Huang M, Dalton MA, Matis S
… +6 more, Teng HAC, Cheung SC, Hwang YT, Ahmed RM, Landin-Romero R, Piguet O
Alzheimers Dement
· 2026 May · PMID 42151626
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INTRODUCTION: The amygdala is critical for social cognition and undergoes profound damage in frontotemporal dementia (FTD). While its atrophy is well documented, changes in its structural connectivity and their behaviora...INTRODUCTION: The amygdala is critical for social cognition and undergoes profound damage in frontotemporal dementia (FTD). While its atrophy is well documented, changes in its structural connectivity and their behavioral relevance remain unclear. METHODS: Using fixel-based analysis and tractography, we examined amygdala connectivity in patients with behavioral variant FTD (bvFTD; n = 21), semantic dementia (SD; n = 19), progressive non-fluent aphasia (PNFA; n = 18), and 28 controls. Associations with empathy and emotion recognition were explored using partial correlations. RESULTS: BvFTD and SD showed marked degeneration of amygdala-associated tracts, while PNFA exhibited subtle left temporal changes. Tractography revealed reduced amygdala connectivity with regions supporting memory, visual, language, semantic, and motor functions, to varying degrees across subtypes. Social cognitive deficits were correlated with amygdala-cerebellum connectivity in bvFTD and with amygdala-hippocampus connectivity in SD. DISCUSSION: These findings were the first to demonstrate subtype-specific patterns of amygdala white matter alteration and their relevance to social cognitive symptoms in FTD.
Oberlin LE, Solis-Urra P, Sewell KR
… +19 more, Collins AM, Kang C, Huang H, Grove G, Wan L, Kramer AF, McAuley E, Burns JM, Hillman CH, Vidoni ED, Marsland AL, Kamboh MI, Szabo-Reed A, Rogers RJ, Morris J, Zeng X, Karikari TK, Jakicic JM, Erickson KI
Alzheimers Dement
· 2026 May · PMID 42151104
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INTRODUCTION: Physical activity (PA) and cardiorespiratory fitness (CRF) are associated with reduced risk of cognitive decline and dementia, yet their relationships with dementia-related pathophysiology remain unclear. I...INTRODUCTION: Physical activity (PA) and cardiorespiratory fitness (CRF) are associated with reduced risk of cognitive decline and dementia, yet their relationships with dementia-related pathophysiology remain unclear. In a community-dwelling older adult cohort, we examined associations between objectively measured PA, CRF, biomarkers of Alzheimer's disease (AD)-related pathology, and cognition. METHODS: Participants (n = 648, 71% female, age 69.88 ± 3.75) completed a comprehensive cognitive evaluation, objective assessments of moderate-to-vigorous PA (MVPA) and CRF (VO), and AD-related brain (positron emission tomography [PET] amyloid beta [Aβ]) and blood biomarkers (Aβ1-42/1-40, phosphorylated tau [p-tau]217, p-tau181, glial fibrillary acidic protein [GFAP], neurofilament light chain [NfL]). RESULTS: Greater MVPA (β = -0.107; p = 0.013) and CRF (β = -0.114; p = 0.027) were associated with lower NfL, but not Aβ PET, p-tau217, Aβ1-42/1-40, or GFAP. Aβ positivity moderated the CRF-NfL relationship, with higher CRF linked to lower NfL specifically among Aβ-positive individuals. NfL mediated relationships between MVPA, CRF, and cognitive performance in select domains. DISCUSSION: Neuroprotective benefits of PA may be conferred through mechanisms influencing neurodegeneration, particularly among those with emerging AD pathology.
