Alzheimer''s and Dementia: Diagnosis, Assessment and Disease Monitoring最新文献

{"title":"Associations of mild behavioral impairment and white matter hyperintensity patterns.","authors":"Zdenek Linha, Rafael Dolezal, Matej Seifert, Tejasvi Ravi, Zahinoor Ismail, Pavla Brennan Kearns","doi":"10.1002/dad2.70500","DOIUrl":"10.1002/dad2.70500","url":null,"abstract":"<p><strong>Introduction: </strong>It is unclear whether cerebrovascular and white matter changes contribute to mild behavioral impairment (MBI). White matter hyperintensities (WMHs) represent a prominent pathology for research due to association with cognitive decline. We investigated associations between MBI measures and WMH volume and spatial distribution.</p><p><strong>Methods: </strong>We analyzed 1273 individuals with normal cognition or mild cognitive impairment. General linear models and voxel-wise analyses were employed to examine WMHs in terms of volume and spatial distribution.</p><p><strong>Results: </strong>Greater WMH volume was associated with higher MBI total score and MBI status in participants with normal cognition and mild cognitive impairment. Voxel-wise analysis revealed a significant cluster in the left inferior longitudinal fasciculus associated with higher MBI total score.</p><p><strong>Discussion: </strong>Our findings suggest a contribution of WMH volume and spatial distribution to persistent later-life behavioral symptoms. WMHs, especially in the left inferior longitudinal fasciculus, may serve as a neuroimaging marker of behavioral symptoms.</p>","PeriodicalId":53226,"journal":{"name":"Alzheimer''s and Dementia: Diagnosis, Assessment and Disease Monitoring","volume":"18 4","pages":"e70500"},"PeriodicalIF":4.4,"publicationDate":"2026-10-17","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13675841/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149217352","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Development and validation of predictive models for undiagnosed Alzheimer's disease and related dementias in the emergency department.","authors":"Natalia Festa, Kelsey Alexovitz, Natalia Sifnugel, Inessa Cohen, Siddarth Khasnavis, Juan Young, Mark Iscoe, Adam P Mecca, Ling Han, Ula Hwang","doi":"10.1002/dad2.70512","DOIUrl":"10.1002/dad2.70512","url":null,"abstract":"<p><strong>Introduction: </strong>The electronic health record (EHR) offers a promising resource to improve recognition of Alzheimer's disease and related dementias (ADRD), yet existing approaches have been developed within cohorts that underrepresent individuals prone to underdiagnosis and do not differentiate disease severity.</p><p><strong>Methods: </strong>We applied a validated computational phenotype to identify probable ADRD (p-ADRD) and its severity within a random sample of 5000 individuals aged ≥65 years who presented to one of nine emergency departments in the Yale New Haven Health System (2014 to 2022). The dichotomous outcome was undiagnosed ADRD, assigned to those meeting criteria for p-ADRD but lacking validated diagnostic codes. We applied logistic regression with elastic net regularization to predict undiagnosed status for the overall cohort and within each severity stratum, assessing performance using 10-fold cross-validation.</p><p><strong>Results: </strong>Of 1358 individuals with p-ADRD (mean age 86.7 years, standard deviation 7.4), 934 (68.8%) were undiagnosed. The overall model discriminated undiagnosed ADRD with an area under the receiver operating characteristic curve (AUROC) of 0.85 (95% confidence interval [CI] 0.83 to 0.87). The severity-stratified models achieved AUROC of 0.80 (95% CI 0.77 to 0.83) for mild and 0.91 (95% CI 0.88 to 0.94) for moderate to severe disease. Although the predictors of undiagnosed status differed by severity, fall-related injury was protective against underdiagnosis within each stratum.</p><p><strong>Discussion: </strong>We developed and validated predictive models using structured EHR elements, which demonstrated robust discrimination of undiagnosed ADRD within a clinical cohort prone to underdiagnosis. The heterogeneous predictors across severity strata underscore the importance of aligning prediction with disease severity, given the distinct clinical needs that attend ADRD progression.