BackgroundThe cellular mechanisms that promote the maintenance of cognitive abilities in very old people designated as successful agers remain under-investigated. Here, we report an episodic memory performance-based criteria that differentiates superior cognitive function from normative cognitive function in adults aged 80 and older.ObjectiveUsing this new criteria, we demonstrate how neuropathological and neurobiological underpinnings of superior cognitive performance can be investigated.MethodsThe most recent verbal episodic memory WMS-R Logical Memory Delayed Recall (LM-DR) score was derived from 144 participants with no cognitive impairment (NCI) 80 years or older participants from the Rush Religious Orders Study classified with Superior Cognitive Performance (SCP, LM-DR ≥ 14) or Normal Cognitive Performance (NCP, LM-DR 13 ≥ 7). Both groups were compared on neuropathological measures for neuritic plaque (NP), diffuse plaque (DP), and neurofibrillary tangle (NFT) load.ResultsNP (p = 0.44), DP (p = 0.27), and NFT (p = 0.28) burden did not differ between SCP and NCP cases. LM-DR scores did not correlate with NP (r = -0.08, p = 0.32), DP (r = -0.14, p = 0.07), or NFT (r = -0.12, p = 0.13) load. Biochemical analysis revealed significantly higher levels of heat-shock protein HSPB6 in SCP compared to NCP (p < 0.001).ConclusionsHeat shock protein differences were observed between NCP and SCP groups. This suggests that our proposed criteria for SCP can help identify neurobiological mechanisms of successful cognitive aging. Our SCP criteria are also concordant with the SuperAger criteria which supports the generalizability of the SCP criteria to other datasets.

INTRODUCTION:Novel capillary-blood collection methods have not yet been evaluated for a wide range of central nervous system (CNS) and neurodegenerative disease-related proteins. Biomarkers of Alzheimer's disease (AD) and related disorders (ADRD) collected from devices like the Tasso+, a minimally invasive upper-arm capillary blood collection device, must be compared to traditional venipuncture to assess for validity. METHODS:Participants underwent blood collection via traditional venipuncture and Tasso+ in a clinical research setting. The Nucleic Acid Linked Immuno-Sandwich Assay (NULISA) CNS panel was used for biomarker quantification in venous and Tasso-derived plasma. RESULTS:Eighty-three participants (age mean±SD 76.8±8.2 years, 79.5% cognitively unimpaired) completed blood collection. Little to no correlation was found between venous and Tasso+ plasma for p-tau217, but the correlation was improved by using a brain-derived (BD)-p-tau217/BD-p-tau181 ratio. Extremely strong correlations were found for neurofilament light (NfL) and glial fibrillary acidic protein (GFAP). Among the 131 biomarkers measured, 51 (38.9%) had a Pearson R ≥ 0.90; 27 (20.6%) had values between 0.70-0.90; 26 (19.9%) had values between 0.30-0.70; and 27 (20.6%) had values ≤0.30. DISCUSSION:The Tasso+ accurately measures NfL and GFAP, but caution is warranted when measuring other AD/ADRD biomarkers, as agreement with venous plasma appears to be protein or ratio dependent. These results highlight that important biomarker-specific differences must be considered when translating capillary blood collection approaches. They also further support foundations for development of these methods, highlighting both the opportunities and remaining challenges for translating the promise of blood-based biomarkers beyond AD/ADRD specialty clinics and research settings.