Alzheimers Dement
· 2026 May · PMID 42138182
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INTRODUCTION: Remote neuropsychological testing can monitor brain health in individuals with or at risk of Alzheimer's disease (AD). We evaluated acceptability and validity of the Cogstate Brief Battery (CBB) for remote...INTRODUCTION: Remote neuropsychological testing can monitor brain health in individuals with or at risk of Alzheimer's disease (AD). We evaluated acceptability and validity of the Cogstate Brief Battery (CBB) for remote administration. METHODS: Non-demented adults from the Alzheimer's Disease Neuroimaging Initiative (ADNI) completed the CBB in-clinic under supervision, then remotely every six months, with annual in-clinic reassessments. Groups included cognitively unimpaired (CU) adults with normal amyloid (CU Aβ-) or elevated amyloid (CU Aβ+), and individuals with mild cognitive impairment with or without amyloid (MCI Aβ+, MCI Aβ-). Performance was compared across contexts and longitudinal changes were examined. RESULTS: At baseline, MCI Aβ+ participants performed worse than CU Aβ-. CBB performance was similar across contexts, with consistent group differences. Over time, MCI Aβ+ participants showed greater decline on remote CBB measures than CU Aβ- adults. DISCUSSION: Remote unsupervised CBB assessments are valid, reliable, and sensitive to AD-related cognitive impairment.
Wanigatunga AA, Wang H, Huang D
… +10 more, Davoudi A, Dougherty RJ, Tian Q, Deal JA, Abraham AG, Simonsick EM, Gross AL, Resnick SM, Ferrucci L, Schrack JA
Alzheimers Dement
· 2026 May · PMID 42132137
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INTRODUCTION: Identifying precursors to mild cognitive impairment (MCI)-the transitional stage between unimpaired cognition and dementia-is a public health priority. While sensory and motor impairments are each linked to...INTRODUCTION: Identifying precursors to mild cognitive impairment (MCI)-the transitional stage between unimpaired cognition and dementia-is a public health priority. While sensory and motor impairments are each linked to MCI, their integrated contribution as a sensorimotor construct remains underexplored. METHODS: We analyzed cross-sectional data from two US cohorts: Atherosclerosis Risk in Communities (ARIC; n = 880) and Baltimore Longitudinal Study of Aging (BLSA; n = 681), excluding individuals with stroke, Parkinson's disease, or dementia. A composite sensorimotor score-based on hearing, vision, olfaction, balance, gait speed, and grip strength-was created using factor analysis. Structural equation modeling assessed associations with MCI, adjusting for key covariates. RESULTS: Higher sensorimotor function was associated with lower odds of MCI: ARIC odds ratio (OR) = 0.53 (95% confidence interval [CI]: 0.40-0.71); BLSA OR = 0.59 (95% CI: 0.43-0.81). DISCUSSION: Sensorimotor function appears robustly related with MCI in a large sample of older adults. These findings highlight the potential value of incorporating sensorimotor assessments in early detection for cognitive decline. Longitudinal research is needed to understand temporality.
Stark M, Wagner M, Kuhn E
… +43 more, Roeske S, Amthauer H, Bartels C, Boecker H, Brosseron F, Buchert R, Buerger K, Daamen M, Drzezga A, Düzel E, Ersözlü E, Essler M, Ewers M, Fliessbach K, Glanz W, Hellmann-Regen J, Incesoy EI, Janowitz D, Kafali K, Kilimann I, Krause BJ, Kronmüller M, Laske C, Maier F, Maurer A, Michely J, Perneczky R, Peters O, Preis L, Priller J, Rauchmann BS, Reimold M, Rominger A, Schmid M, Schneider A, Sodenkamp S, Spottke A, Spruth EJ, Teipel S, Wiltfang J, Alzheimer´s Disease Neuroimaging Initiative (ADNI), Jessen F, Kleineidam L
Alzheimers Dement
· 2026 May · PMID 42129577
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INTRODUCTION: Subtle symptoms, like subjective cognitive decline (SCD) and minor neuropsychological deficits (MNPD), can improve the risk stratification in preclinical Alzheimer´s disease (AD) but their importance is ins...INTRODUCTION: Subtle symptoms, like subjective cognitive decline (SCD) and minor neuropsychological deficits (MNPD), can improve the risk stratification in preclinical Alzheimer´s disease (AD) but their importance is insufficiently elaborated. METHODS: We pooled data from cognitively normal individuals participating in three longitudinal cohort studies (N = 13,192, 8,359[63.3%] female, mean [SD] age 71.0[8.4]). RESULTS: Compared to participants without SCD and MNPD (SCD-/MNPD-), SCD-/MNPD+, SCD+/MNPD-, and SCD+/MNPD+ participants had an increased risk for mild cognitive impairment (MCI) and dementia, including in amyloid-positive individuals. Focusing on SCD+/MNPD+ participants triples the positive predictive value of amyloid biomarker testing for the 5-year prediction of MCI and reduces the required samples size for trials in preclinical AD to one fourth, compared to considering all cognitively normal participants regardless of subtle symptoms. DISCUSSION: SCD and MNPD offer a powerful approach for risk stratification in preclinical AD, which can improve clinical trial designs, risk counseling, and future case identifications for early treatment.
