Feasibility and reliability of online vs in-person cognitive testing in healthy older people.

BACKGROUND: Early evidence in using online cognitive assessments show that they could offer a feasible and resource-efficient alternative to in-person clinical assessments in evaluating cognitive performance, yet there is currently little understanding about how these assessments relate to traditional, in-person cognitive tests. OBJECTIVES: In this preliminary study, we assess the feasibility and reliability of NeurOn, a novel online cognitive assessment tool. NeurOn measures various cognitive domains including processing speed, executive functioning, spatial working memory, episodic memory, attentional control, visuospatial functioning, and spatial orientation. DESIGN: Thirty-two participants (mean age: 70.19) completed two testing sessions, unsupervised online and in-person, one-week apart. Participants were randomised in the order of testing appointments. For both sessions, participants completed questionnaires prior to a cognitive assessment. Test-retest reliability and concurrent validity of the online cognitive battery was assessed using intraclass correlation coefficients (ICCs) and correlational analysis, respectively. This was conducted by comparing performance in repeated tasks across testing sessions as well as with traditional, in-person cognitive tests. RESULTS: Global cognition in the NeurOn battery moderately validated against MoCA performance, and the battery demonstrated moderate test-retest reliability. Concurrent validity was found only between the online and paper versions of the Trail Making Test -A, as well as global cognitive performance between online and in-person testing sessions. CONCLUSIONS: The NeurOn cognitive battery provides a promising tool for measuring cognitive performance online both longitudinally and across short retesting intervals within healthy older adults. When considering cost-effectiveness, flexible administration, and improved accessibility for wider populations, online cognitive assessments show promise for future screening of neurodegenerative diseases.

Combining patient-lesion and big data approaches to reveal hippocampal contributions to spatial memory and navigation.

Classic findings of impaired allocentric spatial learning and memory following hippocampal lesions indicate that the hippocampus supports cognitive maps of one's environment. Many studies assess navigation in vista space virtual reality environments and compare hippocampal-lesioned individuals' performance to that of small control samples, potentially stifling detection of preserved and impaired performance. Using the mobile app Sea Hero Quest, we examined navigation in diverse complex environments in two individuals with hippocampal lesions relative to demographically matched controls (N = 17,734). We found surprisingly accurate navigation in several environments, particularly those containing a constrained set of sub-goals, paths, and/or turns. Areas of impaired performance may reflect a role for the hippocampus in anterograde memory and more flexible and/or precise spatial representations, even when the need for allocentric processing is minimal. The results emphasize the value of combining single cases with big data and illustrate navigation performance profiles in individuals with hippocampal compromise.

Evoking episodic and semantic details with instructional manipulation during autobiographical recall.

Older adults tend to describe experiences from their past with fewer episodic details, such as spatiotemporal and contextually specific information, but more nonepisodic details, particularly personal semantic knowledge, than younger adults. While the reduction in episodic details is interpreted in the context of episodic memory decline typical of aging, interpreting the increased production of semantic details is not as straightforward. We modified the widely used Autobiographical Interview (AI) to create a Semantic Autobiographical Interview (SAI) that explicitly targets personal (P-SAI) and general semantic memories (G-SAI) with the aim of better understanding the production of semantic information in aging depending on instructional manipulation. Overall, older adults produced a lower proportion of target details than young adults. There was an intra-individual consistency in the production of target details in the AI and P-SAI, suggesting a trait level in the production of personal target details or consistency in the narrative style and communicative goals adopted across interviews. Older adults consistently produced autobiographical facts and self-knowledge across interviews, suggesting that they are biased toward the production of personal semantic information regardless of instructions. These results cannot be easily accommodated by accounts of aging and memory emphasizing reduced cognitive control or compensation for episodic memory impairment. Nevertheless, future work is needed to fully disentangle between these accounts. (PsycInfo Database Record (c) 2024 APA, all rights reserved).

The relationship between object-based spatial ability and virtual navigation performance.

