Journal of Alzheimer's Disease

ObjectiveTo identify any mediating effect of vascular and neurodegenerative risk factors of dementia in the association existing between APOE4 and dementia. Methods1,240 participants from the French Three City Dijon Study without prevalent tumor or dementia were included. Among these participants, 76 developed dementia during the 12 years of follow-up. Using regression and mediation analyses, we studied whether known risk factors for dementia i.e smoking status, body mass index, diabetes mellitus, hypercholesterolemia, hypertension, hippocampal volume, rate of hippocampal volume loss or white matter hyperintensities could mediate the association between APOE4 and dementia. Regression models were adjusted for age, sex, education level (and total intracranial volume when imaging metrics were considered). ResultsHippocampal volume was a partial mediator of the association between APOE4 and dementia (mediation ratio = 6.7%, p=0.03). No mediation effect was found for hypercholesterolemia. No mediation analyses could be undertaken for the others factors due to the lack of their association with APOE4 in our sample. ConclusionsIn this study, the association between APOE4 and dementia was partially mediated by hippocampal volume, confirming a deleterious role of APOE4 in the hippocampus. This result warrants further replication in other cohorts, with higher sample sizes.

Background: Social determinants of health (SDOH) are increasingly recognized as contributors to Alzheimer disease (AD) risk, yet the impact of multidimensional social disadvantage early AD-related pathophysiology remains poorly understood. Methods: We studied 1,466 participants from the Coronary Artery Risk Development in Young Adults (CARDIA) cohort with SDOH assessed in early midlife (mean age 40, SD 3.6 years) and plasma AD biomarkers measured 20 years later. A comprehensive SDOH index was constructed from 12 indicators spanning five domains (economic stability, education, neighborhood and physical environment, community and social context, and health care access). We examined associations between SDOH quartile and log-transformed, standardized plasma phosphorylated tau 217 (p-tau217), neurofilament light chain (NfL), and amyloid-lower case Greek beta42/40 (Alower case Greek beta42/40) using linear regression adjusted for age, sex, race, and estimated glomerular filtration rate. Linear trends across SDOH quartile were also evaluated. Results: Participants in the most disadvantaged SDOH quartile had higher p-tau217, higher NfL and lower Alower case Greek beta42/40 level compared with those in the least disadvantaged quartile (p-tau 217: lower case Greek beta = 0.12, 95% CI 0.03-0.21, p = 0.008; NfL: lower case Greek beta = 0.20, 95% CI 0.05-0.35, p = 0.009; lower case Greek beta42/40: lower case Greek beta = -0.15, 95% CI -0.30-0.00, p=0.05). There was also a significant trend across quartile (p-tau 217: p for trend = 0.012; NfL: p for trend= 0.001). Analyses of individual SDOH domains indicated that lower economic stability, poorer health care access, and lower education were associated with higher NfL, and poorer health care access was associated with higher p-tau217. Conclusions: Greater SDOH disadvantage in early midlife was associated with higher levels of plasma AD biomarkers reflecting AD pathology and neurodegeneration decades later. These findings suggest that social disadvantage during midlife may contribute to early AD-related biological changes and highlight potentially modifiable social factors relevant for dementia prevention.

