-LOAD). We examined up to six time points of cognitive measurements in the longitudinal population-based Betula study, covering a 25-year follow-up period. Only participants that remained alive and non-demented until the most recent dementia screening (1–3 years after the last test occasion) were included (n = 1087). Individual differences in rate of cognitive change (composite score) were predicted by the PRS-LOAD and APOE ɛ4, but not by PGS-cog. To control for the possibility that the results reflected a preclinical state of Alzheimer’s disease in some participants, we re-ran the analyses excluding cognitive data from the last test occasion to model cognitive change up-until a minimum of 6 years before potential onset of clinical Alzheimers. Strikingly, the association of PRS-LOAD, but not APOE ɛ4, with cognitive change remained. The results indicate that PRS-LOAD predicts individual difference in rate of cognitive decline in normal aging, but it remains to be determined to what extent this reflects preclinical Alzheimer’s disease brain pathophysiology and subsequent risk to develop the disease.

Focal white matter disruptions along the cingulum tract explain cognitive decline in amnestic mild cognitive impairment (aMCI)

White matter abnormalities of the human brain are implicated in typical aging and neurodegenerative diseases. However, our understanding of how fine-grained changes in microstructural properties along white matter tracts are associated with memory and cognitive decline in normal aging and mild cognitive impairment remains elusive. We quantified tract profiles with a newer method that can reliably measure fine-grained changes in white matter properties along the tracts using advanced multi-shell diffusion magnetic resonance imaging in 25 patients with amnestic mild cognitive impairment (aMCI) and 23 matched healthy controls (HC). While the changes in tract profiles were parallel across aMCI and HC, we found a significant focal shift in the profile at specific locations along major tracts sub-serving memory in aMCI. Particularly, our findings depict white matter alterations at specific locations on the right cingulum cingulate, the right cingulum hippocampus and anterior corpus callosum (CC) in aMCI compared to HC. Notably, focal changes in white matter tract properties along the cingulum tract predicted memory and cognitive functioning in aMCI. The results suggest that white matter disruptions at specific locations of the cingulum bundle may be a hallmark for the early prediction of Alzheimer’s disease and a predictor of cognitive decline in aMCI.

Mapping the patterns of cortical thickness in single- and multiple-domain amnestic mild cognitive impairment patients: a pilot study.

Amnestic mild cognitive impairment (aMCI) is considered as a transitional stage between the expected cognitive decline of normal aging and Alzheimer’s disease (AD). Structural brain difference has shown the potential in cognitive related diagnosis, however cortical thickness patterns transferred from aMCI to AD, especially in the subtypes of aMCI, is still unclear. In this study, we investigated the cortical thickness discrepancies among AD, aMCI and normal control (NC) entities, especially for two subtypes of aMCI - multiple-domain aMCI (aMCI-m) and single-domain aMCI (aMCI-s). Both region of interest (ROI)-based and vertex-based statistical strategies were performed for group-level cortical thickness comparison. Spearman correlation was utilized to identify the correlation between cortical thickness and clinical neuropsychological scores. The result demonstrated that there was a significant cortical thickness decreasing tendency in fusiform gyrus from NC to aMCI-s to aMCI-m to finally AD in both left and right hemispheres. Meanwhile, the two subtypes of aMCI showed cortical thickness difference in middle temporal gyrus in left hemisphere. Spearman correlation indicated that neuropsychological scores had significant correlations with entorhinal, inferior temporal and middle temporal gyrus. The findings suggested that cortical thickness might serve as a potential imaging biomarker for the differential diagnosis of cognitive impairment.

Cell-based assays that predict in vivo neurotoxicity of urban ambient nano-sized particulate matter

Exposure to urban ambient particulate matter (PM) is associated with risk of Alzheimer's disease and accelerated cognitive decline in normal aging. Assessment of the neurotoxic effects caused by urban PM is complicated by variations of composition from source, location, and season. We compared several in vitro cell-based assays in relation to their in vivo neurotoxicity for NF-κB transcriptional activation, nitric oxide induction, and lipid peroxidation. These studies compared batches of nPM, a nanosized subfraction of PM2.5, extracted as an aqueous suspension, used in prior studies. In vitro activities were compared with in vivo responses of mice chronically exposed to the same batch of nPM.The potency of nPM varied widely between batches for NF-κB activation, analyzed with an NF-κB reporter in human monocytes. Three independently collected batches of nPM had corresponding differences to responses of mouse cerebral cortex to chronic nPM inhalation, for levels of induction of pro-inflammatory cytokines, microglial activation (Iba1), and soluble Aβ40 & −42 peptides. The in vitro responses of BV2 microglia for NO-production and lipid peroxidation also differed by nPM batch, but did not correlate with in vivo responses. These data confirm that batches of nPM can differ widely in toxicity. The in vitro NF-κB reporter assay offers a simple, high throughput screening method to predict the in vivo neurotoxic effects of nPM exposure.

Physical Activity and Trajectories of Cognitive Change in Community-Dwelling Older Adults: The Rancho Bernardo Study.

