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As of 2023, it is estimated that 6.7 million individuals in the United States live with Alzheimer's disease (AD). Prior research indicates that AD disproportionality affects females; females have a greater incidence rate, perform worse on a variety of neuropsychological tasks, and have greater total brain atrophy. Recent research shows that hippocampal functional connectivity differs by sex and may be related to the observed sex differences in AD, and apolipoprotein E (ApoE) ε4 carriers have reduced hippocampal functional connectivity. The purpose of this study was to determine if the ApoE genotype plays a role in the observed sex differences in hippocampal functional connectivity in Alzheimer's disease. The resting state fMRI and T2 MRI of individuals with AD (n = 30, female = 15) and cognitively normal individuals (n = 30, female = 15) from the Alzheimer's Disease Neuroimaging Initiative (ADNI) were analyzed using the functional connectivity toolbox (CONN). Our results demonstrated intrahippocampal functional connectivity differed between those without an ε4 allele and those with at least one ε4 allele in each group. Additionally, intrahippocampal functional connectivity differed only by sex when Alzheimer's participants had at least one ε4 allele. These results improve our current understanding of the role of the interacting relationship between sex, ApoE genotype, and hippocampal function in AD. Understanding these biomarkers may aid in the development of sex-specific interventions for improved AD treatment.

BackgroundIndividuals with Down syndrome (DS) are at high risk of early-onset Alzheimer's disease (AD); yet, some 20 percent do not develop any signs of dementia until after 65 years or in their lifetime. Mosaicism could contribute to this phenotypic variation, where some disomic cells could lead to lower levels of gene products from chromosome 21.MethodsWe examined longitudinal neuropsychological and biomarker data from two large studies of DS: the Alzheimer Biomarker Consortium-Down syndrome study (ABC-DS) (n = 357); and a legacy study (n = 468). We assessed mosaicism using karyotyping or GWAS data. Participants had data on plasma AD biomarkers (Aβ40, Aβ42, tau, and NfL) and longitudinal cognitive measures. A subset had cerebrospinal fluid biomarkers (Aβ40, Aβ42, tau, ptau181, and NfL) and amyloid and tau PET data.FindingsFor both cohorts, the prevalence of mosaicism was

We examined the relationship between subjective and objective sleep outcomes and loneliness in older women at risk for Alzheimer's disease (AD). Our sample consisted of 39 participants (aged 65+) with mild cognitive deficits who completed the UCLA Loneliness Scale, the Pittsburgh Sleep Quality Index (PSQI), and an at home sleep test, to determine presence of obstructive sleep apnea. Based on sleep quality scores, individuals categorized as "poor sleepers" had significantly higher loneliness scores than "good sleepers." However, total loneliness scores did not significantly differ between groups with or without sleep apnea. We found that higher loneliness was significantly associated to lower habitual sleep efficiency and sleep duration and was also influenced by use of sleep medication. Our findings suggest that increased loneliness relates to worse subjective sleep quality, but not to sleep apnea. These findings suggest that combined interventions targeting loneliness and sleep quality may be important for older women.

IntroductionThe potential utility of subjective cognitive decline (SCD) as an early risk marker of Alzheimer's disease and related dementias is under consideration. We examined associations between SCD and cognitive change among middle-aged and older Hispanic/Latino adults living in the United States.MethodsThe short-form Everyday Cognition Scale (ECog-12) was assessed to generate global, executive function, and memory-related SCD scores. We used survey generalized regressions to model the change in learning, memory, verbal fluency, executive function, and global cognitive performance over 7 years as a function of SCD (at Visit 2).ResultsThe mean age was 56.37 ± 8.10 years at Visit 1 (n = 6225). Higher ECog-12 was associated with greater decline in global cognitive performance (ECog-12 global: B = -0.17, standard error [SE] = 0.02; ECog-12 executive: B = -0.15, SE = 0.02; ECog-12 memory: B = -0.14, SE = 0.02, p's

The tauopathies are defined by pathological tau protein aggregates within a spectrum of clinically heterogeneous neurodegenerative diseases. The primary tauopathies meet the definition of rare diseases in the United States. There is no approved treatment for primary tauopathies. In this context, designing the most efficient development programs to translate promising targets and treatments from preclinical studies to early-phase clinical trials is vital. In September 2022, the Rainwater Charitable Foundation convened an international expert workshop focused on the translation of tauopathy therapeutics through early-phase trials. Our report on the workshop recommends a framework for principled drug development and a companion lexicon to facilitate communication focusing on reproducibility and achieving common elements. Topics include the selection of targets, drugs, biomarkers, participants, and study designs. The maturation of pharmacodynamic biomarkers to demonstrate target engagement and surrogate disease biomarkers is a crucial unmet need. HIGHLIGHTS: Experts provided a framework to translate therapeutics (discovery to clinical trials). Experts focused on the "5 Rights" (target, drug, biomarker, participants, trial). Current research on frontotemporal degeneration, progressive supranuclear palsy, and corticobasal syndrome therapeutics includes 32 trials (37% on biologics) Tau therapeutics are being tested in Alzheimer's disease; primary tauopathies have a large unmet need.

BackgroundChronic pain leads to tau accumulation and hippocampal atrophy, which may be moderated through inflammation. In older men, we examined associations of chronic pain with Alzheimer's disease (AD)-related plasma biomarkers and hippocampal volume as moderated by systemic inflammation.MethodsParticipants were men without dementia. Chronic pain was defined as moderate-to-severe pain in 2+ study waves at average ages 56, 62, and 68. At age 68, we measured plasma amyloid-beta (Aβ42, n = 871), Aβ40 (n = 887), total tau (t-tau, n = 841), and neurofilament light chain (NfL, n = 915), and serum high-sensitivity C-reactive protein (hs-CRP, n = 968), a marker of systemic inflammation. A subgroup underwent structural MRI to measure hippocampal volume (n = 385). Analyses adjusted for medical morbidities, depressive symptoms, and opioid use.ResultsChronic pain was related to higher Aβ40 (β = 0.25, p = .009), but hs-CRP was unrelated to AD-related biomarkers (ps > .05). There was a significant interaction such that older men with both chronic pain and higher levels of hs-CRP had higher levels of Aβ42 (β = 0.36, p = .001) and Aβ40 (β = 0.29, p = .003). Chronic pain and hs-CRP did not interact to predict levels of Aβ42/Aβ40, t-tau, or NfL. Furthermore, there were significant interactions such that Aβ42 and Aβ40 were associated with lower hippocampal volume, particularly when levels of hs-CRP were elevated (hs-CRP × Aβ42: β = -0.19, p = .002; hs-CRP × Aβ40: β = -0.21, p = .001), regardless of chronic pain status.ConclusionsChronic pain was associated with higher plasma Aβ, especially when hs-CRP was also elevated. Higher hs-CRP and Aβ levels were both related to smaller hippocampal volumes. Chronic pain, when accompanied by systemic inflammation, may elevate the risk of neurodegeneration in AD-vulnerable regions.

