Alzheimer's & Dementia: Translational Research & Clinical Interventions

INTRODUCTIONThis retrospective study investigates whether exposition to levodopa/carbidopa (LA/CA) medication is associated with modified Alzheimers disease (AD) trajectories. METHODSMultivariate analysis used cerebrospinal fluid (CSF) biomarker information included in the National Alzheimers Coordinating Center Uniform Data Set for subjects with normal cognition (NC), mild cognitive impairment (MCI) and dementia (DE). Survival analyses examined the progression to MCI/DE and death events. RESULTSLA/CA use is associated with lower levels of CSF amyloid beta, phosphorylated tau (P-tau) and total Tau. After adjusting for age, sex and APOE {varepsilon}4 allele presence, that effect was quantified by negative coefficients of the fitted linear mixed models - P values <0.01 in all cases except for P-tau in the MCI subgroup (P=0.02). No similar effects were identified for other antiparkinsonian drugs. Exposition to LA/CA decreased the progression from MCI to DE (P=0.03). DISCUSSIONThe identified effects of LA/CA exposition on AD biomarkers and progression deserve further investigation in controlled clinical trials.

BackgroundAlcohol use disorder (AUD) is associated with increased risks of neuropsychiatric conditions and dementia. However, the association between Alzheimer disease (AD) and AUD is poorly characterized. To address this, we studied associations between AUD, cognition, and measures of AD neuropathology. MethodsWe measured a lifetime history of AUD, cognitive decline and blood biomarkers for AD (Amyloid Positivity Score 2, A{beta}42/A{beta}40 and p-tau217/np-tau217 ratio) in older participants from the St. Louis site of the Collaborative Study on the Genetics of Alcoholism (COGA). AUD was defined as having four or more DSM-5 AUD symptoms at the time of heaviest lifetime consumption, as most AUD related morbidity and mortality are associated with moderate/severe AUD. Cognitive decline was measured using the AD8 score (N=356), and AD biomarkers were derived from plasma measurements (N=138). We used Poisson regression models to evaluate the relationship between AUD, age, and cognitive decline, with age modeled as a piecewise linear variable by decade. Linear regressions were used to assess the association between AD blood biomarkers and AUD. ResultsAnalyses revealed a significant association between AUD and increased cognitive decline in older adults (RR=1.31, p<0.001). No statistical association was seen between plasma AD biomarkers and AUD. ConclusionsThese results underscore the importance of addressing AUD as a potentially modifiable risk factor for cognitive decline in older adults. Further study is needed to understand the link between AUD and AD biomarkers.

INTRODUCTIONQuestions remain regarding safety and clinical relevance of anti-amyloid antibodies in Alzheimers disease (AD), with no scientific basis for choosing between different therapies. METHODSSystematic review, frequentist and Bayesian network meta-analyses of phase III randomized placebo-controlled trials were performed to comparatively evaluate cognitive, functional and biomarker efficacy and safety of anti-amyloid antibodies in sporadic AD. Treatments were ranked with P- and SUCRA scores, with rank robustness measured by Cohens kappa, and uncertainty in ranking probabilities estimated with Shannons normalized entropy. RESULTSBased on data from 16,971 patients (16 studies), we found Donanemab the best-ranked antibody on cognitive measures. Lecanemab was the most effective at reducing amyloid burden. Caution is needed concerning brain edema and microbleeding, with clinically important risks for Donanemab, Aducanumab and Lecanemab. DISCUSSIONRisk/benefit profile of anti-amyloid antibodies remains unfavorable. Patients in Donanemab study were stratified by tau load, with greater effects observed in low/medium tau population. HighlightsO_LINo single therapy ranked the best among all outcomes. C_LIO_LIDonanemab was the most effective antibody at reducing cognitive decline across all primary outcomes, while Lecanemab ranked the highest on amyloid PET removal. C_LIO_LIConsistently greater cognitive, functional and biomarker effects of Donanemab were observed in patients with low/medium tau load, suggesting more promising effects in earlier AD stages. C_LIO_LIAll antibodies, except Solanezumab, were significantly less tolerable than Placebo. C_LIO_LIThe risk of cerebral edema and microbleeding may outweigh the benefits, independently of APOE status. C_LI

