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Brain atrophy and cortical thinning are typically observed in people with Alzheimer's disease (AD) and, to a lesser extent, in those with mild cognitive impairment. In asymptomatic middle‐aged apolipoprotein ε4 (ΑPOE4) carriers, who are at higher risk of future AD, study reports are discordant with limited evidence of brain structural differences between carriers and non‐carriers of the ε4 allele. Alternative imaging markers with higher sensitivity at the presymptomatic stage, ideally quantified using typically acquired structural MRI scans, would thus be of great benefit for the detection of early disease, disease monitoring and subject stratification. In the present cross‐sectional study, we investigated textural properties of T1‐weighted 3T MRI scans in relation to APOE4 genotype, age and sex. We pooled together data from the PREVENT‐Dementia and ALFA studies focused on midlife healthy populations with dementia risk factors (analysable cohort: 1585 participants; mean age 56.2 ± 7.4 years). Voxel‐based and texture (examined features: contrast, entropy, energy, homogeneity) based morphometry was used to identify areas of volumetric and textural differences between APOE4 carriers and non‐carriers. Textural maps were generated and were subsequently harmonised using voxel‐wise COMBAT. For all analyses, APOE4, sex, age and years of education were used as model predictors. Interactions between APOE4 and age were further examined. There were no group differences in regional brain volume or texture based on APOE4 carriership or when age × APOE4 interactions were examined. Older people tended to have a less homogeneous textural profile in grey and white matter and a more homogeneous profile in the ventricles. A more heterogeneous textural profile was observed for females in areas such as the ventricles, frontal and parietal lobes and for males in the brainstem, cerebellum, precuneus and cingulate. Overall, we have shown the absence of volumetric and textural differences between APOE4 carriers and non‐carriers at midlife and have established associations of textural features with ageing and sex. [ABSTRACT FROM AUTHOR]

Background and purpose: The Mediterranean diet (MedDiet) has been associated with reduced dementia incidence in several studies. It is important to understand if diet is associated with brain health in midlife, when Alzheimer's disease and related dementias are known to begin. Methods: This study used data from the PREVENT dementia programme. Three MedDiet scores were created (the Pyramid, Mediterranean Diet Adherence Screener [MEDAS] and MEDAS continuous) from a self‐reported food frequency questionnaire. Primary outcomes were hippocampal volume and cube‐transformed white matter hyperintensity volume. Secondary outcomes included cornu ammonis 1 and subiculum hippocampal subfield volumes, cortical thickness and measures of cognition. Sex‐stratified analyses were run to explore differential associations between diet and brain health by sex. An exploratory path analysis was conducted to study if any associations between diet and brain health were mediated by cardiovascular risk factors for dementia. Results: In all, 504 participants were included in this analysis, with a mean Pyramid score of 8.10 (SD 1.56). There were no significant associations between any MedDiet scoring method and any of the primary or secondary outcomes. There were no differences by sex in any analyses and no significant mediation between the Pyramid score and global cognition by cardiovascular risk factors. Conclusions: Overall, this study did not find evidence for an association between the MedDiet and either neuroimaging or cognition in a midlife population study. Future work should investigate associations between the MedDiet and Alzheimer's disease and related dementias biomarkers as well as functional neuroimaging in a midlife population. [ABSTRACT FROM AUTHOR]

INTRODUCTION: Hypertension and diabetes are modifiable risk factors for dementia. We aimed to assess rural‐urban disparities in the diagnosis and treatment of these conditions among aging Indians. METHODS: Participants (n = 6316) were from two parallel, prospective aging cohorts in rural and urban India. Using self‐report and clinical/biochemical assessments, we subdivided participants with diabetes and hypertension into undiagnosed and untreated groups. Logistic regression and Fairlie decomposition analysis were the statistical methods utilized. RESULTS: There was a significant rural‐urban disparity in undiagnosed hypertension (25.14%), untreated hypertension (11.75%), undiagnosed diabetes (16.94%), and untreated diabetes (11.62%). Further, sociodemographic and lifestyle factors, such as age and tobacco use were the common contributors to the disparities in both undiagnosed hypertension and undiagnosed diabetes, whereas education and body mass index (BMI) were significant contributors to the disparity in untreated hypertension. DISCUSSION: Rural Indians face significant healthcare disadvantages as compared to their urban counterparts, which prompts the urgent need for strategies for equitable healthcare. [ABSTRACT FROM AUTHOR]

Summary: Multimorbidity—the coexistence of at least two chronic health conditions within the same individual—is an important global health challenge. In high‐income countries (HICs), multimorbidity is dominated by non‐communicable diseases (NCDs); whereas, the situation may be different in low‐ and middle‐income countries (LMICs), where chronic communicable diseases remain prominent. The aim of this systematic review was to identify determinants (including risk and protective factors) and potential mechanisms underlying multimorbidity from published longitudinal studies across diverse population‐based or community‐dwelling populations in LMICs. We systematically searched three electronic databases (Medline, Embase, and Global Health) using pre‐defined search terms and selection criteria, complemented by hand‐searching. All titles, abstracts, and full texts were independently screened by two reviewers from a pool of four researchers. Data extraction and reporting were according to Preferred Reporting Items for Systematic Reviews and Meta‐Analyses (PRISMA) guidelines. Methodological quality and risk of bias assessment was performed using the Newcastle‐Ottawa Scale for cohort studies. Data were summarized using narrative synthesis. The search yielded 1782 records. Of the 52 full‐text articles included for review, 8 longitudinal population‐based studies were included for final data synthesis. Almost all studies were conducted in Asia, with only one from South America and none from Africa. All studies were published in the last decade, with half published in the year 2021. The definitions used for multimorbidity were heterogeneous, including 3–16 chronic conditions per study. The leading chronic conditions were heart disease, stroke, and diabetes, and there was a lack of consideration of mental health conditions (MHCs), infectious diseases, and undernutrition. Prospectively evaluated determinants included socio‐economic status, markers of social inequities, childhood adversity, lifestyle behaviors, obesity, dyslipidemia, and disability. This review revealed a paucity of evidence from LMICs and a geographical bias in the distribution of multimorbidity research. Longitudinal research into epidemiological aspects of multimorbidity is warranted to build up scientific evidence in regions beyond Asia. Such evidence can provide a detailed picture of disease development, with important implications for community, clinical, and interventions in LMICs. The heterogeneity in study designs, exposures, outcomes, and statistical methods observed in the present review calls for greater methodological standardisation while conducting epidemiological studies on multimorbidity. The limited evidence for MHCs, infectious diseases, and undernutrition as components of multimorbidity calls for a more comprehensive definition of multimorbidity globally. [ABSTRACT FROM AUTHOR]

Background: It is now acknowledged that Alzheimer's Disease (AD) processes are present decades before the onset of clinical symptoms, but it remains unknown whether lifestyle factors can protect against these early AD processes in mid‐life. Intellectually, physically, and socially stimulating lifestyle activities are associated with maintenance of late‐life cognitive abilities (Chan et al., 2018), and lower cognitive impairment in AD (Livingston et al., 2020). We asked whether such activities contribute to cognitive reserve (CR) from mid‐life, in cognitively healthy individuals who are at risk for late‐life AD. Method: Middle‐aged individuals (aged 40‐59 years, mean = 52 years) from the PREVENT Dementia study (www.preventdementia.co.uk) were assessed at baseline (N = 210, 62/148 male/female) and two‐year follow‐up (N = 188, 55/133 male/female), with cognitive ability (multidomain battery) and brain health (total grey matter volume, functional brain network segregation) measures. Mid‐life activities were measured using the Lifetime of Experiences Questionnaire, which comprises occupational as well as intellectually, physically, and socially stimulating leisure activities. Dementia risk was assessed with the Cardiovascular Risk Factors, Aging, and Dementia (CAIDE) score. Result: Multivariable linear regression showed that intellectual, physical, and social activities undertaken in mid‐life made a unique contribution to episodic and relational memory in mid‐life, independent of occupation and CAIDE at baseline (β (se) = 0.04 (0.02), p = 0.02, Figure 1a) and follow‐up (β (se) = 0.07 (0.02), p = 0.002, Figure 1b). Furthermore, these activities moderated the relationship between cognitive ability and brain health at follow‐up (β (se) = 3.47 (1.40), p = 0.01), with verbal and visuospatial functions, and short‐term (conjunctive) memory of people with higher activity levels less dependent on their brain functional integrity (Figure 2), consistent with the concept of CR (Brayne et al., 2010). Such a moderation by these mid‐life activities was more prominent in individuals with higher CAIDE scores (β (se) = 4.28 (1.83), p = 0.02, Figure 3). Conclusion: These findings suggest that modifiable lifestyle activities contribute uniquely to CR and may offset cognitive decrements due to AD risk in mid‐life. They support the targeting of modifiable lifestyle activities for the prevention of Alzheimer's disease. [ABSTRACT FROM AUTHOR]