Background: Cardiovascular health factors are associated with cognitive decline and risk of dementia, including Alzheimer disease (AD); however, this has been mostly studied in late life. We investigated whether vascular and lifestyle factors are associated with AD plasma and imaging biomarkers in midlife. Methods: We investigated 1,406 participants from the Coronary Artery Risk Development in Young Adults (CARDIA) study with information on vascular and lifestyle factors framed from the American Heart Association (AHA) life's essential 8 (LE8) guidelines for cardiovascular health at early midlife (mean age 45.0 SD 3.6) and AD biomarkers in late midlife (mean age 60 SD 3.5). LE8 was calculated and categorized into poor (0-49), intermediate (50-79), and ideal (80-100) cardiovascular health, based on 8 components including smoking, diet, body mass index (BMI), sleep, fasting glucose, blood pressure, cholesterol, and physical activity. We assessed the AD plasma biomarkers phosphorylated tau 217 (ptau-217) and amyloid beta 42/40 ratio (A{beta}42/40) and the Spatial Pattern of Abnormality for Recognition of Early AD (SPARE-AD), an algorithm that characterizes AD-like brain atrophy on brain MRI. We used linear regression to examine the association between LE8 and log-transformed and standardized AD biomarker measures adjusting for age, sex, race, education, and kidney function. Results: Compared to ideal LE8, intermediate (67.9% of participants) and poor (12.6%) LE8 was associated with lower A {beta}42/40 (adjusted mean difference: -2.37, 95% CI: -2.38 to -2.36 and -2.38, 95% CI: -2.40 to -2.36, respectively). There was no association between the LE8 group and ptau-217 level. Moreover, compared to ideal LE8 participants, those with poor LE8 had higher SPARE-AD atrophy pattern (adjusted mean difference: -0.71, 95% CI: -0.81 to -0.62). Conclusion: These findings indicate that poor cardiovascular health in midlife, as defined by the AHA LE8, is linked to less favorable early AD biomarker profiles, particularly reflecting greater amyloid burden and structural brain changes.

BackgroundDecline in cognitive abilities in old age is highly heterogenous, while most show decline, however a small subset called SuperAgers can reach late life with cognitive functioning comparable to those decades younger. We aimed to categorise the potential lifestyle factors that may be responsible for SuperAger status in old age. MethodsSuperAgers were identified in the UK Whitehall II cohort (n = 2701, 25.88% female) as participants 65 years or older at phase 12 who scored above the sex specific mean on a test of verbal memory of participants at phase 5 and who scored within one standard deviation above the mean on a test of fluency at phase 12. Generalised structural equation models for each sex were used to measure the association between lifestyle factors and being a SuperAger. ResultsThe prevalence of SuperAger status was higher in women (48.07%) than men (40.00%), with SuperAgers exhibiting higher education level and lower age. Higher social engagement increased the odds of being a SuperAger in women (odds ratio [OR] = 0.02, p = 0.009), with lower biomedical dementia risk increasing the odds in men (OR = 0.87, p = 0.034), all other factors were insignificant. ConclusionWhile some factors were significant, the results presented are inconsistent with existing literature and future research should examine the role of lifestyle factors across the lifespan and the potential influence of genetic risk factors to better understand what may contribute towards SuperAger status.

INTRODUCTIONAlzheimers disease (AD) is a common and costly neurodegenerative disorder. A large proportion of risk is heritable and many genetic risk factors for AD have been identified. The cumulative genetic risk of known markers has not been benchmarked for dementia in a population-based sample. METHODSIn the United States population-based Health and Retirement Study (HRS) (waves 1995-2014), we evaluated the role of cumulative genetic risk for AD, with and without the APOE-{varepsilon}4 alleles, on dementia status (dementia, cognitive impairment without dementia, borderline cognitive impairment without dementia, cognitively normal). We used logistic regression, accounting for demographic covariates and genetic principal components, and analyses were stratified by European and African genetic ancestry. RESULTSIn the European ancestry sample (n=8399), both AD polygenic score excluding the APOE genetic region (odds ratio (OR)=1.10; 95% confidence interval (CI): 1.00, 1.20) and the presence of any APOE-{varepsilon}4 alleles (OR=2.42; 95% CI: 1.99, 2.95) were associated with the odds of dementia relative to normal cognition in a mutually-adjusted model. In the African ancestry sample (n=1605), the presence of any APOE-{varepsilon}4 alleles was associated with 1.77 (95% CI: 1.20, 2.61) times higher odds of dementia, while the AD polygenic score excluding the APOE genetic region was not significantly associated with the odds of dementia relative to normal cognition 1.06 (95% CI: 0.97, 1.30). DISCUSSIONCumulative genetic risk for AD and APOE-{varepsilon}4 are both independent predictors of dementia. This study provides important insight into the polygenic nature of dementia and demonstrates the utility of polygenic scores in dementia research.