Amyloid-related imaging abnormalities (ARIA) observed on magnetic resonance imaging (MRI) are known adverse events associated with beta-amyloid plaque-lowering monoclonal antibodies. A spectrum of radiographic and clinical presentations of ARIA have been observed. ARIA-E refer to vasogenic edema in the brain parenchyma and/or leptomeningeal/subpial sulcal effusion; ARIA-H refer to hemosiderin deposits including cerebral microhemorrhage and localized superficial siderosis. With clinical availability of anti-amyloid therapies for treatment of early clinical stage Alzheimer's disease, there is an important need for better awareness of ARIA and education among a diversity of clinicians and practice settings. To illustrate the wide spectrum of ARIA, we present the clinical history, course, and MRI findings as well as summarize learnings and implications of 10 ARIA-E cases from the aducanumab phase 3 clinical trials EMERGE and ENGAGE (ClinicalTrials.gov identifiers NCT02484547 and NCT02477800). Monitoring and management of ARIA, including criteria and timing of MRI, and drug dosing actions were defined per protocol and based upon radiographic severity and clinical symptoms associated with ARIA. ARIA were detected by MRI performed at pre-specified intervals or in response to symptoms or for safety follow-up reasons. The majority of ARIA-E events were asymptomatic. Most ARIA-E events occurred within the first 8 aducanumab doses and generally resolved within 3–4 months whether dosing was continued (i.e. when ARIA-E was asymptomatic and of mild radiographic severity) or whether dosing was suspended or discontinued. Occasionally, ARIA-E were recurrent. ARIA-H (microhemorrhages and superficial siderosis) most commonly occurred concurrently with ARIA-E. However, ARIA-H without ARIA-E, termed isolated ARIA-H, occurred at a similar frequency in aducanumab- and placebo-treated groups. 10

INTRODUCTION:Diffusion-weighted imaging derived mean diffusivity (MD) correlates with Alzheimer's disease (AD) biomarkers, yet its neuropathological correlates remain unclear. METHODS:Diffusion-weighted imaging, post mortem neuropathology, and cognitive performance data were obtained from the National Alzheimer's Coordinating Center (N = 97), Alzheimer's Disease Neuroimaging Initiative (N = 21), and Arizona Study of Aging and Neurodegenerative Disorders (N = 15). We examined MD associations with neuropathology, cognitive decline, and expression profiles of AD-implicated genes. RESULTS:Results revealed two latent variables-one linked to amyloid/tau, the other to vascular pathology-explaining between 70% and 16% of MD-pathology covariance, respectively. Higher MD correlated with worse cognitive performance, both cross-sectionally and up to 16 years prior to death. MD was regionally associated with Thal phase, neuritic plaque density, Braak stage (temporal/limbic), and infarcts (thalamus), and reflected gene expression patterns related to AD. DISCUSSION:In vivo MD captures distinct AD-related pathologies across brain regions and relates to cognitive trajectories and gene expression. HIGHLIGHTS:Diffusion-weighted imaging (DWI) can detect early gray matter microstructural differences in the Alzheimer's disease (AD) continuum. Mean diffusivity (MD) is associated with tau, amyloid and vascular neuropathologies. Thal amyloid phase and Braak tau score correlate with MD in temporal and limbic regions. Multivariate MD scores differentially relate to proteinopathies vs. vascular damage. MD can serve as a non-invasive biomarker to predict post mortem AD neuropathology.

Objective To investigate sex differences in Alzheimer's disease (AD) related pathology among autopsy-confirmed Parkinson's disease (PD) cases. Background AD and PD frequently co-occur in older adults, yet the influence of sex on AD pathology in the context of PD remains unexplored. Methods All subjects were enrolled in the Arizona Study of Aging and Neurodegenerative Disorders (AZSAND) and Brain and Body Donation Program (BBDP) and had annual standardized research clinical assessments by neuropsychologists, subspecialty behavioral and movement disorders neurologists, as well as comprehensive neuropathological examinations after death. Results Among 230 autopsy-confirmed PD cases, females exhibited greater amyloid plaque pathology burden than males, regardless of a co-occurring AD diagnosis. Specifically, females with PD had significantly higher mean cortical total plaque scores (mean 6.5/15 vs. 4.9/15, p = 0.045) and greater CERAD neuritic plaque density (mean 1.7/3 vs. 1.3/3, p = 0.035). Females were also more likely to have a higher cortical plaque burden (plaque total ≥ 5: 56.8% vs. 39.7%, p = 0.015). In multivariable logistic regression models, female subjects showed greater than twice the odds of having an amyloid plaque burden ≥5 compared to males (OR = 2.18; 95% CI = 1.17–4.06; p = 0.014), when controlling for ApoE ε4 status, Lewy body density score, and age at death. Conclusions Female sex is associated with increased amyloid plaque pathology in PD, independent of ApoE ε4 status. These findings highlight a sex-specific vulnerability to AD pathology in PD patients and support the need for sex-informed approaches to reseach in mixed neurodegenerative disease.

