Citations

Abstract INTRODUCTION Risk factors associated with sporadic non‐amnestic and early‐onset Alzheimer's disease (AD) remain underexamined. METHODS We investigated a large, clinically heterogeneous, AD cohort for frequencies of established risk factors (hypertension, hypercholesterolemia, diabetes mellitus) alongside novel factors (non–right‐handedness, learning disability, seizures, autoimmune disease). RESULTS Early‐onset AD possessed lower frequencies of established risk factors (hypertension, hypercholesterolemia, diabetes mellitus, all p < 0.001) and higher frequencies of novel factors (non–right‐handedness, learning disability, active seizure, all p < 0.001; remote seizure, p = 0.002; and autoimmune disease, p = 0.007). An age at onset < 70 maximally distinguished novel from typical factors. Principal component analysis loaded novel factors into two components, non–right‐handedness and learning disability versus seizure and autoimmune disease, which combined, resulted in an exponential decrease in age at onset from one factor alone. DISCUSSION Identifying novel factors enriched in early‐onset and non‐amnestic AD introduces new theories of AD susceptibility and phenotypic heterogeneity, with significant implications for disease prediction and treatment. Highlights We identified a suite of novel factors overrepresented in early‐onset and non‐amnestic AD. These factors can be broadly conceptualized as neurodevelopmental (non–right‐handedness and learning disability) and neural environmental (seizure and autoimmunity). The combination of these factors produced exponential decreases in AD age at onset, compared to each alone, supporting a new theoretical framework for understanding AD risk with implications for disease prediction, prevention, and therapeutic intervention.

Background: Progressive apraxia of speech (PAOS) is a neurodegenerative disorder most commonly arising from a 4-repeat tauopathy that affects the programming or planning of speech, although many patients develop a Parkinson-plus syndrome. The role of neuroinflammation as a disease mechanism is unknown. We investigated the spatial pattern of neuroinflammation in PAOS using PET and evaluated whether it is associated with disease severity, presence of Parkinson-plus features, and tau PET uptake. Patients and Methods: Twenty-five PAOS patients (13 with Parkinson-plus features) and 30 controls underwent inflammatory 11C-ER176 and tau 18F-flortaucipir PET scans as well as detailed clinical assessments. Multiple linear regression analyses compared the inflammatory standardized uptake value ratio (SUVR) between PAOS and controls and assessed the relationship with clinical test scores. Pearson correlation analysis examined the relationship between inflammatory and tau SUVRs. Results: PAOS had greater neuroinflammatory SUVR than controls in the precentral, supplementary motor area, frontal gyri, putamen, pallidum, subthalamic nucleus, and red nucleus (adjusted P < 0.05). Greater neuroinflammation was associated with worse parkinsonism, and patients who had developed Parkinson-plus features showed a broader pattern of neuroinflammation, extending to prefrontal, temporal and parietal cortices. Neuroinflammation correlated with tau uptake in most (96%) PAOS patients (r > 0.3, P < 0.05). The higher correlation was associated with worse parkinsonism (r = 0.61, P < 0.05) and disease severity (r = 0.54, P < 0.05). Conclusions: 11C-ER176 PET analysis demonstrates neuroinflammation in frontal and subcortical regions in PAOS which is particularly severe and widespread with the development of Parkinson-plus clinical features. The colocalization of neuroinflammation and tau may support a relationship between these disease mechanisms.

Background Neuropsychiatric symptoms (NPS) progress differently among individuals with autosomal dominant familial frontotemporal dementia (FTD) caused by genetic mutations in granulin ( GRN +) or chromosome 9 open reading frame 72 ( C9orf72 +). Objective To determine whether these differences begin prior to the onset of dementia, we compared the longitudinal rates of change of NPS among C9orf72 +, GRN +, and noncarrier controls in the predementia phase. Additionally, we assessed whether the NPS changes were correlated with gray matter (GM) volume loss or white matter signal abnormalities (WMSAs) on magnetic resonance imaging (MRI). Methods Eighty-two participants (N = 10 GRN +, N = 23 C9orf72 +, N = 49 noncarriers) were followed using various NPS rating scales for an average of 7.8 years. Group differences were compared using generalized linear mixed-effects models. GM volume and WMSA volumes were measured on 42 participants (N = 8 GRN +, N = 11 C9orf72 +, N = 23 noncarriers) who had two MRI visits. These measures were correlated with the rates of NPS score changes. Results C9orf72 + showed higher rates of increase in the Beck Depression Inventory (BDI) total and the Iowa Scales of Personality Change (ISPC) dysexecutive disturbance scores versus noncarriers. GRN + showed higher rates of increase in the BDI total, the ISPC total, and the emotional/social disturbance scores versus noncarriers; and higher rates of increase in the ISPC emotional/social personality and distressed disturbance scores versus C9orf72 +. Across all groups, faster WMSA accumulation correlated with higher rates of increase in the Neuropsychiatric Inventory Questionnaire total score. Conclusions Changes in NPS differ among C9orf72 +, GRN +, and noncarrier controls prior to the onset of overt FTD.