IntroductionFew studies have examined the relationship between education and cognition among the oldest-old.MethodsCognitive assessments were conducted biannually for 803 participants (62.6% women) of LifeAfter90, a longitudinal study of individuals ≥ 90 years old. Gender differences in associations between education (

Background and hypothesisIt remains unclear whether the relation of chronic kidney disease (CKD) with cognitive dysfunction is independent of blood pressure (BP). We evaluated kidney function in relation to premorbid BP measurements, cerebral small vessel disease (CSVD), and incident mild cognitive impairment (MCI) and dementia in Framingham Offspring Cohort participants.MethodsWe included Framingham Offspring participants free of dementia, attending an examination during midlife (exam cycle 6, baseline) for ascertainment of kidney function status, with brain magnetic resonance imaging late in life (exam cycles 7-9), cognitive outcome data, and available interim hypertension and BP assessments. We related CKD (estimated glomerular filtration rate

IntroductionBlood-brain barrier (BBB) dysfunction occurs in Alzheimer's disease (AD). Yet, the stage at which it appears along the AD time course and whether it contributes to neurodegeneration remain unclear.MethodsOlder adults (61 to 90 years) from cognitively normal (CN) to mildly cognitively impaired (CI), enriched for APOE ?4 and amyloid positivity, underwent dynamic contrast-enhanced (DCE) magnetic resonance imaging (MRI) and diffusion MRI to measure BBB permeability and brain microstructure. Analysis of variance compared BBB permeability according to cognitive status, amyloid beta (Aβ), and APOE4. Linear regressions assessed associations of BBB permeability with brain microstructure and interactions with Aβ and APOE4.ResultsBBB permeability was elevated for APOE4 carriers across the cortical gray matter, with the strongest differences among CN amyloid-negative individuals. Associations between entorhinal BBB permeability and microstructure interacted with Aβ and APOE4, with the strongest relationships in amyloid-positive individuals and APOE4 carriers.DiscussionAPOE4 may drive widespread BBB dysfunction in preclinical AD, which may contribute to neurodegenerative changes early along the AD cascade.HighlightsGray matter blood-brain barrier (BBB) permeability is elevated for APOE4 carriers. APOE4-related BBB breakdown appears in the absence of cognitive decline or amyloid. BBB leakage correlates with entorhinal cortex microstructural injury. Associations with microstructure are strongest for amyloid-positive APOE4 carriers.

Early stages of Alzheimer's disease (AD) are associated with volume reductions in specific subregions of the medial temporal lobe (MTL). Using a manual segmentation method-the Olsen-Amaral-Palombo (OAP) protocol-previous work in healthy older adults showed that reductions in grey matter volumes in MTL subregions were associated with lower scores on the Montreal Cognitive Assessment (MoCA), suggesting atrophy may occur prior to diagnosis of mild cognitive impairment, a condition that often progresses to AD. However, current "gold standard" manual segmentation methods are labour intensive and time consuming. Here, we examined the utility of Automatic Segmentation of Hippocampal Subfields (ASHS) to detect volumetric differences in MTL subregions of healthy older adults who varied in cognitive status as determined by the MoCA. We trained ASHS on the OAP protocol to create the ASHS-OAP atlas and then examined how well automated segmentation replicated manual segmentation. Volumetric measures obtained from the ASHS-OAP atlas were also contrasted against those from the ASHS-PMC atlas, a widely used atlas provided by the ASHS team. The pattern of volumetric results was similar between the ASHS-OAP atlas and manual segmentation for anterolateral entorhinal cortex and perirhinal cortex, suggesting that ASHS-OAP is a viable alternative to current manual segmentation methods for detecting group differences based on cognitive status. Although ASHS-OAP and ASHS-PMC produced varying volumes for most regions of interest, they both identified early signs of neurodegeneration in CA2/CA3/DG and identified marginal differences in entorhinal cortex. Our findings highlight the utility of automated segmentation methods but still underscore the need for a unified and harmonized MTL segmentation atlas.

BACKGROUND: The research community has historically failed to enroll diverse groups of participants in dementia clinical trials. A unique aspect of dementia care research is the requirement of a study partner, who can attest to the care recipients clinical and functional capacity. The aim of this study is to assess racial and ethnic differences and the importance of various trial considerations among dementia caregivers, in their decision to participate in clinical research as study partners. METHOD: We embedded a vignette about a hypothetical dementia clinical trial in a nationally representative survey of U.S. dementia caregivers, oversampling non-Hispanic Black and Hispanic caregivers. Dementia caregivers were asked about their willingness to participate in the trial with their care recipient and rated the importance of nine considerations in hypothetical decisions to participate. Caregiver demographic characteristics were analyzed as predictors of trial participation in a base demographic model. In a second reasons model caregiver demographic characteristics and the rated importance of the nine considerations were separately analyzed as predictors; both models used survey-weighted logistic regression. RESULT: The sample consisted of 610 dementia caregivers, including 156 non-Hispanic Black and 122 Hispanic caregiver participants. In the base demographic model, hypothetical trial participation was negatively associated with older caregiver age (OR (odds ratio) = 0.72, p =

Protein aggregation is involved in many human diseases, but characterizing the sizes and shapes of intermediate oligomers (∼10-100 nm) that are important to the formation of macroscale aggregates like amyloid fibrils is a significant analytical challenge. Here, charge detection mass spectrometry (CDMS) is used to characterize individual conformational states of bovine serum albumin oligomers with up to ∼225 molecules (15 MDa). Elongated, partially folded, and globular conformational families for each oligomer can be readily distinguished based on the extent of charging. The abundances of individual conformers vary with changes in the monomer concentration or by adding aggregation inhibitors, such as SDS, heparin, or MgCl2. These results show the potential of CDMS for investigating intermediate oligomers in protein aggregation processes that are important for understanding aggregate formation and inhibition mechanisms and could accelerate formulation buffer development to prevent the aggregation of biotherapeutics.

Study objectivesInsomnia symptoms are prevalent along the trajectory of Alzheimer's disease (AD), but the neurobiological underpinning of their interaction is poorly understood. Here, we assessed structural and functional brain measures within and between the default mode network (DMN), salience network, and central executive network (CEN).MethodsWe selected 320 participants from the ADNI database and divided them by their diagnosis: cognitively normal (CN), Mild Cognitive Impairment (MCI), and AD, with and without self-reported insomnia symptoms. We measured the gray matter volume (GMV), structural covariance (SC), degrees centrality (DC), and functional connectivity (FC), testing the effect and interaction of insomnia symptoms and diagnosis on each index. Subsequently, we performed a within-group linear regression across each network and ROI. Finally, we correlated observed abnormalities with changes in cognitive and affective scores.ResultsInsomnia symptoms were associated with FC alterations across all groups. The AD group also demonstrated an interaction between insomnia and diagnosis. Within-group analyses revealed that in CN and MCI, insomnia symptoms were characterized by within-network hyperconnectivity, while in AD, within- and between-network hypoconnectivity was ubiquitous. SC and GMV alterations were nonsignificant in the presence of insomnia symptoms, and DC indices only showed network-level alterations in the CEN of AD individuals. Abnormal FC within and between DMN and CEN hubs was additionally associated with reduced cognitive function across all groups, and increased depressive symptoms in AD.ConclusionsWe conclude that patients with clinical AD present with a unique pattern of insomnia-related functional alterations, highlighting the profound interaction between both conditions.