BackgroundMild behavioural impairment (MBI), characterized by later-life emergence of persistent neuropsychiatric symptoms (NPS), is an early clinical indicator of dementia risk. MBI as a global construct has been associated with Alzheimer disease (AD) pathology; studies have also explored MBI domains. Prior work has linked MBI-apathy to cerebrospinal fluid (CSF) biomarkers of AD, but whether similar associations are detectable using plasma-based biomarkers such as phosphorylated tau (p-tau) is unknown. Establishing such relationships is critical, as plasma biomarkers are more accessible than CSF. ObjectiveTo explore cross-sectional and longitudinal associations between MBI-apathy and plasma p-tau181 using Alzheimers Disease Neuroimaging Initiative data. MethodsOlder adults with normal cognition or mild cognitive impairment were categorized as MBI-apathy (n=69), non-MBI NPS (n=112), and no-NPS (n=215) based on Neuropsychiatric Inventory scores and symptom persistence over one year. Linear regression modelled cross-sectional associations between NPS group and plasma p-tau181 levels, adjusting for age, sex, education, apolipoprotein E4 status, and Mini-Mental State Examination score. Hierarchical linear mixed-effects modelling assessed associations over two and three years, including time-by-NPS group interactions. ResultsMBI-apathy was associated with significantly higher plasma p-tau181 levels at baseline (24.05% [6.06-45.08%]; adjusted p=0.014), and over two (26.46% [7.24-49.12%]; adjusted p=0.012) and three years (29.28% [10.17-51.72%]; adjusted p=0.004) compared to no-NPS. No significant associations were observed for non-MBI NPS. ConclusionsMBI-apathy is associated with elevated plasma p-tau181 cross-sectionally and longitudinally. These findings support MBI-apathy as a potential proxy marker of tau pathology for early AD detection.

The urgent need for safe and effective therapies for Alzheimers disease (AD) has spurred a growing interest in repurposing existing drugs to treat or prevent AD. In this study, we combined multi-omics and clinical data to investigate possible repurposing opportunities for AD. We performed transcriptome-wide association studies (TWAS) to construct gene expression signatures of AD from publicly available GWAS summary statistics, using both transcriptome prediction models for 49 tissues from the Genotype-Tissue Expression (GTEx) project and microglia-specific models trained on eQTL data from the Microglia Genomic Atlas (MiGA). We then identified compounds capable of reversing the AD-associated changes in gene expression observed in these signatures by querying the Connectivity Map (CMap) drug perturbation database. Out of >2,000 small-molecule compounds in CMap, aspirin emerged as the most promising AD repurposing candidate. To investigate the longitudinal effects of aspirin use on AD, we collected drug exposure and AD coded diagnoses from three independent sources of real-world data: electronic health records (EHRs) from Vanderbilt University Medical Center (VUMC) and the National Institutes of Health All of Us Research Program, along with national healthcare claims from the MarketScan Research Databases. In meta-analysis of EHR data from VUMC and All of Us, we found that aspirin use before age 65 was associated with decreased risk of incident AD (hazard ratio=0.76, 95% confidence interval [CI]: 0.64-0.89, P=0.001). Consistent with the findings utilizing EHR data, analysis of claims data from MarketScan revealed significantly lower odds of aspirin exposure among AD cases compared to matched controls (odds ratio=0.32, 95% CI: 0.28-0.38, P<0.001). Our results demonstrate the value of integrating genetic and clinical data for drug repurposing studies and highlight aspirin as a promising repurposing candidate for AD, warranting further investigation in clinical trials.