Background: The APOE ε4 allele is the primary genetic risk factor for the sporadic type of Alzheimer's disease (AD). However, the mechanisms by which APOE ε4 is associated with neurodegeneration are still poorly understood. Here, we applied the NODDI to characterise the effects of APOE ε4 and its interactions with age and education on cortical microstructure in cognitively normal individuals. Method: Data from 1954 participants were included from the PREVENT‐Dementia and ALFA (ALzheimer and FAmilies) studies (mean age = 57, 1197 non‐carriers, 757 APOE ε4 carriers). T1 MRIs were processed with FreeSurfer v7.2. The Microstructure Diffusion Toolbox was used to derive Orientation Dispersion Index (ODI) maps from diffusion MRI. Primary analyses were focused on the (a) main effects of APOE ε4, and the (b) interactions of APOE ε4 with age and education on lobar and vertex‐wise ODI and implemented using Permutation Analysis of Linear Models. Result: APOE ε4 carriers and non‐carriers did not differ in terms of lobar ODI. However, there were APOE ε4 × age interactions in the temporo‐parietal and frontal lobes (TFCE p FWE < 0.05), indicating steeper age‐dependent ODI changes in APOE ε4 (Figure 1). Lobar analyses revealed decreased temporal ODI in APOE ε4 carriers after age = 60 (Figure 2). There was a three‐way interaction of APOE ε4 x age x education; steeper age‐related ODI declines among APOE ε4 carriers with lower years of education (Figure 3, TFCE p FWE < 0.05). There were no significant main effects or interactions of APOE ε4 on cortical thickness. Conclusion: We found novel evidence that APOE ε4 worsened age‐related ODI decreases in brain regions typically associated with atrophy patterns of AD. This finding also suggests that APOE ε4 may hasten the onset age of dementia by accelerating age‐dependent reductions in cortical ODI, although additional studies are needed to verify this hypothesis. These findings were independent of cortical thickness. While conclusions are limited due to the cross‐sectional design, our findings imply that APOE ε4 related changes in ODI may precede macroscopically visible changes in cortical atrophy and may be a more sensitive marker of incipient AD. [ABSTRACT FROM AUTHOR]

Background: It is now acknowledged that Alzheimer's Disease (AD) processes are present decades before the symptoms manifest, but whether lifestyle activities can protect against these early AD processes in mid‐life remains poorly understood. Furthermore, the impact of sex as a biological variable on associations between dementia risk, protective lifestyle activities and cognition is unknown. In this study, we aimed to replicate findings from our two recent studies (Deng et al., 2022; Heneghan et al., 2022) on the contribution of mid‐life modifiable activities to cognition in individuals with dementia risk, in a larger independent cohort (N = 461 vs N = 208 used previously). Second, we investigated associations between biological sex, dementia risk, protective lifestyle activities and cognitive performance. Method: Cognitively unimpaired middle‐aged participants (40‐59 years; N = 461) completed cognitive and clinical assessments cross‐sectionally. Risk factors (Apolipoprotein E [APOE] ε4 allele status, family history of dementia, and the Cardiovascular Risk Factors Aging and Dementia score [CAIDE]) were assessed and mid‐life activities were measured with the Lifetime of Experiences Questionnaire. Result: Replicating our key previous findings, we found that episodic and relational memory was (a) significantly negatively associated with the CAIDE risk score (Figure 1a), (b) positively associated with stimulating lifestyle activities (Figure 1b), and (c) that females performed significantly better than males in episodic and relational memory (Figure 2a). The key novel finding of this study was that APOE ε4 genotype modulated the association between sex, lifestyle and cognition. Only for APOE ε4+ females, not APOE ε4‐, higher occupational attainment was associated with better episodic and relational memory (Figure 2c, 2d). Conversely, only for APOE ε4+ males, not APOE ε4‐, higher occupational attainment was associated with worse episodic and relational memory (Figure 2c, 2d). Conclusion: These findings suggest that modifiable lifestyle activities offset cognitive decrements due to inherited AD risk in mid‐life and support the targeting of modifiable lifestyle activities for the prevention of AD. Furthermore, these findings suggest an urgent need for targeted research on female‐specific risk factors, to inform personalised strategies for AD prevention and the promotion of female brain health. [ABSTRACT FROM AUTHOR]

Aims: The aim of this study is to estimate the association between anticholinergic burden, general cognitive ability and various measures of brain structural MRI in relatively healthy middle‐aged and older individuals. Methods: In the UK Biobank participants with linked health‐care records (n = 163,043, aged 40–71 at baseline), of whom about 17 000 had MRI data available, we calculated the total anticholinergic drug burden according to 15 different anticholinergic scales and due to different classes of drugs. We then used linear regression to explore the associations between anticholinergic burden and various measures of cognition and structural MRI, including general cognitive ability, 9 separate cognitive domains, brain atrophy, volumes of 68 cortical and 14 subcortical areas and fractional anisotropy and median diffusivity of 25 white‐matter tracts. Results: Anticholinergic burden was modestly associated with poorer cognition across most anticholinergic scales and cognitive tests (7/9 FDR‐adjusted significant associations, standardised betas (β) range: −0.039, −0.003). When using the anticholinergic scale exhibiting the strongest association with cognitive functions, anticholinergic burden due to only some classes of drugs exhibited negative associations with cognitive function, with β‐lactam antibiotics (β = −0.035, PFDR < 0.001) and opioids (β = −0.026, PFDR < 0.001) exhibiting the strongest effects. Anticholinergic burden was not associated with any measure of brain macrostructure or microstructure (PFDR > 0.08). Conclusions: Anticholinergic burden is weakly associated with poorer cognition, but there is little evidence for associations with brain structure. Future studies might focus more broadly on polypharmacy or more narrowly on distinct drug classes, instead of using purported anticholinergic action to study the effects of drugs on cognitive ability. [ABSTRACT FROM AUTHOR]

Introduction: Neuropsychological assessments are inexpensive and efficient methods to understand the cognitive abilities of individuals in research studies and clinical settings. Normative scores for such measures are crucial in serving as a reference standard for identifying cognitively healthy and impaired individuals belonging to similar sociodemographic characteristics. Methods: Study subjects in rural India recruited into the Srinivaspura Aging, Neuro Senescence and Cognition (SANSCOG) study were administered the COGNITO battery of tests, which traverse cognitive domains of attention, memory, language, and visuospatial abilities. Percentile norms based on age and education stratification were derived for the above cohort. Results: Percentile norms are commensurate with literacy levels in this population. The percentile scores for the cognitive tests show a decline for the individuals aged 75 years and above indicating lower cognitive functioning in this age group. Discussion: This is the first‐ever study reporting norms for diverse cognitive domains for illiterate, literate, low‐literate individuals enrolled in a large‐scale community‐based cohort study in rural India. [ABSTRACT FROM AUTHOR]

Objectives: Assessing for recovery in delirium is essential in guiding ongoing investigation and treatment. Yet, there is little scrutiny and no research or clinical consensus on how recovery should be measured. We reviewed studies which used tests of neuropsychological domains and functional ability to track recovery of delirium longitudinally in acute hospital settings. Methods/Design: We systematically searched databases (MEDLINE, PsycInfo, CINAHL, Embase, ClinicalTrials.gov, Cochrane Central Register of Controlled Trials), from inception to October 14th, 2022. Inclusion criteria were: adult acute hospital patients (≥18 years) diagnosed with delirium by a validated tool; 1+ repeat assessment using an assessment tool measuring domains of delirium/functional recovery ≤7 days from baseline. Two reviewers independently screened articles, performed data extraction, and assessed risk of bias. A narrative data synthesis was completed. Results: From 6533 screened citations, we included 39 papers (reporting 32 studies), with 2370 participants with delirium. Studies reported 21 tools with an average of four repeat assessments including baseline (range 2–10 assessments within ≤7 days), measuring 15 specific domains. General cognition, functional ability, arousal, attention and psychotic features were most commonly assessed for longitudinal change. Risk of bias was moderate to high for most studies. Conclusions: There was no standard approach for tracking change in specific domains of delirium. The methodological heterogeneity of studies was too high to draw firm conclusions on the effectiveness of assessment tools to measure delirium recovery. This highlights the need for standardised methods for assessing recovery from delirium. Key points: Assessing for recovery is an essential part of delirium care, to guide clinicians' ongoing investigation and treatment and to provide accurate information to patients and carers.It is unclear what assessment tools are used to measure delirium recovery on a longitudinal basis, specifically which neuropsychological and functional domains should be assessed.A total of 21 assessment tools measuring 15 different symptom domains of delirium were used in the included studies, however, there was no standard approach for tracking change in these domains over time.The symptom domains most frequently assessed for longitudinal change in the included studies were general cognition, functional ability, arousal, attention and psychotic features. [ABSTRACT FROM AUTHOR]

Objectives: Motoric Cognitive Risk (MCR) is a gait-based predementia syndrome that is easy to measure and prognostic of dementia and falls. We aimed to examine the prevalence and risk factors for MCR, and assess its overlap with Mild Cognitive Impairment, Prefrailty, and Frailty, in a cohort of older Scottish adults without dementia.Methods: In this longitudinal prospective study, we classified 690 participants (mean [SD] age 76.3 [0.8] years; wave 3) of the Lothian Birth Cohort 1936 (LBC1936) into non-MCR or MCR groups. We examined their baseline (age 69.5 [0.8] years; wave 1) risk factors for MCR at waves 3, 4, and 5 (6, 9, and 12 years later respectively).Results: MCR prevalence rate ranged from 5.3% to 5.7% across the three waves. The presence of MCR was associated with older baseline age (6 and 9 years later), lower occupational socioeconomic status (6 years later), and worse scores in a range of tests of executive function (6, 9 and 12 years later). Approximately 46% of the MCR group also had Mild Cognitive Impairment, and almost everyone in the MCR group had either Prefrailty or Frailty.Conclusions: The prevalence of MCR in this Scottish cohort is lower than the pooled global average, possibly reflecting the general good health of the LBC cohort. However, it is higher than the prevalence in two neighbouring countries' cohorts, which may reflect the younger average ages of those cohorts. Future LBC1936 research should assess the risk factors associated with MCR to validate previous findings and analyse novel predictive factors, particularly socioeconomic status. [ABSTRACT FROM AUTHOR]