While Alzheimers disease and other neurodegenerative diseases have traditionally been viewed as brain disorders, there is growing evidence indicating their manifestation in the eyes as well. The retina, being a developmental extension of the brain, represents the only part of the central nervous system that can be noninvasively imaged at a high spatial resolution. The discovery of the specific pathological hallmarks of Alzheimers disease in the retina of patients holds great promise for disease diagnosis and monitoring, particularly in the early stages where disease progression can potentially be slowed. Among various retinal imaging methods, hyperspectral imaging has garnered significant attention in this field. It offers a label-free approach to detect disease biomarkers, making it especially valuable for large-scale population screening efforts. In this review, we discuss recent advances in the field and outline the current bottlenecks and enabling technologies that could propel this field toward clinical translation.

IntroductionCardiovascular health is important for brain aging, yet its role in the clinical manifestation of autosomal dominant or atypical forms of dementia has not been fully elucidated. We examined relationships between Life's Simple 7 (LS7) and clinical trajectories in individuals with autosomal dominant frontotemporal lobar degeneration (FTLD).MethodsTwo hundred forty-seven adults carrying FTLD pathogenic genetic variants (53% asymptomatic) and 189 non-carrier controls completed baseline LS7, and longitudinal neuroimaging and neuropsychological testing.ResultsAmong variant carriers, higher baseline LS7 is associated with slower accumulation of frontal white matter hyperintensities (WMHs), as well as slower memory and language declines. Higher baseline LS7 associated with larger baseline frontotemporal volume, but not frontotemporal volume trajectories.DiscussionBetter baseline cardiovascular health related to slower cognitive decline and accumulation of frontal WMHs in autosomal dominant FTLD. Optimizing cardiovascular health may be an important modifiable approach to bolster cognitive health and brain integrity in FTLD.HighlightsBetter cardiovascular health associates with slower cognitive decline in frontotemporal lobar degeneration (FTLD). Lifestyle relates to the accumulation of frontal white matter hyperintensities in FTLD. More optimal cardiovascular health associates with greater baseline frontotemporal lobe volume. Optimized cardiovascular health relates to more favorable outcomes in genetic dementia.

The magnetic resonance imaging (MRI) Core has been operating since Alzheimer's Disease Neuroimaging Initiative's (ADNI) inception, providing 20 years of data including reliable, multi-platform standardized protocols, carefully curated image data, and quantitative measures provided by expert investigators. The overarching purposes of the MRI Core include: (1) optimizing and standardizing MRI acquisition methods, which have been adopted by many multicenter studies and trials worldwide and (2) providing curated images and numeric summary values from relevant MRI sequences/contrasts to the scientific community. Over time, ADNI MRI has become increasingly complex. To remain technically current, the ADNI MRI protocol has changed substantially over the past two decades. The ADNI 4 protocol contains nine different imaging types (e.g., three dimensional [3D] T1-weighted and fluid-attenuated inversion recovery [FLAIR]). Our view is that the ADNI MRI data are a greatly underutilized resource. The purpose of this paper is to educate the scientific community on ADNI MRI methods and content to promote greater awareness, accessibility, and use. HIGHLIGHTS: The MRI Core provides multi-platform standardized protocols, carefully curated image data, and quantitative analysis by expert groups. The ADNI MRI protocol has undergone major changes over the past two decades to remain technically current. As of April 25, 2024, the following numbers of image series are available: 17,141 3D T1w; 6877 FLAIR; 3140 T2/PD; 6623 GRE; 3237 dMRI; 2846 ASL; 2968 TF-fMRI; and 2861 HighResHippo (see Table 1 for abbreviations). As of April 25, 2024, the following numbers of quantitative analyses are available: FreeSurfer 10,997; BSI 6120; tensor based morphometry (TBM) and TBM-SYN 12,019; WMH 9944; dMRI 1913; ASL 925; TF-fMRI NFQ 2992; and medial temporal subregion volumes 2726 (see Table 4 for abbreviations). ADNI MRI is an underutilized resource that could be more useful to the research community.

BackgroundDigital cognitive assessments, particularly those that can be done at home, present as low-burden biomarkers for participants and patients alike, but their effectiveness in the diagnosis of Alzheimer's disease (AD) or predicting its trajectory is still unclear. Here, we assessed what utility or added value these digital cognitive assessments provide for identifying those at high risk of cognitive decline.MethodsWe analyzed >500 Alzheimer's Disease Neuroimaging Initiative participants who underwent a brief digital cognitive assessment and amyloid beta (Aβ)/tau positron emission tomography scans, examining their ability to distinguish cognitive status and predict cognitive decline.ResultsPerformance on the digital cognitive assessment was superior to both cortical Aβ and entorhinal tau in detecting mild cognitive impairment and future cognitive decline, with mnemonic discrimination deficits emerging as the most critical measure for predicting decline and future tau accumulation.DiscussionDigital assessments are effective at identifying at-risk individuals, supporting their utility as low-burden tools for early AD detection and monitoring.HighlightsPerformance on digital cognitive assessments predicts progression to mild cognitive impairment at a higher proficiency compared to amyloid beta and tau. Deficits in mnemonic discrimination are indicative of future cognitive decline. Impaired mnemonic discrimination predicts future entorhinal and inferior temporal tau.

IntroductionAlzheimer's disease (AD) disproportionately affects minoritized populations who remain underrepresented in AD trials.MethodsWe partnered with local nursing community-based organizations to implement a culturally tailored educational intervention and recruit Hispanic/Latino American, Filipino American, and Korean American adults aged 55 to 80 for the AHEAD study, a preclinical AD trial, at the University of California, Irvine.ResultsWe engaged 654 individuals across 21 events, leading to 71 prescreenings: 21.1% Filipino, 11.2% Hispanic/Latino, and 67.6% Korean adults. Ineligibility due to age and language barriers was common among Hispanic/Latino and Korean adults, respectively. Filipino adults often withdrew interest or were lost to follow-up. Ultimately, 25 participants enrolled: eight Filipino, two Hispanic/Latino, and 15 Korean adults. Tailored, culturally relevant content significantly contributed to the engagement success.DiscussionThis study demonstrates the value and impact of novel partnerships with health-related provider organizations that provide trusted care and access to underrepresented communities.HighlightsSix hundred and fifty four underrepresented individuals were reached, and 25 enrolled in the AHEAD 3-45 trial. Twenty-one community events were held via partnerships with nursing and community organizations. The study engaged 21% Filipino, 11% Hispanic/Latino, 68% Korean adults. Community-Based Participatory Research (CBPR) principles enhanced the recruitment process. Transparent communication and joint planning were key.

BackgroundThe Mnemonic Similarity Task (MST) is a popular memory task designed to assess hippocampal integrity. We assessed whether analyzing MST performance using a multinomial processing tree (MPT) cognitive model could detect individuals with elevated Alzheimer's disease (AD) biomarker status prior to cognitive decline.MethodWe analyzed MST data from >200 individuals (young, cognitively healthy older adults and individuals with mild cognitive impairment [MCI]), a subset of which also had existing cerebrospinal fluid (CSF) amyloid beta (Aβ) and phosphorylated tau (pTau) data using both traditional and model-derived approaches. We assessed how well each could predict age group, memory ability, MCI status, Aβ, and pTau status using receiver operating characteristic analyses.ResultsBoth approaches predicted age group membership equally, but MPT-derived metrics exceeded traditional metrics in all other comparisons.DiscussionA MPT model of the MST can detect individuals with AD prior to cognitive decline, making it a potentially useful tool for screening and monitoring older adults during the asymptomatic phase of AD.HighlightsThe MST, along with cognitive modeling, identifies individuals with memory deficits and cognitive impairment. Cognitive modeling of the MST identifies individuals with increased AD biomarkers prior to changes in cognitive function. The MST is a digital biomarker that identifies individuals at high risk of AD.

