Impact of Short-Term Computerized Cognitive Training on Cognition in Older Adults With and Without Genetic Risk of Alzheimer's Disease: Outcomes From the START Randomized Controlled Trial.

OBJECTIVES: To establish the impact of a 3-minute computerized cognitive training program (START) on cognition in older adults with and without genetic risk of Alzheimer's disease. DESIGN: Two-arm randomized controlled trial of the START program. SETTING AND PARTICIPANTS: Remote online trial in adults older than 50 taking part from home. METHODS: The trial compared the START program with placebo in 6544 people older than 50. Primary outcome was executive function measured through Trailmaking B, with other secondary cognitive measures. Genetic risk profile and ApoE4 status were determined by Illumina Array. RESULTS: START conferred benefit to executive function, attention, memory, and a composite measure, including in people with the ApoE4 genotype. CONCLUSIONS AND IMPLICATIONS: The 3-minute START task offers a means of supporting cognitive health in older adults and could be used at scale and within a precision medicine approach to reduce risk of cognitive decline in a targeted way.

Progress in Pharmacologic Management of Neuropsychiatric Syndromes in Neurodegenerative Disorders: A Review.

Importance: Neuropsychiatric syndromes (NPSs) are common in neurodegenerative disorders (NDDs); compromise the quality of life of patients and their care partners; and are associated with faster disease progression, earlier need for nursing home care, and poorer quality of life. Advances in translational pharmacology, clinical trial design and conduct, and understanding of the pathobiology of NDDs are bringing new therapies to clinical care. Observations: Consensus definitions have evolved for psychosis, agitation, apathy, depression, and disinhibition in NDDs. Psychosocial interventions may reduce mild behavioral symptoms in patients with NDD, and pharmacotherapy is available for NPSs in NDDs. Brexpiprazole is approved for treatment of agitation associated with Alzheimer disease dementia, and pimavanserin is approved for treatment of delusions and hallucinations associated with psychosis of Parkinson disease. Trials are being conducted across several of the NDDs, and a variety of mechanisms of action are being assessed for their effect on NPSs. Conclusions and Relevance: Detection and characterization of NPSs in patients with NDDs is the foundation for excellent care. New definitions for NPSs in NDDs may inform choices regarding clinical trial populations and translate into clinical practice. Psychosocial and pharmacologic therapies may reduce behavioral symptoms and improve quality of life for patients and caregivers. Approved agents may establish regulatory precedents, demonstrate successful trial strategies, and provide the foundation for further advances in treatment development.

Is lifetime traumatic brain injury a risk factor for mild cognitive impairment in veterans compared to non-veterans?

Background: Traumatic brain injury (TBI) is prevalent in veterans and may occur at any stages of their life (before, during, or after military service). This is of particular concern, as previous evidence in the general population has identified TBI as a strong risk factor for mild cognitive impairment (MCI), a known precursor of dementia.Objectives: This study aimed to investigate whether exposure to at least one TBI across the lifetime was a risk factor for MCI in ageing UK veterans compared to non-veterans.Method: This cross-sectional study comprised of data from PROTECT, a cohort study comprising UK veterans and non-veterans aged ≥ 50 years at baseline. Veteran and TBI status were self-reported using the Military Service History Questionnaire (MSHQ) and the Brain Injury Screening Questionnaire (BISQ), respectively. MCI was the outcome of interest, and was defined as subjective cognitive impairment and objective cognitive impairment.Results: The sample population comprised of veterans (n = 701) and non-veterans (n = 12,389). TBI was a significant risk factor for MCI in the overall sample (OR = 1.21, 95% CI 1.11-1.31) compared to individuals without TBI. The prevalence of TBI was significantly higher in veterans compared to non-veterans (69.9% vs 59.5%, p < .001). There was no significant difference in the risk of MCI between veterans with TBI and non-veterans with TBI (OR = 1.19, 95% CI 0.98-1.45).Conclusion: TBI remains an important risk factor for MCI, irrespective of veteran status. The clinical implications indicate the need for early intervention for MCI prevention after TBI.

Data from the PROTECT study, a longitudinal study comprising over 25,000 middle-aged and ageing adults in the UK, were used in this first UK comparative study to explore the association between a lifetime history of traumatic brain injury (TBI) and mild cognitive impairment (MCI) in UK veterans and non-veterans.Lifetime TBI was more prevalent in veterans compared to non-veterans. TBI events in military veterans could be attributed to non-military events.Exposure to a history of TBI irrespective of veteran status increased the risk of MCI by 21% compared to adults with no history of TBI.The risk of MCI did not significantly differ between veterans and non-veterans with TBI.

