@article {pmid41444689,
year = {2025},
author = {Vanderlip, CR},
title = {Clinical Manifestations.},
journal = {Alzheimer's & dementia : the journal of the Alzheimer's Association},
volume = {21 Suppl 3},
number = {},
pages = {e098712},
doi = {10.1002/alz70857_098712},
pmid = {41444689},
issn = {1552-5279},
abstract = {BACKGROUND: Apolipoprotein E4 (APOE4) is the strongest genetic risk factor for sporadic Alzheimer's disease (AD) and is linked to earlier and more extensive amyloid-beta (Aβ) deposition. Nearly all individuals homozygous for APOE4 show elevated Aβ levels by age 80, and these individuals often experience more pronounced episodic memory deficits compared to non-carriers. Here, we investigated whether cognitive trajectories differ by APOE status and explored whether the heightened cognitive decline in APOE4 carriers stems from increased Aβ deposition or greater sensitivity to Aβ-related effects.

METHOD: Using data from the Alzheimer's Disease Research Initiative, we modeled amyloid duration (i.e., the estimated number of years an individual has been Aβ+) and examined its impact on cognitive trajectories across a range of neuropsychological assessments. These assessments measured episodic memory, processing speed, executive function, visuospatial skills, language, and crystallized intelligence.

RESULT: Our findings demonstrate that APOE4 is associated with a more rapid decline in episodic memory as a function of amyloid duration, with APOE4 homozygotes showing faster declines than heterozygotes. This decline began almost immediately after Aβ positivity was reached and was more pronounced compared to non-carriers. Notably, this pattern was specific to episodic memory and was not observed in the other cognitive domains assessed.

CONCLUSION: These findings indicate that cognitive trajectories in AD vary by APOE genotype. Future studies should explore whether these differences reflect distinct pathological mechanisms in APOE4 carriers.},
}

@article {pmid41444683,
year = {2025},
author = {Weissmann, C and Castellanos, LCS and Montes, MM and Uruk, G and Youssef, H and Reichard, RR and Gatto, RG and Josephs, KA},
title = {4R-tau isoform induction via TDP-43 in neurons in response to insulin: converging signaling pathways with implications for neurodegenerative disease.},
journal = {Acta neuropathologica communications},
volume = {13},
number = {1},
pages = {258},
pmid = {41444683},
issn = {2051-5960},
support = {PIP Grant No. 11220210100589CO//Consejo Nacional de Investigaciones Científicas y Técnicas/ ; PICT 2020-01211//Agencia Nacional de Promoción de la Investigación, el Desarrollo Tecnológico y la Innovación/ ; UBACYT (Grant No. 20020220400291BA)//Universidad de Buenos Aires/ ; R01-AG37491//National Institute for Health Care Management Foundation/ ; },
abstract = {Tau protein isoforms, regulated during development, are influenced by the nuclear factor TDP-43, which plays a crucial role in tau mRNA stability and exon 10 inclusion. Both tau and TDP-43 are prone to pathological phosphorylation and aggregation, with specific phosphorylated forms of TDP-43 linked to cytoplasmic mislocalization and alterations in the 3R/4R tau ratio as detected in different pathologies. In this study, we show that insulin treatment of embryonic mouse primary cortical neurons-cells that normally express only 3R-tau-induces the expression of 4R-tau, suggesting that metabolic signaling can influence tau isoform expression in a developmentally immature neuronal context. In addition, experiments in HEK293 cells revealed isoform-specific stabilization effects and showed that insulin promotes TDP-43 redistribution to the cytoplasm along with a phosphorylation pattern. These results underscore the complex interplay between TDP-43 and tau isoforms and metabolic signaling pathways that play a crucial role in their expression and localization with potential implications for understanding mechanisms of neurodegenerative disease onset and progression.},
}