</p>","PeriodicalId":53226,"journal":{"name":"Alzheimer''s and Dementia: Diagnosis, Assessment and Disease Monitoring","volume":"18 4","pages":"e70512"},"PeriodicalIF":4.4,"publicationDate":"2026-10-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13673010/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149217331","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Lifestyle, <i>APOE</i> ε4, amyloid burden, and race/ethnicity differences in cognition, mood, and anxiety among cognitively unimpaired older adults.","authors":"Shiwen Li, Yu Yu, Vanessa Cunanan, Kamal Masaki, G Webster Ross","doi":"10.1002/dad2.70494","DOIUrl":"https://doi.org/10.1002/dad2.70494","url":null,"abstract":"<p><strong>Introduction: </strong>We assessed whether lifestyle, race/ethnicity, and apolipoprotein E gene (<i>APOE</i>) ε4 were associated with cognition or mood/anxiety.</p><p><strong>Methods: </strong>This secondary cohort analysis used data from the Anti-Amyloid Treatment in Asymptomatic Alzheimer's Disease (A4) Study and the Longitudinal Evaluation of Amyloid Risk and Neurodegeneration (LEARN) cohort. Cognitively unimpaired adults aged 65 to 85 years (<i>n</i> = 1705) reported baseline lifestyle behaviors (summed as healthy lifestyle index [HLI]). <i>APOE</i> ε4 carrier status and amyloid positron emission tomography were assessed at baseline, while cognitive, anxiety, and depressive outcomes were assessed longitudinally. Associations were tested using mixed-effects models.</p><p><strong>Results: </strong>Among Non-Hispanic White participants, higher HLI was associated with fewer depressive symptoms, sufficient sleep was associated with smaller ε4-related increases in anxiety, and excessive alcohol use amplified ε4-related cognitive decline. Among participants from other racial/ethnic groups, walking and higher HLI were associated with more favorable anxiety/depression trajectories.</p><p><strong>Discussion: </strong>Adequate sleep, limited alcohol, walking, and no smoking may support emotional and cognitive health.</p>","PeriodicalId":53226,"journal":{"name":"Alzheimer''s and Dementia: Diagnosis, Assessment and Disease Monitoring","volume":"18 4","pages":"e70494"},"PeriodicalIF":4.4,"publicationDate":"2026-10-14","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13662955/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149197256","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Early anhedonia distinguishes behavioral variant frontotemporal dementia from Alzheimer's disease.","authors":"Siobhán Shaw, Samuel L Warren, Claris Teng, Jody Huynh, Rebekah Ahmed, Olivier Piguet, Alexis E Whitton, Muireann Irish","doi":"10.1002/dad2.70501","DOIUrl":"https://doi.org/10.1002/dad2.70501","url":null,"abstract":"<p><strong>Introduction: </strong>Differentiating behavioral variant frontotemporal dementia (bvFTD) from Alzheimer's disease (AD) remains challenging due to overlapping early behavioral and cognitive features. Anhedonia has emerged as a promising clinical marker, yet its multidimensional nature and temporal emergence across dementia syndromes remain unclear.</p><p><strong>Methods: </strong>Anticipatory and consummatory components of anhedonia were assessed in bvFTD and AD using the Temporal Experience of Pleasure Scale. Event-based modeling was applied in each group to stage the probabilistic emergence of anticipatory and consummatory anhedonia dimensions relative to apathy and cognitive symptoms.</p><p><strong>Results: </strong>Relative to controls, bvFTD showed marked loss of pleasure across anticipatory and consummatory components, whereas AD showed selective anticipatory anhedonia in the context of preserved consummatory pleasure. Event-based modeling placed consummatory and anticipatory anhedonia dimensions as early features of bvFTD occurring prior to overt cognitive changes. In contrast, for AD, anhedonia was probabilistically more likely to arise at later stages of the disease sequence, subsequent to cognitive decline.</p><p><strong>Discussion: </strong>These findings highlight consummatory anhedonia as an early, clinically informative marker of bvFTD and support the value of multidimensional hedonic assessment for improving dementia differentiation.