INTRODUCTIONMachine learning (ML) may harbor the potential to capture the metabolic complexity in Alzheimers Disease (AD). Here we set out to test the performance of metabolites in blood to categorise AD when compared to CSF biomarkers. METHODSThis study analysed samples from 242 cognitively normal (CN) people and 115 with AD-type dementia utilizing plasma metabolites (n=883). Deep Learning (DL), Extreme Gradient Boosting (XGBoost) and Random Forest (RF) were used to differentiate AD from CN. These models were internally validated using Nested Cross Validation (NCV). RESULTSOn the test data, DL produced the AUC of 0.85 (0.80-0.89), XGBoost produced 0.88 (0.86-0.89) and RF produced 0.85 (0.83-0.87). By comparison, CSF measures of amyloid, p-tau and t-tau (together with age and gender) produced with XGBoost the AUC values of 0.78, 0.83 and 0.87, respectively. DISCUSSIONThis study showed that plasma metabolites have the potential to match the AUC of well-established AD CSF biomarkers in a relatively small cohort. Further studies in independent cohorts are needed to validate whether this specific panel of blood metabolites can separate AD from controls, and how specific it is for AD as compared with other neurodegenerative disorders

ObjectivesPolygenic hazard score (PHS) models can be used to predict the age-associated risk for complex diseases, including Alzheimers disease (AD). In this study, we present an improved PHS model for AD that incorporates a large number of genetic variants and demonstrates enhanced predictive accuracy for age of onset in European populations compared to alternative models. MethodsWe used the genotyped European Alzheimer & Dementia Biobank (EADB) sample (n=42,120) to develop and evaluate the performance of the PHS model. We developed a PHS model building on 720 genetic variants, including Apolipoprotein E (APOE) {varepsilon}2 and {varepsilon}4 alleles. We used Elastic Net-regularized Cox regression approach to develop the PHS model. ResultsThe new PHS model (EADB720) improved prediction accuracy compared to alternative models in European populations, with the Odds Ratio OR80/20 from the highest quintile of risk (80th risk percentile and above) to the lowest quintile of risk (20th risk percentile and below) varying between 5.10 and 13.15 within the range of age of onset from 65 - 85 years. Our model also improved risk stratification across {varepsilon}3/3 individuals of European ancestry (OR80/20 ranges from 1.95 to 3.52). It was also successfully validated in independent datasets (HUSK, DemGene and ADNI) by achieving OR80/20 up to 10.00 in each independent dataset. ConclusionOur EADB720 model significantly improves the accuracy of age-associated risk of AD across European populations (pval<0.03). Accurately predicting the age of onset of AD is of large clinical importance to implementing new AD medication and early intervention in clinical settings.

AO_SCPLOWBSTRACTC_SCPLOWO_ST_ABSINTRODUCTIONC_ST_ABSTreatment response in Alzheimers disease (AD) varies substantially across patients, yet no validated frameworks exist to estimate heterogeneous treatment effects (HTE) from observational data while controlling for confounding bias. METHODSWe developed a causal machine learning framework integrating expert-guided causal graphs, complementary HTE estimators, sensitivity analyses, and policy learning. We applied it to cholinesterase inhibitors (ChEIs) in MCI due to AD to patients from the NACC and ADNI cohorts. RESULTSAnalysing 4,049 patients with 12-month and 2,223 with 36-month follow-up, all estimators indicated null or negative long-term ChEI effects on cognitive and functional outcomes, notably on functional measures. ChEIs showed slightly more deleterious effects among men than women. DISCUSSIONThis framework provides a methodology for estimating HTE from observational data. It revealed no beneficial responder subgroups, highlighting the challenge of detecting treatment heterogeneity in moderately sized cohorts. This approach can inform treatment selection for other AD therapies including memantine, anti-amyloid agents, and emerging treatments.