Liu Z, Che C, He G
… +4 more, Wu H, Cai L, Cui L, Liang L
Alzheimers Dement
· 2026 May · PMID 42129462
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INTRODUCTION: Alzheimer's disease (AD) poses a global health challenge. Early intervention during the stage of subjective cognitive decline (SCD) - a potential window for delaying disease progression - is crucial. This s...INTRODUCTION: Alzheimer's disease (AD) poses a global health challenge. Early intervention during the stage of subjective cognitive decline (SCD) - a potential window for delaying disease progression - is crucial. This study aims to assess an exploratory speech-based model for rapid SCD screening. METHOD: This study included 459 participants, comprising individuals with AD, mild cognitive impairment (MCI), SCD, and normal controls. We used Pic-Talk clips and Mandarin speech with residual network features for SCD screening. RESULTS: In this cross-sectional study, our model achieved high performance with accuracy, recall, precision, F1, and area under the curve of 81.77 ± 2.78%, 80.53 ± 2.64%, 82.27 ± 2.38%, 81.39 ± 1.85%, and 82.85 ± 2.01%, respectively, outperforming other speech models. DISCUSSION: This non-invasive exploratory approach to SCD assessment shows potential, revealing acoustic differences at the group level between SCD and other diagnostic groups. It is expected that the future integration of biomarkers will enhance the model's accuracy and expand its applicability.
Mutz J, Gilchrist L, Pain O
… +2 more, Proitsi P, Lewis CM
Alzheimers Dement
· 2026 May · PMID 42126002
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INTRODUCTION: Identifying individuals at risk of dementia is essential for prevention and targeted disease-modifying strategies. We investigated whether mid-life metabolomic ageing is associated with incident dementia an...INTRODUCTION: Identifying individuals at risk of dementia is essential for prevention and targeted disease-modifying strategies. We investigated whether mid-life metabolomic ageing is associated with incident dementia and its age of onset and assessed joint associations and interactions with APOE genotype and dementia polygenic scores. METHODS: In the UK Biobank, plasma metabolites were quantified at baseline. Metabolomic age (MileAge) delta reflects the difference between metabolite-predicted and chronological age. Dementia was identified via health records. RESULTS: Amongst 223,496 participants, 3976 developed dementia. A higher MileAge delta was associated with higher hazards of all-cause, unspecified and vascular dementia (HR = 1.61, 95% CI 1.28-2.02, p = 0.001) and earlier onset. Key metabolites were lipids, lipoproteins and amino acids. MileAge delta and genetic risk were jointly associated with dementia. Individuals with a high MileAge delta and two APOE ε4 alleles had a 10.30-fold higher all-cause dementia risk (95% CI 7.95-13.34, p < 0.001). DISCUSSION: Metabolomic ageing and genetic risk likely represent independent biological pathways contributing to dementia risk.
Alzheimers Dement
· 2026 May · PMID 42125995
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INTRODUCTION: Countries have varying, limited healthcare budgets for emerging disease-modifying therapies. Cost-effectiveness analysis, combined with country-level cost-effectiveness thresholds, can be used to estimate v...INTRODUCTION: Countries have varying, limited healthcare budgets for emerging disease-modifying therapies. Cost-effectiveness analysis, combined with country-level cost-effectiveness thresholds, can be used to estimate value-based prices (VBPs) for lecanemab and donanemab across 174 countries. METHODS: The cost-effectiveness of lecanemab and donanemab was estimated using incremental cost and quality-adjusted life years (QALYs) compared to usual care. Published cost-effectiveness thresholds were used to estimate VBPs of these drugs across 174 countries. RESULTS: Compared to usual care, lecanemab and donanemab respectively increased average QALYs by 0.38 and 0.51. By country income status, VBPs for lecanemab and donanemab respectively ranged between $254 to $9434 and $387 to $13,964 (high income), $90 to $1025 and $137 to $1507 (upper middle income), $11 to $623 and $21 to $956 (lower middle income) and $4 to $18 and $9 to $32 (low income). DISCUSSION: VBPs indicate how much 174 countries should be willing to pay. This framework can also be adapted and refined in the negotiation of country pricing.