Spatial navigation is a multi-faceted behaviour drawing on many different aspects of cognition. Visuospatial abilities, such as mental rotation and visuospatial working memory, in particular, may be key factors. A range of tests have been developed to assess visuospatial processing and memory, but how such tests relate to navigation ability remains unclear. This understanding is important to advance tests of navigation for disease monitoring in various disorders (e.g., Alzheimer's disease) where spatial impairment is an early symptom. Here, we report the use of an established mobile gaming app, Sea Hero Quest (SHQ), as a measure of navigation ability in a sample of young, predominantly female university students (N = 78; 20; female = 74.3%; mean age = 20.33 years). We used three separate tests of navigation embedded in SHQ: wayfinding, path integration and spatial memory in a radial arm maze. In the same participants, we also collected measures of mental rotation (Mental Rotation Test), visuospatial processing (Design Organization Test) and visuospatial working memory (Digital Corsi). We found few strong correlations across our measures. Being good at wayfinding in a virtual navigation test does not mean an individual will also be good at path integration, have a superior memory in a radial arm maze, or rate themself as having a strong sense of direction. However, we observed that participants who were good in the wayfinding task of SHQ tended to perform well on the three visuospatial tasks examined here, and to also use a landmark strategy in the radial maze task. These findings help clarify the associations between different abilities involved in spatial navigation.

The 2022 symposium on dementia and brain aging in low- and middle-income countries: Highlights on research, diagnosis, care, and impact.

Two of every three persons living with dementia reside in low- and middle-income countries (LMICs). The projected increase in global dementia rates is expected to affect LMICs disproportionately. However, the majority of global dementia care costs occur in high-income countries (HICs), with dementia research predominantly focusing on HICs. This imbalance necessitates LMIC-focused research to ensure that characterization of dementia accurately reflects the involvement and specificities of diverse populations. Development of effective preventive, diagnostic, and therapeutic approaches for dementia in LMICs requires targeted, personalized, and harmonized efforts. Our article represents timely discussions at the 2022 Symposium on Dementia and Brain Aging in LMICs that identified the foremost opportunities to advance dementia research, differential diagnosis, use of neuropsychometric tools, awareness, and treatment options. We highlight key topics discussed at the meeting and provide future recommendations to foster a more equitable landscape for dementia prevention, diagnosis, care, policy, and management in LMICs. HIGHLIGHTS: Two-thirds of persons with dementia live in LMICs, yet research and costs are skewed toward HICs. LMICs expect dementia prevalence to more than double, accompanied by socioeconomic disparities. The 2022 Symposium on Dementia in LMICs addressed advances in research, diagnosis, prevention, and policy. The Nairobi Declaration urges global action to enhance dementia outcomes in LMICs.

Effects of the COVID-19 associated United Kingdom lockdown on physical activity in older adults at high risk of cardiovascular disease: a mixed methods perspective from the MedEx-UK multicenter trial.

Introduction: Physical inactivity and sedentary behaviour are linked to increased risk of cardiovascular disease, infections and dementia, as well as placing a significant economic burden on healthcare systems. The implementation of COVID-19 pandemic lockdown measures aimed at reducing virus transmission posed challenges to the opportunity to be physically active. This study investigates how the first UK COVID-19 lockdown affected objectively measured physical activity in older adults at higher risk of cardiovascular disease. Methods: We studied 48 individuals aged 55-74 years (81.3% female) with self-reported PA levels < 90 min/week and a QRISK2 score ≥ 10 (indicative of a ≥ 10% risk of a major cardiovascular event in the next 10 years) without mild cognitive impairment or dementia. Physical activity data was collected using objective wrist-based activity monitors and analysed across three time periods, usual activity (pre-pandemic), the precautionary phase when the UK began advising on limiting social contact and finally during the first UK lockdown period was collected (27 January 2020 and 07 June 2020). Data was analysed using linear mixed effects model was used to investigate PA levels over the measured 12-week period. Effects of BMI, age, deprivation score and baseline PA levels on PA across the three measurement periods were also examined. Focus-group and individual interviews were conducted, and data were thematically analysed. Results: Average daily step count (-34% lower, p < 0.001) and active energy expenditure (-26% lower, p < 0.001) were significantly lower during the precautionary period compared with the usual activity period. Physical activity remained low during the UK lockdown period. Participants with a lower BMI engaged in significantly more (+45% higher daily steps p < 0.001) physical activity and those over 70 years old were more physically active than those under 70 years across the 12-week period (+23% higher daily steps p < 0.007). The risk of COVID-19 infection and restrictions because of lockdown measures meant some individuals had to find alternative methods to staying physical active. Participants described a lack of access to facilities and concerns over health related to COVID-19 as barriers to engaging in physical activity during lockdown. For some, this resulted in a shift towards less structured activities such as gardening or going for a walk. Discussion: The data presented shows that lockdown measures during the COVID-19 pandemic significantly reduced physical activity among older individuals at risk of cardiovascular disease, particularly those with a higher body mass index. To support this population group in staying active during future lockdowns, a multifaceted strategy is needed, emphasizing psychosocial benefits and home-based physical activity. The MedEx-UK study was pre-registered with ClinicalTrials.gov (NCT03673722).