Previous studies have reported associations between risk of Alzheimers disease (AD) or dementia and rare coding variants in a number of genes. A two stage strategy was used in which a previously released whole exome sequenced sample was used to prioritise 100 genes showing the strongest evidence for association with AD. These genes were then analysed in a newly released whole genome sequenced sample to identify those which showed statistically significant evidence for rare coding variant association. Association analysis of loss of function (LOF) and nonsynonymous variants was carried out in 18,998 protein coding genes using 11,188 controls and 5,808 cases, with nonsynonymous variants being annotated using 45 different pathogenicity predictors. The 100 genes showing strongest evidence for association were then analysed in a new sample of 27,749 controls and 13,234 cases using only the pathogenicity predictor which had performed best in the first sample. Four genes were statistically significant after correction for multiple testing: ABCA7, PSEN1, SORL1 and TREM2. The association of different categories of variant with AD was characterised and the pattern was seen to vary between genes. This study quantifies the contribution of different types of variant within each gene to AD risk. In general these variants are probably too rare to be clinically useful for assessing individual risk of AD. Further research into the mechanisms whereby the products of these genes affect AD pathogenesis may aid development of novel therapeutic strategies.

BackgroundSecond-generation antipsychotics (SGAs) are frequently used off-label to manage behavioral symptoms in Alzheimers disease (AD), despite ongoing concerns about their safety. Comparative evidence on mortality risk across specific SGAs remains limited. ObjectiveTo compare all-cause mortality among AD patients treated with commonly prescribed SGAs and to explore treatment effect heterogeneity using causal machine learning. MethodsWe conducted a retrospective cohort study using de-identified electronic health records from the Truveta platform (2018-2024). Patients with incident AD initiating treatment with aripiprazole, risperidone, quetiapine, or olanzapine were identified using an active-comparator, new-user design. Drug exposure was modeled as a time-varying covariate in Cox proportional hazards models, with propensity score matching applied to control for confounding. Causal tree and targeted maximum likelihood estimation (TMLE) were used to identify subgroups with heterogeneous treatment effects. ResultsAmong 17,004 AD patients, aripiprazole was associated with significantly lower mortality than olanzapine (HR = 0.667, 95% CI: 0.472-0.941) and quetiapine (HR = 0.677, 95% CI: 0.462-0.990). Quetiapine was also associated with lower mortality than olanzapine (HR = 0.833, 95% CI: 0.702-0.990) and risperidone (HR = 0.830, 95% CI: 0.705-0.978). Causal tree analysis revealed treatment effect heterogeneity by clinical characteristics, particularly among patients using type 2 diabetes (T2DM) medications. In subgroup analyses, aripiprazole remained protective in T2DM users (HR = 0.604 vs. quetiapine and risperidone, p = 0.002). ConclusionsMortality risks vary substantially across SGAs in AD patients. Aripiprazole and quetiapine were associated with lower mortality compared to olanzapine and risperidone. Treatment effect heterogeneity suggests the need for individualized prescribing based on patient characteristics such as comorbid T2DM.

ImportanceWhile apathy and affective neuropsychiatric symptoms (NPS) are common in the clinical spectrum of Alzheimers disease (AD), their neurobiological correlates remain unclear. ObjectiveTo longitudinally examine plasma markers of neurodegeneration (neurofilament light chain; NfL) and tau pathology (phosphorylated at threonine 181; p-tau181) and their associations with apathy and affective symptoms in individuals with clinical diagnoses of AD dementia and mild cognitive impairment (MCI). Design, Setting, Participants and ExposureThis cohort study used longitudinal data from the Alzheimer Disease Neuroimaging Initiative (ADNI). Individuals with clinical diagnoses of MCI and AD dementia were enrolled in ADNI with serial annual blood samples over a four-year period, which were analyzed for NfL and p-tau181 using ultrasensitive techniques. Study data were accessed between July and September 2024. Main Outcomes and MeasuresThe presence of neuropsychiatric symptoms was determined using the Neuropsychiatric Interview (NPI). We analyzed the trajectory of plasma NfL and p-tau181 in each NPS using general linear mixed-effects models adjusted for age and sex. ResultsThere were 790 participants with AD dementia and MCI (mean [SD] age 72.7 [7.6] years; 333 females, 42%) and 417 healthy controls. The most common NPS was depression (n = 428; 54%), followed by irritability (n = 419; 53%), apathy (n = 348; 44%) and anxiety (n = 341; 43%). In the AD dementia and MCI group, apathy and anxiety were associated with higher levels of both NfL and p-tau181 after controlling for cognitive and functional decline. Moreover, apathy was associated with higher rate of NfL increase longitudinally. Depression at baseline was initially associated with higher NfL and p-tau181 levels, but this did not remain significant in the sensitivity analyses. Conclusion and RelevanceThis study found that in individuals with clinical AD, apathy and anxiety are associated greater tau and neurodegenerative burden. Furthermore, those with apathy had a higher rate of NfL increase, which suggests an accelerated neurodegenerative process. These findings highlight that these symptoms be indicative of AD pathology severity and have implications for potential treatments which target tau pathology. Key PointsQuestion: Do apathy and affective neuropsychiatric symptoms correlate with the rate of tau pathology and neurodegeneration, as measured by plasma phosphorylated-tau181 (p-tau181) and neurofilament light chain protein (NfL), in individuals across the clinical spectrum of Alzheimers disease (AD)? Findings: In a longitudinal study of 790 patients with mild cognitive impairment (MCI) and AD dementia, serial measurements of plasma p-tau181 and NfL were collected annually over four years. P-tau181 and NfL levels were elevated in those with apathy or anxiety compared to those without. The rate of NfL increase, an indicator of neurodegeneration, was significantly higher in those with apathy. Meaning: The presence of anxiety and apathy was associated with elevated biomarkers of neurodegeneration in MCI and AD dementia. Notably, apathy was linked to a faster rate of NfL increase, suggesting an accelerated neurodegenerative process.