</p>","PeriodicalId":53226,"journal":{"name":"Alzheimer''s and Dementia: Diagnosis, Assessment and Disease Monitoring","volume":"18 4","pages":"e70501"},"PeriodicalIF":4.4,"publicationDate":"2026-10-09","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13650516/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149168320","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Residualized occipital amyloid burden and plasma biomarker profiles in relation to ARIA-E during anti-amyloid treatment.","authors":"Federica Agosta, Giordano Cecchetti, Alma Ghirelli, Edoardo G Spinelli, Giulia Rugarli, Stefano Pisano, Federico Coraglia, Ana Maria Samanes Gajate, Paolo Vezzulli, Sonia Calloni, Elisa Canu, Veronica Castelnovo, Anna Gilioli, Chiara Tripodi, Fabiola Freri, Alessandra Bianchi, Andrea Panzacchi, Gino Pepe, Andrea Falini, Arturo Chiti, Massimo Filippi","doi":"10.1002/dad2.70401","DOIUrl":"https://doi.org/10.1002/dad2.70401","url":null,"abstract":"<p><strong>Introduction: </strong>Amyloid-related imaging abnormalities with edema (ARIA-E) represent the main safety concern of anti-amyloid monoclonal antibodies. Whether regional amyloid topology refines ARIA-E risk in real-world practice remains unclear.</p><p><strong>Methods: </strong>We analyzed 31 treatment courses in early Alzheimer's disease under European Medicines Agency labeling. Residualized occipital amyloid burden was defined as observed occipital standardized uptake value ratio (SUVR) minus occipital SUVR predicted from global composite SUVR in an expanded baseline positron emission tomography derivation sample (<i>n</i> = 53). Associations with ARIA-E and baseline plasma biomarkers were assessed.</p><p><strong>Results: </strong>ARIA-E occurred only in the elevated occipital amyloid group: 4/13 treatment courses, versus 0/18 low or comparable courses (Fisher exact <i>p</i> = 0.055). All ARIA-E events involved posterior regions. The elevated pattern showed higher baseline glial fibrillary acidic protein (GFAP), phosphorylated tau (p-tau)181, and p-tau217 levels, whereas amyloid beta 42/40 did not differ between groups. A GFAP + p-tau217 model showed exploratory discrimination of the elevated phenotype (area under the curve: 0.76).</p><p><strong>Discussion: </strong>Disproportionate occipital amyloid burden may identify a biologically vulnerable subgroup requiring validation in larger cohorts.</p>","PeriodicalId":53226,"journal":{"name":"Alzheimer''s and Dementia: Diagnosis, Assessment and Disease Monitoring","volume":"18 4","pages":"e70401"},"PeriodicalIF":4.4,"publicationDate":"2026-10-09","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13650514/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149167891","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"The Advanced Therapeutics for Alzheimer's Disease Review Board: A multidisciplinary model to facilitate safe access to amyloid-targeting therapies in general neurology across the Sutter Health system.","authors":"Armen J Moughamian, Lisamarie La Vallee, Shawn Kile, Travis Urban, Austin Momii, Michelle Manifield, Jean Minton","doi":"10.1002/dad2.70479","DOIUrl":"https://doi.org/10.1002/dad2.70479","url":null,"abstract":"<p><p>Amyloid-targeting therapies (ATTs) require workup and monitoring that some general neurologists are uncomfortable with. Sutter Health treats over 3.5 million patients with more than 100 neurologists, but only 5 cognitive specialists. We developed the Advanced Therapeutics for Alzheimer's Disease (ATAD) Review Board, a system-wide model to address the shortage of specialists while enhancing safe access to ATTs across the health system. The ATAD Review Board comprises cognitive specialists, a neuroradiologist, a pharmacist, and a registered nurse program manager. Neurologists submit cases to the board for appropriate patient selection and re-review of cases with side effects. We reviewed 447 cases from 51 neurologists and 77% were eligible for treatment. The annual volume increased 148% in 2025. Total amyloid-related imaging abnormality rate was 17.4% for lecanemab and 28.8% for donanemab. We describe a system-wide review board model that supported ATT prescribing by general neurologists and expanded safe access to ATTs across a large integrated health system.</p>","PeriodicalId":53226,"journal":{"name":"Alzheimer''s and Dementia: Diagnosis, Assessment and Disease Monitoring","volume":"18 4","pages":"e70479"},"PeriodicalIF":4.4,"publicationDate":"2026-10-09","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13651009/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149170226","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Regional amyloid-PET clearance dynamics and anti-Aβ monoclonal antibody therapy: a preliminary real-world study.","authors":"Alma Ghirelli, Giordano Cecchetti, Edoardo G Spinelli, Ana Maria Samanes Gajate, Giulia Rugarli, Stefano Pisano, Isabella Aurora Lucilla Zamboni, Elisa Canu, Veronica Castelnovo, Elisa Sibilla, Anna Gilioli, Chiara Tripodi, Fabiola Freri, Andrea Panzacchi, Gino Pepe, Arturo Chiti, Massimo Filippi, Federica Agosta","doi":"10.1002/dad2.70448","DOIUrl":"https://doi.org/10.1002/dad2.70448","url":null,"abstract":"<p><strong>Introduction: </strong>Amyloid positron emission tomography (PET) is the reference biomarker for treatment target engagement in anti-amyloid beta (Aβ) therapies in early symptomatic Alzheimer's disease (AD), yet global metrics may mask a regional heterogeneity of amyloid clearance.