Imagery and Verbal Strategies in Spatial Memory for Route and Survey Descriptions.

Being able to represent and remember verbally-encoded information about spatial environments from different perspectives is important for numerous daily activities. The present study examined how frequently individuals spontaneously engage in visual mental imagery and verbal rehearsal strategies in memory recall of spatial descriptions, and whether using certain strategies is associated with better recall performance. Memory recall for route (person-centred) and survey (object-centred) spatial descriptions was examined in a sample of 105 neurotypical individuals, who also reported to what extent they used route- and survey-based mental imagery and verbal rehearsal strategies in each description. Results showed that participants favoured a path visualisation strategy to recall the route description and a map visualisation strategy to recall the survey description. Regression models further showed that employing both imagery and verbal strategies was associated with better recall for both route and survey descriptions, although imagery strategies held a higher predictive power. The present findings highlight the fact that the spontaneous use of internal strategies in the form of visual imagery and verbal rehearsal is ubiquitous when recalling spatial descriptions and a core part of efficient spatial memory functioning.

Shorter self-reported sleep duration is associated with worse virtual spatial navigation performance in men.

Sleep has been shown to impact navigation ability. However, it remains unclear how different sleep-related variables may be independently associated with spatial navigation performance, and as to whether gender may play a role in these associations. We used a mobile video game app, Sea Hero Quest (SHQ), to measure wayfinding ability in US-based participants. Wayfinding performance on SHQ has been shown to correlate with real-world wayfinding. Participants were asked to report their sleep duration, quality, daytime sleepiness and nap frequency and duration on a typical night (n = 766, 335 men, 431 women, mean age = 26.5 years, range = 18-59 years). A multiple linear regression was used to identify which self-reported sleep variables were independently associated with wayfinding performance. Shorter self-reported sleep durations were significantly associated with worse wayfinding performance in men only. Other self-reported sleep variables showed non-significant trends of association with wayfinding performance. When removing non-typical sleepers (< 6 or > 9 h of sleep on a typical night), the significant association between sleep duration and spatial navigation performance in men was no longer present. These findings from U.S.-based participants suggest that a longer self-reported sleep duration may be an important contributor to successful navigation ability in men.

Investigating the synergistic effects of hormone replacement therapy, apolipoprotein E and age on brain health in the UK Biobank.