The relationship between playing musical instruments and cognitive trajectories: Analysis from a UK ageing cohort.

BACKGROUND: The accumulation of age-associated cognitive deficits can lead to Mild Cognitive Impairment (MCI) and dementia. This is a major public health issue for the modern ageing population, as it impairs health, independence and overall quality of life. Keeping the brain active during life has been associated with an increased cognitive reserve, therefore reducing the risk of cognitive impairment in older age. Previous research has identified a potential relationship between musicality and cognition. OBJECTIVES: Explore the relationship between musicality and cognitive function in a large cohort of older adults. METHODS: This was a nested study within the PROTECT-UK cohort, which collects longitudinal computerised assessments of cognitive function in adults over 40. Participants were invited to complete the validated Edinburgh Lifetime Musical Experience Questionnaire (ELMEQ) to assess their musical experience and lifetime exposure to music. Linear regression analysis was performed using cognitive data from PROTECT-UK. RESULTS: Analysis identified an association between musicality and cognition in this cohort. Playing a musical instrument was associated with significantly better performance in working memory and executive function. Significant associations were also found between singing and executive function, and between overall musical ability and working memory. CONCLUSIONS: Our findings confirm previous literature, highlighting the potential value of education and engagement in musical activities throughout life as a means of harnessing cognitive reserve as part of a protective lifestyle for brain health.

Impact of the iWHELD digital person-centered care program on quality of life, agitation and psychotropic medications in people with dementia living in nursing homes during the COVID-19 pandemic: A randomized controlled trial.

INTRODUCTION: iWHELD is a digital person-centered care program for people with dementia in nursing homes adapted for remote delivery during the COVID-19 pandemic. METHODS: A 16-week two-arm cluster-randomized controlled trial in 149 UK nursing homes compared iWHELD with treatment as usual (TAU). Primary outcome was the overall quality of life with secondary outcomes of agitation and psychotropic use. RESULTS: iWHELD conferred benefit to quality of life on the primary (F = 4.3, p = 0.04) and secondary measures of quality of life (F = 6.45, p = 0.01) and reduced psychotropic medication use (χ2  = 4.08, p = 0.04) with no worsening of agitation. Benefit was seen in participants who contracted COVID-19, those with agitation at baseline, and those taking psychotropic medications. DISCUSSION: iWHELD confers benefits to quality of life and key measures of well-being, can be delivered during the challenging conditions of a pandemic, and should be considered for use alongside any emerging pharmacological treatment for neuropsychiatric symptoms. HIGHLIGHTS: iWHELD is the only remote, digital delivery nursing home training programme for dementia care iWHELD improved quality of life in people with dementia and reduced antipsychotic use without worsening of agitation Residents who contracted Covid-19 during the study also experienced benefits from iWHELD iWHELD offers a valuable, pandemic-safe tool for improving dementia care.

Proof-of-concept recall-by-genotype study of extremely low and high Alzheimer's polygenic risk reveals autobiographical deficits and cingulate cortex correlates.

BACKGROUND: Genome-wide association studies demonstrate that Alzheimer's disease (AD) has a highly polygenic architecture, where thousands of independent genetic variants explain risk with high classification accuracy. This AD polygenic risk score (AD-PRS) has been previously linked to preclinical cognitive and neuroimaging features observed in asymptomatic individuals. However, shared variance between AD-PRS and neurocognitive features are small, suggesting limited preclinical utility. METHODS: Here, we recruited sixteen clinically asymptomatic individuals (mean age 67; range 58-76) with either extremely low / high AD-PRS (defined as at least 2 standard deviations from the wider sample mean (N = 4504; N EFFECTIVE = 90)) with comparable age sex and education level. We assessed group differences in autobiographical memory and T1-weighted structural neuroimaging features. RESULTS: We observed marked reductions in autobiographical recollection (Cohen's d = - 1.66; P FDR = 0.014) and midline structure (cingulate) thickness (Cohen's d = - 1.55, P FDR = 0.05), with no difference in hippocampal volume (P > 0.3). We further confirm the negative association between AD-PRS and cingulate thickness in a larger study with a comparable age (N = 31,966, ß = - 0.002, P = 0.011), supporting the validity of our approach. CONCLUSIONS: These observations conform with multiple streams of prior evidence suggesting alterations in cingulate structures may occur in individuals with higher AD genetic risk. We were able to use a genetically informed research design strategy that significantly improved the efficiency and power of the study. Thus, we further demonstrate that the recall-by-genotype of AD-PRS from wider samples is a promising approach for the detection, assessment, and intervention in specific individuals with increased AD genetic risk.