INTRODUCTIONMild cognitive impairment (MCI), a prodromal stage of Alzheimers disease and related dementias (ADRD), represents a critical window for intervention. Although mitochondrial dysfunction is increasingly implicated in neurodegeneration, most therapies target downstream protein aggregation. Transcranial photobiomodulation (tPBM) delivers near-infrared light to enhance mitochondrial respiration. We hypothesized that tPBM in MCI would be safe, feasible, and associated with improvements in cognition, mitochondrial function, and default-modenetwork (DMN) functional connectivity (FC). METHODSWe conducted a single-blind, randomized, sham-controlled pilot trial (NCT05563298) in adults [&ge;]50 years with MCI. Twenty participants were randomized 1:1 to active or sham devices. Active devices delivered pulsed 810-nm light for 20 minutes per session; shams emitted light for 2 seconds. Stimulation targeted DMN hubs and the olfactory bulb. Participants self-administered treatment at home six days per week for six weeks. RESULTSAdherence was high (active 96.9%; sham 94.2%). Adverse events (Aes) were reported by 10 of 20 participants (4 active, 6 sham) No serious AE occurred. Compared with sham, active tPBM produced greater improvement in global cognition (MMSE; p=0.03) and episodic memory (CVLT-II long-delay recognition; p=0.02). Serum pyruvate and lactate increased with a reduced lactate-to-pyruvate ratio (p=0.007). DMN FC increased (p=0.014), and plasma IL-6 declined (p=0.02). DISCUSSIONHome-based tPBM was safe, tolerable, and feasible, with strong adherence and mild AEs. Cognitive, metabolic, and network-level findings suggest enhanced mitochondrial efficiency and anti-inflammatory effects. These results support larger, double-blind multicenter trials to evaluate tPBM as a mitochondria-targeted therapy in early ADRD.