Global prevalence of Alzheimer's Disease has a strong sex bias, with women representing approximately two-thirds of the patients. Yet, the role of sex-specific risk factors during midlife, including hormone replacement therapy (HRT) and their interaction with other major risk factors for Alzheimer's Disease, such as apolipoprotein E (APOE)-e4 genotype and age, on brain health remains unclear. We investigated the relationship between HRT (i.e., use, age of initiation and duration of use) and brain health (i.e., cognition and regional brain volumes). We then consider the multiplicative effects of HRT and APOE status (i.e., e2/e2, e2/e3, e3/e3, e3/e4 and e4/e4) via a two-way interaction and subsequently age of participants via a three-way interaction. Women from the UK Biobank with no self-reported neurological conditions were included (N = 207,595 women, mean age = 56.25 years, standard deviation = 8.01 years). Generalised linear regression models were computed to quantify the cross-sectional association between HRT and brain health, while controlling for APOE status, age, time since attending centre for completing brain health measure, surgical menopause status, smoking history, body mass index, education, physical activity, alcohol use, ethnicity, socioeconomic status, vascular/heart problems and diabetes diagnosed by doctor. Analyses of structural brain regions further controlled for scanner site. All brain volumes were normalised for head size. Two-way interactions between HRT and APOE status were modelled, in addition to three-way interactions including age. Results showed that women with the e4/e4 genotype who have used HRT had 1.82% lower hippocampal, 2.4% lower parahippocampal and 1.24% lower thalamus volumes than those with the e3/e3 genotype who had never used HRT. However, this interaction was not detected for measures of cognition. No clinically meaningful three-way interaction between APOE, HRT and age was detected when interpreted relative to the scales of the cognitive measures used and normative models of ageing for brain volumes in this sample. Differences in hippocampal volume between women with the e4/e4 genotype who have used HRT and those with the e3/e3 genotype who had never used HRT are equivalent to approximately 1-2 years of hippocampal atrophy observed in typical health ageing trajectories in midlife (i.e., 0.98%-1.41% per year). Effect sizes were consistent within APOE e4/e4 group post hoc sensitivity analyses, suggesting observed effects were not solely driven by APOE status and may, in part, be attributed to HRT use. Although, the design of this study means we cannot exclude the possibility that women who have used HRT may have a predisposition for poorer brain health.

Cut-off scores for mild and moderate dementia on the Addenbrooke's Cognitive Examination-III and the Mini-Addenbrooke's Cognitive Examination compared with the Mini-Mental State Examination.

AIMS AND METHOD: We aimed to establish cut-off scores to stage dementia on the Addenbrooke's Cognitive Examination-III (ACE-III) and the Mini-Addenbrooke's Cognitive Examination (M-ACE) compared with scores traditionally used with the Mini-Mental State Examination (MMSE). Our cross-sectional study recruited 80 patients and carers from secondary care services in the UK. RESULTS: A score ≤76 on the ACE-III and ≤19 on the M-ACE correlated well with MMSE cut-offs for mild dementia, with a good fit on the receiver operating characteristic analysis for both the ACE-III and M-ACE. The cut-off for moderate dementia had lower sensitivity and specificity. There were low to moderate correlations between the cognitive scales and scales for everyday functioning and behaviour. CLINICAL IMPLICATIONS: Our findings allow an objective interpretation of scores on the ACE-III and the M-ACE relative to the MMSE, which may be helpful for clinical services and research trials.

The Impact of Spatial Orientation Changes on Driving Behavior in Healthy Aging.

OBJECTIVES: Global cognitive changes in older age affect driving behavior and road safety, but how spatial orientation differences affect driving behaviors is unknown on a population level, despite clear implications for driving policy and evaluation during aging. The present study aimed to establish how spatial navigation changes affect driving behavior and road safety within a large cohort of older adults. METHODS: Eight hundred and four participants (mean age: 71.05) were recruited for a prospective cohort study. Participants self-reported driving behavior followed by spatial orientation (allocentric and egocentric) testing and a broader online cognitive battery (visuomotor speed, processing speed, executive functioning, spatial working memory, episodic memory, visuospatial functioning). RESULTS: Spatial orientation performance significantly predicted driving difficulty and frequency. Experiencing more driving difficulty was associated with worse allocentric spatial orientation, processing speed, and source memory performance. Similarly, avoiding challenging driving situations was associated with worse spatial orientation and episodic memory. Allocentric spatial orientation was the only cognitive domain consistently affecting driving behavior in under 70 and over 70 age groups, a common age threshold for driving evaluation in older age. DISCUSSION: We established for the first time that worse spatial orientation performance predicted increased driving difficulty and avoidance of challenging situations within an older adult cohort. Deficits in spatial orientation emerge as a robust indicator of driving performance in older age, which should be considered in future aging driving assessments, as it has clear relevance for road safety within the aging population.

Unravelling phenolic metabotypes in the frame of the COMBAT study, a randomized, controlled trial with cranberry supplementation.