Cognitive decline in older adults in the UK during and after the COVID-19 pandemic: a longitudinal analysis of PROTECT study data.

BACKGROUND: Although the long-term health effects of COVID-19 are increasingly recognised, the societal restrictions during the COVID-19 pandemic hold the potential for considerable detriment to cognitive and mental health, particularly because major dementia risk factors-such as those related to exercise and dietary habits-were affected during this period. We used longitudinal data from the PROTECT study to evaluate the effect of the pandemic on cognition in older adults in the UK. METHODS: For this longitudinal analysis, we used computerised neuropsychology data from individuals aged 50 years and older participating in the PROTECT study in the UK. Data were collected from the same participants before the COVID-19 pandemic (March 1, 2019-Feb 29, 2020) and during its first (March 1, 2020-Feb 28, 2021) and second (March 1, 2021-Feb 28, 2022) years. We compared cognition across the three time periods using a linear mixed-effects model. Subgroup analyses were conducted in people with mild cognitive impairment and in people who reported a history of COVID-19, and an exploratory regression analysis identified factors associated with changes in cognitive trajectory. FINDINGS: Pre-pandemic data were included for 3142 participants, of whom 1696 (54·0%) were women and 1446 (46·0%) were men, with a mean age of 67·5 years (SD 9·6, range 50-96). Significant worsening of executive function and working memory was observed in the first year of the pandemic across the whole cohort (effect size 0·15 [95% CI 0·12-0·17] for executive function and 0·51 [0·49-0·53] for working memory), in people with mild cognitive impairment (0·13 [0·07-0·20] and 0·40 [0·36-0·47]), and in people with a history of COVID-19 (0·24 [0·16-0·31] and 0·46 [0·39-0·53]). Worsening of working memory was sustained across the whole cohort in the second year of the pandemic (0·47; 0·44-0·49). Regression analysis indicated that cognitive decline was significantly associated with reduced exercise (p=0·0049; executive function) and increased alcohol use (p=0·049; working memory) across the whole cohort, as well as depression (p=0·011; working memory) in those with a history of COVID-19 and loneliness (p=0·0038; working memory) in those with mild cognitive impairment. In the second year of the pandemic, reduced exercise continued to affect executive function across the whole cohort, and associations were sustained between worsening working memory and increased alcohol use (p=0·0040), loneliness (p=0·042), and depression (p=0·014) in those with mild cognitive impairment, and reduced exercise (p=0·0029), loneliness (p=0·031) and depression (p=0·036) in those with a history of COVID-19. INTERPRETATION: The COVID-19 pandemic resulted in a significant worsening of cognition in older adults, associated with changes in known dementia risk factors. The sustained decline in cognition highlights the need for public health interventions to mitigate the risk of dementia-particularly in people with mild cognitive impairment, in whom conversion to dementia within 5 years is a substantial risk. Long-term intervention for people with a history of COVID-19 should be considered to support cognitive health. FUNDING: National Institute for Health and Care Research.

Microglial activation, tau and amyloid deposition in TREM2 p.R47H carriers and mild cognitive impairment patients: a multi-modal/multi-tracer PET/MRI imaging study with influenza vaccine immune challenge.

BACKGROUND: Microglia are increasingly understood to play an important role in the pathogenesis of Alzheimer's disease. The rs75932628 (p.R47H) TREM2 variant is a well-established risk factor for Alzheimer's disease. TREM2 is a microglial cell surface receptor. In this multi-modal/multi-tracer PET/MRI study we investigated the effect of TREM2 p.R47H carrier status on microglial activation, tau and amyloid deposition, brain structure and cognitive profile. METHODS: We compared TREM2 p.R47H carriers (n = 8; median age = 62.3) and participants with mild cognitive impairment (n = 8; median age = 70.7). Participants underwent two [18F]DPA-714 PET/MRI scans to assess TSPO signal, indicative of microglial activation, before and after receiving the seasonal influenza vaccination, which was used as an immune stimulant. Participants also underwent [18F]florbetapir and [18F]AV1451 PET scans to assess amyloid and tau burden, respectively. Regional tau and TSPO signal were calculated for regions of interest linked to Braak stage. An additional comparison imaging healthy control group (n = 8; median age = 45.5) had a single [18F]DPA-714 PET/MRI. An expanded group of participants underwent neuropsychological testing, to determine if TREM2 status influenced clinical phenotype. RESULTS: Compared to participants with mild cognitive impairment, TREM2 carriers had lower TSPO signal in Braak II (P = 0.04) and Braak III (P = 0.046) regions, despite having a similar burden of tau and amyloid. There were trends to suggest reduced microglial activation following influenza vaccine in TREM2 carriers. Tau deposition in the Braak VI region was higher in TREM2 carriers (P = 0.04). Furthermore, compared to healthy controls TREM2 carriers had smaller caudate (P = 0.02), total brain (P = 0.049) and white matter volumes (P = 0.02); and neuropsychological assessment revealed worse ADAS-Cog13 (P = 0.03) and Delayed Matching to Sample (P = 0.007) scores. CONCLUSIONS: TREM2 p.R47H carriers had reduced levels of microglial activation in brain regions affected early in the Alzheimer's disease course and differences in brain structure and cognition. Changes in microglial response may underlie the increased Alzheimer's disease risk in TREM2 p.R47H carriers. Future therapeutic agents in Alzheimer's disease should aim to enhance protective microglial actions.