ObjectiveWith the growing number of older people in the Norwegian population and the associated rapid rise in dementia and cognitive impairment, novel and more efficient methodologies are needed to facilitate research, improve diagnostic triage and deliver effective brain health interventions in the community. Methods: PROTECT-Norge is an online, remote cohort study in adults aged 50 and over. At-home assessments of cognition are completed annually using validated computerized neuropsychological tests (including Paired Associate Learning, Self-Ordered Search, Digit Span and Verbal Reasoning). Demographic data (age, gender, ethnicity, education, height, weight), medical and lifestyle information are also collected. Results: The current article describes analysis of baseline data from the first 3000 participants recruited to PROTECT-Norge (74.5% female, mean age 64.1 sd 7.7). It demonstrates that established risk factors for dementia such as Body Mass Index > 30, hypertension, smoking, and hearing loss are associated with significant detriments on cognitive performance on the computerized neuropsychological test battery. The level of data capture was excellent, and 94% of participants agreed to be contacted for further research programmes. Conclusion: This data shows excellent feasibility of the PROTECT-Norge cohort, demonstrating high completion rates and accessibility for people with early cognitive impairment. PROTECT-Norge represents a tremendous opportunity for cost-efficient, large-scale brain health research and potentially for clinical digital cognitive health programmes. Key PointsO_LIPROTECT Norge is an online cohort study focusing on cognitive assessment and dementia risk factors in a population of Norwegian adults aged 50 and over. C_LIO_LIThe study utilizes validated computerized neuropsychological test battery for annual at-home assessments, in addition to capturing demographic, medical, and lifestyle data. C_LIO_LIStudy findings indicate significant associations between established dementia risk factors (e.g., obesity, hypertension, smoking, hearing loss) and poorer cognitive performance, highlighting the potential for early intervention strategies. C_LIO_LIHigh participant engagement and willingness for further research involvement highlights PROTECT Norges feasibility and potential for large-scale brain health initiatives and clinical trials, using its built-in clinical trials infrastructure. C_LI

INTRODUCTIONCognitive SuperAgers (SA) are individuals aged 80+ with exceptional episodic memory performance for their age, exceeding middle-aged adult norms. This study integrates family- and association-based methods to identify genetic variants associated with SA in the Midwestern Amish population. METHODS83 Amish SA were grouped into 16 pedigrees for parametric and non-parametric linkage analysis. Variants in linked regions (HLOD/LOD*[≥]3) were tested for association with SA using two contrasts: SA vs. Alzheimers disease (AD; n=40), and SA vs. cognitively unimpaired (CU), age-matched non-SA individuals (CU80+; n=157). RESULTSEvidence of linkage for SA was observed on chromosomes 1, 2, 7, 16, and 20, with the strongest signal around the AD-associated locus WDR12 on chromosome 2. Association analysis for SA vs. AD identified eight variants in HIVEP3 (chromosome 1) that were nominally significant when comparing SA vs. CU80+. DISCUSSIONWDR12 and HIVEP3 are potential candidate genes contributing to SA in the Amish population.

IntroductionThe goal of this study was to compare accuracy for pattern-recognition protocols to prospectively identify dementia due to Alzheimers disease and related dementias (ADRD) or stroke. MethodsWe used data from cognitively unimpaired respondents who completed at least 5 cognitive assessments during waves 3-12 of the Health and Retirement Study (HRS), a longitudinal study of older US residents. Participants were assessed at wave 12 (in 2019) for cognitive status. Patterns of participants cognitive decline were analyzed to differentially identify ADRD and stroke and were compared against self-reported and objective diagnoses of amnestic, executive, and multidomain mild cognitive impairment (MCI) and ADRD. We reported sensitivity/specificity to detect new-onset dementia at the final wave of observation. ResultsAfter applying inclusion/exclusion criteria, 43 (1.69%) of cognitively unimpaired participants developed dementia, while 165 (6.49%) developed amnestic MCI. Patterns of cognitive decline consistent with ADRD affected 372 (14.6%) of respondents, while patterns of cognitive decline consistent with stroke were evident in 917 (36.1%) participants. ADRD- consistent cognitive declines were evident in 75.8% and 76.7% cases of amnestic MCI and dementia, respectively, though only 24.5% reported receiving a clinical diagnosis of dementia. Sensitivity/Specificity of ADRD was 94.3%/87.0% when detecting dementia without stroke. DiscussionThis study implies that we can reliably use longitudinal patterns of cognitive decline to differentially diagnose ADRD from Stroke in most participants with dementia.