INTRODUCTION:The glucagon-like peptide-1 receptor agonist semaglutide may impact neuroinflammation and reduce neurodegeneration. We present baseline characteristics of participants enrolled in the evoke (NCT04777396) and evoke+ (NCT04777409) trials, referred to as "evoke (+)" hereafter. METHODS:Evoke (+) are two ongoing global, multicenter, randomized, double-blind, parallel-group, placebo-controlled phase 3 trials investigating semaglutide in participants with early-stage symptomatic Alzheimer's disease (AD) with confirmed amyloid positivity (by positron emission tomography or cerebrospinal fluid testing). Inclusion criteria are the same for both trials, except that by design, evoke+ also includes participants with significant small vessel pathology. Both trials include a 12-week screening phase before randomization (1:1) to receive oral semaglutide titrated to 14 mg or placebo for 156 weeks. Baseline data were summarized and analyzed descriptively. Additionally, data were pooled and assessed by five main geographical regions. RESULTS:Evoke (+) recruited 9996 participants from 566 sites in 40 countries. The mean (standard deviation) age of participants was 71.8 (7.1) and 72.6 (7.1) years in evoke and evoke+, respectively; more participants were female than male (female: 53.0% and 51.9%, respectively) and most had a Clinical Dementia Rating (CDR) global score of 0.5 (72.8% and 71.4%; CDR global score of 1: 26.5% and 27.6%). Both trial populations had similar demographics, and clinical and cognitive baseline characteristics, except that 2.8% of participants in evoke+ had magnetic resonance imaging-documented significant small vessel pathology as per protocol inclusion criteria. Regional-level data demonstrated some differences in AD treatment characteristics, including cholinesterase inhibitor use of 41.7% in North America versus 61.6% in Asia. DISCUSSION:Evoke (+) are the only large-scale, phase 3 trials investigating the longer-term efficacy and safety of semaglutide in early AD as a potential disease-modifying treatment. The baseline characteristics from evoke (+) reflect a varied, global population with early-stage symptomatic AD. Primary readouts are expected in the second half of 2025. Highlights:evoke and evoke+ are the only large-scale randomized controlled trials (RCTs) investigating the longer-term efficacy and safety of semaglutide in early AD.Baseline characteristics reflect a varied, global population.The trials' primary readouts are expected in the second half of 2025.

BACKGROUND AND OBJECTIVES:Using RT-QuIC seeding assays determine the presence of pathogenic alpha-synuclein (aSyn) aggregates in the submandibular gland (SMG), skin, and CSF from autopsy-confirmed cases of incidental Lewy body disease (ILBD), Parkinson disease (PD), and controls. METHODS:Submandibular gland, skin, and CSF samples from autopsied cases in the Arizona Study of Aging and Neurodegenerative Disorders (AZSAND) were assayed using RT-QuIC methods. Correlations with the Unified Staging System for Lewy Body Disorders (USSLB) was performed. RESULTS:A total of 19 controls, 40 ILBD, and 15 PD cases were studied. While aSyn seeding assays were positive in all 3 tissues from ILBD cases, the sensitivity was much lower in the SMG (13/37, 35.1%) and skin (6/16, 37.5%) than in CSF (25/33, 75.8%). In PD sensitivity was good in all tissues: SMG (7/8, 87.5%), skin (7/8, 87.5%), and CSF (10/10, 100%), as was specificity in CSF (9/12, 75%), skin (8/9, 88.9%), and SMG (7/9, 77.8%). USSLB stage correlated with aSyn SAA positivity in all 3 tissues with CSF most sensitive to stages I and II (IIa and IIb) cases. In the 20 cases that had all 3 tissues tested only 2 were positive in the SMG but not CSF and one in skin but not CSF. There were 6 ILBD cases that had positive CSF but not SMG or skin, and one of these ILBD cases was USSLB stage I (olfactory bulb only). DISCUSSION:In this small study of autopsy-confirmed ILBD, aSyn seeding assays had moderately high sensitivity (75.8%) in the CSF but not in skin or SMG. In PD, the skin, SMG, and CSF showed high sensitivity, with specificity being similar in all tissues, although sample sizes were small. These results, although preliminary, suggest that detecting aSyn using seeding assays of CSF, but not the skin or SMG, may be valuable for identifying individuals with prodromal Lewy body disease. This is especially true for ILBD cases that often had Lewy bodies in the olfactory bulb only (USSLB Stage I) or in brainstem regions (Stage IIa), suggesting that detecting these cases may require CSF and not biopsies of the skin or SMG.