Oliveira D, Catalán L, Bozanic A
… +3 more, Pedrero V, Miranda-Castillo C, Brun P
Alzheimers Dement
· 2026 May · PMID 42121297
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INTRODUCTION: The aim of this study was to explore practices and experiences of nursing staff involved with care delivery to people with dementia in surgical-medical wards at public hospitals in Chile. METHODS: A qualita...INTRODUCTION: The aim of this study was to explore practices and experiences of nursing staff involved with care delivery to people with dementia in surgical-medical wards at public hospitals in Chile. METHODS: A qualitative study was conducted through one-on-one semi-structured interviews with 30 registered nurses and nursing technicians in two hospitals. Reflexive thematic analysis was undertaken. RESULTS: Nursing care took place in a context of multidimensional precarity, where multiple factors interacted to shape the type of care delivered to people with dementia. The intersection between negative views toward aging and dementia, with a risk-aversion culture, resulted in a widespread application of agency-limiting practices. Nursing staff were largely untrained and overly reliant on families and other professionals, resulting in an approach to dementia care based on individual levels of stress, tolerance, and moral standards. DISCUSSION: Multiple factors hinder the delivery of quality nursing care for people with dementia in Chile and require urgent attention.
Bernick C, Kleven BC, Alosco ML
… +22 more, Arciniega H, Ashton N, Bender A, Bieniek KF, Cordes D, Cordes L, Katz DI, Keene D, Kinney J, Mandarino L, Matthews D, McKee A, Mez J, Oh EC, Peskind E, Rabinovici GD, Reiman EM, Stern RA, Vasdev N, Zetterberg H, Zhuang X, Cummings JL
Alzheimers Dement
· 2026 May · PMID 42121201
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The 2025 Leon Thal Summit convened an international panel of clinicians, neuroscientists, neuropathologists, and neuroimaging specialists to evaluate the current state of biomarker development for chronic traumatic encep...The 2025 Leon Thal Summit convened an international panel of clinicians, neuroscientists, neuropathologists, and neuroimaging specialists to evaluate the current state of biomarker development for chronic traumatic encephalopathy (CTE) and to outline priorities for advancing translational research for this important area. Discussions integrated emerging findings from longitudinal cohorts, new molecular and neuroimaging approaches, expanding post mortem evidence, and evolving insights into exposure biology and genetic modifiers. Consensus themes emphasized the need for biomarkers that detect CTE-specific tau proteoforms, integration of existing imaging and fluid markers into traumatic encephalopathy syndrome research criteria, and refinement of multimodal magnetic resonance imaging and blood-based tools that capture early CTE pathology. The group underscored the importance of coordinated, longitudinal clinicopathological studies and collaborative research frameworks to validate candidate biomarkers and accelerate progress toward accurate diagnosis, disease monitoring, and therapeutic development for individuals at risk for or exhibiting signs of CTE.
Kolling LJ, Balasubramanian N, Ismail S
… +6 more, Feller AJ, Alberhasky JMH, Wang R, Jennings L, Hefti M, Marcinkiewcz CA
Alzheimers Dement
· 2026 May · PMID 42117485
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INTRODUCTION: Our previous studies demonstrate that htau mice recapitulate many of the neuropsychiatric features of early Alzheimer's disease (AD), and that the dorsal raphe nucleus (DRN) contains distinct subregions. He...INTRODUCTION: Our previous studies demonstrate that htau mice recapitulate many of the neuropsychiatric features of early Alzheimer's disease (AD), and that the dorsal raphe nucleus (DRN) contains distinct subregions. Herein, we investigate the vulnerability of the centromedial DRN to pathologically phosphorylated tau (p-tau), a region composed predominantly of dually serotonergic/glutamatergic (5HT/glut) neurons. METHODS: We use a battery of computational, molecular, biophysical, and behavioral techniques to assess molecular changes in the centromedial DRN across preclinical and post mortem settings. RESULTS: The centromedial DRN contains 5HT/glut neurons that differentially express ion-channel genes in the htau mouse. This is associated with increased neuronal excitability, which may promote p-tau accumulation. At Braak II, KCNA4 is reduced in 5HT/glut neurons in AD, which are especially vulnerable to p-tau compared to 5HT-nonglut neurons. DISCUSSION: Tau-mediated dysfunction of the DRN may be driven by changes in ion channel activity that concomitantly promote the spread of p-tau in Braak progression.