Abstract INTRODUCTION Sex differences are apparent in neurodegenerative diseases but have not been comprehensively characterized in frontotemporal dementia (FTD). METHODS Participants included 337 adults with autosomal dominant FTD enrolled in the ALLFTD Consortium. Clinical assessments and plasma were collected annually for up to 6 years. Linear mixed‐effects models investigated how sex and disease stage are associated with longitudinal trajectories of cognition, function, and neurofilament light chain (NfL). RESULTS While sex differences were not apparent at asymptomatic stages, females showed more rapid declines across all outcomes in symptomatic stages compared to males. In asymptomatic participants, the association between baseline NfL and clinical trajectories was weaker in females versus males, a difference that was not present in symptomatic participants. DISCUSSION In genetic FTD, females show cognitive resilience in early disease stages followed by steeper clinical declines later in the disease. Baseline NfL may be a less sensitive prognostic tool for clinical progression in females with FTD‐causing mutations. Highlights Females with genetic FTD exhibit overall steeper increases in plasma neurofilament light chain (NfL) than males. Females with genetic FTD outperform NfL levels in asymptomatic stages compared to males. Once symptomatic, females with genetic FTD decline more rapidly than males. Plasma NfL is a stronger prognostic marker in asymptomatic males than females.

AbstractBackgroundThe 17q21.31 region with various structural forms characterized by the H1/H2 haplotypes and three large copy number variations (CNVs) represents the strongest risk locus in progressive supranuclear palsy (PSP).ObjectiveTo investigate the association between CNVs and structural forms on 17q.21.31 with the risk of PSP.MethodsUtilizing whole genome sequencing data from 1684 PSP cases and 2392 controls, the three large CNVs (α, β, and γ) and structural forms within 17q21.31 were identified and analyzed for their association with PSP.ResultsWe found that the copy number of γ was associated with increased PSP risk (odds ratio [OR] = 1.10, P = 0.0018). From H1β1γ1 (OR = 1.21) and H1β2γ1 (OR = 1.24) to H1β1γ4 (OR = 1.57), structural forms of H1 with additional copies of γ displayed a higher risk for PSP. The frequency of the risk sub‐haplotype H1c rises from 1% in individuals with two γ copies to 88% in those with eight copies. Additionally, γ duplication up‐regulates expression of ARL17B, LRRC37A/LRRC37A2, and NSFP1, while down‐regulating KANSL1. Single‐nucleus RNA‐seq of the dorsolateral prefrontal cortex analysis reveals γ duplication primarily up‐regulates LRRC37A/LRRC37A2 in neuronal cells.ConclusionsThe copy number of γ is associated with the risk of PSP after adjusting for H1/H2, indicating that the complex structure at 17q21.31 is an important consideration when evaluating the genetic risk of PSP. © 2025 The Author(s). Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society.

Abstract The largest risk factor for dementia is age. Heterochronic blood exchange studies have uncovered age-related blood factors that demonstrate ‘pro-aging’ or ‘pro-youthful’ effects on the mouse brain. The clinical relevance and combined effects of these factors for humans is unclear. We examined five previously identified brain rejuvenation factors in cerebrospinal fluid of adults with autosomal dominant forms of frontotemporal dementia and sporadic Alzheimer’s disease. Our frontotemporal dementia cohort included 100 observationally followed adults carrying autosomal dominant frontotemporal dementia mutations (Mage = 49.6; 50% female; 43% C9orf72, 24% GRN, 33% MAPT) and 62 non-carriers (Mage = 52.6; 45% female) with cerebrospinal fluid analysed on Somascan, and longitudinal (Mvisits = 3 years, range 1–7 years) neuropsychological and functional assessments and plasma neurofilament light chain. Our Alzheimer’s disease cohort included 35 adults with sporadic Alzheimer’s disease (Mage = 69.4; 60% female) and 56 controls (Mage = 68.8, 50% female) who completed the same cerebrospinal fluid and clinical outcome measures cross-sectionally. Levels of C-C motif chemokine ligand 11, C-C motif chemokine ligand 2, beta-2-micorglobulin, bone gamma-carboxyglutamate protein (aka Osteocalcin) and colony stimulating factor 2 in cerebrospinal fluid were linearly combined into a composite score, with higher values reflecting ‘pro-youthful’ levels. In genetic frontotemporal dementia, higher baseline cerebrospinal fluid rejuvenation proteins predicted slower decline across cognitive, functional, and neurofilament light chain trajectories; estimates were similar across genotypes. In transdiagnostic analyses, higher cerebrospinal fluid rejuvenation proteins associated with better functional, cognitive, and neurofilament light chain outcomes in adults with sporadic Alzheimer’s disease. Proteins with pre-clinical evidence for brain rejuvenation show translational clinical relevance in adults with Alzheimer’s disease and related dementias and warrant further investigation.