Cognitive trajectories: exploring the predictive role of subjective cognitive decline and awareness of age-related changes for cognitive functioning.

Background: We investigated whether aspects of subjective cognitive aging, including awareness of age-related gains and losses in cognition (AARC-gains, AARC-losses) and subjective cognitive decline (SCD), predict change in objective cognitive function as measured by verbal reasoning (VR) and working memory (WM). Methods: We used longitudinal data for 3,299 cognitively healthy UK residents aged 65+. We used data on AARC and SCD assessed in 2019, and cognitive tasks assessed in 2019, 2020, and 2021. We used latent growth curve modeling, latent class growth analysis, and growth mixture modeling. Results: For VR, multiple growth trajectories were not evident. Mean VR at baseline was 37.45; this remained stable over time. Higher AARC-gains in cognition (mean intercept = -0.23; 95%CI: -0.31; -0.16), higher AARC-losses in cognition (mean intercept = -0.37; 95%CI: -0.46; -0.28), and lower SCD (mean intercept = 2.92; 95%CI: 2.58; 3.58) were associated with poorer VR at baseline. A three-class growth mixture model-class varying best represented trajectories of WM. In Class 1 (N = 182) mean WM at baseline was 31.20; this decreased by 2.48 points each year. In Class 2 (N = 119) mean WM at baseline was 23.12; this increased by 3.28 points each year. In Class 3 (N = 2,998) mean WM at baseline was 30.11; and it remained stable. Higher AARC-gains (Odds Ratio = 1.08; 95%CI: 1.03; 1.14) and AARC-losses (Odds Ratio = 1.10; 95%CI: 1.04; 1.16) in cognition predicted greater likelihood of being in Class 2 than Class 3. Conclusion: Although both higher AARC-gains and AARC-losses indicate poorer concurrent cognition, higher AARC-gains may be a resource that facilitates future cognitive improvement.

A pragmatic, multicentre, double-blind, placebo-controlled randomised trial to assess the safety, clinical and cost-effectiveness of mirtazapine and carbamazepine in people with Alzheimer's disease and agitated behaviours: the HTA-SYMBAD trial.