Skin biopsies analyzed with α-synuclein seed amplification assays (SAAs) are a simple way to clinically interrogate the presence of α-synuclein aggregates. We determined the accuracy of skin biopsy SAA in predicting the clinical diagnoses of Parkinson disease (PD), PD with dementia (PDD) and dementia with Lewy bodies (DLB). Blinded SAAs were performed in 3 independent laboratories. Subjects diagnosed with PD, PDD and DLB were analyzed together as group 1, clinically unaffected subjects as group 2 and those with risk factors for LBD as group 3. Punch biopsies were taken from the posterior neck and analyzed by the 3 labs in 6 separate SAAs. Pairwise agreement between labs and assays ranged from excellent (kappa 0.82) to moderate (kappa 0.40-0.68). Sensitivity across assays ranged between 50.0% and 61.3%; specificity ranged between 68.6% and 100%. Comparisons of group 1 vs group 2 produced the greatest specificities, between 77.3% and 100%. In 17 cases that subsequently came to autopsy, 93% of SAAs were positive in those at the neocortical LBD stage but in only <10% of those at lower stages. Skin biopsy α-synuclein SAA may be useful as a diagnostic and progression biomarker in Lewy body dementia clinical trials.

Objectives Agitation is a common and distressing phenomenon across neurocognitive disorders (NCD). It is linked to decreased quality of life of the person with NCD, cognitive and functional decline, increased health-care utilization and institutionalization rates, and substantial burden for family carers and care professionals. Its management is particularly challenging. The objective of this International Psychogeriatric Association’s (IPA) task force was to synthesize recent advances in nomenclature and assessment, epidemiology, progression, etiology, detection, impact, approaches to managing agitation; and to make recommendations to guide IPA’s next 10-year strategy. Methods A multidisciplinary expert workgroup met multiple times virtually and during the 2024 IPA Congress in person to discuss the current scientific and clinical practice landscape for agitation in NCD. The group integrated evidence about validated behavioral measures, biomarkers, digital monitoring, psychosocial and environmental interventions, and pharmacological options. Results Agitation is attributed to disruptions in fronto-limbic circuitry with contributions from neuroimmune dysregulation, neurotransmitter alterations, and mitochondrial dysfunction, and various psychosocial and environmental factors. Psychosocial and environmental strategies can reduce agitation, though magnitude and durability of responses vary. Pharmacological options can have short-term benefits but carry risks that require strict patient selection, counseling, monitoring and medication stewardship. Approved medications based on controlled clinical trials remain limited. Conclusion Care and support in agitation in NCD should involve the implementation of person-centered, rights-based psychosocial and environmental approaches, with time-limited pharmacological adjuncts as second-line. Key evidence gaps include head-to-head and longer-term trials, active safety surveillance, validated agitation measures, and equity-focused implementation across settings and cultures.