BackgroundPain is ubiquitous, yet understudied. The objective of this study was to analyze inequities in pain assessment and management for hospitalized older adults focusing on demographic and geriatric-related variables.MethodsThis was a retrospective cohort study from January 2013 through September 2021 of all adults 65 years or older on the general medicine service at UCSF Medical Center. Primary exposures included (1) demographic variables including race/ethnicity and limited English proficiency (LEP) status and (2) geriatric-related variables including age, dementia or mild cognitive impairment diagnosis, hearing or visual impairment, end-of-life care, and geriatrics consult involvement. Primary outcomes included (1) adjusted odds of numeric pain assessment versus other assessments and (2) adjusted opioids administered, measured by morphine milligram equivalents (MME).ResultsA total of 15,809 patients were included across 27,857 hospitalizations with 1,378,215 pain assessments, with a mean age of 77.8 years old. Patients were 47.4% White, 26.3% with LEP, 49.6% male, and 50.4% female. Asian (OR 0.75, 95% CI 0.70-0.80), Latinx (OR 0.90, 95% CI 0.83-0.99), and Native Hawaiian or Pacific Islander (OR 0.77, 95% CI 0.64-0.93) patients had lower odds of a numeric assessment, compared with White patients. Patients with LEP (OR 0.70, 95% CI 0.66-0.74) had lower odds of a numeric assessment, compared with English-speaking patients. Patients with dementia, hearing impairment, patients 75+, and at end-of-life were all less likely to receive a numeric assessment. Compared with White patients (86 MME, 95% CI 77-96), Asian patients (55 MME, 95% CI 46-65) received fewer opioids. Patients with LEP, dementia, hearing impairment and those 75+ years old also received significantly fewer opioids.ConclusionOlder, hospitalized, general medicine patients from minoritized groups and with geriatric-related conditions are uniquely vulnerable to inequitable pain assessment and management. These findings raise concerns for pain underassessment and undertreatment.

The objective of this 18-month walking intervention was to evaluate the effect on rest–activity rhythm (RAR) for older adults with mild-to-moderate dementia (65.8% female; aged M = 82.4 [SD = 6.5]). The intervention group (n = 44) was intended to walk 30 min, five times per week for 18 months. The control group (n = 35) received sedentary activities or usual care. RAR was measured at baseline to after 18 months and five times in between actigraphy outcome variables (interdaily stability, intradaily variability, relative amplitude, activity 10 most active hours, and activity 5 least active hours). Hierarchical mixed model analyses revealed no significant intervention effects (with or without baseline confounders as covariate) on RAR. However, participants in the intervention group were able to significantly increase their daily life activity (activity 10 most active hours) from the onset of the preceding measurement, b = 0.10, t(239.32) = 2.36, p =.019. More research is warranted to study the effect of regular walks on older persons with dementia whose RAR is worst at baseline. [ABSTRACT FROM AUTHOR]

Microglia-driven neuroinflammation plays an important role in the development of Alzheimers disease. Microglia activation is accompanied by the formation and chronic expression of TLR4 inflammarafts, defined as enlarged and cholesterol-rich lipid rafts serving as an assembly platform for TLR4 dimers and complexes of other inflammatory receptors. The secreted apoA-I binding protein (APOA1BP or AIBP) binds TLR4 and selectively targets cholesterol depletion machinery to TLR4 inflammaraft-expressing inflammatory, but not homeostatic microglia. Here we demonstrated that amyloid-beta (Aβ) induced formation of TLR4 inflammarafts in microglia in vitro and in the brain of APP/PS1 mice. Mitochondria in Apoa1bp-/- APP/PS1 microglia were hyperbranched and cupped, which was accompanied by increased reactive oxygen species and the dilated endoplasmic reticulum. The size and number of Aβ plaques and neuronal cell death were significantly increased, and the animal survival was decreased in Apoa1bp-/-APP/PS1 compared to APP/PS1 female mice. These results suggest that AIBP exerts control of TLR4 inflammarafts and mitochondrial dynamics in microglia and plays a protective role in Alzheimers disease associated oxidative stress and neurodegeneration.

In frontotemporal lobar degeneration (FTLD), pathological protein aggregation in specific brain regions is associated with declines in human-specialized social-emotional and language functions. In most patients, disease protein aggregates contain either TDP-43 (FTLD-TDP) or tau (FTLD-tau). Here, we explored whether FTLD-associated regional degeneration patterns relate to regional gene expression of human accelerated regions (HARs), conserved sequences that have undergone positive selection during recent human evolution. To this end, we used structural neuroimaging from patients with FTLD and human brain regional transcriptomic data from controls to identify genes expressed in FTLD-targeted brain regions. We then integrated primate comparative genomic data to test our hypothesis that FTLD targets brain regions linked to expression levels of recently evolved genes. In addition, we asked whether genes whose expression correlates with FTLD atrophy are enriched for genes that undergo cryptic splicing when TDP-43 function is impaired. We found that FTLD-TDP and FTLD-tau subtypes target brain regions with overlapping and distinct gene expression correlates, highlighting many genes linked to neuromodulatory functions. FTLD atrophy-correlated genes were strongly enriched for HARs. Atrophy-correlated genes in FTLD-TDP showed greater overlap with TDP-43 cryptic splicing genes and genes with more numerous TDP-43 binding sites compared with atrophy-correlated genes in FTLD-tau. Cryptic splicing genes were enriched for HAR genes, and vice versa, but this effect was due to the confounding influence of gene length. Analyses performed at the individual-patient level revealed that the expression of HAR genes and cryptically spliced genes within putative regions of disease onset differed across FTLD-TDP subtypes. Overall, our findings suggest that FTLD targets brain regions that have undergone recent evolutionary specialization and provide intriguing potential leads regarding the transcriptomic basis for selective vulnerability in distinct FTLD molecular-anatomical subtypes.