INTRODUCTIONChanges in mental health symptoms, and their timing in the preclinical period of dementia, are not well characterised. METHODSWe followed 5,495 Whitehall II participants (median age 68.5; 72.1% male) from their mental health symptoms assessment using the Clinical Interview Schedule-Revised (CIS-R) starting in 2012/13 to dementia diagnosis, death, or 2024. Linear mixed effects regression assessed CIS-R score changes preceding dementia. Flexible parametric models estimated associations of mental health symptoms with dementia. RESULTSTotal CIS-R score increased (2.56 points [0.85-4.27]) in the 12 years preceding dementia. Having any mental health condition was associated with dementia in the short-term (HR at 3 years=4.04 [2.53-6.50]) but not the long-term (HR at 6 years=1.26 [0.63-2.49]). This pattern held for severe mental health conditions, concentration problems, depression, irritability, fatigue, anxiety, and worry. DISCUSSIONAwareness of mental health symptoms as preclinical indicators of dementia in the short-term may support timely diagnosis of dementia.

Major initiatives are currently attempting to prevent dementia by targeting modifiable risk factors. Low education is frequently pointed to as a potential key factor, due to its robust relationship with dementia risk. Impact of education is notoriously difficult to assess, however, because of associations with multiple other risk and protective factors, and large population-representative samples are required to tease the relationships apart. Here, we studied 207,814 Norwegian men born between 1950 and 1959 who underwent compulsory cognitive testing during military conscription as young adults, to systematically test associations of education, cognition, and other potentially important factors. While low education was associated with increased risk for dementia diagnosis (Hazard ratio [HR] = 1.37, CI: 1.17-1.60), this association was fully explained by earlier cognitive test scores (HR = 1.08, CI: .91-1.28). In contrast, low cognitive score was associated with double risk of later dementia diagnosis, even when taking education into account (HR = 2.00, CI: 1.65-2.42). This relationship survived controlling for early-life socioeconomic status and was replicated within pairs of brothers. The latter finding suggests that genetic and environmental factors shared within families, such as common genetics, parental education, childhood socioeconomic status, or other shared experiences, cannot account for the association. Rather, independent, non-familial factors are more important. In contrast, within-family factors accounted for the relationship between low education and diagnosis risk. In conclusion, implementing measures to increase cognitive function in childhood and adolescence appears to be a more promising strategy for reducing dementia burden.