@article {pmid41444650,
year = {2025},
author = {Ringman, JM},
title = {Clinical Manifestations.},
journal = {Alzheimer's & dementia : the journal of the Alzheimer's Association},
volume = {21 Suppl 3},
number = {},
pages = {e098880},
doi = {10.1002/alz70857_098880},
pmid = {41444650},
issn = {1552-5279},
mesh = {Humans ; *Presenilin-1/genetics ; *Alzheimer Disease/genetics/pathology/physiopathology ; *Mutation/genetics ; },
abstract = {BACKGROUND: Autosomal dominant Alzheimer's disease (ADAD) is a rare subtype of AD in which the disease is caused by mutations in the PSEN1, APP, or PSEN2 genes which are essentially fully penetrant. Mutations in PSEN1 are most common and several populations have been described within which the same causative variant appears to have arisen from a common founder. The study of such populations allows for an increased sensitivity for identification of genetic and non-genetic variables affecting phenotype and for studying the effects of interventions.

METHOD: Review of the literature on the A431E PSEN1 mutation.

RESULT: Over the last 20 years collaborators in the U.S and Mexico have seen over 100 superficially distinct families with the common A431E substitution in PSEN1, apparently arising as a founder effect concentrated in the Los Altos region of Jalisco State. With a mean age of onset of 41 years, approximately 40% of affected persons feature significant leg stiffness (spastic paraparesis) as an early symptom. Cognitive features can be that of a typical onset of episodic memory problems though disproportionate language problems or a dysexecutive syndrome can occur. Preliminary data show that this mutation is associated with severe cerebral amyloid angiopathy (CAA) and atypical "cotton wool" amyloid plaques on pathology. Flortaucipir PET scans shows atypical involvement of primary motor and parieto-occipital cortex and diffusion MRI shows widespread abnormalities in white matter ultrastructure.

CONCLUSION: As the number of persons at-risk for inheriting it has been estimated at 1,260, the A431E mutation in PSEN1 is an attractive target for both mutation-specific genetic interventions and for anti-AD therapy in general. Supported by P30AG066530, U01AG051218, R01AG062007, R01AG069013.},
}

Humans
*Presenilin-1/genetics
*Alzheimer Disease/genetics/pathology/physiopathology
*Mutation/genetics

@article {pmid41444475,
year = {2025},
author = {Bradley, J and Western, D and Wang, C and da Fonseca, EL and Neupane, A and Kurup, JT and Ray, NR and Jean-Francois, M and Bergmann, K and Budde, JP and Martin, ER and Pericak-Vance, M and Cuccaro, ML and Naj, AC and Kunkle, BW and , and , and Schellenberg, GD and Fernández, V and Haines, JL and Morris, JC and Holtzman, DM and Perrin, RJ and Cruchaga, C and Reitz, C and Beecham, GW},
title = {Basic Science and Pathogenesis.},
journal = {Alzheimer's & dementia : the journal of the Alzheimer's Association},
volume = {21 Suppl 1},
number = {},
pages = {e107379},
doi = {10.1002/alz70855_107379},
pmid = {41444475},
issn = {1552-5279},
mesh = {Humans ; Genome-Wide Association Study ; *Alzheimer Disease/genetics ; Quantitative Trait Loci/genetics ; *Genetic Predisposition to Disease/genetics ; Aged ; Male ; Female ; Polymorphism, Single Nucleotide ; White People/genetics ; },
abstract = {BACKGROUND: Alzheimer Disease (AD) is a highly polygenic dementia that presents with relatively earlier onset (≤65yo; EOAD) in about 5% of cases. Around 90% of these EOAD cases remain unexplained by pathogenic mutations.