Chan CK, Lane KA, Gao S
… +5 more, Adeoye-Olatunde OA, Shih P, Johnson DK, Saykin AJ, Wang S
Alzheimers Dement
· 2026 May · PMID 42115824
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BACKGROUND: As Alzheimer's disease and related dementias studies incorporate remote assessments, people at higher risk, such as individuals from minority racial and ethnic groups, may be disadvantaged due to imbalances i...BACKGROUND: As Alzheimer's disease and related dementias studies incorporate remote assessments, people at higher risk, such as individuals from minority racial and ethnic groups, may be disadvantaged due to imbalances in access. METHODS: Using data from the National Alzheimer's Coordinating Center Uniform Data Set, logistic regression models using generalized estimating equations with a random effect for study site were used to test the association of race and ethnicity, education, and their interactions with technology preferences and internet access. RESULTS: A total of 3,803 participants across 17 ADRCs (mean age 73.3 years [standard deviation [SD] = 9.9], education 16.4 years [SD = 2.7], 79% non-Hispanic White) were included. The effect of education on internet access via desktop, laptop computer, and tablet was greater in non-White participants than in non-Hispanic White participants. A similar pattern was observed for interest in using devices for study visits. DISCUSSION: Education may have a role in racial and ethnic differences in technological access and preferences.
Yu G, Thorpe A, Zeng Q
… +5 more, Wang E, Goate A, Cai D, Wang M, Zhang B
Alzheimers Dement
· 2026 May · PMID 42108391
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INTRODUCTION: Alzheimer's disease (AD) is the most common form of dementia, with approximately two-thirds of AD patients being female. Basic and clinical research studies provide strong evidence that sex-specific differe...INTRODUCTION: Alzheimer's disease (AD) is the most common form of dementia, with approximately two-thirds of AD patients being female. Basic and clinical research studies provide strong evidence that sex-specific differences contribute to AD complexity. Additionally, sex-specific interactions between apolipoprotein E (APOE) 𝜀4, the primary genetic risk factor of AD, and AD-associated neurodegenerative processes are well documented. However, there has been no comprehensive investigation into the interplay between sex and APOE genotypes at the single-cell level. METHODS: In this study, we systematically explore sex- and APOE-associated differences in single-cell transcriptomics in AD. RESULTS: Our work provides a high-resolution landscape of sex and APOE genotype-specific transcriptomic changes across 54 high-resolution cell types in AD and highlights genes and brain cell populations that show significant sex- and APOE-specific differences in AD. DISCUSSION: This study lays the groundwork for understanding the complex molecular mechanisms of AD and informs the development of targeted sex- and APOE-stratified interventions for AD.