BACKGROUND AND OBJECTIVES:Early-onset Alzheimer disease (EOAD) is associated with substantial variability in clinical progression, and reliable biomarkers to predict the transition from mild cognitive impairment (MCI) to dementia remain limited. Structural MRI measures have demonstrated prognostic value in late-onset Alzheimer disease, but their utility for predicting progression in EOAD is less well understood. The goal was to examine whether baseline cortical atrophy predicts progression to dementia in patients with MCI because of EOAD. METHODS:This study included a well-characterized cohort of patients with EOAD enrolled in the large multisite natural history Longitudinal Early-Onset Alzheimer's Disease Study. Participants underwent standardized clinical assessments and structural MRI at baseline. Participants were aged between 40 and 64 years with biomarker-supported sporadic EOAD at the MCI stage. Cortical atrophy was measured within the EOAD-signature, a set of predominantly parieto-temporal regions showing greater atrophy in EOAD than in controls. Clinical severity was measured with the global Clinical Dementia Rating. Cox proportional hazards models estimated the association between baseline EOAD-signature atrophy burden and the hazard of progression to dementia over time. We evaluated whether EOAD-signature atrophy improved prognostic performance beyond baseline clinical severity using likelihood ratio tests, Akaike Information Criterion (AIC), and Harrell concordance index. RESULTS:A total of 130 patients with MCI due to EOAD (mean age 59.6 ± 4.1 years; 49% female) and 97 cognitively normal controls (mean age 56.9 ± 6.0 years; 64% female) were included. Greater baseline atrophy within the EOAD-signature predicted faster progression to dementia (hazard ratio [HR] = 1.24 per 1-SD increase in atrophy; 95% CI 1.13-1.37; p < 0.002). Adding EOAD-signature atrophy burden to a model including baseline clinical severity significantly improved model fit (ΔAIC = -4.5; likelihood ratio test p = 0.011). DISCUSSION:Baseline cortical atrophy within the EOAD-signature predicts progression from MCI to dementia in EOAD and provides prognostic information beyond baseline clinical severity. These findings support the potential value of EOAD-signature atrophy as an MRI-based biomarker for individualized prognostication and clinical trial stratification.

The growing availability of large-scale biomarker datasets has allowed data-driven methods to characterize Alzheimer's disease biological heterogeneity. However, most prior studies have focused on cohorts of late-onset amnestic cases, leaving early-onset Alzheimer's disease underexplored. We aimed to characterize tau-PET-based subtypes through a robust data-driven approach in the Longitudinal Early-Onset Alzheimer's Disease Study. Baseline [18F]Flortaucipir PET scans from 365 amyloid-PET-positive participants with sporadic early-onset Alzheimer's disease were quantified in the left and right medial temporal, lateral temporal, occipital, parietal, and frontal cortices. Tau PET values were z-scored against 85 amyloid-PET-negative cognitively normal age-matched participants and fitted into Subtype and Stage Inference (SuStaIn)-an unsupervised clustering algorithm that simultaneously models subtypes and progression from cross-sectional data. The derived subtypes were subsequently characterized by baseline and longitudinal clinical, cognitive, MRI, tau and amyloid PET features. We identified three tau-PET-based subtypes: on average, Subtype 1/Typical (n = 144, 40%) showed a predominant bilateral temporoparietal pattern typical of Alzheimer's disease. Subtype 2/Left temporal (n = 111, 31%) showed predominant left temporal binding. Subtype 3/Posterior (n = 104, 29%) showed early and permeating occipitoparietal involvement. Subtypes did not differ in demographics or global amyloid burden, but were relatively more enriched for specific clinical presentations: S1/Typical for amnestic presentations, S2/Left Temporal for primary progressive aphasia, and S3/Posterior for posterior cortical atrophy. Baseline tau PET subtypes aligned with cortical atrophy patterns and domain-specific cognitive impairment. When follow-up tau PET scans were fitted to SuStaIn trained on baseline data, 85.6% (n = 172/201) of participants retained the same subtype classification, indicating subtype temporal stability, and progressed within subtypes by 0.56 ± 0.70 SuStaIn stage/year. Longitudinal voxel-wise linear mixed-effects modelling revealed tau accumulation patterns for each subtype in regions relatively spared at baseline: occipital lobe accumulation predominated in S1/Typical, bilateral frontal and right temporal in S2/Left Temporal, and bilateral frontotemporal lobes in S3/Posterior. All subtypes showed longitudinal increases in Clinical Dementia Rating-Sum of Boxes, but with slower worsening in S3/Posterior compared with the other subtypes. Our findings reveal robust subtypes in sporadic early-onset Alzheimer's disease characterized by distinct spatiotemporal tau patterns that parallel differences in clinical presentations and trajectories of neurodegeneration. These subtypes extend beyond traditional clinical syndromes and support a more nuanced framework for individualized prognosis and care. Incorporating tau PET subtyping into clinical trial design could enable more targeted therapeutic approaches for this younger population.