INTRODUCTIONAlzheimers disease (AD) biomarkers can help differentiate cognitively unimpaired (CU) individuals from mild cognitive impairment (MCI) and dementia. The role of AD biomarkers in predicting cognitive impairment and AD needs examination. METHODSIn 628 CU individuals from a multi-ethnic cohort, A{beta}42, A{beta}40, phosphorylated tau-181 (P-tau181), glial fibrillary acid protein (GFAP), and neurofilament light chain (NfL) were measured in plasma. RESULTSHigher baseline levels of P-tau181/A{beta}42 ratio were associated with increased risk of incident dementia. A biomarker pattern (with elevated A{beta}42/A{beta}40 but low P-tau181/A{beta}42) was associated with decreased dementia risk. Compared to CU, participants who developed MCI or dementia had a rapid decrease in the biomarker pattern reflecting AD-specific pathological change. DISCUSSIONElevated levels of AD biomarker P-tau181/A{beta}42, by itself or combined with a low A{beta}42/A{beta}40 level, predicts clinically diagnosed AD. Individuals with a rapid change in these biomarkers may need close monitoring for the potential downward trajectory of cognition. Research in ContextO_LISystematic Review: Few studies have evaluated the clinical application of AD blood-based biomarkers longitudinally as antecedent risk predictors. Data from multiethnic populations are even more limited. How preclinical trajectories of blood-based biomarkers are related with the risk of developing clinically diagnosed MCI or AD is largely unknown. C_LIO_LIInterpretation: High circulating level of P-tau181/A{beta}42, by itself or combined with a low level of A{beta}42/A{beta}40, may predict development of incident clinical AD. Biomarkers levels of P-tau181, P-tau181/A{beta}42, and NfL increase with age even among individuals who remain cognitively healthy. A rapid change in biomarkers may indicate the individuals in the active trajectory to develop clinically diagnosed MCI or AD. C_LIO_LIFuture Directions: Larger studies or meta-analyses are needed to examine whether the predictive utility of blood-based biomarkers for AD differs across racial/ethnic groups. Well-designed studies are needed to evaluate the optimal duration between repeated measures of biomarkers. C_LI

ObjectiveTo study how activities of daily living (ADLs) decline over the progressive course of rarer dementias (prevalence below 10%), in a systematic review of the literature. Methods Relevant studies were identified by searching Medline, Embase, Emcare, PsycINFO and Cinahl. The databases were searched for terms relating to (rarer dementias) AND (activities of daily living) AND (longitudinal OR cross-sectional studies), using a pre-established protocol registered with the international prospective register of systematic reviews (registration: CRD42021283302). ResultsA total of 579 articles were screened for relevant content, of which 20 full-text publications were included in the analysis. Nineteen studies were about rarer dementias on the frontotemporal dementia/primary progressive aphasia spectrum, and one was about posterior cortical atrophy. Long term description of decline was limited to just seven studies following patients for longer than five years. The rate of decline, sequence of symptom onset, and symptom duration were also highlighted. ConclusionDescriptions of ADL progression were inadequately long term, covering an average of 3.5 years from symptom onset, and lacked phenotypic specificity. The literature disproportionately studied dementias on the frontotemporal dementia spectrum. To facilitate better care, more longitudinal data, quantitative analyses, and development of rarer dementia-specific ADL scales is needed. Given the low prevalence of rarer dementias, big data analyses may never be applicable and so personalised medicine approaches should be pursued, including innovative possibilities in digital biomarkers such as from wearable technology.

INTRODUCTION: Bilingualism is a proposed cognitive reserve factor that delays symptom onset in Alzheimer's disease (AD), though current evidence lacks biomarker confirmation. This retrospective study examined bilingualism's association with symptom onset across AD clinical stages, including biomarker-confirmed cases. METHODS: Participants from the Sant Pau Memory Unit spanning amnestic mild cognitive impairment (MCI), amnestic dementia, and biomarker-confirmed AD were analyzed, with balanced representation of active and passive Spanish-Catalan bilinguals. Linear regression models evaluated associations between bilingualism and reported age at symptom onset, controlling for education, sex, and disease severity. RESULTS: Active bilingualism was associated with delayed symptom onset in amnestic MCI (2.21 years), amnestic dementia (1.42 years), and biomarker-confirmed AD (1.45 years; ps < .05). Higher education was associated with earlier onset, likely representing healthcare seeking behavior. DISCUSSION: Bilingualism protects against earlier symptom manifestation in MCI and AD, supporting bilingualism as a contributor to cognitive reserve.