Chao Y, Chen Y, Chadwick TA
… +7 more, Harrison TM, Iaccarino L, Heinsen H, Ushizima D, Tosun D, Jagust WJ, Grinberg LT
Alzheimers Dement
· 2026 May · PMID 42108381
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INTRODUCTION: Clinicopathological studies offer crucial interpretations of F-flortaucipir (FTP) tau positron emission tomography (PET) signal but are limited by methods. We leveraged whole-brain, quantitative immunohisto...INTRODUCTION: Clinicopathological studies offer crucial interpretations of F-flortaucipir (FTP) tau positron emission tomography (PET) signal but are limited by methods. We leveraged whole-brain, quantitative immunohistochemical (IHC) Alzheimer's Disease (AD) tau density maps to comprehensively evaluate the FTP tracer. METHODS: We generated IHC maps for three AD-tau antibodies-AT8, AT100, and MC1-using two human brains histologically staged at Braak IV and VI. FTP-PET scans were acquired 6 and 10 weeks prior to death. Using region-wise and voxelwise methods, we correlated FTP-PET with IHC signals. RESULTS: Only AT8 (p-tau Ser202/Thr205; neuronal and neuritic tau pathology) showed a notable correlation with FTP standardized uptake value ratios (SUVRs) in the Braak VI case (Spearman's rank correlation coefficient [r] = 0.461, p < 0.001). FTP SUVRs failed to capture medial temporal lobe (MTL) tau burden, whereas neocortical regions showed lower IHC burden but more variability in FTP uptake. DISCUSSION: Although FTP signals correlate well with AT8-positive tau in the more advanced case, they underestimate the severity of MTL burden, potentially confounding assessments of tau-targeted therapies.
Alzheimers Dement
· 2026 May · PMID 42092346
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INTRODUCTION: Although nearly two-thirds of all dementia cases occur in low- and middle-income countries, evidence on dementia-related mortality in these settings remains scarce. METHODS: We analyzed 5249 participants ag...INTRODUCTION: Although nearly two-thirds of all dementia cases occur in low- and middle-income countries, evidence on dementia-related mortality in these settings remains scarce. METHODS: We analyzed 5249 participants aged ≥60 years from the Brazilian Longitudinal Study of Aging (ELSI-Brazil). Dementia was defined using an algorithm or self-reported diagnosis. Mortality rates were estimated by dementia status, sex, and age. Among individuals with dementia (n = 392), multivariate Cox models assessed predictors of all-cause mortality. RESULTS: Mortality was higher in individuals with dementia even after adjusting for age and sex (hazard ratio: 2.65; 95% confidence interval: 2.08 to 3.39). Among people with dementia, male sex, higher education, poorer functional status, and lower cognitive performance increased mortality risk, while having a partner was protective. DISCUSSION: Dementia markedly increased mortality risk. Functional impairment, cognitive decline, social support, and schooling were key determinants of survival, emphasizing the importance of targeted, context-specific strategies to improve outcomes for people living with dementia.
Butler CA, Gee MS, O'Gara K
… +27 more, Milinkeviciute G, Da Cunha C, Kawauchi S, Lu YH, Kwang N, Tsourmas KI, Prekopa C, Shi Z, Liang HY, Collins SD, Pashkutz ZA, Sanchez JA, Shi KX, Walker AD, Wang S, Wong MLA, Genaro K, Neumann J, Gomez-Arboledas A, Duong DM, Seyfried NT, Tenner AJ, LaFerla FM, Mortazavi A, Swarup V, MacGregor GR, Green KN
Alzheimers Dement
· 2026 May · PMID 42092345
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BACKGROUND: Genetic variants affecting microglial function can influence Alzheimer's disease (AD) risk, yet the underlying mechanisms remain unclear. The AD-associated ABI3 (Abi3 in mouse) variant regulates cytoskeletal...BACKGROUND: Genetic variants affecting microglial function can influence Alzheimer's disease (AD) risk, yet the underlying mechanisms remain unclear. The AD-associated ABI3 (Abi3 in mouse) variant regulates cytoskeletal dynamics, but its in vivo impact on pathology is unknown. METHODS: An Abi3 mouse was developed and crossed with two humanized amyloid beta (Aβ) models. Amyloid pathology, microglial survival, and remodeling were analyzed using confocal imaging, biochemical assays, spatial transcriptomics, and single-cell analyses across the lifespan. RESULTS: Abi3 produced a dysfunctional microglial state that reduced dense-core plaque compaction, selectively lowering dense-core burden without affecting diffuse or total Aβ. The variant also caused microglial loss via apoptosis and pyroptosis, requiring aging and human Aβ but occurring even without plaques, indicating plaque-independent vulnerability. Spatial transcriptomics revealed an age-dependent shift toward an Abi3-high state that predisposes microglia to degeneration. DISCUSSION: Abi3 produces microglial dysfunction and vulnerability, highlighting cytoskeletal and cell death pathways as therapeutic targets.