Background: Motoric cognitive risk (MCR) is a syndrome characterised by measured slow gait speed and self‐reported cognitive complaints. MCR is a high‐risk state for adverse health outcomes in older adults, particularly cognitive impairment and dementia. Previous studies have identified risk factors for MCR, but the effect of socioeconomic status has, to date, been insufficiently examined. This study explored the association between MCR and socioeconomic status, as determined by occupational social class and years of education. Methods: Some 692 community‐based adults of the Lothian Birth Cohort 1936 (LBC1936), aged 70 years at baseline, were followed up after 6 years and classified into non‐MCR and MCR groups. We applied logistic regression analyses adjusting for demographic, lifestyle, and health covariates to investigate the association between MCR and years of education and occupational social class, categorised into manual versus non‐manual occupations. Results: MCR prevalence at age 76 years was 5.6% (95% CI 4.0–7.6). After multivariate adjustment, participants of lower socioeconomic status (manual occupation) had a greater than three‐fold increased likelihood of MCR (adjusted odds ratio 3.55, 95% CI 1.46–8.74; p = 0.005) compared with those of higher socioeconomic status (non‐manual occupation). Conclusions: Working in a manual job earlier in life triples the risk of MCR later in life, regardless of education. Unravelling this association will likely reveal important pathophysiological mechanisms underlying MCR and may unearth modifiable risk factors which could be targeted to reduce the incidence of MCR and, ultimately, dementia. Policy and healthcare practice addressing dementia risks such as MCR in their social context and early in the lifecourse could be effective strategies for reducing health inequalities in older age. [ABSTRACT FROM AUTHOR]

We aimed to refine the hypothesis that motoric cognitive risk (MCR), a syndrome combining measured slow gait speed and self‐reported cognitive complaints, is prognostic of incident dementia and other major causes of morbidity in older age. We propose mechanisms on the relationship between motor and cognitive function and describe a roadmap to validate these hypotheses. We systematically searched major electronic databases from inception to August 2021 for original longitudinal cohort studies of adults aged ≥60 years that compared an MCR group to a non‐MCR group with any health outcome. Fifteen cohorts were combined by meta‐analysis. Participants with MCR were at an increased risk of cognitive impairment (adjusted hazard ratio [aHR] 1.76, 95% CI 1.49–2.08; I2 = 24.9%), dementia (aHR 2.12, 1.85–2.42; 33.1%), falls (adjusted Relative Risk 1.38, 1.15–1.66; 62.1%), and mortality (aHR 1.49, 1.16–1.91; 79.2%). The prognostic value of MCR is considerable and mechanisms underlying the syndrome are proposed. [ABSTRACT FROM AUTHOR]

Background: The COVID‐19 pandemic has impacted daily life worldwide, with possible negative consequences for cognitive health. Self‐reported cognitive symptoms are linked to the development of Alzheimer's disease and related dementias (ADRDs). Identifying risk and protective factors for cognitive symptoms during the pandemic is an important step towards the development of ADRD prevention efforts. We aimed to examine correlates of cognitive symptoms among middle‐ and older‐age adults in Latin America before the availability of vaccines to prevent COVID‐19, including sociodemographic factors and changes in life. Method: Spanish‐speaking adults ages 55‐95 (N = 2,382, Table 1) living in Latin America completed an online survey between May and December 2020. Cognitive symptoms were assessed via the 12‐item Everyday Cognition (ECog) questionnaire. Negative (e.g., economic difficulties, limited social activities) and positive (e.g., more quality time with close others, increased time in nature/outside) life changes associated with the pandemic were measured via a subset of items from the Epidemic‐Pandemic Impacts Inventory. Sociodemographic factors included age, years of education, gender, occupation and socioeconomic status (SES). Covariates included time since March 2020 (estimated onset of the pandemic in Latin America), country of survey completion, and having experienced COVID‐19 symptoms. Multivariable linear regression models were ran on ECog total scores including covariates and sociodemographic factors (Model 1), and then adding terms for negative and positive life changes and their interaction (Model 2). Results: Model 1 showed female gender (p =.04), not currently working (p =.02) and lower SES (p<.001) were independently associated with more cognitive symptoms. Model 2 showed a significant interaction between negative and positive life changes (p<.001), indicating that negative life changes were significantly associated with more cognitive symptoms, but this association was weaker among participants who reported at least one positive life change during the pandemic (Figure 1). Conclusion: Cognitive symptoms might be more common among certain segments of the Latin American population, including women, and those who are not working and have low SES. The experience of positive life changes during the pandemic might buffer the detrimental impact of negative life changes on cognitive symptoms. These risk and protective factors might be considered in ADRD prevention efforts. [ABSTRACT FROM AUTHOR]

Type 2 diabetes is a robust predictor of cognitive impairment. Impairment in allocentric processing may help identify those at increased risk for Alzheimer's disease dementia. The objective of this study was to investigate the performance of participants with and without diabetes on a task of allocentric spatial processing. This was a cross‐sectional secondary data analysis study using baseline data from the European Prevention of Alzheimer's Dementia Longitudinal Cohort Study (EPAD LCS). Participants were aged 50 years and above and were free of dementia at baseline. Participants with no missing data on the variables of interest were included in this study. Our exposure variable was diabetes reported in the medical history. Our primary outcome was the Four Mountains Test (4MT), a novel task of allocentric processing. Covariates included demographics (age, sex, family history of dementia and years of education), APOEε4 carrier status, cognitive status (Clinical Dementia Rating scale), cerebrospinal fluid phosphorylated tau and amyloid‐beta 1–42. Of 1324 participants (mean age = 65.95 (±7.45)), 90 had diabetes. Participants with diabetes scored 8.32 (±2.32) on the 4MT compared with 9.24 (±2.60) for participants without diabetes. In a univariate model, diabetes was significantly associated with worse 4MT total scores (β = −.92, p =.001), remaining significant in a fully adjusted model (β = −.64, p =.01). Cerebrospinal fluid phosphorylated tau was significantly higher in participants with diabetes compared with those without. Novel cognitive tests, such as the 4MT, may be appropriate to identify early cognitive changes in this high‐risk group. Identifying those at greatest risk for future neurodegeneration is key to prevention efforts. [ABSTRACT FROM AUTHOR]

A biomarker associated with cognition in neurodegenerative dementias would aid in the early detection of disease progression, complement clinical staging and act as a surrogate endpoint in clinical trials. The current systematic review evaluates the association between cerebrospinal fluid protein markers of synapse loss and neuronal injury and cognition. We performed a systematic search which revealed 67 studies reporting an association between cerebrospinal fluid markers of interest and neuropsychological performance. Despite the substantial heterogeneity between studies, we found some evidence for an association between neurofilament‐light and worse cognition in Alzheimer's diseases, frontotemporal dementia and typical cognitive ageing. Moreover, there was an association between cerebrospinal fluid neurogranin and cognition in those with an Alzheimer's‐like cerebrospinal fluid biomarker profile. Some evidence was found for cerebrospinal fluid neuronal pentraxin‐2 as a correlate of cognition across dementia syndromes. Due to the substantial heterogeneity of the field, no firm conclusions can be drawn from this review. Future research should focus on improving standardization and reporting as well as establishing the importance of novel markers such as neuronal pentraxin‐2 and whether such markers can predict longitudinal cognitive decline. [ABSTRACT FROM AUTHOR]

Executive functions (EF), either conceptualized as skills involved in regulation of cognition and emotion in service of goal‐oriented behavior, or reductively as working memory, flexibility and inhibitory control, are commonly invoked constructs in developmental science. Two main traditions on EFs measurement prevail, one consisting of ratings obtained through questionnaires that inquire on behavior in common situations, the other based on performance in laboratory tasks. Whether both types of assessment actually refer to the same constructs is not consensual. Further, the role of school context in the degree of correspondence between both types of measures remains largely unexplored. Here, we show in a sample of over 220 children (age M = 5.6, SD = 0.4 years), by means of multilevel models, that whether EF tasks can predict BRIEF‐P ratings and vice‐versa, depends on the process considered and on the school SES. Inhibitory control, planning, and global executive functioning are associated with BRIEF‐P ratings in all schools. In contrast, we found no association among measures of flexibility independently of school SES. For working memory, we found that questionnaire rating predicts span only in high SES schools, but span predicts behaviors across schools. Our findings contribute to a growing body of literature that proposes constructs assessed by questionnaires and tasks only partially overlap and suggests that school SES may be a relevant factor to consider when questionnaires are answered by teachers. [ABSTRACT FROM AUTHOR]