By age 40 years, over 90% of adults with Down syndrome have Alzheimer's disease pathology and most progress to dementia. Despite having few systemic vascular risk factors, individuals with Down syndrome have elevated cerebrovascular disease markers that track with the clinical progression of Alzheimer's disease, suggesting a role of cerebrovascular disease that is hypothesized to be mediated by inflammatory factors. This study examined the pathways through which small vessel cerebrovascular disease contributes to Alzheimer's disease-related pathophysiology and neurodegeneration in adults with Down syndrome. One hundred eighty-five participants from the Alzheimer's Biomarkers Consortium-Down Syndrome [mean (SD) age = 45.2 (9.3) years] with available MRI and plasma biomarker data were included in this study. White matter hyperintensity (WMH) volumes were derived from T2-weighted fluid-attenuated inversion recovery MRI scans, and plasma biomarker concentrations of amyloid beta 42/40, phosphorylated tau 217, astrocytosis (glial fibrillary acidic protein) and neurodegeneration (neurofilament light chain) were measured with ultrasensitive immunoassays. We examined the bivariate relationships of WMH, amyloid beta 42/40, phosphorylated tau 217 and glial fibrillary acidic protein with age-residualized neurofilament light chain across Alzheimer's disease diagnostic groups. A series of mediation and path analyses examined statistical pathways linking WMH and Alzheimer's disease pathophysiology to promote neurodegeneration in the total sample and groups stratified by clinical diagnosis. There was a direct and indirect bidirectional effect through the glial fibrillary acidic protein of WMH on phosphorylated tau 217 concentration, which was associated with neurofilament light chain concentration in the entire sample. Amongst cognitively stable participants, WMH was directly and indirectly, through glial fibrillary acidic protein, associated with phosphorylated tau 217 concentration, and in those with mild cognitive impairment, there was a direct effect of WMH on phosphorylated tau 217 and neurofilament light chain concentrations. There were no associations of WMH with biomarker concentrations among those diagnosed with dementia. The findings from this cross-sectional study suggest that among individuals with Down syndrome, cerebrovascular disease promotes neurodegeneration by increasing astrocytosis and tau pathophysiology in the presymptomatic phases of Alzheimer's disease, but future studies will need to confirm these associations with longitudinal data. This work joins an emerging literature that implicates cerebrovascular disease and its interface with neuroinflammation as a core pathological feature of Alzheimer's disease in adults with Down syndrome.

IntroductionAmid recent approvals, early Alzheimer's disease (AD) remains an active area of treatment development.MethodsWe performed a conjoint experiment to compare preferences among 26 patients with mild cognitive impairment for four trial features including designs incorporating active aducanumab-control (vs. placebo), returning tau positron emission tomography (PET) results (vs. no disclosure), remote study partner participation (vs. in person), and increased risk of brain swelling (vs. lower risk). We used a generalized estimating equation to model the utility of factor levels.ResultsReturning tau PET results had the highest utility (est: 0.47; 95% confidence interval [CI]: 0.13, 0.81; P = 0.007); remote study partner participation showed a similar trend (est: 0.29; 95% CI: -0.05, 0.63; P = 0.097). Trials with active-controlled design (est: 0.01; 95% CI: -0.33, 0.35; P = 0.956) did not demonstrate utility and higher risk of brain swelling had negative utility (est: -0.64; 95% CI: -0.99, -0.30; P

BackgroundPlasma neurofilament light chain (NfL) is a blood biomarker of neurodegeneration, including Alzheimer's disease. However, its usefulness may be influenced by common conditions in older adults, including amyloid-β (Aβ) deposition and cardiometabolic risk factors like hypertension, diabetes mellitus (DM), impaired kidney function, and obesity. This longitudinal observational study using the Alzheimer's Disease Neuroimaging Initiative cohort investigated how these conditions influence the prognostic capacity of plasma NfL.MethodsNon-demented participants (cognitively unimpaired or mild cognitive impairment) underwent repeated assessments including the Alzheimer's Disease Assessment Scale-Cognitive subscale (ADAS-Cog) scores, hippocampal volumes, and white matter hyperintensity (WMH) volumes at 6- or 12-month intervals. Linear mixed-effect models were employed to examine the interaction between plasma NfL and various variables of interest, such as Aβ (evaluated using Florbetapir positron emission tomography), hypertension, DM, impaired kidney function, or obesity.ResultsOver a mean follow-up period of 62.5 months, participants with a mean age of 72.1 years (n = 720, 48.8% female) at baseline were observed. Higher plasma NfL levels at baseline were associated with steeper increases in ADAS-Cog scores and WMH volumes, and steeper decreases in hippocampal volumes over time (all p-values

IntroductionUnderstanding attitudes toward participation among diverse preclinical Alzheimer's disease (AD) trial participants could yield insights to instruct future recruitment.MethodsUsing data from the Anti-Amyloid Treatment in Asymptomatic AD (A4) Study, we examined differences among mutually exclusive racial and ethnic groups in views and perceptions of amyloid imaging (VPAI), a measure of motivations to undergo amyloid biomarker testing in the setting of preclinical AD. We used linear regression to quantify differences at baseline.ResultsCompared to non-Hispanic or Latino (NH) White participants, Hispanic or Latino (3.52 points, 95% confidence interval [CI]: [2.61, 4.42]); NH Asian (2.97 points, 95% CI: [1.71, 4.22]); and NH Black participants (2.79 points, 95% CI: [1.96, 3.63]) participants demonstrated higher levels of endorsement of the VPAI items at baseline.DiscussionDifferences may exist among participants from differing ethnic and racial groups in motivations to undergo biomarker testing in the setting of a preclinical AD trial.HighlightsRepresentative samples in AD clinical trials are vital to result in generalizability. We assessed motivations to undergo amyloid imaging in a preclinical AD trial. Racial and ethnic minority groups showed higher endorsement of VPAI items. Differences were driven by perceived risk, plan/prepare, and curiosity domains. Few observations among racial and ethnic groups changed after biomarker disclosure.

IntroductionTau-positron emission tomography (PET) outcome data of patients with Alzheimer's disease (AD) cannot currently be meaningfully compared or combined when different tracers are used due to differences in tracer properties, instrumentation, and methods of analysis.MethodsUsing head-to-head data from five cohorts with tau PET radiotracers designed to target tau deposition in AD, we tested a joint propagation model (JPM) to harmonize quantification (units termed "CenTauR" [CTR]). JPM is a statistical model that simultaneously models the relationships between head-to-head and anchor point data. JPM was compared to a linear regression approach analogous to the one used in the amyloid PET Centiloid scale.ResultsA strong linear relationship was observed between CTR values across brain regions. Using the JPM approach, CTR estimates were similar to, but more accurate than, those derived using the linear regression approach.DiscussionPreliminary findings using the JPM support the development and adoption of a universal scale for tau-PET quantification.HighlightsTested a novel joint propagation model (JPM) to harmonize quantification of tau PET. Units of common scale are termed "CenTauRs". Tested a Centiloid-like linear regression approach. Using five cohorts with head-to-head tau PET, JPM outperformed linearregressionbased approach. Strong linear relationship was observed between CenTauRs values across brain regions.

COVID-19 is associated with increased risk for cognitive decline but very little is known regarding the neural mechanisms of this risk. We enrolled 49 adults (55% female, mean age = 30.7 ± 8.7), 25 with and 24 without a history of COVID-19 infection. We administered standardized tests of cognitive function and acquired brain connectivity data using MRI. The COVID-19 group demonstrated significantly lower cognitive function (W = 475, p

IntroductionThe incidence of Alzheimer's disease (AD) and obesity rise concomitantly. This study examined whether factors affecting metabolism, race/ethnicity, and sex are associated with AD development.MethodsThe analyses included patients ≥ 65 years with AD diagnosis in six University of California hospitals between January 2012 and October 2023. The controls were race/ethnicity, sex, and age matched without dementia. Data analyses used the Cox proportional hazards model and machine learning (ML).ResultsHispanic/Latino and Native Hawaiian/Pacific Islander, but not Black subjects, had increased AD risk compared to White subjects. Non-infectious hepatitis and alcohol abuse were significant hazards, and alcohol abuse had a greater impact on women than men. While underweight increased AD risk, overweight or obesity reduced risk. ML confirmed the importance of metabolic laboratory tests in predicting AD development.DiscussionThe data stress the significance of metabolism in AD development and the need for racial/ethnic- and sex-specific preventive strategies.HighlightsHispanics/Latinos and Native Hawaiians/Pacific Islanders show increased hazards of Alzheimer's disease (AD) compared to White subjects. Underweight individuals demonstrate a significantly higher hazard ratio for AD compared to those with normal body mass index. The association between obesity and AD hazard differs among racial groups, with elderly Asian subjects showing increased risk compared to White subjects. Alcohol consumption and non-infectious hepatitis are significant hazards for AD. Machine learning approaches highlight the potential of metabolic panels for AD prediction.