Background: Agitation is common and impacts negatively on people with dementia and carers. Non-drug patient-centred care is first-line treatment, but we need other treatment when this fails. Current evidence is sparse on safer and effective alternatives to antipsychotics. Objectives: To assess clinical and cost-effectiveness and safety of mirtazapine and carbamazepine in treating agitation in dementia. Design: Pragmatic, phase III, multicentre, double-blind, superiority, randomised, placebo-controlled trial of the clinical effectiveness of mirtazapine over 12 weeks (carbamazepine arm discontinued). Setting: Twenty-six UK secondary care centres. Participants: Eligibility: probable or possible Alzheimer's disease, agitation unresponsive to non-drug treatment, Cohen-Mansfield Agitation Inventory score ≥ 45. Interventions: Mirtazapine (target 45 mg), carbamazepine (target 300 mg) and placebo. Outcome measures: Primary: Cohen-Mansfield Agitation Inventory score 12 weeks post randomisation. Main economic outcome evaluation: incremental cost per six-point difference in Cohen-Mansfield Agitation Inventory score at 12 weeks, from health and social care system perspective. Data from participants and informants at baseline, 6 and 12 weeks. Long-term follow-up Cohen-Mansfield Agitation Inventory data collected by telephone from informants at 6 and 12 months. Randomisation and blinding: Participants allocated 1 : 1 : 1 ratio (to discontinuation of the carbamazepine arm, 1 : 1 thereafter) to receive placebo or carbamazepine or mirtazapine, with treatment as usual. Random allocation was block stratified by centre and residence type with random block lengths of three or six (after discontinuation of carbamazepine, two or four). Double-blind, with drug and placebo identically encapsulated. Referring clinicians, participants, trial management team and research workers who did assessments were masked to group allocation. Results: Two hundred and forty-four participants recruited and randomised (102 mirtazapine, 102 placebo, 40 carbamazepine). The carbamazepine arm was discontinued due to slow overall recruitment; carbamazepine/placebo analyses are therefore statistically underpowered and not detailed in the abstract. Mean difference placebo-mirtazapine (-1.74, 95% confidence interval -7.17 to 3.69; p = 0.53). Harms: The number of controls with adverse events (65/102, 64%) was similar to the mirtazapine group (67/102, 66%). However, there were more deaths in the mirtazapine group (n = 7) by week 16 than in the control group (n = 1). Post hoc analysis suggests this was of marginal statistical significance (p = 0.065); this difference did not persist at 6- and 12-month assessments. At 12 weeks, the costs of unpaid care by the dyadic carer were significantly higher in the mirtazapine than placebo group [difference: £1120 (95% confidence interval £56 to £2184)]. In the cost-effectiveness analyses, mean raw and adjusted outcome scores and costs of the complete cases samples showed no differences between groups. Limitations: Our study has four important potential limitations: (1) we dropped the proposed carbamazepine group; (2) the trial was not powered to investigate a mortality difference between the groups; (3) recruitment beyond February 2020, was constrained by the COVID-19 pandemic; and (4) generalisability is limited by recruitment of participants from old-age psychiatry services and care homes. Conclusions: The data suggest mirtazapine is not clinically or cost-effective (compared to placebo) for agitation in dementia. There is little reason to recommend mirtazapine for people with dementia with agitation. Future work: Effective and cost-effective management strategies for agitation in dementia are needed where non-pharmacological approaches are unsuccessful. Study registration: This trial is registered as ISRCTN17411897/NCT03031184. Funding: This project was funded by the National Institute for Health and Care Research (NIHR) Health Technology Assessment programme and will be published in full in Health Technology Assessment; Vol. 27, No. 23. See the NIHR Journals Library website for further project information.

It is common for people with Alzheimer's disease to experience agitation, for example feeling restless or unsettled. If left untreated, agitation can lead to poorer quality of life and increased hospitalisation and strain for family carers. Often these symptoms are treated with medications that are usually used to manage psychosis (antipsychotic drugs), but such medication has limited effectiveness and can cause serious adverse effects to patients, including risk of increased death. Two medications that are already commonly prescribed for other health issues, mirtazapine (an antidepressant) and carbamazepine (a drug used to treat epilepsy), had been identified as a possible alternative way of treating agitation in Alzheimer's disease that might not have the harms associated with antipsychotic medication. In this study, we compared the effects of giving mirtazapine or carbamazepine with a dummy drug (placebo) in people with Alzheimer's disease who were experiencing agitation. The results of the study showed that neither medication was any more effective than the placebo in reducing agitation over 12 weeks in terms of improving symptoms, or in economic terms. Mirtazapine may lead to additional carer costs as compared to placebo. The study findings are stronger for mirtazapine than carbamazepine because the carbamazepine arm was stopped when it had recruited less than half the numbers needed. That was done because the study was not recruiting quickly enough to support both the mirtazapine and the carbamazepine arms. The findings from this study show that mirtazapine should not be recommended to treat agitation in Alzheimer's disease. More work is needed to formulate effective ways and to test new drug and non-drug treatments for agitation in dementia.

Self-reported sleep fragmentation and sleep duration and their association with cognitive function in PROTECT, a large digital community-based cohort of people over 50.