Background: Depressive symptoms vary over the life course and may result from a multitude of causes. With consolidating evidence about depressive symptoms as risk factor of dementia, and previous findings suggesting shared biological pathways of depression and dementia, involving e.g., inflammation, it remains unclear if depressive symptoms reflect a causal risk factor, or an early sign of dementia. We sought to explore the role of depressive symptoms accumulation over time regarding dementia incidence in old age. Method: We applied the functional relevant life course exposure model (fRLM) to the Survey of Health Aging and Retirement in Europe (SHARE). More precisely, we modelled the accumulation of depressive symptoms, measured with the EURO‐D scale, over time utilizing functional regressions. Data from waves 2 (2006) to 8 (2020) of SHARE was used to examine the association of depressive symptoms with incident self‐report physician‐diagnosis of dementia. Result: In total, 3,717 participants aged 65 to 70 without dementia at baseline (M [SD] age at baseline = 67.42 [1.70] years) with complete data, participation in at least 2 waves prior to dementia diagnosis or 3 waves prior to loss to follow‐up (M [SD] participation = 3.67 [0.88] waves, MD [SD] follow‐up = 8.0 [2.9] years) were included (58.7% female). Higher exposure to depressive symptoms over time was associated to higher dementia incidence (OR [95% CI] = 3.66 [1.84‐5.87]). Moreover, relevance of depressive symptoms for dementia incidence varied across time windows, suggesting differential associations of depressive symptoms to dementia risk as a function of age. Highest relevance of exposure to depressive symptoms was observed for age 72‐75, i.e., close to diagnosis (Median [SD] age at diagnosis = 76 [3.26] years). Conclusion: While we observed an association of depressive symptoms with dementia risk, our novel approach extends on previous findings suggesting highest relevance, i.e., predictive ability of depressive symptoms close to diagnosis. Given a build‐up of pathological changes relating to dementia starting as early as two decades prior to cognitive impairment and diagnosis, this suggests depressive symptoms not to be a causal risk factor but rather an early sign or accompanying symptom of dementia. [ABSTRACT FROM AUTHOR]

Background: Brain Age Gap (BAG) represents the difference between an individual's predicted age, derived from machine learning models trained on neuroimaging data, and their chronological age. BAG has been associated with dementia and cognition in old age. Less is known relating BAG to dementia risk‐factors or cognitive performance in middle‐age. Method: Cognitively healthy, middle‐aged (40‐59 years) subjects from PREVENT‐Dementia had an array of neuropsychological, neuroimaging and genetic assessments. Brain Ages were predicted from T1‐weighted 3T MRI scans. Cognition was assessed using COGNITO. Multiple linear robust regression models tested hypotheses that: (i) BAG is positively associated with dementia risk‐factors; (ii) increased BAG is associated with worse cognition; (iii) longitudinal BAG change is positively associated with longitudinal cognitive deterioration. A range of machine learning algorithms with nested cross‐validation was used to assess whether BAG and cognition could predict each other. Result: 552 middle‐aged participants (median age 52.8 years) had all baseline assessments; 68 had amyloid PET data and 138 had longitudinal data. Median BAG was ‐2.0 years with a range from ‐21.2 to 18.4 years (Figure 1). BAG in middle‐age was associated with hypertension (p = 0.007) and alcohol intake (p = 0.008) but not APOE4 carrier status (p = 0.14) or amyloid centiloids (p = 0.53). BAG was not associated with cognitive performance either cross‐sectionally (p = 0.74) or longitudinally (p = 0.30), and there was no added predictive value between BAG and cognition. More education was associated with better cognition (p = 4.7×10−11) but not with BAG (p = 0.32). Conclusion: Even in midlife, substantial inter‐individual heterogeneity exists in the extent to which brains have aged. BAG in middle‐age is associated with modifiable dementia risk‐factors, suggesting that lifestyle risk‐factor modification needs to start at, or before, midlife to optimise brain health. BAG in middle‐age was not associated with risk‐factors for Alzheimer's disease (APOE4, amyloid deposition) or cognitive performance, despite there being a plausible and expected association between more education and better cognitive performance. These results are important for understanding brain‐age in middle‐aged populations who might be the target of future dementia‐preventing therapies. [ABSTRACT FROM AUTHOR]

Background: The Mediterranean diet (MedDiet) has been associated with better cardiometabolic and brain health. Research has suggested differences in these associations between men and women, with men typically reported to benefit more from higher MedDiet adherence. However there remains a lack of research in this area in non‐Mediterranean countries. This study aimed to explore cross‐sectional associations between MedDiet adherence in the PREVENT Dementia cohort (UK and Ireland), stratified by sex. Method: After deriving scores to quantify adherence to the MedDiet (MEDAS, MEDAS continuous and Pyramid), we used linear regression and linear mixed effects models to test for associations between the MedDiet scores, cardiometabolic health (blood pressure, BMI, glycemia, cholesterol, triglycerides) and brain health (white matter hyperintensity volume (WMHV), cortical thickness, hippocampal subfield volumes, cognition). Propensity scores were calculated to strengthen causality inferences from the data, and used as covariates along with total energy intake and Western diet scores. Result: We included 533 participants, mean age 51.25 (±5.40) years, majority women (60.0%). Higher MedDiet scores (MEDAS data presented) were associated with lower blood pressure (systolic ß: ‐1.16, p:0.009; diastolic ß: ‐1.00, p<0.001) and BMI (ß: ‐0.53, p<0.001). There were significant interactions between MedDiet and sex for diastolic blood pressure and hip‐to‐waist ratio. When stratified by sex, women had significant positive associations between MedDiet scores and blood pressure (systolic ß: ‐1.45, p: 0.006; diastolic ß: ‐1.29, p<0.001), BMI (ß: ‐0.51, p: 0.02) and glycemia (Pyramid only: ß: ‐0.11, p: 0.02), whereas men only had a significant association with BMI (ß: ‐0.45, p: 0.02) (Figure 1). There were no significant associations between dietary scores and any markers of brain health. An exploratory path analysis found a significant mediation between the Pyramid MedDiet score, pulse pressure and WMHV (Figure 2), which was only seen in women. Conclusion: There were significant associations between higher MedDiet scores and better cardiometabolic health, particularly for women. There were no direct associations with brain health outcomes, however a path analysis suggested a mediating effect of pulse pressure between the MedDiet and WMHV. Sex‐stratified nutritional guidelines to support better cardiometabolic health, may lead to better brain health and warrant further investigation. [ABSTRACT FROM AUTHOR]

Background: It is essential both drug and lifestyle‐based interventions aimed to delay the onset of advanced cognitive decline deliver a meaningful outcome for the patient. In the early stages of Alzheimer's disease and related dementias (ADRDs), patient‐reported outcome (PRO) measures should be used in parallel with biological investigations of ADRDs to provide a complementary endpoint offering further proof of intervention's effectiveness from the patients' point of view. The aim of the electronic Person‐Specific Outcome Measure (ePSOM) programme is to develop a scalable, easily accessible and efficient PRO tool for monitoring personally meaningful outcomes in early ADRD. Method: We designed and ran an online nation‐wide study to understand what matters to people about their brain health in the US. The ePSOM US survey started in Jan 2023 and collects primarily free‐text responses along with sociodemographic information and self‐reported neurodegenerative disease diagnosis. Respondents are presented with five domains and asked to describe in their own words their brain‐health priorities. Free‐text data will be analysed using Natural Language Processing (NLP) techniques to identify the most common brain‐health priorities by key sociodemographic groups. We will also compare these results with previously published UK results to look for any notable differences between the US and UK respondents' priorities. Result: The survey aims to recruit n = 6,000 respondents. Data collection started early 2023 and is planned to be complete by Spring/Summer 2023. The previously published ePSOM UK study (Saunders et al., 2021) with n = 5,808 respondents resulted in over 80,000 free‐text responses and 184 unique priority themes about brain health. We will present the preliminary results of the US study at AAIC and contextualising the results in light of new pharmacological treatments approved for AD. Conclusion: This large‐scale population‐based study will offer an evidence base for what outcomes constitute a meaningful impact of new treatments. Previous work from our group suggests that brain health priorities shift along the preclinical, prodromal and dementia continuum. The ultimate aim of the ePSOM programme is to design an electronic outcomes app which would allow an individual to define the most important outcomes against which we should measure treatment success across a range of severities. [ABSTRACT FROM AUTHOR]

Background: Carriership of the apolipoprotein ε4 (APOE4) allele confers a heightened risk for the development of Alzheimer's disease (AD). Cerebral blood flow (CBF) is decreased in prodromal and established AD, however findings in the preclinical stage are mixed, with some studies reporting increases. CBF can be impacted by many factors including the haematocrit. We investigated in a cohort at risk of developing AD how haematological variables relate to CBF and if this relationship is differentially moderated by APOE4. Method: 375 participants from the PREVENT‐Dementia study underwent arterial spin labelling (ASL) and structural 3Tesla MRI. ASL data were analysed using BASIL/FSL and structural scans with SPM12. CBF maps were corrected for partial volume effects. A vascular territory mask with nine territories, the middle, proximal and distal branches of the anterior, middle and posterior cerebral arteries (ACA, MCA, PCA) was used for region‐of‐interest analysis and registered to the native ASL space. Regional gray matter (GM) CBF values were harmonised using COMBAT. Linear regression was used to examine differences between APOE4 carriers and non‐carriers controlling for age, sex and years of education. Associations between haematological properties and CBF were examined with Pearson's correlations. Differential relationships between CBF, haematocrit, and measures of red blood cell size and shape (distribution width (RDW) and mean corpuscular volume (MCV)) were investigated by including interaction terms of APOE4 and haematological variables in the models. Result: APOE4 carriers had significantly higher CBF in the proximal MCA (t = 2.54, p = 0.01). Across all subjects, RDW and MCV were not associated with GM CBF, though several significant interactions were observed between APOE4 and RDW in predicting CBF (Figure 1). Haematocrit was associated with GM CBF (ρ = ‐0.19, p < 0.01). No significant interactions were seen between APOE4 and haematocrit or MCV in predicting CBF. Conclusion: The variability of the size and shapes of erythrocytes was differentially associated with CBF between APOE4 carriers and non‐carriers suggesting a different response to morphological erythrocyte alterations. This could further relate to underlying factors such as inflammation, which is associated with a higher RDW. Such associations should be examined in further studies. [ABSTRACT FROM AUTHOR]