In clinical studies, it is scientifically important, and a regulatory expectation, that objectives be translated into key clinical questions by specifically defining treatment effects to be estimated. Estimands are part of a structured framework, as presented in International Council for Harmonisation (ICH) E9(R1), by which study objectives are linked to a suitable study design and tools for estimation. Estimands are constructed using five attributes: treatment, population, variable (or endpoint), population-level summary for the variable, and intercurrent events (ICEs). ICEs occur after treatment initiation and can affect the existence or interpretation of the measurements. In Alzheimer's disease (AD), potential ICEs include additional AD medication use, discontinuation of treatment, and death. We describe estimands in recent clinical studies of anti-amyloid therapies, including gantenerumab, lecanemab, and donanemab, in AD and use the evoke and evoke+ studies of semaglutide in early-stage symptomatic AD as examples of estimand application in AD trials.

Antibody therapies can remove amyloid plaques from the brain and slow cognitive decline in people with Alzheimer's disease who are mildly impaired. These drugs are now being evaluated in participants who are cognitively unimpaired but positive for a biomarker of Alzheimer's disease for their safety, tolerability, disease-modifying and cognitive preserving effects, and ability to avert the onset of cognitive impairment. If these studies are successful, and the drugs get regulatory approval, they could accelerate the evaluation and approval of related Alzheimer's disease-modifying treatments in people who are unimpaired with or without a biomarker of the disease. Preclinical Alzheimer's disease therapies that modify the underlying disease in people who are unimpaired with a biomarker of Alzheimer's disease and primary prevention therapies that avert the onset of amyloid plaques in those with a negative test have the potential to substantially prevent ensuing biological and clinical manifestations of Alzheimer's disease. In this Policy View, we assess the challenges and opportunities that trials of these drug treatments will bring, and consider the blood tests, cognitive assessments, and post-marketing strategies needed to enable the approval, affordability, health-care insurance coverage, and equitable use. Our recommendations are intended for consideration in the USA, and relevant refinement in other countries.

Importance:Decline in olfactory function may be used as a predictor of cognitive decline, to enhance early detection models, improve risk stratification, and enable early intervention. Objective:To assess the longitudinal association between olfactory decline, cognitive decline, and postmortem neuropathology. Design setting and participants:Retrospective longitudinal analysis with clinicopathological correlations of a prospective population-based cohort study using data from the Arizona Study of Aging and Neurodegenerative Disorders (AZSAND) and its Brain and Body Donation Program. Participants included cognitively unimpaired individuals without parkinsonism that converted to mild cognitive impairment (MCI) and/or dementia or remained cognitively stable. Main Outcomes and Measures:longitudinal change in olfaction, neuropsychiatric symptoms, motor function and memory, conversion to MCI/dementia, postmortem neuropathology. Results:Over a mean follow-up period of 7.7 ± 5.4 years, out of 922 participants who were cognitively unimpaired at the first cognitive conference, 643 remained cognitively unimpaired, 279 converted to MCI, and 82 developed dementia. Of these, 633 individuals had at least 2 olfactory tests.Converters showed reduced olfactory function (t=-12.6, p <0.0001), faster progression in neuropsychiatric symptom burden (t=3.42, p < 0.001), and faster decline in memory (t= -7.33, p <0.0001) prior to conversion while no significant differences were observed in motor scores between converters and non-converters. Using ROC analysis, olfactory decline, increased neuropsychiatric symptom burden, as well as motor and memory decline predicted conversion to MCI with a consistent accuracy of ~ 70% up to 5 years before conversion, while UPSIT alone had an accuracy of ~ 60%. Longitudinal decline in olfaction was associated with a higher burden of a-synuclein (t= -8.21, p <0.0005), tau tangle (t= -2.66, p < 0.01) and amyloid plaque burden (t= -2.85, p < 0.005) and a faster decline over time was associated with a higher burden of tau (t=5.66, p<0.0001). Conclusions and Relevance:A reduction in olfactory identification ability is observed up to a decade prior to conversion to MCI and is associated with underlying burden of neuropathology markers, underscoring the value of incorporating olfactory testing in cognitively unimpaired individuals to identify those at-risk of future cognitive decline.