</p><p><strong>Methods: </strong>We report real-world longitudinal amyloid-PET data from 26 patients treated with lecanemab or donanemab for 6 months. Global Centiloids and regional standardized uptake value ratios (SUVRs) were quantified at baseline and 6 months and examined according to treatment, clinical diagnosis, and clinical stage.</p><p><strong>Results: </strong>Amyloid removal was regionally heterogeneous. Patients with mild cognitive impairment showed greater cortical amyloid reduction than those with mild dementia, while early- and late-onset AD exhibited comparable clearance. Frontal, anterior cingulate, and parietal regions showed the largest SUVR reductions, whereas the occipital cortex and temporal mesial cortex were consistently spared, including in patients reaching global amyloid-PET negativity.</p><p><strong>Discussion: </strong>Early amyloid clearance following anti-amyloid treatment is regionally heterogeneous and incompletely captured by global PET measures.</p>","PeriodicalId":53226,"journal":{"name":"Alzheimer''s and Dementia: Diagnosis, Assessment and Disease Monitoring","volume":"18 4","pages":"e70448"},"PeriodicalIF":4.4,"publicationDate":"2026-10-09","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13650510/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149170427","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Dementia knowledge and attitude in rural Kenya: Associations with sociodemographic, religious, and experiential factors.","authors":"Christine Musyimi, David Ndetei, Pascalyne Nyamai, Victoria Mutiso, Nicolas Farina","doi":"10.1002/dad2.70504","DOIUrl":"https://doi.org/10.1002/dad2.70504","url":null,"abstract":"<p><strong>Introduction: </strong>Misconceptions about dementia are widespread internationally, leading to stigmatizing attitudes and discrimination. This study aimed to understand how sociodemographic, religious, and experiential factors are associated with dementia knowledge and attitudes in rural Kenya.</p><p><strong>Methods: </strong>A cross-sectional survey was conducted among the general public in Makueni County, Kenya. Regression models examined associations between sociodemographic, religious, and experiential variables with dementia knowledge and attitudes. An attitude target for dementia was calculated to estimate knowledge level required to improve attitudes.</p><p><strong>Results: </strong>A total of 630 participants were recruited. Dementia experiences were associated with better dementia knowledge (ΔR² = 0.10, <i>p</i> < 0.001) and attitudes (ΔR²= 0.06, p < 0.001), although sociodemographics accounted for the greatest variance. Religious factors had small but significant variance in the models (ΔR² ≤ 0.03), with visiting a spiritual healer being associated with poorer dementia knowledge (<i>B</i> = -1.47, 95% confidence interval [CI] -2.53 to -0.42). Regression models revealed that a target knowledge score of 49.5/50 on the Dementia Knowledge Assessment Scale (DKAS) would be required to statistically achieve the aspirational threshold of 102 on the Dementia Attitude Scale (DAS) in this sample.</p><p><strong>Conclusions: </strong>Geographic disparities and cultural factors influence dementia-related stigma. Having past experiences of dementia is key to improving attitudes.</p>","PeriodicalId":53226,"journal":{"name":"Alzheimer''s and Dementia: Diagnosis, Assessment and Disease Monitoring","volume":"18 4","pages":"e70504"},"PeriodicalIF":4.4,"publicationDate":"2026-10-09","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13650597/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149171281","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Social determinants of health modify the association of Alzheimer's disease pathology with cognitive abilities but not of apolipoprotein E-<i>ε</i>4 with Alzheimer's disease pathology.","authors":"Naomi V Ferreira, Laiss Bertola, Regina S Paradela, Aline M Ciciliati, Caroline M Silva, Lea T Grinberg, Carlos A Pasqualucci, Vitor R Paes, Eduardo Ferriolli, Michel Naslavsky, Renata P Leite, Claudia K Suemoto","doi":"10.1002/dad2.70462","DOIUrl":"https://doi.org/10.1002/dad2.70462","url":null,"abstract":"<p><strong>Introduction: </strong>Apolipoprotein E (APOE) -<i>ε</i>4 and social determinants of health (SDoH) are major Alzheimer's disease (AD) risk factors, yet whether SDoH modify the relationship between APOE-<i>ε</i>4, AD pathology, and cognition remains unclear.