Background: Cerebral microbleeds (CMB) are predictive of increased risk of dementia and stroke. Although commonly regarded as vascular markers, CMB can also stem from non‐vascular aetiologies like head injuries or traumatic brain injury (TBI), although these are often overlooked. Therefore, this study examines CMB in relation to TBI, and their differential causes (i.e., risk factors) and consequences (i.e., clinical outcomes). Method: In 605 healthy middle‐aged adults (aged 40‐59), CMB were rated on 3T susceptibility weighted imaging (SWI) MRI. TBI was assessed using the Brain Injury Screening Questionnaire (BISQ). TBI+ was defined as at least one blow to the head resulting in loss of consciousness (36.0%; n = 217). Memory was assessed using the COGNITO battery. Interaction analyses examined TBI*CMB interactions on hypertension, gait, and memory. Dominance analysis examined the relative contribution of TBI and vascular risk factors on predicting gait disturbances and memory. All models adjusted for sex, age, education, and study site. Result: TBI was related to higher CMB count (t = 2.06, p =.039), and were more common in males (48.3%) than females (28.0%) (Χ2 = 28.91, p<.001). Number of TBI events related to poorer memory (t = ‐2.62, p =.009) and gait disturbances (t = 3.54, p<.001). Interaction analyses demonstrated that hypertension (t = ‐2.26, p =.024), memory (t = 2.70, p =.007) and gait (t = ‐2.29, p =.023) were less closely related to CMB in individuals with greater number of TBI events, relative to those with fewer TBIs. Regionally, these interactions were significant for lobar CMB, but not deep subcortical CMB. Within the TBI+ group, dominance analysis demonstrated that number of TBI events outperformed vascular risk factors in predicting gait disturbances (Contribution to R2: TBI = 52.9%, vascular risk = 32.6%) and memory (TBI = 28.7%, vascular risk = 1.2%). Conclusion: CMB appeared to differ aetiologically and clinically in those with and without TBI. In individuals with TBI, TBI itself was the dominant driver of clinical deficits. When compared to CMB of presumed vascular origins cross‐sectionally, TBI‐related CMB may appear to be less detrimental. However, longitudinal analysis is required to determine how TBI‐related CMB differ in clinical trajectory and downstream pathologies. This study highlights the importance of differentiating between CMB of vascular origins vs. TBI in both research and clinically to aid prognosis and treatment decisions. [ABSTRACT FROM AUTHOR]

Background: It is well acknowledged that Alzheimer's Disease (AD) neuropathology start decades before clinical manifestations, but the brain mechanism of sporadic AD in midlife remains unclear. Resting‐state functional connectivity (FC) is increasingly used to understand early brain changes in Alzheimer's disease (AD) (Sperling, 2011; van den Heuvel & Sporns, 2019). We asked whether risk for late‐life dementia impacts functional connectivity in cognitively healthy middle‐aged individuals. Method: Functional Magnetic Resonance Imaging and detailed neuropsychological assessments were obtained for 585 (207/378 female/male) cognitively healthy individuals, aged 40‐59 years (mean = 50.9), from the PREVENT‐Dementia study. Dementia risk was calculated with the Cardiovascular Risk Factors, Aging, and Dementia (CAIDE) score. A novel connectome‐based predictive method called NBS‐Predict was used to investigate the association between FC and CAIDE score and its role in cognition. Result: FC significantly predicted CAIDE scores across the whole cohort (r = 0.207, p < 0.001). FC within and between the cingulo‐opercular network (CON) and sensorimotor network (SMN), as well as between CON and fronto‐parietal network (FPN), and between SMN with default mode network (DMN), and FPN contributed the most (Figure 1). Furthermore, we found that, in the high dementia risk group (CAIDE > 6) only, FC, mainly in DMN‐SMN and DMN‐CON (Figure 2), significantly predicted multisensory processing cognitive score (r = 0.114, p<0.05). Conclusion: Our results show that FC can be used to detect early brain changes associated with risk of future dementia in cognitively healthy individuals. This method has implications of the early detection of dementia in preclinical populations. [ABSTRACT FROM AUTHOR]

Background: There is emerging evidence that speech could be a potential indicator and manifestation of early Alzheimer's disease (AD) pathology. Symptomatic AD may change an individual's language, especially certain elements in speech such as elaboration and attribution. Therefore, the University of Edinburgh and Sony Group Corporation are collaborating within the Sony Research Award Program to create the SIDE‐AD study which aims to develop digital speech‐based biomarkers technology for AD. The study is designed to assess disease status in the pre‐dementia stages in a real‐world at‐risk population in Brain Health Services. Method: SIDE‐AD is an observational longitudinal study developing speech biomarkers for use in neurodegenerative disease. Participants are recruited from Brain Health Services in Scotland with data collection starting in spring 2023. In the context of the SIDE‐AD study, we have developed a secured online data collection infrastructure for collecting voice data by prompting individuals to record a voice sample talking about their brain health. Individuals are asked to rate their mood, anxiety and apathy. The baseline speech biomarkers will be compared to the follow‐up visit's speech recordings as well as to other variables from routinely collected health care data. The SIDE‐AD study will employ signal processing and machine learning technologies to automate the assessment of the respondents' speech. Result: The objective of the SIDE‐AD study is to recruit participants (n = 150) across the AD spectrum. The developed infrastructure will be used to collect data of participants with an objective of analysing baseline speech markers in relation to self‐reported mood, anxiety and apathy as well as clinical outcomes from patients' health care records. Conclusion: The SIDE‐AD study is carrying out research and development of a speech‐based application recording data on individuals' self‐perceived brain health. A secured online data collection infrastructure is developed to collect speech data with an objective to analyse speech data in combination with routinely available clinical data in Brain Health Clinics, enabling real world validation of speech‐based digital biomarkers for the early detection of AD. We plan to use automatic speech recognition and acoustic patterns for the automatic assessment of brain health status relevant to emergent AD‐specific speech biomarkers. [ABSTRACT FROM AUTHOR]

Introduction: Physical frailty is associated with multiple adverse health outcomes. Since physical characteristics markedly vary with different populations, population‐specific norms for physical frailty parameters are necessary. Such norms are lacking for the Indian population, especially for older, rural Indians. We aimed to develop normative values for three quantitative, frailty parameters—handgrip strength, “Timed Up‐and‐Go” (TUG) test time, and physical activity in an aging, rural Indian population. Methods: The study sample is from an ongoing, prospective, cohort (Srinivaspura NeuoSenescence and COGnition, SANSCOG) comprised of rural, community‐dwelling, cognitively healthy, aging Indians. Subjects are recruited through area sampling strategy, from villages of Srinivaspura, Kolar district, Karnataka state, India. Three physical frailty parameters of Fried's phenotype—handgrip strength (n = 1787), TUG time (n = 1863), and physical activity (n = 1640) were assessed using digital hand dynamometry, TUG test, and General Physical Activity Questionnaire (GPAQ), respectively. Results: The 10th, 25th, 50th, 75th, 90th percentiles for the three frailty parameters were: right‐hand grip strength (kg): males—13.9, 18.6, 23.8, 28.7, 33.7 and females—7.8, 10.6, 14.2, 17.9, 21.3; left‐hand grip strength (kg): males—13.3, 18.3, 23.6, 28.9, 32.9 and females—7.9, 10.5, 14.3, 17.8, 21.2; TUG time (s): males—9.1, 10.1, 11.4, 13.4, 15.5 and females—9.5, 10.7, 12.4, 14.5, 16.6; physical activity (MET‐minutes/week): males—1680; 4320; 8880; 15,840; 23,352 and females—1680; 4320; 9240; 15,120; 20,160. Discussion: Our findings show that from 45 years onwards, overall grip strength decreases and TUG time increases, with women performing significantly poorer than men across all age groups, except >75 years, where no differences were seen. Physical activity did not show any consistent trend according to age or gender. Reference values for this aging, rural Indian population were substantially lower for grip strength and higher for TUG time than aging populations in several Western and other Asian countries. [ABSTRACT FROM AUTHOR]

Background: The use of prescription drugs with anticholinergic properties has been associated with multiple negative health outcomes in older people. Moreover, recent evidence suggests that associated adverse effects may occur even decades after stopping anticholinergic use. Despite the implicated importance of examining longitudinal patterns of anticholinergic prescribing for different age groups, few such data are available. Methods: We performed an age‐period‐cohort (APC) analysis to study trends in an aggregate measure of anticholinergic burden between the years 1990 and 2015, utilising data from >220 000 UK Biobank participants with linked prescription data from primary care. Results: Anticholinergic burden in the sample increased up to 9‐fold over 25 years and was observed for both period and age effects across most classes of drugs. The greatest increase was seen in the prescribing of antidepressants. Female sex, lower education and greater deprivation were associated with greater anticholinergic burden. Conclusions: The increase in anticholinergic prescribing is mostly due to an increase in polypharmacy and is attributable to both ageing of participants and period‐related changes in prescribing practices. Research is needed to clarify the implications of rising anticholinergic use for public health and to contextualise this rise in light of other relevant prescribing practices. [ABSTRACT FROM AUTHOR]