Background and objectivesAmyloid pathology, vascular disease pathology, and pathologies affecting the medial temporal lobe are associated with cognitive trajectories in older adults. However, only limited evidence exists on how these pathologies influence cognition in the oldest old. We evaluated whether amyloid burden, white matter hyperintensity (WMH) volume, and hippocampal volume (HV) are associated with cognitive level and decline in the oldest old.MethodsThis was a longitudinal, observational community-based cohort study. We included participants with 18F-florbetapir PET and MRI data from the 90+ Study. Amyloid load was measured using the standardized uptake value ratio in the precuneus/posterior cingulate with eroded white matter mask as reference. WMH volume was log-transformed. All imaging measures were standardized using sample means and SDs. HV and log-WMH volume were normalized by total intracranial volume using the residual approach. Global cognitive performance was measured by the Mini-Mental State Examination (MMSE) and modified MMSE (3MS) tests, repeated every 6 months. We used linear mixed-effects models with random intercepts; random slopes; and interaction between time, time squared, and imaging variables to estimate the associations of imaging variables with cognitive level and cognitive decline. Models were adjusted for demographics, APOE genotype, and health behaviors.ResultsThe sample included 192 participants. The mean age was 92.9 years, 125 (65.1%) were female, 71 (37.0%) achieved a degree beyond college, and the median follow-up time was 3.0 years. A higher amyloid load was associated with a lower cognitive level (βMMSE = -0.82, 95% CI -1.17 to -0.46; β3MS = -2.77, 95% CI -3.69 to -1.84). A 1-SD decrease in HV was associated with a 0.70-point decrease in the MMSE score (95% CI -1.14 to -0.27) and a 2.27-point decrease in the 3MS score (95% CI -3.40 to -1.14). Clear nonlinear cognitive trajectories were detected. A higher amyloid burden and smaller HV were associated with faster cognitive decline. WMH volume was not significantly associated with cognitive level or decline.DiscussionAmyloid burden and hippocampal atrophy are associated with both cognitive level and cognitive decline in the oldest old. Our findings shed light on how different pathologies contributed to driving cognitive function in the oldest old.

Brain rhythms provide the timing for recruitment of brain activity required for linking together neuronal ensembles engaged in specific tasks. The γ-oscillations (30 to 120 Hz) orchestrate neuronal circuits underlying cognitive processes and working memory. These oscillations are reduced in numerous neurological and psychiatric disorders, including early cognitive decline in Alzheimers disease (AD). Here, we report on a potent brain-permeable small molecule, DDL-920 that increases γ-oscillations and improves cognition/memory in a mouse model of AD, thus showing promise as a class of therapeutics for AD. We employed anatomical, in vitro and in vivo electrophysiological, and behavioral methods to examine the effects of our lead therapeutic candidate small molecule. As a novel in central nervous system pharmacotherapy, our lead molecule acts as a potent, efficacious, and selective negative allosteric modulator of the γ-aminobutyric acid type A receptors most likely assembled from α1β2δ subunits. These receptors, identified through anatomical and pharmacological means, underlie the tonic inhibition of parvalbumin (PV) expressing interneurons (PV+INs) critically involved in the generation of γ-oscillations. When orally administered twice daily for 2 wk, DDL-920 restored the cognitive/memory impairments of 3- to 4-mo-old AD model mice as measured by their performance in the Barnes maze. Our approach is unique as it is meant to enhance cognitive performance and working memory in a state-dependent manner by engaging and amplifying the brains endogenous γ-oscillations through enhancing the function of PV+INs.

Sex and gender-biological and social constructs-significantly impact the prevalence of protective and risk factors, influencing the burden of Alzheimer's disease (AD; amyloid beta and tau) and other pathologies (e.g., cerebrovascular disease) which ultimately shape cognitive trajectories. Understanding the interplay of these factors is central to understanding resilience and resistance mechanisms explaining maintained cognitive function and reduced pathology accumulation in aging and AD. In this narrative review, the ADDRESS! Special Interest Group (Alzheimer's Association) adopted a multidisciplinary approach to provide the foundations and recommendations for future research into sex- and gender-specific drivers of resilience, including a sex/gender-oriented review of risk factors, genetics, AD and non-AD pathologies, brain structure and function, and animal research. We urge the field to adopt a sex/gender-aware approach to resilience to advance our understanding of the intricate interplay of biological and social determinants and consider sex/gender-specific resilience throughout disease stages. HIGHLIGHTS: Sex differences in resilience to cognitive decline vary by age and cognitive status. Initial evidence supports sex-specific distinctions in brain pathology. Findings suggest sex differences in the impact of pathology on cognition. There is a sex-specific change in resilience in the transition to clinical stages. Gender and sex factors warrant study: modifiable, immune, inflammatory, and vascular.

The under-representation of non-European cohorts in neurodegenerative disease genome-wide association studies (GWAS) hampers precision medicine efforts. Despite the inherent genetic and phenotypic diversity in these diseases, GWAS research consistently exhibits a disproportionate emphasis on participants of European ancestry. This study reviews GWAS up to 2022, focusing on non-European or multi-ancestry neurodegeneration studies. We conducted a systematic review of GWAS results and publications up to 2022, focusing on non-European or multi-ancestry neurodegeneration studies. Rigorous article inclusion and quality assessment methods were employed. Of 123 neurodegenerative disease (NDD) GWAS reviewed, 82% predominantly featured European ancestry participants. A single European study identified over 90 risk loci, compared to a total of 50 novel loci in identified in all non-European or multi-ancestry studies. Notably, only six of the loci have been replicated. The significant under-representation of non-European ancestries in NDD GWAS hinders comprehensive genetic understanding. Prioritizing genomic diversity in future research is crucial for advancing NDD therapies and understanding. HIGHLIGHTS: Eighty-two percent of neurodegenerative genome-wide association studies (GWAS) focus on Europeans. Only 6 of 50 novel neurodegenerative disease (NDD) genetic loci have been replicated. Lack of diversity significantly hampers understanding of NDDs. Increasing diversity in NDD genetic research is urgently required. New initiatives are aiming to enhance diversity in NDD research.