OBJECTIVE: Sleep is vital for normal cognitive function in daily life, but is commonly disrupted in older adults. Poor sleep can be detrimental to mental and physical health, including cognitive function. This study assessed the association between self-reported short (<6 h) and long (>9 h) sleep duration and sleep fragmentation (3≥ nightly awakenings) in cognitive function. METHODS: Cross-sectional data from 8508 individuals enroled in the PROTECT study aged 50 and above formed the basis of the univariate linear regression analysis conducted on four cognitive outcomes assessing visuospatial episodic memory (VSEM), spatial working memory, verbal working memory (VWM), and verbal reasoning (VR). RESULTS: Short (ß = -0.153, 95% CI [-0.258, -0.048], p = 0.004) and long sleep duration (ß = -0.459, 95% CI [-0.826, -0.091], p = 0.014) were significantly associated with poorer cognitive performance in VWM. Long sleep duration (ß = -2.986, 95% CI [-5.453, -0.518], p = 0.018) was associated with impaired VR. Short sleep (ß = -0.133, 95% CI [-0.196, -0.069], p = <0.001) and sleep fragmentation (ß = -0.043, 95% CI [-0.085, -0.001], p = 0.043) were associated with reduced VSEM. These associations remained significant when including other established risk factors for dementia and cognitive decline (e.g., depression, hypertension). CONCLUSIONS: Our findings suggest that short and long sleep durations and fragmented sleep, may be risk factors for a decline in cognitive processes such as working memory, VR and episodic memory thus might be potential targets for interventions to maintain cognitive health in ageing.

The Role of Awareness of Age-Related Change in the Longitudinal Association between Pain and Physical Activity.

We examined how physical pain impacts the developmental construct of Awareness of Age-Related Change (AARC-gains and AARC-losses) and, in turn, how AARC mediates and moderates the association between pain and subsequent physical activity. We used longitudinal data from 434 participants of the UK PROTECT Study (mean age = 65.5 years; SD = 6.94 years). We found that pain in 2019 predicted higher AARC-losses (ß = .07; p = .036) and less physical activity (ß = -.13; p-value = .001) in 2020. Additionally, we found that AARC-losses partially mediated, but did not moderate, the association of pain in 2019 and physical activity in 2020. AARC-losses may explain physical inactivity in middle-aged and older adults experiencing pain. Incorporating developmental constructs such as AARC into theories and empirical studies on pain and pain management may be necessary to more fully capture people's responses to pain.

Estimating the prevalence of diagnosed Alzheimer disease in England across deprivation groups using electronic health records: a clinical practice research datalink study.

OBJECTIVE: Estimate the prevalence of diagnosed Alzheimer's disease (AD) and early Alzheimer's disease (eAD) overall and stratified by age, sex and deprivation and combinations thereof in England on 1 January 2020. DESIGN: Cross-sectional. SETTING: Primary care electronic health record data, the Clinical Practice Research database linked with secondary care data, Hospital Episode Statistics (HES) and patient-level deprivation data, Index of Multiple Deprivation (IMD). OUTCOME MEASURES: The prevalence per 100 000 of the population and corresponding 95% CIs for both diagnosed AD and eAD overall and stratified by covariates. Sensitivity analyses were conducted to assess the sensitivity of the population definition and look-back period. RESULTS: There were 448 797 patients identified in the Clinical Practice Research Datalink that satisfied the study inclusion criteria and were eligible for HES and IMD linkage. For the main analysis of AD and eAD, 379 763 patients are eligible for inclusion in the denominator. This resulted in an estimated prevalence of diagnosed AD of 378.39 (95% CI, 359.36 to 398.44) per 100 000 and eAD of 292.81 (95% CI, 276.12 to 310.52) per 100 000. Prevalence estimates across main and sensitivity analyses for the entire AD study population were found to vary widely with estimates ranging from 137.48 (95% CI, 127.05 to 148.76) to 796.55 (95% CI, 768.77 to 825.33). There was significant variation in prevalence of diagnosed eAD when assessing the sensitivity with the look-back periods, as low as 120.54 (95% CI, 110.80 to 131.14) per 100 000, and as high as 519.01 (95% CI, 496.64 to 542.37) per 100 000. CONCLUSIONS: The study found relatively consistent patterns of prevalence across both AD and eAD populations. Generally, the prevalence of diagnosed AD increased with age and increased with deprivation for each age category. Women had a higher prevalence than men. More granular levels of stratification reduced patient numbers and increased the uncertainty of point prevalence estimates. Despite this, the study found a relationship between deprivation and prevalence of AD.

Testing Bidirectionality in Associations of Awareness of Age-Related Gains and Losses With Physical, Mental, and Cognitive Functioning Across 1 Year: The Role of Age.