Background: The entorhinal cortex (EC) is the first cortical brain region to exhibit neurodegeneration in Alzheimer's disease (AD). Given that the EC contains unique grid cells underpinning path integration, tests probing this aspect of navigation may have added value in detecting AD in its earliest preclinical stages. Building on our past work showing that a VR path integration task was highly sensitive and specific for prodromal AD (Howett et al., 2019 Brain), we tested the hypothesis that path integration may be affected in asymptomatic middle‐aged individuals at increased risk of AD. Method: 100 cognitively healthy adults (aged 43–66) from the PREVENT Dementia cohort performed an immersive VR path integration task in a simulated environment with distal boundary cues to generate allocentric spatial representations. We manipulated EC‐dependence by pseudo‐randomly removing supportive spatial cues from the virtual environment (Figure 1). Participants additionally performed a battery of cognitive tasks including the ACE‐R and COGNITO episodic memory. Linear mixed effects models and Tukey‐corrected post‐hoc contrasts were used to explore the contributions to task performance of parental family history, APOE‐e4 status, global amyloid PET uptake value (N = 46) and CAIDE lifestyle dementia risk score, adjusted for age, sex and education. Result: Individuals with a positive family history, APOE‐e4 allele or higher CAIDE dementia risk score showed a selective impairment in path integration only when supportive boundary cues were removed. Significant sex interactions indicated that the family history effect (t = 2.31, pTukey = 0.022, Figure 2) and APOE‐e4 effect (t = 3.18, pTukey = 0.023) was specific to males. The effect of CAIDE risk score was specific to individuals with a family history (t = 2.45, pTukey = 0.038) (Figure 3). Conversely, these AD risk factors showed no effect on performance for the other cognitive tasks. Global amyloid PET uptake values showed no association to any task performance. Conclusion: These results suggest that navigation tests based on EC grid cell function may identify the earliest cognitive changes in individuals at greater risk of AD. The additional moderation by sex indicates a future need to consider male/female differences when using family history or APOE status to inform detection of initial stages of AD. [ABSTRACT FROM AUTHOR]

Background: Previous studies on the relationship between anticholinergic drugs and dementia have reported heterogeneous results. This variability could be due to different anticholinergic scales and differential effects of distinct classes of drugs. Methods: Using Cox proportional hazards models, we computed the association between annual anticholinergic burden (AChB) and the risk of dementia inUK Biobank with linked general practitioner prescription records between the years 2000 and 2015 (n = 171,775). Results:AChB according to most anticholinergic scales (standardized odds ratio range: 1.027-1.125) and the slope of the AChB trajectory (hazard ratio = 1.094; 95% confidence interval: 1.068-1.119) were predictive of dementia. However, the association between AChB and dementia held only for some classes of drugs, especially antidepressants, antiepileptics, and antidiuretics. Discussion: The heterogeneity in previous findings may partially be due to different effects for different classes of drugs. Future studies should establish differences in more detail and further examine the practicality of a general measure of AChB relating to the risk of dementia. [ABSTRACT FROM AUTHOR]

Background: We classified non‐demented European Prevention of Alzheimer's Dementia (EPAD) participants through the amyloid/tau/neurodegeneration (ATN) scheme and assessed their neuropsychological and imaging profiles. Materials and methods: From 1500 EPAD participants, 312 were excluded. Cerebrospinal fluid cut‐offs of 1000 pg/mL for amyloid beta (Aß)1‐42 and 27 pg/mL for p‐tau181 were validated using Gaussian mixture models. Given strong correlation of p‐tau and t‐tau (R2 = 0.98, P < 0.001), neurodegeneration was defined by age‐adjusted hippocampal volume. Multinomial regressions were used to test whether neuropsychological tests and regional brain volumes could distinguish ATN stages. Results: Age was 65 ± 7 years, with 58% females and 38% apolipoprotein E (APOE) ε4 carriers; 57.1% were A–T–N–, 32.5% were in the Alzheimer's disease (AD) continuum, and 10.4% suspected non‐Alzheimer's pathology. Age and cerebrovascular burden progressed with biomarker positivity (P < 0.001). Cognitive dysfunction appeared with T+. Paradoxically higher regional gray matter volumes were observed in A+T–N– compared to A–T–N– (P < 0.001). Discussion: In non‐demented individuals along the AD continuum, p‐tau drives cognitive dysfunction. Memory and language domains are affected in the earliest stages. [ABSTRACT FROM AUTHOR]

As the world navigates unchartered territories and witnesses the overwhelming impact of COVID‐19, investigators face important challenges to ensure continuity of research studies in a scientifically sound manner. Given the susceptibility of the older population to COVID‐19, research in the field of aging and dementia may be more severely impacted than other areas. With in‐person testing halted, researchers are considering remote testing to collect data on questionnaires and functioning, including cognitive functioning. This is not without challenges. Here, we discuss psychometric properties of the scales that need to be considered and evaluated when implementing remote testing to ensure the quality of the studies is preserved. We encourage the community to join efforts to improve practice sharing and facilitating access to item‐level data. [ABSTRACT FROM AUTHOR]

Combining data from different studies has a long tradition within the scientific community. It requires that the same information is collected from each study to be able to pool individual data. When studies have implemented different methods or used different instruments (e.g., questionnaires) for measuring the same characteristics or constructs, the observed variables need to be harmonized in some way to obtain equivalent content information across studies. This paper formulates the main concepts for harmonizing test scores from different observational studies in terms of latent variable models. The concepts are formulated in terms of calibration, invariance, and exchangeability. Although similar ideas are present in measurement reliability and test equating, harmonization is different from measurement invariance and generalizes test equating. In addition, if a test score needs to be transformed to another test score, harmonization of variables is only possible under specific conditions. Observed test scores that connect all of the different studies, are necessary to be able to test the underlying assumptions of harmonization. The concepts of harmonization are illustrated on multiple memory test scores from three different Canadian studies. [ABSTRACT FROM AUTHOR]

Introduction: We classified individuals based on their baseline performance on cognitive measures and investigated the association between cognitive classifications and neuropathological findings ∼7 years later, as an external validator. Methods: Brain autopsies of 779 decedents were examined. Baseline latent class analysis on 10 neuropsychological measures was previously assigned: mixed‐domains impairment (n = 39, 5%), memory‐specific impairment (n = 210, 27%), frontal impairment (n = 113, 14.5%), average cognition (n = 360, 46.2%), and superior cognition (n = 57, 7.3%). Linear regressions and risks ratios were used to examine the relation of latent class assignment at enrollment with neuropathological indices. Results: Amyloid β, tau, and transactive response DNA‐binding protein 43 were associated with mixed‐domains impairment and memory‐specific impairment classes ∼7 years before death. Moderate arteriolosclerosis was associated with membership in the frontal impairment class. Discussion: Our findings support the use of latent class models that incorporate more comprehensive neuropsychological measures to classify cognitive impairment. [ABSTRACT FROM AUTHOR]

Aim: To quantify variations in health‐related behaviors (HRB) clustering of older adults in Western and Eastern countries. Methods: Using six aging cohorts from the USA, England, Europe, Japan, Korea and China, latent class analysis was applied to access the clustering of smoking, alcohol consumption, physical activity and social activity. Results: A total of 104 552 participants (55% women) aged ≥50 years in 2010 were included. Despite a different number of clusters identified, three consistent cluster profiles emerged: "Multiple‐HRB" (ex‐/never smoking, moderate drinking, frequent physical and social activity); "Inactives" (socially and physically inactive without other risk behaviors); and "(ex‐)Smokers with Risk Behaviors". Sex and cohort variations were shown. For men in Western cohorts, "Multiple‐HRB" was the predominant cluster, whereas their Asian counterparts were more likely to be members of the "Smokers with risk behavior" and "Inactives" clusters. Most women, particularly those in Asian cohorts, were never smokers and non‐drinkers, and most of them belonged to the socially "Inactives" cluster. Conclusions: We provide a person‐centered understanding of HRB clustering of older adults over selected countries by sex, informing tailored health promotion for the target population. Geriatr Gerontol Int 2019; 19: 930–937. [ABSTRACT FROM AUTHOR]