IntroductionAlzheimer's disease (AD) pathology is defined by β-amyloid (Aβ) plaques and neurofibrillary tau, but Lewy bodies (LBs; ?-synuclein aggregates) are a common co-pathology for which effective biomarkers are needed.MethodsA validated α-synuclein Seed Amplification Assay (SAA) was used on recent cerebrospinal fluid (CSF) samples from 1638 Alzheimer's Disease Neuroimaging Initiative (ADNI) participants, 78 with LB-pathology confirmation at autopsy. We compared SAA outcomes with neuropathology, Aβ and tau biomarkers, risk-factors, genetics, and cognitive trajectories.ResultsSAA showed 79% sensitivity and 97% specificity for LB pathology, with superior performance in identifying neocortical (100%) compared to limbic (57%) and amygdala-predominant (60%) LB-pathology. SAA+ rate was 22%, increasing with disease stage and age. Higher Aβ burden but lower CSF p-tau181 associated with higher SAA+ rates, especially in dementia. SAA+ affected cognitive impairment in MCI and Early-AD who were already AD biomarker positive.DiscussionSAA is a sensitive, specific marker for LB-pathology. Its increase in prevalence with age and AD stages, and its association with AD biomarkers, highlights the clinical importance of α-synuclein co-pathology in understanding AD's nature and progression.HighlightsSAA shows 79% sensitivity, 97% specificity for LB-pathology detection in AD. SAA positivity prevalence increases with disease stage and age. Higher Aβ burden, lower CSF p-tau181 linked with higher SAA+ rates in dementia. SAA+ impacts cognitive impairment in early disease stages. Study underpins need for wider LB-pathology screening in AD treatment.

IntroductionThe understanding of the pathological events in Alzheimer's disease (AD) has advanced dramatically, but the successful translation from rodent models into efficient human therapies is still problematic.MethodsTo examine how tau pathology can develop in the primate brain, we injected 12 macaques with a dual tau mutation (P301L/S320F) into the entorhinal cortex (ERC). An investigation was performed using high-resolution microscopy, magnetic resonance imaging (MRI), positron emission tomography (PET), and fluid biomarkers to determine the temporal progression of the pathology 3 and 6 months after the injection.ResultsUsing quantitative microscopy targeting markers for neurodegeneration and neuroinflammation, as well as fluid and imaging biomarkers, we detailed the progression of misfolded tau spreading and the consequential inflammatory response induced by glial cells.DiscussionBy combining the analysis of several in vivo biomarkers with extensive brain microscopy analysis, we described the initial steps of misfolded tau spreading and neuroinflammation in a monkey model highly translatable to AD patients.HighlightsDual tau mutation delivery in the entorhinal cortex induces progressive tau pathology in rhesus macaques. Exogenous human 4R-tau coaptates monkey 3R-tau during transneuronal spread, in a prion-like manner. Neuroinflammatory response is coordinated by microglia and astrocytes in response to tau pathology, with microglia targeting early tau pathology, while astrocytes engaged later in the progression, coincident with neuronal death. Monthly collection of CSF and plasma revealed a profile of changes in several AD core biomarkers, reflective of neurodegeneration and neuroinflammation as early as 1 month after injection.

Alzheimers disease typically progresses in stages, which have been defined by the presence of disease-specific biomarkers: amyloid (A), tau (T) and neurodegeneration (N). This progression of biomarkers has been condensed into the ATN framework, in which each of the biomarkers can be either positive (+) or negative (-). Over the past decades, genome-wide association studies have implicated ∼90 different loci involved with the development of late-onset Alzheimers disease. Here, we investigate whether genetic risk for Alzheimers disease contributes equally to the progression in different disease stages or whether it exhibits a stage-dependent effect. Amyloid (A) and tau (T) status was defined using a combination of available PET and CSF biomarkers in the Alzheimers Disease Neuroimaging Initiative cohort. In 312 participants with biomarker-confirmed A-T- status, we used Cox proportional hazards models to estimate the contribution of APOE and polygenic risk scores (beyond APOE) to convert to A+T- status (65 conversions). Furthermore, we repeated the analysis in 290 participants with A+T- status and investigated the genetic contribution to conversion to A+T+ (45 conversions). Both survival analyses were adjusted for age, sex and years of education. For progression from A-T- to A+T-, APOE-e4 burden showed a significant effect [hazard ratio (HR) = 2.88; 95% confidence interval (CI): 1.70-4.89; P < 0.001], whereas polygenic risk did not (HR = 1.09; 95% CI: 0.84-1.42; P = 0.53). Conversely, for the transition from A+T- to A+T+, the contribution of APOE-e4 burden was reduced (HR = 1.62; 95% CI: 1.05-2.51; P = 0.031), whereas the polygenic risk showed an increased contribution (HR = 1.73; 95% CI: 1.27-2.36; P < 0.001). The marginal APOE effect was driven by e4 homozygotes (HR = 2.58; 95% CI: 1.05-6.35; P = 0.039) as opposed to e4 heterozygotes (HR = 1.74; 95% CI: 0.87-3.49; P = 0.12). The genetic risk for late-onset Alzheimers disease unfolds in a disease stage-dependent fashion. A better understanding of the interplay between disease stage and genetic risk can lead to a more mechanistic understanding of the transition between ATN stages and a better understanding of the molecular processes leading to Alzheimers disease, in addition to opening therapeutic windows for targeted interventions.

Standard single-cell (sc) proteomics of disease states inferred from multicellular organs or organoids cannot currently be related to single-cell physiology. Here, a scPatch-Clamp/Proteomics platform is developed on single neurons generated from hiPSCs bearing an Alzheimer's disease (AD) genetic mutation and compares them to isogenic wild-type controls. This approach provides both current and voltage electrophysiological data plus detailed proteomics information on single-cells. With this new method, the authors are able to observe hyperelectrical activity in the AD hiPSC-neurons, similar to that observed in the human AD brain, and correlate it to ≈1400 proteins detected at the single neuron level. Using linear regression and mediation analyses to explore the relationship between the abundance of individual proteins and the neuron's mutational and electrophysiological status, this approach yields new information on therapeutic targets in excitatory neurons not attainable by traditional methods. This combined patch-proteomics technique creates a new proteogenetic-therapeutic strategy to correlate genotypic alterations to physiology with protein expression in single-cells.

BACKGROUND: Amyloid beta protein (Aβ) is a treatment target in Alzheimers Disease (AD). Lowering production of its parent protein, APP, has benefits in preclinical models. Posiphen, an orally administered small molecule, binds to an iron-responsive element in APP mRNA and decreases translation of APP and Aβ. To augment human data for Posiphen, we evaluated safety, tolerability and pharmacokinetic and pharmacodynamic (PD) effects on Aβ metabolism using Stable Isotope Labeling Kinetic (SILK) analysis. METHODS: Double-blind phase 1b randomized ascending dose clinical trial, at five sites, under an IRB-approved protocol. Participants with mild cognitive impairment or mild AD (Early AD) confirmed by low CSF Aβ42/40 were randomized (within each dose arm) to Posiphen or placebo. Pretreatment assessment included lumbar puncture for CSF. Participants took Posiphen or placebo for 21-23 days, then underwent CSF catheter placement, intravenous infusion of 13C6-leucine, and CSF sampling for 36 h. Safety and tolerability were assessed through participant reports, EKG and laboratory tests. CSF SILK analysis measured Aβ40, 38 and 42 with immunoprecipitation-mass spectrometry. Baseline and day 21 CSF APP, Aβ and other biomarkers were measured with immunoassays. The Mini-Mental State Exam and ADAS-cog12 were given at baseline and day 21. RESULTS: From June 2017 to December 2021, 19 participants were enrolled, randomized within dose cohorts (5 active: 3 placebo) of 60 mg once/day and 60 mg twice/day; 1 participant was enrolled and completed 60 mg three times/day. 10 active drug and 5 placebo participants completed all study procedures. Posiphen was safe and well-tolerated. 8 participants had headaches related to CSF catheterization; 5 needed blood patches. Prespecified SILK analyses of Fractional Synthesis Rate (FSR) for CSF Aβ40 showed no significant overall or dose-dependent effects of Posiphen vs. placebo. Comprehensive multiparameter modeling of APP kinetics supported dose-dependent lowering of APP production by Posiphen. Cognitive measures and CSF biomarkers did not change significantly from baseline to 21 days in Posiphen vs. placebo groups. CONCLUSIONS: Posiphen was safe and well-tolerated in Early AD. A multicenter SILK study was feasible. Findings are limited by small sample size but provide additional supportive safety and PK data. Comprehensive modeling of biomarker dynamics using SILK data may reveal subtle drug effects. TRIAL REGISTRATION: NCT02925650 on clinicaltrials.gov (registered on 10-24-2016).