BackgroundChanges to sleep, weight, and endocrine function are common in Alzheimers disease (AD) and Lewy-body dementia (LBD). The cause of these is not known, but they may be related to hypothalamic neurodegeneration. MethodsWe performed a systematic search of MEDLINE and EMBASE of studies using structural magnetic resonance imaging to examine hypothalamic volume in people with AD or LBD. The Newcastle-Ottawa scale was used to assess the risk of bias. A random-effects meta-analysis was conducted using the standardised mean difference (SMD) in hypothalamic volume as the effect measure, and a narrative synthesis was used to examine the relationship between hypothalamic volume and sleep, eating, and endocrine function. ResultsWe identified 6542 articles which resulted in 12 included studies, most which had a low to moderate risk of bias. The meta-analysis included 454 people with mild-moderate AD (Mini-Mental State (MMSE) range: 19.2-26.1) and 715 controls. We found that people with AD had a significantly smaller hypothalamus (pooled SMD: -0.49, t=-3.47, p=0.018, 95%CI: -0.86 to - 0.13). There was significant heterogeneity of a moderate degree (Tau2=0.0665, 95%CI:0.005-0.8090; I2=67%, 95%CI:21.5%-86.1%; Q=15.16, p<0.01), but no evidence of publication bias. Only one study examined people with LBD, finding qualitative evidence of lower hypothalamic volume compared to controls. Hypothalamic volume loss in AD was more marked in men and may be associated with plasma levels of sex hormones and decreased bone mineral density. ConclusionReduced hypothalamic volume is seen early in AD and LBD and this may influence endocrine function. A better understanding of hypothalamic degeneration in dementia may help elucidate how pathology relates to symptoms in AD and LBD and reveal new targets for intervention.

BACKGROUNDMild Behavioral Impairment (MBI) is a neuropsychiatric syndrome describing later-life emergent apathy, mood/anxiety symptoms, impulse dyscontrol, social inappropriateness and psychosis that are not attributable to psychiatric diagnoses. MBI is an at-risk state for incident cognitive decline and dementia, and is associated with dementia biomarkers including A{beta} and neurofilament light. Thus, MBI may be an early clinical marker of neurodegenerative disease. In this study, we hypothesized that stratification by MBI in a cognitively normal sample would moderate the signal between Alzheimers disease (AD) genetic risk and cognition. METHODSGenetic, cognitive and MBI data was available for 3,126 PROTECT study participants over 50 without dementia. A general cognitive composite score was constructed based on scores on paired associates learning, digit span, self-ordered search and verbal reasoning. MBI was assessed using the MBI Checklist. Polygenic scores for AD were split by tertile (representing low, medium and high risk) and the sample was stratified by MBI into those with no symptoms and those with any symptoms. RESULTSAD genetic risk was associated with poorer cognition in the MBI strata only (MBI: F(2,1746)=4.95, p=0.007; no MBI: F(2,1366)=0.72, p=0.49). The mean difference between low and high genetic risk groups was significant (p=0.005) and thestandardised effect size in the MBI sample was higher than in the whole sample. CONCLUSIONSThese findings justify MBI screening to enrich samples with at-risk individuals, and underscore the importance of late-life neuropsychiatric symptoms in cognitive ageing.

IntroductionChange-point analyses are increasingly used to identify the temporal stages of accelerated cognitive decline in the preclinical stages of Alzheimers Disease (AD). However, statistical comparisons of change-points between specific cognitive measures have not been reported. Methods165 older adults (baseline age range: 61.1-91.2) from the Baltimore Longitudinal Study of Aging developed AD during follow-up. Linear and non-linear mixed models were fit for 11 cognitive measures to determine change-points in rates of decline before AD diagnosis. Bootstrapping was used to compare the timing of change-points across cognitive measures. ResultsChange-points followed by accelerated decline ranged from 15.5 years (Card Rotations) to 1.9 years (Trail-Making A) before AD diagnosis. Accelerated decline in Card Rotations occurred significantly earlier than all other measures, including learning and memory measures. DiscussionResults suggest that visuospatial ability, as assessed by Card Rotations, may have the greatest utility as an early predictive tool in identifying preclinical AD.

INTRODUCTIONAlzheimers disease (AD) is a public health priority. AD biomarkers may vary based on race, but recruitment of diverse participants has been challenging. METHODSThree groups of Black and White participants with and without prior research advocacy or participation were interviewed individually or in focus groups to better understand perspectives related to AD biomarker research participation. Thematic analytic approach was used to analyze the data. RESULTSIdentified barriers to AD biomarker research participation included hesitancy due to fear, distrust of research and researchers, lack of relevant knowledge, and lack of research test results disclosure. Drivers for engagement in biomarker research procedures included knowledge about research, AD, and related clinical procedures, perceived benefits of participation, and outreach from trusted sources. DISCUSSIONParticipants comments related to the need for diversity in research and desire for results disclosure suggest opportunities to engage Black individuals.