OBJECTIVES: The bidirectionality between self-perceptions of aging and health-related outcomes may depend on age group. Therefore, we tested such bidirectionality among individuals in late midlife (50-64 years), young-old age (65-74 years), and old-old age (75+ years), taking advantage of the construct of Awareness of Age-Related Change (AARC) and its 2-dimensionality in terms of AARC-gains and AARC-losses. Various conceptualizations of physical, mental, and cognitive functioning were used as outcomes. METHODS: Data from 2 measurement occasions (2019 and 2020) from the UK PROTECT study for individuals in late midlife (N = 2,385), young-old age (N = 2,430), and old-old age (N = 539) were used. Data on self-reported functional difficulties, depression, anxiety, and performance on four computerized cognitive tasks (i.e., verbal reasoning, paired associate learning, self-ordered search, and digit span) providing a score for verbal reasoning and a score for working memory were analyzed using cross-lagged panel models. RESULTS: Across all 3 age groups, the bidirectional associations of AARC-gains with indicators of functioning were not significant, whereas higher AARC-losses significantly predicted slightly greater functional difficulties and higher depression and anxiety levels. Higher AARC-losses predicted slightly poorer Verbal Reasoning only in old-old age and poorer Working Memory predicted slightly higher AARC-losses only in young-old age. The remaining associations of AARC-losses with cognitive tasks were not statistically significant. DISCUSSION: In accordance with previous research targeting other indicators of self-perceptions of aging, this study supported a stronger impact of AARC-losses on indicators of physical functioning and mental health than vice versa from midlife to old-old age.

Physical and mental health conditions account for variability in awareness of age-related changes.

Background: The concept of Awareness of Age-Related Changes captures people's perceptions of the positive (AARC-gains) and negative (AARC-losses) age-related changes they experience in several life domains, including their health. We investigated the cross-sectional associations of number and type of physical and mental health conditions with AARC-gains and AARC-losses. Methods: The sample comprised 3,786 middle-aged and older adults (mean age = 67.04 years; SD = 6.88) participating to the UK PROTECT study. We used hierarchical regression models to analyze whether after having included sociodemographic variables (model 1), number of physical (model 2) and of mental (model 3) health conditions explained a significant additional amount of variance in AARC-gains and AARC-losses, and whether the association between number of conditions and AARC depended on participants' age. We used multiple regression models to analyze the associations of types of physical and mental health conditions with AARC-gains and AARC-losses. Results: A higher number of physical health conditions was associated with higher AARC-gains and higher AARC-losses, but the association did not depend on participant age. After controlling for the number of physical health conditions, a higher number of mental health conditions was associated with higher AARC-losses but not with AARC-gains, and the association was stronger among older participants. Small effects were found between greater AARC-gains and current cancer and between greater AARC-losses and diagnoses of mild cognitive impairment, Parkinson's disease, arthritic condition, cancer in full remission, osteoporosis, depression, anxiety disorders, and personality disorder. The remaining health conditions were either negligibly or non-statistically related to AARC-losses. Conclusion: Middle-aged and older adults having more physical health conditions and more mental health conditions may be at higher risk of negative views on their own aging. However, specific physical health conditions, such as arthritis, and certain mental health conditions, such as depression, may make adults particularly vulnerable to negative age-related perceptions.

Neurodegenerative Disease Associated Pathways in the Brains of Triple Transgenic Alzheimer's Model Mice Are Reversed Following Two Weeks of Peripheral Administration of Fasudil.

The pan Rho-associated coiled-coil-containing protein kinase (ROCK) inhibitor fasudil acts as a vasodilator and has been used as a medication for post-cerebral stroke for the past 29 years in Japan and China. More recently, based on the involvement of ROCK inhibition in synaptic function, neuronal survival, and processes associated with neuroinflammation, it has been suggested that the drug may be repurposed for neurodegenerative diseases. Indeed, fasudil has demonstrated preclinical efficacy in many neurodegenerative disease models. To facilitate an understanding of the wider biological processes at play due to ROCK inhibition in the context of neurodegeneration, we performed a global gene expression analysis on the brains of Alzheimer's disease model mice treated with fasudil via peripheral IP injection. We then performed a comparative analysis of the fasudil-driven transcriptional profile with profiles generated from a meta-analysis of multiple neurodegenerative diseases. Our results show that fasudil tends to drive gene expression in a reverse sense to that seen in brains with post-mortem neurodegenerative disease. The results are most striking in terms of pathway enrichment analysis, where pathways perturbed in Alzheimer's and Parkinson's diseases are overwhelmingly driven in the opposite direction by fasudil treatment. Thus, our results bolster the repurposing potential of fasudil by demonstrating an anti-neurodegenerative phenotype in a disease context and highlight the potential of in vivo transcriptional profiling of drug activity.

Decreased DHA-containing phospholipids in the neocortex of dementia with Lewy bodies are associated with soluble Aß42 , phosphorylated α-synuclein, and synaptopathology.