ObjectiveNeuropsychiatric symptoms (NPS) are very common and associated with high levels of distress, both in dementia patients and their caregivers. Especially at more advanced dementia disease stages, NPS rarely occur in isolation, and the presence of two or more NPS may affect disease severity as well as the response to therapy. There is limited quantitative information on prevalence of specific symptom combinations in the general population, as well as in the populations recruited for symptom-specific investigations. MethodsWe performed cross-sectional analyses of publicly accessible Neuropsychiatric Inventory and Mini Mental State Examination (MMSE) data from three longitudinal studies (Aging, Demographics, and Memory Study (ADAMS), Alzheimers Disease Neuroimaging Initiative (ADNI) and the National Alzheimers Coordinating Center data (NACC)). Mean (with 95% confidence interval) prevalence was calculated for all possible pairs of symptoms (aberrant motor behavior, agitation/aggression, anxiety, apathy/indifference, appetite/eating changes, delusions; depression/dysphoria; disinhibition; elation/euphoria; hallucinations; irritability/lability and nighttime behavioral disturbances) in different MMSE strata. In addition, the conditional prevalence of one symptom given another symptom was provided for all possible combinations. ResultsIn all three studies and MMSE strata, we observed every possible pair combination, from commonly recognized and discussed associations (e.g., hallucinations and delusions) to what might be seen as rather counter-intuitive patterns (e.g., apathy and agitation). Prevalence of symptom pairs cannot be readily predicted based on prevalence of individual symptoms. Presence of cognitive deficit and degree of cognitive impairment affected prevalence of all symptoms and symptom pairs, albeit to a different degree. For example, prevalence of the most common symptom, depression, in subjects without and with cognitive deficit, differed less than two-fold. In contrast, differences in the prevalence of psychotic symptoms (hallucinations and/or delusions) in subjects with and without cognitive deficit were much stronger (6- to 38-fold). ConclusionsThe present study illustrates that, while there is the possibility of any combination of neuropsychiatric symptoms presenting during the course of dementia, their co-occurrence cannot be readily predicted based on the prevalence of individual symptoms. Thus, our study results can serve as a source of reference information to inform the design and recruitment strategies for future clinical studies and epidemiological research on neuropsychiatric symptoms in people with dementia. HighlightsO_LIWhat is the primary question addressed by this study?--The question addressed by the study must limited to only one sentence. There is very limited quantitative information on prevalence of neuropsychiatric symptom combinations despite the growing number of epidemiological and drug development studies in the field. C_LIO_LIWhat is the main finding of this study?--The finding must be limited to two sentences. All possible pair combinations frequently occur even in subjects with mild, minimal or no cognitive deficit in the general population, as well as in protocol-based dementia research studies. Co-occurrence of neuropsychiatric symptoms cannot be readily predicted based on the prevalence of individual symptoms. C_LIO_LIWhat is the meaning of the finding?--The meaning of the finding must be limited to one sentence. We provide reference information on neuropsychiatric symptom pair prevalence to inform the design and recruitment strategies for future clinical studies, as well as epidemiological research on neuropsychiatric symptoms. C_LI

IntroductionAlzheimers Disease (AD) is the leading cause of dementia, accounting for 80% of cases globally. With an aging population, AD poses a growing concern due to its increasing mortality rate and associated healthcare costs. Early diagnosis or prediction of AD is crucial for managing and potentially slowing its progression, particularly with the advent of disease-modifying therapies. MethodsThis study involved a total of 60 participants: 15 with mild AD, 23 with mild cognitive impairment (MCI), and 22 healthy controls, comprising both males and females aged 50-85 years. Data collection included blood samples, the Montreal Cognitive Assessment (MoCA), and the Integrated Cognitive Assessment (ICA). Serum phosphorylated tau181 (p-tau181) levels were measured using enzyme-linked immunosorbent assay (ELISA) kits. Linear regression models were applied to predict serum biomarker levels based on the ICA index, demographic data, and APOE {varepsilon}4 status. Aims and ObjectivesThe primary aim was to examine the association between ICA scores and blood-based p-tau181 levels in individual with MCI, mild AD, and elderly healthy controls. Additionally, the study compared the correlation of ICA and MoCA with APOE {varepsilon}4 status. FindingsThe study found that the ICA can significantly differentiate between diagnostic groups and that elevated serum p-tau181 levels are associated with cognitive decline, as measured by the ICA. Additionally, a significant correlation was observed between APOE {varepsilon}4 status and cognitive decline, but not between APOE {varepsilon}4 status and serum p-tau181 levels. Using a model that incorporates the ICA, demographic data, and APOE {varepsilon}4 status, we were able to modestly predict serum p-tau181 levels, indicating the potential of combining cognitive assessment with biological markers for AD prediction. DiscussionThe findings suggest that ICA is a valuable tool in detecting cognitive decline associated with AD and correlates with increased p-tau181 levels. The significant correlation between APOE {varepsilon}4 status and cognitive decline highlights its potential role in risk assessment, independent of p-tau181 levels. The study supports the use of a computerized, self-administered cognitive assessment in conjunction with blood-based biomarkers for early AD detection. Limitations include the small sample size and cross-sectional design, which restricts causal inference and longitudinal analysis. Future research should focus on larger, longitudinal studies to further validate these associations and their implications for early diagnosis and monitoring of AD progression.