Cranberry (poly)phenols may have potential health benefits. Circulating (poly)phenol metabolites can act as mediators of these effects, but they are subjected to an extensive inter-individual variability. This study aimed to quantify both plasma and urine (poly)phenol metabolites following a 12-week intake of a cranberry powder in healthy older adults, and to investigate inter-individual differences by considering the existence of urinary metabotypes related to dietary (poly)phenols. Up to 13 and 67 metabolites were quantified in plasma and urine respectively. Cranberry consumption led to changes in plasma metabolites, mainly hydroxycinnamates and hippuric acid. Individual variability in urinary metabolites was assessed using different data sets and a combination of statistical models. Three phenolic metabotypes were identified, colonic metabolism being the main driver for subject clustering. Metabotypes were characterized by quali-quantitative differences in the excretion of some metabolites such as phenyl-γ-valerolactones, hydroxycinnamic acids, and phenylpropanoic acids. Metabotypes were further confirmed when applying a model only focused on flavan-3-ol colonic metabolites. 5-(3',4'-dihydroxyphenyl)-γ-valerolactone derivatives were the most relevant metabolites for metabotyping. Metabotype allocation was well preserved after 12-week intervention. This metabotyping approach for cranberry metabolites represents an innovative step to handle the complexity of (poly)phenol metabolism in free-living conditions, deciphering the existence of metabotypes derived from the simultaneous consumption of different classes of (poly)phenols. These results will help contribute to studying the health effects of cranberries and other (poly)phenol-rich foods, mainly considering gut microbiota-driven individual differences.

Examining individual learning patterns using generalised linear mixed models.

Everyone learns differently, but individual performance is often ignored in favour of a group-level analysis. Using data from four different experiments, we show that generalised linear mixed models (GLMMs) and extensions can be used to examine individual learning patterns. Producing ellipsoids and cluster analyses based on predicted random effects, individual learning patterns can be identified, clustered and used for comparisons across various experimental conditions or groups. This analysis can handle a range of datasets including discrete, continuous, censored and non-censored, as well as different experimental conditions, sample sizes and trial numbers. Using this approach, we show that learning a face-named paired associative task produced individuals that can learn quickly, with the performance of some remaining high, but with a drop-off in others, whereas other individuals show poor performance throughout the learning period. We see this more clearly in a virtual navigation spatial learning task (NavWell). Two prominent clusters of learning emerged, one showing individuals who produced a rapid learning and another showing a slow and gradual learning pattern. Using data from another spatial learning task (Sea Hero Quest), we show that individuals' performance generally reflects their age category, but not always. Overall, using this analytical approach may help practitioners in education and medicine to identify those individuals who might need extra help and attention. In addition, identifying learning patterns may enable further investigation of the underlying neural, biological, environmental and other factors associated with these individuals.

Spatial cognition is associated with levels of phosphorylated-tau and ß-amyloid in clinically normal older adults.

Spatial cognition is associated with Alzheimer's disease (AD) biomarkers in the symptomatic stages of the disease. We investigated whether cerebrospinal fluid (CSF) biomarkers (phosphorylated-tau [p-tau] and ß-amyloid) are associated with poorer spatial cognition in clinically normal older adults. Participants were 1875 clinically normal adults (age 67.8 [8.5] years) from the European Prevention of Alzheimer's Dementia Consortium. Mixed effect models assessed the cross-sectional association between p-tau181, ß-amyloid1-42 (Aß1-42) and p-tau181/Aß1-42 ratio and spatial cognition measured using semi-automated Supermarket Task and the 4 Mountains Task. Levels of p-tau181, Aß1-42, and p-tau181/Aß1-42 ratio were significantly associated with spatial cognition scores on both tasks. The p-tau181/Aß1-42 ratio showed the largest effect sizes (ß = -0.04/0.05, p < 0.001). Lower entorhinal cortical volume was associated with poorer outcomes on both tasks (ß = 0.06, p < 0.002) and accounted for 18%-22% of the direct association between p-tau181 and spatial cognition scores. In conclusion, degeneration of the entorhinal cortex mediates a significant proportion of the association between p-tau181 and spatial assessments in cognitively normal adults. Future studies should focus on increasing the sensitivity of digital spatial assessments.

Thalamic nuclei changes in early and late onset Alzheimer's disease.