Docosahexaenoic acid (DHA) is an essential omega-3 polyunsaturated fatty acid implicated in cognitive functions by promoting synaptic protein expression. While alterations of specific DHA-containing phospholipids have been described in the neocortex of patients with Alzheimer's disease (AD), the status of these lipids in dementia with Lewy bodies (DLB), known to manifest aggregated α-synuclein-containing Lewy bodies together with variable amyloid pathology, is unclear. In this study, post-mortem samples from the parietal cortex of 25 DLB patients and 17 age-matched controls were processed for phospholipidomics analyses using a liquid chromatography-tandem mass spectrometry (LC-MS/MS) platform. After controlling for false discovery rate, six out of the 46 identified putative DHA-phospholipid species were significantly decreased in DLB, with only one showing increase. Altered putative DHA-phospholipid species were subsequently validated with further LC-MS/MS measurements. Of the DHA-containing phospholipid (DCP) species showing decreases, five negatively correlated with soluble beta-amyloid (Aß42) levels, whilst three also correlated with phosphorylated α-synuclein (all p < 0.05). Furthermore, five of these phospholipid species correlated with deficits of presynaptic Rab3A, postsynaptic neurogranin, or both (all p < 0.05). Finally, we found altered immunoreactivities of brain lysolipid DHA transporter, MFSD2A, and the fatty acid binding protein FABP5 in DLB parietal cortex. In summary, we report alterations of specific DCP species in DLB, as well as their associations with markers of neuropathological burden and synaptopathology. These results support the potential role of DHA perturbations in DLB as well as therapeutic targets.

Optimizing detection of Alzheimer's disease in mild cognitive impairment: a 4-year biomarker study of mild behavioral impairment in ADNI and MEMENTO.

BACKGROUND: Disease-modifying drug use necessitates better Alzheimer disease (AD) detection. Mild cognitive impairment (MCI) leverages cognitive decline to identify the risk group; similarly, mild behavioral impairment (MBI) leverages behavioral change. Adding MBI to MCI improves dementia prognostication over conventional approaches of incorporating neuropsychiatric symptoms (NPS). Here, to determine if adding MBI would better identify AD, we interrogated associations between MBI in MCI, and cerebrospinal fluid biomarkers [ß-amyloid (Aß), phosphorylated-tau (p-tau), and total-tau (tau)-ATN], cross-sectionally and longitudinally. METHODS: Data were from two independent referral-based cohorts, ADNI (mean[SD] follow-up 3.14[1.07] years) and MEMENTO (4.25[1.40] years), collected 2003-2021. Exposure was based on three-group stratification: 1) NPS meeting MBI criteria; 2) conventionally measured NPS (NPSnotMBI); and 3) noNPS. Cohorts were analyzed separately for: 1) cross-sectional associations between NPS status and ATN biomarkers (linear regressions); 2) 4-year longitudinal repeated-measures associations of MBI and NPSnotMBI with ATN biomarkers (hierarchical linear mixed-effects models-LMEs); and 3) rates of incident dementia (Cox proportional hazards regressions). RESULTS: Of 510 MCI participants, 352 were from ADNI (43.5% females; mean [SD] age, 71.68 [7.40] years), and 158 from MEMENTO (46.2% females; 68.98 [8.18] years). In ADNI, MBI was associated with lower Aß42 (standardized ß [95%CI], -5.52% [-10.48-(-0.29)%]; p = 0.039), and Aß42/40 (p = 0.01); higher p-tau (9.67% [3.96-15.70%]; p = 0.001), t-tau (7.71% [2.70-12.97%]; p = 0.002), p-tau/Aß42 (p < 0.001), and t-tau/Aß42 (p = 0.001). NPSnotMBI was associated only with lower Aß42/40 (p = 0.045). LMEs revealed a similar 4-year AD-specific biomarker profile for MBI, with NPSnotMBI associated only with higher t-tau. MBI had a greater rate of incident dementia (HR [95%CI], 3.50 [1.99-6.17; p < 0.001). NPSnotMBI did not differ from noNPS (HR 0.96 [0.49-1.89]; p = 0.916). In MEMENTO, MBI demonstrated a similar magnitude and direction of effect for all biomarkers, but with a greater reduction in Aß40. HR for incident dementia was 3.93 (p = 0.004) in MBI, and 1.83 (p = 0.266) in NPSnotMBI. Of MBI progressors to dementia, 81% developed AD dementia. CONCLUSIONS: These findings support a biological basis for NPS that meet MBI criteria, the continued inclusion of MBI in NIA-AA ATN clinical staging, and the utility of MBI criteria to improve identification of patients for enrollment in disease-modifying drug trials or for clinical care.