BackgroundUnderstanding geographical variation of dementia could highlight important modifiable socio-environmental risk factors. A previous systematic review (2012) identified an increased risk of Alzheimer dementia in rural living in High-Income Countries (HICs), with a dearth of studies in Low to Middle-Income Countries (L-MICs). We updated this review to examine geographical variations in dementia, to encompass the growing number of studies in this field. MethodsWe systematically reviewed the literature for cross-sectional or longitudinal observational studies that compared dementia incidence or prevalence between two or more geographical areas including rural and urban settings. We conducted a narrative synthesis of included papers. Where possible, we undertook meta-analysis, generating odds ratios for rural versus urban dementia prevalence and stratified the analysis by HICs and L-MICs. ResultsWe identified 38 relevant papers, encompassing approximately 98,502,147 people. Twenty-seven papers were included in the quantitative synthesis. Study methodologies varied widely. Dementia rates varied geographically (0.43-38.5%). Overall, rural living was associated with small increased odds of dementia (OR, 1.20, 95% CI 1.03-1.40; P value = 0.0182). Stratification by HICs and L-MICs demonstrated further variation, with increased odds of dementia in rural areas in L-MICs but not HICs. ConclusionsThere is some evidence of geographical variation of dementia. Rural living was associated with small increased odds of dementia, with stratification showing evidence in rural areas of L-MICs but not HICs. We believe this has not been reported previously. Future research must consider life course geographical exposure and addressing heterogeneity in definitions of rural and urban. What this study addsWe confirm that rural living (compared to urban living) is associated with a small increased odds of dementia (OR 1.20, 95%CI 1.03-1.40). We demonstrate for the first time that this is driven by increased odds of dementia in rural areas in Low to Middle-Income Countries (L-MICs) rather than High Income Countries (HICs), and that the odds of dementia were higher in urban areas in large studies in HICs. Future studies need to carefully consider study setting, method of dementia ascertainment, when exposures may occur, and risk of bias, to understand the role of environment and geography in dementia risk.

INTRODUCTIONAlzheimer disease (AD) plasma biomarkers are noninvasive measures of the key amyloid beta (A{beta}) and tau pathologies. Validation and generalization studies are needed to fully understand their potential for AD prediction and diagnosis in the elderly population. METHODSIn 1,067 Amish individuals aged [&ge;] 65, we measured plasma A{beta} and tau to assess their relationships with AD-related outcomes. RESULTSAmong Amish individuals with AD, plasma p-tau181 was significantly higher (p = 0.04), and plasma A{beta}42/p-tau181 ratio was significantly lower (p = 0.01) than cognitively normal individuals. The association of AD with elevated p-tau181 was driven by APOE {varepsilon}4 carriers (OR = 6.02, p < 0.001). Cluster analysis identified two subgroups defined by differing A{beta} and tau levels, with the high-risk cluster having more APOE {varepsilon}4 carriers (p < 0.001). DISCUSSIONPlasma biomarkers, particularly p-tau181, A{beta}42/A{beta}40, and A{beta}42/p- tau181 ratio, are promising surrogate biomarkers for AD-related pathology and clinical outcomes in the Amish.