This study evaluated the measurement invariance of a neuropsychological battery across rural and urban older adults from Costa Rica. Rural and urban older adults (N = 295) from the Epidemiology and Development of Alzheimer's Disease (EDAD) study in Costa Rica were assessed. The baseline factor model for the EDAD neuropsychological measures was identified with nine neuropsychological measures and three cognitive constructs: Verbal Memory, Spatial Reasoning, and Cognitive Flexibility. Measurement and structural invariance were established, and, then, group comparisons of the latent cognitive factors were conducted to explore regional disparities. The findings showed that most of the neuropsychological tests in EDAD can be directly compared across the groups, allowing for cognitive constructs comparisons. The rural sample showed a disadvantage in the Spatial Reasoning and Cognitive Flexibility abilities. When age and education were included in the models, differences between the regions disappeared. Having more years of education was associated with higher cognitive abilities, with a larger effect for the rural group. Norms for Costa Rican older adults should consider age and education adjustments. This study contributes to the growing area of measurement invariance in neuropsychological assessment as it highlights the importance of examining the comparability of assessment measures across different cultural groups.

Elucidating the mechanisms by which late-life neurodegeneration causes cognitive decline requires understanding why some individuals are more resilient than others to the effects of brain change on cognition (cognitive reserve). Currently, there is no way of measuring cognitive reserve that is valid (e.g. capable of moderating brain-cognition associations), widely accessible (e.g. does not require neuroimaging and large sample sizes), and able to provide insight into resilience-promoting mechanisms. To address these limitations, this study sought to determine whether a machine learning approach to combining standard clinical variables could (i) predict a residual-based cognitive reserve criterion standard and (ii) prospectively moderate brain-cognition associations. In a training sample combining data from the University of California (UC) Davis and the Alzheimer's Disease Neuroimaging Initiative-2 (ADNI-2) cohort (N = 1665), we operationalized cognitive reserve using an MRI-based residual approach. An eXtreme Gradient Boosting machine learning algorithm was trained to predict this residual reserve index (RRI) using three models: Minimal (basic clinical data, such as age, education, anthropometrics, and blood pressure), Extended (Minimal model plus cognitive screening, word reading, and depression measures), and Full [Extended model plus Clinical Dementia Rating (CDR) and Everyday Cognition (ECog) scale]. External validation was performed in an independent sample of ADNI 1/3/GO participants (N = 1640), which examined whether the effects of brain change on cognitive change were moderated by the machine learning models' cognitive reserve estimates. The three machine learning models differed in their accuracy and validity. The Minimal model did not correlate strongly with the criterion standard (r = 0.23) and did not moderate the effects of brain change on cognitive change. In contrast, the Extended and Full models were modestly correlated with the criterion standard (r = 0.49 and 0.54, respectively) and prospectively moderated longitudinal brain-cognition associations, outperforming other cognitive reserve proxies (education, word reading). The primary difference between the Minimal model-which did not perform well as a measure of cognitive reserve-and the Extended and Full models-which demonstrated good accuracy and validity-is the lack of cognitive performance and informant-report data in the Minimal model. This suggests that basic clinical variables like anthropometrics, vital signs, and demographics are not sufficient for estimating cognitive reserve. Rather, the most accurate and valid estimates of cognitive reserve were obtained when cognitive performance data-ideally augmented by informant-reported functioning-was used. These results indicate that a dynamic and accessible proxy for cognitive reserve can be generated for individuals without neuroimaging data and gives some insight into factors that may promote resilience.

The Hispanic/Latino population is one of the largest and most diverse ethnoracial groups in the United States at high risk for dementia. We examined cognitive constructs and associations with subsequent hippocampal volume (HV) and white matter hyperintensity volume (WMHV). Participants were from the Hispanic Community Health Study/Study of Latinos-Magnetic Resonance Imaging Study (n = 2029). We examined confirmatory factor analysis and longitudinal invariance using neurocognitive scores at Visits 1 (2008-2011) and 2 (2014-2018) and path analyses. We obtained a longitudinally invariant two-factor episodic memory (EM) and working memory (WM) construct. Lower EM profile at both visits was associated with greater WMHV and smaller HV at Visit 2. Lower WM profile at both visits was associated with larger WMHV and smaller HV at Visit 2. Neurocognitive profiles were associated with subsequent neurodegeneration in a sample of Hispanics/Latinos. Identifying neurocognitive risk profiles may lead to early detection and intervention, and significantly impact the course of neurodegeneration.HighlightsCognitive profiles predict brain integrity up to 10 years later.We observed two-factor latent memory constructs and longitudinal invariance.These findings were observed in a Hispanic/Latino cohort.

IntroductionAlzheimer's disease (AD) neuropathological changes present with amnestic and nonamnestic (atypical) syndromes. The contribution of comorbid neuropathology as a substratum of atypical expression of AD remains under investigated.MethodsWe examined whether atypical AD exhibited increased comorbid neuropathology compared to typical AD and if such neuropathologies contributed to the accelerated clinical decline in atypical AD.ResultsWe examined 60 atypical and 101 typical AD clinicopathological cases. The number of comorbid pathologies was similar between the groups (p = 0.09). Argyrophilic grain disease was associated with atypical presentation (p = 0.008) after accounting for sex, age of onset, and disease duration. Vascular brain injury was more common in typical AD (p = 0.022). Atypical cases had a steeper Mini-Mental Status Examination (MMSE) decline over time (p = 0.033).DiscussionComorbid neuropathological changes are unlikely to contribute to atypical AD presentation and the steeper cognitive decline seen in this cohort.HighlightsAutopsy cohort of 60 atypical and 101 typical AD; does comorbid pathology explain atypical presentation?Atypical versus Typical AD: No significant differences in comorbid neuropathologies were found (p = 0.09).Argyrophilic Grain Disease Association: significantly correlates with atypical AD presentations, suggesting a unique neuropathological pattern (p = 0.008).Vascular Brain Injury Prevalence: Vascular brain injury is more common in typical AD than in atypical AD (p = 0.022).Cognitive Decline in Atypical AD: Atypical AD patients experience a steeper cognitive decline measured by MMSE than those with typical AD despite lacking more comorbid neuropathology, highlighting the severity of atypical AD pathogenesis (p = 0.033).