Structured AbstractO_ST_ABSObjectiveC_ST_ABSMild Behavioral Impairment (MBI) is a syndrome of late-life-onset persistent neuropsychiatric symptoms. Anticholinergic medication is commonly prescribed in older adults. Both MBI and anticholinergic exposure are associated with increased dementia risk. We sought to understand the association of anticholinergic burden (ACB) with MBI. Design, Setting, participantsWe mapped ratings on the Neuropsychiatric Inventory Questionnaire to the MBI checklist (MBI-C) using an established algorithm to define MBI status in cognitively unimpaired individuals in the National Alzheimers Coordinating Center database. We then assessed the association between time-varying ACB ratings and risk of incident MBI. Results4865 participants met inclusion criteria and were followed for a mean (SD) of 5.64 (3.92) years. ACB scores ranged from 0-11. 63.3% of participants had a score of 0, 27.7% had a score of 1-2, and 9% had a score of [&ge;]3. Higher maximum total ACB score was associated with a higher likelihood of developing MBI (p=<0.001). When assessed as a time varying covariate, ACB score was associated with incident MBI (HR 1.12, 95% CI 1.05-1.19, p=<0.001). This association remained significant when adjusted for 10-year mortality risk. ConclusionsMBI risk should be considered when prescribing anticholinergic medication in older adults.

Mild Behavioural Impairment (MBI) is defined by later-life onset of persistent behavioural changes and is recognized as a risk marker for cognitive decline and dementia. Apathy, a core MBI domain characterized by diminished interest, initiative, and emotional reactivity, can emerge before dementia and is hypothesized to be associated with structural brain changes. While previous studies have explored Alzheimer disease (AD)-related neuroanatomical substrates of apathy in the dementia clinical stage, few have investigated these associations in cognitively normal (CN) or mild cognitive impairment (MCI) individuals with persistent apathy consistent with MBI. Thus, this study explores structural brain differences between individuals with MBI-apathy and those without neuropsychiatric symptoms (no-NPS). Participants (n = 446; mean age = 69.6 years; 79.8% CN; 62.8% female) were drawn from the National Alzheimers Coordinating Center and categorized into MBI-apathy (n = 59) and no-NPS (n = 387) groups. Linear regressions were used to model associations between NPS group and regional brain measures, with adjustments for age, sex, years of education, apolipoprotein E4 carrier status, intracranial volume, and Mini-Mental State Examination score, with false discovery rate (FDR) correction for multiple comparisons. Primary outcomes included two predefined AD meta-regions-of-interest (ROIs): 1) thickness: a composite measure of mean cortical thickness across the entorhinal cortex, inferior temporal gyrus, middle temporal gyrus, inferior parietal lobule, fusiform gyrus, and precuneus; and 2) volume: a composite measure of mean cortical and subcortical grey matter volume across the hippocampus, entorhinal cortex, amygdala, middle temporal gyrus, inferior parietal lobule, and precuneus. Primary outcomes also included cortical thickness and grey matter volume among individual ROIs including the ventral striatum (VS), anterior cingulate cortex (ACC), orbitofrontal cortex (OFC), ventrolateral prefrontal cortex (vlPFC), and dorsolateral prefrontal cortex (dlPFC). MBI-apathy status was associated with significantly lower AD-meta-ROI cortical thickness (Z-score difference [95% CI]; FDR-corrected p-value, -0.43 [-0.73 - [-0.12]]; 0.025) and lower AD meta-ROI grey matter volume (-0.50 [-0.71 - [-0.30]]; <0.001). MBI-apathy was also associated with significantly lower dlPFC thickness (-0.40, [-0.70 - [-0.09]]; 0.02) and volume (-0.28 [-0.50- [-0.06]]; 0.026) and lower OFC volume (-0.32, [-0.57 - [-0.07]]; 0.026) compared to the no-NPS group. Within a non-dementia sample, MBI-apathy was more strongly associated with established AD-vulnerable regions than with regions that have been traditionally implicated in apathy in dementia. Results suggests that during CN and MCI stages, MBI-apathy may reflect early AD-related neurodegeneration, with conventional apathy-related structural changes becoming more prominent as disease progresses.