Objective: Ageing is associated with changes in cognition in some, but not all domains. In young-old adults, defined as persons aged 65-84 years, baseline cognitive function has been shown to impact on cognitive trajectories. Whether similar patterns occur in the very-old, defined as persons aged 85 years and over, is not known.Methods: Longitudinal changes (5 years' follow-up) in global and domain specific cognitive function including memory, attention and speed were investigated in participants from the Newcastle 85+ Study (n = 845). At baseline, participants were grouped using Mini-Mental State Examination cut-off scores and dementia status into the following: not impaired, mildly impaired or severely impaired/dementia groups.Results: Only a limited number of cognitive measures showed significant decline in performance over time. Where observed, change generally occurred only in the severely impaired group. In the severely impaired group, small differences in baseline age were associated with poorer performance over time on most measures. Education was not protective against cognitive decline in any group.Conclusions: There are individuals who maintain a high level of cognitive function or only show mild impairments even into their ninth decade of life. This group of successful cognitive agers may provide insight for identifying predictors of cognitive integrity in later life. In individuals with severe impairment, cognitive performance shows significant decline over time, especially in measures of attention and speed. Further work to identify those individuals at highest risk of cognitive decline is necessary to implement early support and intervention strategies in this rapidly expanding age group. © 2017 The Authors. International Journal of Geriatric Psychiatry published by John Wiley & Sons Ltd. [ABSTRACT FROM AUTHOR]

Background: The Mediterranean diet (MedDiet) is a primarily plant‐based eating pattern. High adherence to a MedDiet has been associated with a 10‐40% lower incidence of dementia. There is limited evidence exploring associations between the MedDiet and Alzheimer's disease (AD) pathology. Method: Our study explored cross‐sectional associations between MedDiet and AD outcomes in the European Prevention of Alzheimer's Dementia Longitudinal Cohort Study (EPAD LCS), comparing effects between those living within and outside of the Mediterranean region. After deriving MEDAS scores, to quantify adherence to the MedDiet, we used linear regression analyses to test for associations between the MedDiet and hippocampal volume, white matter lesion volume (WMLV) cerebrospinal fluid Abeta 1‐42 and phosphorylated tau and cognition. Participants were categorised by Mediterranean or non‐Mediterranean region according to European Union classification. Result: We included 1625 participants from the EPAD LCS baseline dataset, mean age 65.48 (±7.40) years, majority female (55.9%), majority with family history (66.3%) and minority APOEε4 carriers (39.0%). Mediterranean participants had higher MEDAS scores compared to non‐Mediterranean participants (7.44 (±1.60) vs 7.20 (±1.74), p = 0.007). Higher adherence to the MedDiet was associated with lower log WMLV in fully adjusted models (b: ‐0.06, standard error (SE): 0.02, p<0.001), indicating better brain health. Geographical region analysis found this effect only in Mediterranean participants (fully adjusted: b: ‐0.10, SE: 0.03, p<0.001). Exploratory analysis further showed this effect was only apparent in male, and not female, participants. For non‐Mediterranean participants, higher adherence to the MedDiet was associated with lower Four Mountains Test scores (fully adjusted: b: ‐0.25, SE: 0.08, p = 0.003), indicating poorer brain health. Analyses are corrected using the Benjamini‐Hochberg False Discovery Rate estimation. Conclusion: Our findings suggest that adherence to the MedDiet is associated with better brain health in those living within, but not outside of, the Mediterranean region. One explanation may be a difference in the duration of exposure to this diet (i.e., life‐long versus later life adoption in Mediterranean vs. non‐Mediterranean regions). This study highlights the need to further explore who the MedDiet is particularly effective for with regard to brain health outcomes, to better inform public health campaigns and patient level interventions. [ABSTRACT FROM AUTHOR]

Background: Alzheimer's disease (AD) is recognized as one of the greatest global public health challenges. There is increasing consensus that optimal disease modification using pharmaceuticals may best be achieved earlier in the disease continuum before symptoms occur. However, more needs to be understood about what outcomes are meaningful to potential participants in clinical trials within this preventative paradigm and how people make trade‐offs between risks and benefits. The Electronic Person‐Specific Outcome Measure (ePSOM) programme is developing an app to capture person‐specific outcomes and preferences in clinical trials. Objective: As one phase in the ePSOM programme, this study explored what matters when developing new treatments to prevent AD and how trade‐offs are made between risks and benefits, from three perspectives. Design: Focus groups were conducted with people living with memory problems (n = 21) and healthy volunteers (n = 10), and telephone interviews with health and social care professionals (n = 10). Differences and overlap between the three groups were explored. Results: Outcomes that matter lie in five key domains in relation to what matters in everyday life: Everyday Functioning; Relationships and Social Connections; Enjoying Life; Sense of Identity; and Alleviating  Symptoms. Insights were gained into the significance of reducing the risk of developing dementia with drugs and the processes of weighing up risks versus benefits. Discussion and conclusions: The key domains identified are being used to inform the next stage of the ePSOM programme which is to develop a survey to be distributed nationally in the UK to explore these issues further. [ABSTRACT FROM AUTHOR]

Background: Physical frailty is associated with multiple adverse health outcomes. Since physical characteristics markedly vary with different populations, population‐specific norms for physical frailty parameters are necessary. Such norms are lacking for the Indian population, especially for older, rural Indians. We aimed to develop normative values for three quantitative, frailty parameters – hand grip strength, 'Timed Up‐and‐Go' (TUG) time and physical activity in an aging, rural Indian population Method: The study sample is from an ongoing, prospective, cohort (Srinivaspura NeuoSenescence and COGnition, SANSCOG) comprising of rural, community‐dwelling, cognitively healthy, aging Indians. Subjects are recruited through area sampling strategy, from villages of Srinivaspura, Kolar district, Karnataka state, India. Three physical frailty parameters of Fried's phenotype – hand grip strength (n = 1787), TUG time (n = 1863) and physical activity (n = 1640) were assessed using digital hand dynamometry, TUG test and General Physical Activity Questionnaire (GPAQ), respectively. Result: The 10th, 25th, 50th, 75th, 90th percentiles for age groups 45‐55, 56‐65, 66‐75 and >75 years were: right hand grip strength(kg): males–13.90, 18.60, 23.80, 28.70, 33.70 & females–7.80, 10.60, 14.20, 17.90, 21.30; left hand grip strength(kg): males–13.30, 18.30, 23.60, 28.90, 32.86 & females–7.90, 10.53, 14.30, 17.80, 21.20; TUG time(seconds): males–9.05, 10.09, 11.43, 13.38, 15.50 & females–9.51, 10.73, 12.40, 14.50, 16.57; physical activity(MET‐minutes/week): males–1680, 4320, 8880, 15840, 23352 & females–1680, 4320, 9240, 15120, 20160. Conclusion: Our findings show that from 45 years onwards, overall grip strength decreases and TUG time increases, with women performing significantly poorer than men across all age groups, except >75 years, where no differences were seen. Physical activity did not show any consistent trend according to age or gender. Reference values for this aging, rural Indian population were substantially lower for grip strength and higher for TUG time than aging populations in several Western and other Asian countries [ABSTRACT FROM AUTHOR]

Background: Polypharmacy, the concurrent use of multiple medicines, is increasing. Population‐wide studies of its association with dementia are lacking. We examined this relationship longitudinally, at a national level. Method: We used National Health Service community prescribing data from all adults in Scotland aged ≥50 years who received at least one drug in the first quarter of 2009. These data were linked to death records, including cause of death. We used Cox proportional hazards models to assess associations between the number of unique medicines dispensed in one quarter and mortality with any subtype of dementia over 8.5 years, in the whole sample and stratified by age. Result: The sample contained 1,225,894 people aged ≥50 years (mean age 67.4 (SD = 10.8) years, 56.1% female, 3.8% care home residents). The mean number of drugs dispensed at baseline was 5.0 (SD = 3.7). Over 8.5 years, there were 336,244 deaths, of which 58,358 had any subtype of dementia on the death certificate. Among the whole sample, the hazard ratio (HR) for dementia mortality with each additional medicine was 1.027 (95% CI 1.024‐1.028). In people aged 50‐64 years, the HR was 1.075 (1.061‐1.089); for 65‐79 year‐olds, HR = 1.043 (1.040‐1.047) and for those aged ≥80 years, HR = 1.009 (1.006‐1.012). All models were adjusted for baseline age, gender, care home residence status and deprivation index based on postcode. Conclusion: There was higher mortality with dementia as the number of dispensed medicines increased. Age‐stratified analyses showed that the association was stronger in younger age groups, perhaps reflecting that younger people taking medication for more comorbidities had an increased risk of dying with dementia. These analyses did not allow adjustment for multimorbidity or the consideration of individual drug classes. [ABSTRACT FROM AUTHOR]

Objective: Cognitive performance shows a marked deterioration in close proximity to death, as postulated by the terminal decline hypothesis. The effect of education on the rate of terminal decline in the oldest people (i.e. persons 85+ years) has been controversial and not entirely understood. In the current study, we investigated the rate of decline prior to death with a special focus on the role of education and socioeconomic position, in two European longitudinal studies of ageing: the Origins of Variance in the Old-Old: Octogenarian Twins (OCTO-Twin) and the Newcastle 85+ study.Methods: A process-based approach was used in which individuals' cognitive scores were aligned according to distance to death. In a coordinated analysis, multilevel models were employed to examine associations between different markers of cognitive reserve (education and socioeconomic position) and terminal decline using the mini-mental state examination (MMSE), controlling for age at baseline, sex, dementia incidence and time to death from the study entry to the time of death within each cohort.Results: The current findings suggest that education was positively associated with higher MMSE scores prior to death in the OCTO-Twin, but not in the Newcastle 85+ study, independent of socioeconomic position and other factors such as baseline age, sex and time to death from the study entry. However, education was not associated with the rate of terminal decline in both of these studies.Conclusions: Our results offer only partial support to the cognitive reserve hypothesis and cognitive performance prior to death. [ABSTRACT FROM AUTHOR]