Abstract Limbic predominant age‐related TDP‐43 encephalopathy neuropathologic change (LATE‐NC) is highly prevalent in late life and a common co‐pathology with Alzheimer's disease neuropathologic change (ADNC). LATE‐NC is a slowly progressive, amnestic clinical syndrome. Alternatively, when present with ADNC, LATE‐NC is associated with a more rapid course. With the emergence of anti‐amyloid therapeutics, discrimination of LATE‐NC from ADNC is critical and will lead to greater clinical recognition of amnestic patients without ADNC. Furthermore, co‐pathology with LATE‐NC may influence outcomes of these therapeutics. Thus there is a need to identify patients during life with likely LATE‐NC. We propose criteria for clinical diagnosis of LATE as an initial framework for further validation. In the context of progressive memory loss and substantial hippocampal atrophy, criteria are laid out for probable (amyloid negative) or possible LATE (amyloid biomarkers are unavailable or when amyloid is present, but hippocampal neurodegeneration is out of proportion to expected pure ADNC). Highlights Limbic‐predominant age‐related TDP‐43 encephalopathy (LATE) is a highly prevalent driver of neuropathologic memory loss in late life. LATE neuropathologic change (LATE‐NC) is a common co‐pathology with Alzheimer's disease neuropathologic change (ADNC) and may influence outcomes with emerging disease‐modifying medicines. We provide initial clinical criteria for diagnosing LATE during life either when LATE‐NC is the likely primary driver of symptoms or when observed in conjunction with AD. Definitions of possible and probable LATE are provided.

AbstractBackgroundAs new anti‐amyloid immunotherapies emerge for Alzheimer’s disease (AD), it is clear that early diagnosis of AD pathology is crucial for treatment success. This can be challenging in atypical presentations of AD and, together with our reliance on CSF or PET scans, can, at times, lead to delayed diagnosis. Here, we further explore the possible role of plasma tau phosphorylated at threonine 217 (P‐tau217) for the detection of primary AD or AD co‐pathology when frontotemporal dementia spectrum disorders are the main clinical presentation.MethodParticipants were recruited through ALLFTD, a North American multisite research consortium for the longitudinal assessment of frontotemporal lobar degeneration. After excluding cases with known FTD‐causing mutations, 573 participants with sporadic disease, mild cognitive/behavioral impairment, or healthy familial controls evaluated between 2014 and 2023 were included in this analysis (45.8% female, median age 66 years). 39 of those cases underwent neuropathological evaluation. Plasma P‐tau217 was measured with the Eli Lilly electrochemiluminescence‐based assay. P‐tau217 concentrations were compared by phenotype, disease severity, genotype, and, when available, neuropathological diagnosis with non‐parametric tests. Its diagnostic performance was tested with ROC curves. Associations between plasma P‐tau217 concentrations and clinical scales of global cognition, memory, executive function, motor function, and social cognition with linear regressions and non‐parametric tests.ResultPlasma P‐tau217 concentrations were higher in logopenic variant primary progressive aphasia (lvPPA) and amnestic dementia (AmDem), compared to participants with normal cognition or other FTD phenotypes. P‐tau217 concentrations were higher in APOE e4 carriers, compared to non‐carriers, regardless of phenotype, but were not affected by disease severity. P‐tau217 concentrations showed associations with clinical measures of global cognition, memory, and executive function, but had no associations with measures of motor function or social cognition. Plasma P‐tau217 concentrations were elevated in high and intermediate ADNC scoring, or more advanced Braak stages, even when AD was not the primary pathology.ConclusionEven when FTD is suspected, high plasma p‐tau 217 concentrations are strongly associated with underlying AD as primary pathology or contributing co‐pathology. Plasma P‐tau217 could be a tool to support the development of disease‐modifying therapies for atypical Alzheimer’s disease presentations or for FTD cases with Alzheimer’s disease co‐pathology.