Alzheimer's disease (AD) is the most common cause of dementia worldwide. Increasing evidence points to the thalamus as an important hub in the clinical symptomatology of the disease, with the 'limbic thalamus' been described as especially vulnerable. In this work, we examined thalamic atrophy in early-onset AD (EOAD) and late-onset AD (LOAD) compared to young and old healthy controls (YHC and OHC, respectively) using a recently developed cutting-edge thalamic nuclei segmentation method. A deep learning variant of Thalamus Optimized Multi Atlas Segmentation (THOMAS) was used to parcellate 11 thalamic nuclei per hemisphere from T1-weighted MRI in 88 biomarker-confirmed AD patients (49 EOAD and 39 LOAD) and 58 healthy controls (41 YHC and 17 OHC) with normal AD biomarkers. Nuclei volumes were compared among groups using MANCOVA. Further, Pearson's correlation coefficient was computed between thalamic nuclear volume and cortical-subcortical regions, CSF tau levels, and neuropsychological scores. The results showed widespread thalamic nuclei atrophy in EOAD and LOAD compared to their respective healthy control groups, with EOAD showing additional atrophy in the centromedian and ventral lateral posterior nuclei compared to YHC. In EOAD, increased thalamic nuclei atrophy was associated with posterior parietal atrophy and worse visuospatial abilities, while LOAD thalamic nuclei atrophy was preferentially associated with medial temporal atrophy and worse episodic memory and executive function. Our findings suggest that thalamic nuclei may be differentially affected in AD according to the age at symptoms onset, associated with specific cortical-subcortical regions, CSF total tau and cognition.

Heterogeneous factors influence social cognition across diverse settings in brain health and age-related diseases.

Aging may diminish social cognition, which is crucial for interaction with others, and significant changes in this capacity can indicate pathological processes like dementia. However, the extent to which non-specific factors explain variability in social cognition performance, especially among older adults and in global settings, remains unknown. A computational approach assessed combined heterogeneous contributors to social cognition in a diverse sample of 1063 older adults from 9 countries. Support vector regressions predicted the performance in emotion recognition, mentalizing, and a total social cognition score from a combination of disparate factors, including clinical diagnosis (healthy controls, subjective cognitive complaints, mild cognitive impairment, Alzheimer's disease, behavioral variant frontotemporal dementia), demographics (sex, age, education, and country income as a proxy of socioeconomic status), cognition (cognitive and executive functions), structural brain reserve, and in-scanner motion artifacts. Cognitive and executive functions and educational level consistently emerged among the top predictors of social cognition across models. Such non-specific factors showed more substantial influence than diagnosis (dementia or cognitive decline) and brain reserve. Notably, age did not make a significant contribution when considering all predictors. While fMRI brain networks did not show predictive value, head movements significantly contributed to emotion recognition. Models explained between 28-44% of the variance in social cognition performance. Results challenge traditional interpretations of age-related decline, patient-control differences, and brain signatures of social cognition, emphasizing the role of heterogeneous factors. Findings advance our understanding of social cognition in brain health and disease, with implications for predictive models, assessments, and interventions.

Wayfinding and path integration deficits detected using a virtual reality mobile app in patients with traumatic brain injury.

The ability to navigate is supported by a wide network of brain areas which are particularly vulnerable to disruption brain injury, including traumatic brain injury (TBI). Wayfinding and the ability to orient back to the direction you have recently come (path integration) may likely be impacted in daily life but have so far not been tested with patients with TBI. Here, we assessed spatial navigation in thirty-eight participants, fifteen of whom had a history of TBI, and twenty-three control participants. Self-estimated spatial navigation ability was assessed using the Santa Barbara Sense of Direction (SBSOD) scale. No significant difference between TBI patients and a control group was identified. Rather, results indicated that both participant groups demonstrated 'good' self-inferred spatial navigational ability on the SBSOD scale. Objective navigation ability was tested via the virtual mobile app test Sea Hero Quest (SHQ), which has been shown to predict real-world navigation difficulties and assesses (a) wayfinding across several environments and (b) path integration. Compared to a sub-sample of 13 control participants, a matched subsample of 10 TBI patients demonstrated generally poorer performance on all wayfinding environments tested. Further analysis revealed that TBI participants consistently spent a shorter duration viewing a map prior to navigating to goals. Patients showed mixed performance on the path integration task, with poor performance evident when proximal cues were absent. Our results provide preliminary evidence that TBI impacts both wayfinding and, to some extent, path integration. The findings suggest long-lasting clinical difficulties experienced in TBI patients affect both wayfinding and to some degree path integration ability.