Background: Adherence to the Mediterranean diet (MedDiet) has been associated with better cognitive performance, lower incidence of dementia, stroke and lower Alzheimer's disease (AD) biomarker burden (Scarmeas et al, 2018). Improving dietary patterns in at‐risk populations may improve brain health, reducing incidence of dementia and stroke (Lewis et al, 2014; Feigin et al, 2019). The aim of this systematic review was to evaluate the evidence base for the MedDiet in relation to hippocampal volume and white matter hyperintensity volume (WMHV) (PROSPERO Registration: CRD42021269620). Method: We systematically searched for studies on MedDiet and hippocampal volume or WMHV in MedLine, EMBASE, CINAHL and PsycInfo. The review was carried out in line with PRISMA methodology. We included studies with adult participants in any setting, time or language. Searches were initially carried out between 21st July 2021 and 19th August 2021. Papers were screened independently by two authors against eligibility criteria. Data on participant demographics, MedDiet calculation and adherence, hippocampal volume and/or WMHV was extracted and narratively synthesised. Result: Of an initial 112 papers identified, six papers, enrolling 21,750 participants, were eligible for inclusion in the review. The mean age of participants in studies ranged from 53.8 years to 80.3 years and participants were healthy volunteers, had subjective cognitive decline, or dementia. All studies included in the review were cross‐sectional or cohort studies. Four studies reported on hippocampal volume, with inconclusive or no associations seen with MedDiet adherence. One study found a significant association between higher MedDiet adherence and lower WMHV, while two other studies found no significant associations. Conclusion: Overall, these results highlight a gap in our knowledge about the associations between MedDiet and AD and cerebrovascular related structural neuroimaging findings. Future research is needed including increased frequency of dietary assessments, more sensitive and specific imaging outcomes and the inclusion of data from low‐ and middle‐income countries. [ABSTRACT FROM AUTHOR]

Background: Alzheimer's Disease, the leading cause of dementia, is over‐represented in females. The apolipoprotein E (APOE) ε4 allele is the strongest genetic risk factor for late‐onset AD and is associated with aberrant cerebrospinal fluid levels (CSF) of total tau (t‐tau), phosphorylated tau (p‐tau), and amyloid‐β (Aβ). There is some evidence that sex may mediate the relationship between APOE status and CSF tau, however, evidence is mixed. Method: We aimed to examine the association between sex, APOE ε4 status, CSF Aβ on t‐tau and p‐tau in 1776 mid‐to‐late life individuals without a diagnosis of dementia in the European Prevention of Alzheimer's Dementia (EPAD) longitudinal cohort study. Result: We found a significant interaction between APOE status, sex, and CSF Aβ on CSF p‐tau levels. Specifically, the association between CSF Aβ and CSF p‐tau was stronger in male ε4 carriers relative to female ε4 carriers. Further, in females with high Aβ levels (reflecting less cortical deposition), ε4 carriers had significantly elevated p‐tau levels relative to non‐carriers. However, there were no significant differences in p‐tau between male ε4 carriers and non‐carriers with high Aβ. Conclusion: An interaction between sex and cerebrospinal fluid Aβ may mediate the relationship between APOE status and CSF p‐tau. These data suggest tau accumulation may be independent of Aβ in females, but not males. Future work would benefit from replication in separate cohorts, longitudinal examination, and the consideration of the role of sex hormones on CSF markers. [ABSTRACT FROM AUTHOR]

Background: Promising memory markers for Alzheimer´s dementia (AD) tap into either relational (face‐name) or conjunctive (object‐colour) functions (Rentz et al., 2013). Whereas relational functions appear affected in the early symptomatic stages of AD, conjunctive functions have been found impaired in the pre‐symptomatic stages. Relational but not conjunctive functions are age sensitive. This can delay the detection of AD‐related impairments. No study to date has traced the progression or memory decline in people at risk of AD using these markers. This is an aim of the PREVENT study. Methods: A cohort of 183 healthy adults with age ranging from 40‐60 years (M: 52) underwent assessment at baseline and two‐year follow up (T1). The assessment consisted of the neuropsychological test battery COGNITO (Ritchie et al., 2017), a demographic questionnaire, and four memory tests (relational: Virtual Reality Supermarket Trolley Task (VRST), Name‐Face Association Test (NFAT), and 4 Mountain Test (4MT), and conjunctive: Visual Short‐Term Memory Binding Test (VSTMBT)). Participants also underwent genetic testing to identify APOE genotypes. Risk profiles were defined by the present of Family History and APOE4, with High Risk subjects being positive to both, Middle Risk to either, and Low Risk to neither. Cross‐sectional and longitudinal comparisons were carried out within and across risk groups. Results: Neither cross‐sectional nor longitudinal comparisons revealed differences across risk groups on the memory markers. Only the NFAT significantly correlated with age (p<0.01). The VRST and VSTMBT were not associated to the level of education while the NFAT and 4MT were (p<0.05). Correlations between baseline and T1 were large for all the tests. Performance on the VSTMBT did not correlate with that on any relational memory tasks. The VSRT and 4MT did reveal significant correlations (p<0.001). Conclusion: We have identified an early time window in the ageing continuum where people at risk of dementia show intact cognitive functions known to be markers of AD. We have replicated the previously reported patterns of sensitivity to demographic variables (age and education) and confirmed their potential to dissociate trajectories of memory decline across constructs and risk profiles. [ABSTRACT FROM AUTHOR]

Objectives: To explore whether it is possible to detect decline in global scores of cognitive function in the proximity of death whilst simultaneously investigating potential risk profiles. Methods: Using the Mini Mental State Examination in a population study of the oldest old in which 99% of participants have died, a linear and quadratic time-to-death repeated measures random effects models were used to detect decline and potential factors which might indicate individual variation. Results: Decline and acceleration of this decline were detectable in the period before death. Some between person variation was detected in this pattern, which included differences in cognitive performance by age at death (-0.2 (SE=0.02)), sex (-1.2 (SE=0.2)), initial cognitive impairment (-7.5 (SE=0.2)) and mobility (-0.6 (SE=0.2)), in rate of decline by age at death (-0.04 (SE=0.005)), sex (-0.1 (SE=0.06)), initial cognitive impairment (-0.3 (SE=0.07)) and mobility (-0.1 (SE=0.05)) and differences in change in rate of decline by sex (-0.008 (SE=0.004)), initial cognitive impairment (-0.02 (SE=0.04)) and mobility (-0.01 (SE=0.003)). Conclusion: Using an extension of existing methods for exploring terminal decline, the phenomenon of decline in global cognition measures in the proximity of death was clearly detected as well as potential variables which could influence that pattern. Further work is required to explore whether similar methods can be used to detect the onset of the acceleration of this decline in each individual together with the potential to identify individual level factors that can allow clinicians to distinguish between the normal and preterminal phases of change in extreme old age. [ABSTRACT FROM AUTHOR]

The article discusses a new smooth polynomial change point model. The authors used data from a population-based longitudinal study of ageing, the Cambridge City over 75 Cohort Study. The study also aimed to identify how individuals many years before death experience a change in the rate of decline in their cognitive ability. They illustrated how the new model together with the Bacon-Watts model can be used as a mixed effects model.

Objectives Investigate the impact of the changes in eligibility within England and Wales (E&W) for prescription within the UK National Health Service for treatment of Alzheimer's disease (AD). Methods A population-based study in England and Wales with 13 004 individuals measured with MMSE at baseline was used to examine the distributions of individuals within eligibility criteria. Information obtained from informants enabled classification of the study defined dementia cases to ICD10 diagnosis of subtype (AD, dementia with vascular risk, both or other). Results Fifty six per cent of dementia patients (representing 323 000 individuals in E&W) fall into the new MMSE criteria band. A further 120 000, 20% of dementia patients, are estimated to have disease that is considered too mild for treatment. Further examination of type of dementia showed that those with mixed AD and vascular dementia had similar proportions of dementia cases within the treatable MMSE group as the subgroup with AD alone, though with mixed disease individuals more often score below the lower threshold. There is substantial instability in the eligibility groupings over a short time period. Conclusions The population impact of new NICE criteria of excluding high MMSE scores is to exclude one in five individuals with AD and a further one in ten of those with a mixed disease. Changing the guidance has almost balanced the loss of treatment for the high MMSE group (13%) with the introduction of treatment for those scoring 10/11 (11%). Copyright © 2009 John Wiley & Sons, Ltd. [ABSTRACT FROM AUTHOR]

This study examined how socioeconomic status (SES) influences on decision‐making processing. The roles of anticipatory/outcome‐related cardiac activity and awareness of task contingencies were also assessed. One hundred twelve children (Mage = 5.83, SDage = 0.32; 52.7% female, 51.8% low‐SES; data collected October–December 2018 and April–December 2019) performed the Children's Gambling Task, while heart rate activity was recorded. Awareness of gain/loss contingencies was assessed after completing the task. Distinct decision‐making strategies emerged among low and middle/high‐SES children. Despite similar awareness levels between SES groups, future‐oriented decision‐making was linked solely to the middle/high‐SES group. Somatic markers did not manifest unequivocally. However, contrasting cardiac patterns were evident concerning feedback processing and the association between anticipatory activity and awareness (low: acceleration vs. middle/high: deceleration). Results are interpreted from an evolutionary‐developmental perspective. [ABSTRACT FROM AUTHOR]