INTRODUCTIONWhile preclinical studies suggest that Phosphodiesterase 5 (PDE5) inhibition may reduce cognitive impairment, findings from observational studies on whether PDE5 inhibitors reduce Alzheimers disease (AD) risk have been inconsistent. METHODSA two-sample cis-Mendelian Randomisation (MR) analysis was conducted to estimate the causal effect of PDE5 inhibition on AD risk. The analysis was performed across four different genome-wide association studies (GWAS) of AD to enhance evidence reliability through triangulation. Additionally, a sex-stratified MR analysis using data from UK Biobank was performed to assess potential sex-specific effects. RESULTSNo evidence of a causal association between PDE5 inhibition and AD risk was found in the main analyses or sex-stratified analysis. DISCUSSIONMR findings suggest that PDE5 inhibitors are unlikely to decrease the risk of AD. Further research is needed to thoroughly understand the impact of PDE5 inhibitors on the risk of Alzheimers disease.

INTRODUCTIONRelationships between core Alzheimers disease (AD) biomarker accumulation and cognitive decline are well-established and the literature generally suggests a favorable relationship of cardiorespiratory fitness (CRF) on AD biomarker accumulation and cognition. Differences in risk of biomarker status conversion or accumulation rates by CRF, or their potential interactive relationships with cognitive decline remain largely unknown. METHODSParticipants (N=533; MeanAGE=65, 70% female) from the Wisconsin Alzheimers Disease Research Center and the Wisconsin Registry for Alzheimers Prevention underwent serial blood draws, and cognitive and imaging assessments (MeanFollow-up=6.0 years). PET imaging of amyloid-{beta} (A{beta}) and tau (T) and plasma phosphorylated tau-217 (pTau-217) were used to determine biomarker status (+/-). Sex-specific estimated CRF (eCRF) tertiles were created using a validated equation. Kaplan-Meier survival curves and Cox-proportional hazards models characterized the risk of becoming biomarker-positive. Linear mixed effects models estimated associations between baseline eCRF and core AD biomarker accumulation and whether eCRF modified relationships between biomarker accumulation and cognitive decline. Analyses were stratified by biomarker +/- status. RESULTSNo significant relationships were observed between eCRF and biomarker trajectories. However, those in the high eCRF group who were also A{beta}-(HR[95%CI]=0.42[0.20, 0.88]) and pTau-217-(HR[95%CI]=0.45[0.21, 0.97]) at baseline had a significantly lower risk of becoming biomarker-positive. There was a significant attenuation of the detrimental relationship between A{beta} accumulation and cognitive decline for those with high eCRF and A{beta}+/T+. DISCUSSIONWhile CRF did not influence core AD biomarker accumulation trajectories, high CRF did seem to protect against becoming biomarker-positive and attenuate the known deleterious relationship between biomarker accumulation and cognitive decline in A{beta}+/T+.

Alzheimers disease (AD) is associated with a range of non-cognitive symptoms that can be early or even presenting features. Better recognition of pre-diagnostic symptoms of AD would support improved early detection and diagnosis. To identify possible prodromal symptoms of AD, we systematically searched electronic databases for prospective longitudinal studies to March 2023, that reported the risk of AD diagnosis associated with non-cognitive symptoms. We conducted random-effects meta-analyses to obtain pooled odds of subsequent AD. Thirty studies met eligibility criteria. Most studies (n=18) reported on the association of depression with subsequent AD diagnosis (pooled OR= 1.80; 95% CI: 1.29 to 2.50; I2=95.8%). Hearing loss, weight loss, spondylosis and hypotension also predicted a subsequent AD diagnosis. This evidence suggests that these features that may be recorded during routine healthcare encounters are risk markers for incident AD and could therefore support improved early detection and diagnosis.