</p><p><strong>Methods: </strong>Using Biobank for Aging Studies (BAS) data, we assessed APOE-<i>ε</i>4 using polymerase chain reaction (PCR), AD pathology using immunohistochemistry, and cognitive abilities using Clinical Dementia Rating - Sum of Boxes (CDR-SB).</p><p><strong>Results: </strong>In 1,193 individuals (mean [SD] age 73.4 [13.0] years; 50.1% women; 65.4% White), APOE-<i>ε</i>4 carriers had higher odds of AD pathology (odds ratio [OR]: 3.95, 95% confidence interval [CI]: 2.85; 5.51; <i>p</i> < 0.001), and AD pathology was associated with poorer cognition (<i>β</i> = 8.07, 95% CI: 7.47; 8.67; <i>p</i> < 0.001). SDoH modified this pathology-cognition association (<i>p</i> = 0·002), which was stronger in the unfavorable (<i>β</i> = 9.09, 95% CI: 8.00; 10.19, <i>p</i> < 0.001) versus the favorable SDoH profile (<i>β</i> = 6.39, 95% CI: 5.42; 7.37; <i>p</i> < 0.001). SDoH did not modify the APOE-<i>ε</i>4-pathology association (<i>p</i> = 0.806), and no race effect modification was observed.</p><p><strong>Discussion: </strong>AD pathology was more strongly associated with poorer cognition in unfavorable SDoH profiles, highlighting SDoH as targets for AD prevention.</p>","PeriodicalId":53226,"journal":{"name":"Alzheimer''s and Dementia: Diagnosis, Assessment and Disease Monitoring","volume":"18 4","pages":"e70462"},"PeriodicalIF":4.4,"publicationDate":"2026-10-09","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13650497/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149169182","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Depression severity and sleep efficiency's associations with amyloid burden are additive but dependent on underlying genetic risk in late life depression.","authors":"Anita Shankar, Maria Kryza-Lacombe, Philip S Insel, Edith Harris, Michelle T Kassel, Lizabeth Goldstein, Andrew D Krystal, Susan M Landau, Duygu Tosun, Meryl A Butters, Paul Aisen, Rema Raman, Arthur W Toga, Clifford R Jack, J Craig Nelson, R Scott Mackin","doi":"10.1002/dad2.70478","DOIUrl":"https://doi.org/10.1002/dad2.70478","url":null,"abstract":"<p><strong>Introduction: </strong>Evidence linking late-life depression (LLD) to amyloid beta (Aβ) burden remains mixed, possibly in part due to limited examinations of the confounding role of comorbid sleep disturbance and the moderating role of the apolipoprotein E (<i>APOE</i>) ɛ4 gene.</p><p><strong>Methods: </strong>We analyzed 110 older adults (ages 65-88, 66% female) with LLD to jointly model depression severity and sleep disturbance's relationship with Aβ, and to examine the moderating role of <i>APOE</i> ɛ4 genotype.</p><p><strong>Results: </strong>Depression severity, sleep efficiency, and sleep duration did not demonstrate a direct relationship with Aβ; however, a significant <i>APOE</i> ɛ4 moderation effect occurred for depression severity and sleep efficiency. In <i>APOE</i> ɛ4 carriers only, higher depression severity and lower sleep efficiency were associated with greater total Aβ burden and indicated greater likelihood of reaching clinical cutoffs for amyloid positivity. The effects of depressive symptoms and sleep efficiency were statistically unique and additive. Exploratory analyses demonstrated <i>APOE</i> ɛ4 also moderated the effect of lifetime duration of untreated depression on increased Aβ.</p><p><strong>Discussion: </strong>Depression severity and sleep efficiency's relationship with Aβ may be dependent on the presence of the <i>APOE</i> ɛ4 allele. This, among other individual differences, may partially explain mixed findings examining LLD as a risk factor for Alzheimer's disease. Furthermore, these findings do not suggest that the relationship between depression severity and amyloid is explained by the confounding role of sleep duration or sleep efficiency.</p>","PeriodicalId":53226,"journal":{"name":"Alzheimer''s and Dementia: Diagnosis, Assessment and Disease Monitoring","volume":"18 4","pages":"e70478"},"PeriodicalIF":4.4,"publicationDate":"2026-10-09","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13650511/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149166791","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}