Although physical activity has been associated with better cognitive function and reduced dementia risk, its association with cognitive decline in normal aging remains uncertain. To determine whether physical activity in youth and older age are associated with age-related cognitive change. Over a period of 27 years, 2,027 community-dwelling adults (mean age 73.5; 60% women) of the Rancho Bernardo Study of Healthy Aging completed up to seven cognitive assessments, including tests of global cognitive function, executive function, verbal fluency, and episodic memory. At each visit, participants reported concurrent physical activity. At baseline (1988- 1992), participants additionally reported physical activity as a teenager and at age 30. For each age period, participants were classified as regularly active (3+ times/week) or inactive. Associations between concurrent physical activity and better cognitive function were stronger with advancing age on all tests, even after accounting for education, health, and lifestyle factors, as well as survival differences (ps < 0.05). Baseline physical activity did not predict rates of cognitive decline (ps > 0.40). Individuals who were physically active at age 30 and older age maintained the highest global cognitive function with advancing age (p = 0.002). Regular physical activity is associated with better cognitive function with advancing age. Physical activity in young adulthood may contribute to cognitive reserve, which together with physical activity in later years, may act to preserve cognitive function with age.

Effects of APOE on cognitive aging in community-dwelling older adults.

The apolipoprotein E (APOE) gene is an established risk factor for sporadic Alzheimer's disease, with elevated risk for ε4-carriers and reduced risk for ε2-carriers. However, it is unclear whether APOE modifies risk for cognitive decline in normal aging. The objective of this study was to determine whether ε2 and ε4 are associated with rates of normal cognitive aging, and whether associations of ε4 with cognitive decline are modified by sex, education or health behaviors (exercise, alcohol consumption, smoking). A community-based sample of 1,393 older adults were genotyped for APOE and underwent cognitive assessment up to seven times over a maximum of period of 27 years. ε2-carriers showed slower executive function decline with age relative to ε3 homozygotes or ε4-carriers, whereas ε4-carriers demonstrated more rapid executive function and verbal fluency decline. Accelerated executive function decline was particularly pronounced in ε4-carriers with lower education. After excluding individuals with cognitive impairment, faster executive function decline was still apparent in ε4-carriers, and the effect of ε4 on episodic memory interacted with alcohol consumption, such that only ε4-carriers who did not drink showed more rapid memory decline than ε4 noncarriers. The influence of ε4 on cognitive aging did not differ by sex, nor was it modified by smoking or exercise. These findings indicate that the ε2 and ε4 alleles have differential effects on cognitive aging, and that negative effects of ε4 may be partly mitigated by behavioral choices. (PsycINFO Database Record (c) 2019 APA, all rights reserved).

The impact of amyloid-beta and tau on prospective cognitive decline in older individuals.

Amyloid-beta (Aβ) and tau pathologies are commonly observed among clinically normal older individuals at postmortem and can now be detected with in vivo neuroimaging. The association and interaction of these proteinopathies with prospective cognitive decline in normal aging and preclinical Alzheimer's disease (AD) remains to be fully elucidated. One hundred thirty-seven older individuals (age = 76.3 ± 6.22 years) participating in the Harvard Aging Brain Study underwent Aβ (11 C-Pittsburgh compound B) and tau (18 F-flortaucipir) positron emission tomography (PET) with prospective neuropsychological assessments following PET imaging (mean number of cognitive visits = 2.8 ± 1.1). Tau and Aβ PET measures were assessed in regions of interest (ROIs) as well as vertex-wise map analyses. Cognitive change was evaluated with Memory and Executive Function composites. Higher levels of Aβ and tau were both associated with greater memory decline, but not with change in executive function. Higher cortical Aβ was associated with higher tau levels in all ROIs, independent of age, and very elevated levels of tau were observed primarily in clinically normal with elevated Aβ. A significant interaction between tau and Aβ was observed in both ROI and map-level analyses, such that rapid prospective memory decline was observed in participants who had high levels of both pathologies. Our results are consistent with the supposition that both Aβ and tau are necessary for memory decline in the preclinical stages of AD. These findings may be relevant for disambiguating aging and early cognitive manifestations of AD, and to inform secondary prevention trials in preclinical AD. Ann Neurol 2019;00:1-3 ANN NEUROL 2019;85:181-193.

Neurotransmitter Pathway Genes in Cognitive Decline During Aging: Evidence for GNG4 and KCNQ2 Genes.

Experimental studies support the role of neurotransmitter genes in dementia risk, but human studies utilizing single variants in candidate genes have had limited success. We used the gene-based testing program Versatile Gene-based Association Study to assess whether aggregate variation across 6 neurotransmitter pathways influences risk of cognitive decline in 8159 cognitively normal elderly (≥65 years old) adults from 3 community-based cohorts. Common genetic variation in GNG4 and KCNQ2 was associated with cognitive decline. In human brain tissue data sets, both GNG4 and KCNQ2 show higher expression in hippocampus relative to other brain regions; GNG4 expression decreases with advancing age. Both GNG4 and KCNQ2 show highest expression in fetal astrocytes. Genetic variation analyses and gene expression data suggest that GNG4 and KCNQ2 may be associated with cognitive decline in normal aging. Gene-based testing of neurotransmitter pathways may confirm and reveal novel risk genes in future studies of healthy cognitive aging.