Early-onset Alzheimer's disease (EOAD) and Late-onset AD (LOAD) differ in clinical presentations and rates of progression. We aimed to compare baseline and longitudinal tau PET burden, and their relationship with clinical variables in amyloid-PET positive, cognitively impaired participants from the Longitudinal Early-Onset Alzheimer's Disease Study (EOAD; n=390) and Alzheimer's Disease Neuroimaging Initiative (LOAD; n=211). Patients with EOAD showed higher baseline tau PET retention, broader neuroanatomical involvement and faster accumulation rates over time compared to LOAD, after adjusting for amyloid load and clinical stage. Tau PET showed stronger correlations with baseline amyloid burden and clinical measures of global cognition and function in EOAD than LOAD. We conclude that earlier age of onset in AD is linked to a more aggressive tauopathy, which in turn is a primary driver of clinical decline. These findings suggest that optimal therapeutic targets and strategies may differ between EOAD and LOAD.

Braak and others have proposed that Lewy body pathology (LBP) in Parkinson's disease (PD) may arise not only in the brain but alternatively from an initial site in the gastrointestinal (GI) tract with subsequent passage to the central nervous system CNS through the vagus nerve or other routes. We tested this hypothesis by using both immunohistochemistry (IHC) and RT QuIC a form of alpha synuclein seed amplification assay (SAA) to detect alpha synuclein LBP in samples from selected brain regions and 10 GI tract sites taken from autopsies of 50 PD subjects and 128 elderly subjects without parkinsonism or dementia including 34 with IHC identified CNS incidental Lewy body disease (ILBD) and 94 with no Lewy body IHC pathology detected (NLB). A positive SAA or IHC result was restricted to the GI tract in only 2 subjects while LBP by either SAA or IHC was restricted to the brain in 11 subjects. To fairly compare GI-only with brain-only synucleinopathy, however, we would have to do SAA on brain samples from all ILBD and NLB cases in at least 4 critical brain regions: olfactory bulb, medulla, pons, and amygdala. Further SAA of brain regions is estimated, based on the proportional results to date, to potentially identify 21 additional brain-only LBP subjects, for a total of 32, if it were done on all of the NLB subjects. From this brain-only LBP is estimated to be 16 times more common than GI-only LBP. To assess the clinical impact of SAA-positive GI sites we found that the number of positive sites per subject is significantly correlated with UPDRS motor score and SCOPA-AUT GI related scores including those for salivation, straining, constipation, and bowel movement.

INTRODUCTION:Recent work has identified unique cognitive profiles for early-onset Alzheimer's disease (EOAD) relative to late-onset Alzheimer's disease (LOAD), however, examination has been limited in determining whether the association between age and cognitive severity at presentation also differs across conditions. METHODS:A series of linear spline regression models was conducted across baseline cognitive data from 325 EOAD and 314 LOAD participants, after accounting for education, sex, and apolipoprotein ε4 status. RESULTS:Significant differences existed in the relationship between baseline age and cognitive performance between EOAD and LOAD samples for Processing Speed/Attention, Executive Functioning, and Episodic Immediate Memory. Younger participants from both EOAD and LOAD groups performed disproportionately worse on non-amnestic cognitive domains, with this occurring to a greater extent in EOAD than LOAD. DISCUSSION:In the age of disease-modifying treatments, results highlight the importance of assessing for cognitive declines in individuals starting much earlier than age 65. HIGHLIGHTS:Early-onset Alzheimer's disease (EOAD) and late-onset Alzheimer's disease (LOAD) participants each displayed cognitive impairments relative to same-aged peers across most domains. Both groups displayed positive relationships between impairment among non-amnestic cognitive domains and baseline age. This relationship displayed a significantly greater effect in EOAD than LOAD, with domains of Processing Speed/Attention and Executive Functioning skills being the most pronounced. Of those participants developing AD, age displayed a disproportionate impact on their symptom onset.