Multimorbidity pattern and risk of dementia in later life: an 11-year follow-up study using a large community cohort and linked electronic health records.

BACKGROUND: Several long-term chronic illnesses are known to be associated with an increased risk of dementia independently, but little is known how combinations or clusters of potentially interacting chronic conditions may influence the risk of developing dementia. METHODS: 447 888 dementia-free participants of the UK Biobank cohort at baseline (2006-2010) were followed-up until 31 May 2020 with a median follow-up duration of 11.3 years to identify incident cases of dementia. Latent class analysis (LCA) was used to identify multimorbidity patterns at baseline and covariate adjusted Cox regression was used to investigate their predictive effects on the risk of developing dementia. Potential effect moderations by C reactive protein (CRP) and Apolipoprotein E (APOE) genotype were assessed via statistical interaction. RESULTS: LCA identified four multimorbidity clusters representing Mental health, Cardiometabolic, Inflammatory/autoimmune and Cancer-related pathophysiology, respectively. Estimated HRs suggest that multimorbidity clusters dominated by Mental health (HR=2.12, p<0.001, 95% CI 1.88 to 2.39) and Cardiometabolic conditions (2.02, p<0.001, 1.87 to 2.19) have the highest risk of developing dementia. Risk level for the Inflammatory/autoimmune cluster was intermediate (1.56, p<0.001, 1.37 to 1.78) and that for the Cancer cluster was least pronounced (1.36, p<0.001, 1.17 to 1.57). Contrary to expectation, neither CRP nor APOE genotype was found to moderate the effects of multimorbidity clusters on the risk of dementia. CONCLUSIONS: Early identification of older adults at higher risk of accumulating multimorbidity of specific pathophysiology and tailored interventions to prevent or delay the onset of such multimorbidity may help prevention of dementia.

Hormone replacement therapy is associated with improved cognition and larger brain volumes in at-risk APOE4 women: results from the European Prevention of Alzheimer's Disease (EPAD) cohort.

BACKGROUND: The risk of dementia is higher in women than men. The metabolic consequences of estrogen decline during menopause accelerate neuropathology in women. The use of hormone replacement therapy (HRT) in the prevention of cognitive decline has shown conflicting results. Here we investigate the modulating role of APOE genotype and age at HRT initiation on the heterogeneity in cognitive response to HRT. METHODS: The analysis used baseline data from participants in the European Prevention of Alzheimer's Dementia (EPAD) cohort (total n= 1906, women= 1178, 61.8%). Analysis of covariate (ANCOVA) models were employed to test the independent and interactive impact of APOE genotype and HRT on select cognitive tests, such as MMSE, RBANS, dot counting, Four Mountain Test (FMT), and the supermarket trolley test (SMT), together with volumes of the medial temporal lobe (MTL) regions by MRI. Multiple linear regression models were used to examine the impact of age of HRT initiation according to APOE4 carrier status on these cognitive and MRI outcomes. RESULTS: APOE4 HRT users had the highest RBANS delayed memory index score (P-APOE*HRT interaction = 0.009) compared to APOE4 non-users and to non-APOE4 carriers, with 6-10% larger entorhinal (left) and amygdala (right and left) volumes (P-interaction= 0.002, 0.003, and 0.005 respectively). Earlier introduction of HRT was associated with larger right (standardized ß= -0.555, p=0.035) and left hippocampal volumes (standardized ß= -0.577, p=0.028) only in APOE4 carriers. CONCLUSION: HRT introduction is associated with improved delayed memory and larger entorhinal and amygdala volumes in APOE4 carriers only. This may represent an effective targeted strategy to mitigate the higher life-time risk of AD in this large at-risk population subgroup. Confirmation of findings in a fit for purpose RCT with prospective recruitment based on APOE genotype is needed to establish causality.