BackgroundIn dementia research, affective neuropsychiatric symptoms (NPS) - depression, anxiety, and apathy - remain understudied. Improving strategies to accurately identify clinically relevant NPS is essential for more robust research. ObjectivesWe sought to determine how often objective metrics and clinical gestalt metrics agree on NPS presence or absence. We further sought to determine optimal cut-offs for affective NPS presence/absence using the Neuropsychiatric Inventory Questionnaire (NPI-Q) severity ratings. MethodsWe assessed agreement for NPS presence/absence among 5 different depression metrics, 4 anxiety metrics, and 2 apathy metrics via Jaccard indices using the National Alzheimers Coordinating Centers (NACC) dataset. Analysis included exploring different NPIQ severity rating thresholds of >0, >1, >2, and 0 and >1. ResultsNPIQ cut-off >1 for presence and =0 for absence of an NPS led to the best agreement with other metrics. However, there was poor agreement for NPS presence across depression metrics (6%) and across anxiety metrics (7%). Choice of metric could greatly skew the frequency of an NPS being present. All 3 affective NPS were more common in Lewy Body Disorder compared to Alzheimers Disease or Vascular Cognitive Impairment, regardless of metric. ConclusionsThough NPIQ severity rating cut-off choice should depend on study design, using a severity score of >1 for presence and =0 for absence may best fit clinical gestalt for affective NPS. Lewy Body Disorders present with more affective NPS than other common dementia etiologies. Future consensus on criteria for depression and anxiety syndromes in dementia may improve their identification.

BackgroundPsychological distress has been linked with later cognitive impairment and dementia, although the nature of the association remains unclear. Using a multi-cohort approach, we examined longitudinal associations of psychological distress with subsequent cognition and dementia, testing whether findings varied by age of assessment, severity, and persistence of psychological distress. MethodsWe used five longitudinal studies: Caerphilly Prospective Study, English Longitudinal Study of Ageing, National Child Development Study, National Survey of Health and Development, and Whitehall II. We examined associations with changes in cognition using linear and mixed effects models, and dementia using logistic regression. Results were pooled using two-stage individual participant data meta-analysis. FindingsPooled analyses (total N=24,564) showed that greater psychological distress was associated with lower subsequent cognitive level ({beta}=-0.03 [95% CI: -0.06; -0.01]; I2=69.7%). Associations were present for clinically-significant ({beta}=-0.06 [-0.12; -0.00]; I2=62.2%), persistent ({beta}=-0.12 [-0.23; -0.02]; I2=82.5%) and intermittent distress ({beta}=-0.09 [-0.12; -0.05]; I2=0%). Baseline distress was not associated with rates of subsequent cognitive decline. Psychological distress was associated with subsequent dementia (OR=1.12 [1.04; 1.20]; I2=0%), including for clinically-significant (OR=1.28 [1.07; 1.52; I2=0%]), persistent (OR=1.43 [1.04; 1.98]; I2=44.0%) and intermittent symptoms (OR=1.32 [1.02; 1.71]; I2=40.3%). Dementia was associated with psychological distress assessed in later life (age 65-75 OR: 1.29 [1.18; 1.40]; I2=13.9%), but not mid-life (age 45-54 OR: 1.09 [0.93; 1.28]; I2=34.0%). InterpretationIn this multi-cohort study, psychological distress was associated with subsequent dementia and lower subsequent cognitive level, including for both persistent and intermittent distress. Associations with dementia were present when distress was assessed at older ages but not at ages 45-54 years, suggesting that associations might partly represent early preclinical markers of dementia neuropathology. Findings highlight the potential relevance of psychological distress in informing dementia prevention and supporting identification of high-risk groups, both of which are major global public health priorities.