METHOD: We used data from EOAD cases ≤ 70 and controls > 70 to ensure they would not develop AD. genome-wide association study (GWAS) and trans-ancestry meta-analysis were performed for non-Hispanic European (EUR, NCase=6,282, NControl=13,386), African (AFR NCase=782, NControl=3,663) and East Asian (ASN: NCase=375, NControl=838 CO) ancestries. We performed QTL mapping and in-silico annotation to identify the functional gene for each genome-wide loci, and PRS and LDSC to compare the genetic architecture of EOAD vs LOAD RESULT: We identified a total of 15 genome-wide significant loci, 7 already reported to be associated with LOAD and 8 novel loci. Of the novel loci: six were found in the ancestry-specific analyses and two in the trans-ancestry analysis. By integrating gene-based analysis, eQTL, pQTL and functional annotations, we nominate four novel functional genes (CDH12, FOLH1, ALG10B and LRRC25) for four loci that are involved in microglia activation, glutamate production, and signaling pathways. LOAD-derived PRS showed a strong association with EOAD (R[2]=0.170, p <10[-300], and R[2]=0.048, p = 1.20×10[-143]: for PRS with and without APOE). LDSC found strong overall genetic covariance between EOAD and LOAD (rg=0.791, p = 6.80×10[-12]) CONCLUSION: These results indicate that EOAD, although sharing many genes with LOAD, harbors unique genes and pathways that could be used to create better prediction models or target identification for this type of AD.},
}

Humans
Genome-Wide Association Study
*Alzheimer Disease/genetics
Quantitative Trait Loci/genetics
*Genetic Predisposition to Disease/genetics
Aged
Male
Female
Polymorphism, Single Nucleotide
White People/genetics

@article {pmid41444466,
year = {2025},
author = {Dubbelman, MA and Ma, G and Amariglio, RE and Munro, CE and Udeogu, O and Yu, M and Aibel, CR and Marshall, GA and Gatchel, JR},
title = {Clinical Manifestations.},
journal = {Alzheimer's & dementia : the journal of the Alzheimer's Association},
volume = {21 Suppl 3},
number = {},
pages = {e104488},
doi = {10.1002/alz70857_104488},
pmid = {41444466},
issn = {1552-5279},
mesh = {Humans ; Female ; Male ; Aged ; *Activities of Daily Living/psychology ; Neuropsychological Tests ; *Cognitive Dysfunction/psychology ; Psychiatric Status Rating Scales ; Middle Aged ; Depression/psychology ; Aged, 80 and over ; Anxiety/psychology ; Apathy ; Independent Living ; },
abstract = {BACKGROUND: Neuropsychiatric symptoms (NPS) in late-life (e.g., changes in mood, motivation, sleep, and perception) may precede changes in cognition and indicate an underlying neurodegenerative process in the absence of noticeable cognitive decline. Changes in an older adult's ability to perform instrumental activities of daily living (IADLs; e.g., managing medications/finances, shopping and preparing meals) are often the first observable sign of cognitive impairment and may be affected by NPS. In this study, we examine associations between NPS and daily functioning reported by cognitively unimpaired older adults and their study-partners, focusing on both overall symptoms and affective symptoms (e.g., depression, anxiety) typically seen in preclinical and prodromal stages. We hypothesize that increased self- and study-partner-reported NPS will be associated with worse daily functioning.

METHOD: The sample included 177 community-dwelling older adults without cognitive impairment or history of major psychiatric disorders (mean age 70.5±6.1 years; 63% female). All participants completed assessments of NPS (Mild Behavioral Impairment Checklist (MBI-C), Apathy Evaluation Scale (AES), Geriatric Depression Scale (GDS), Geriatric Anxiety Index (GAI), and Snaith Hamilton Pleasure Scale (SHAPS)) and a measure of daily functioning (Alzheimer's Disease Cooperative Study ADL-Prevention Instrument (ADCS ADL-PI)). Study-partners also completed the MBI-C, AES, and ADCS ADL-PI. We examined cross-sectional relationships between participant and study-partner-reported functional and NPS assessments using separate linear regression models adjusted for age, sex, and education (in years).

RESULT: Self-reported MBI-C, GDS, GAI, and self- and study-partner-reported AES, were found to have significant relationships with self-reported ADCS ADL-PI (Table 1). Additionally, study-partner-reported ADCS ADL-PI scores were associated with the SHAPS, MBI-C (self- and study-partner-reported), AES (study-partner-reported only), GDS, and GAI, such that worse IADL performance was correlated with greater NPS (Table 2).

CONCLUSION: In cognitively unimpaired older adults, greater overall NPS and greater affective symptoms, including depression, anxiety, anhedonia, and apathy, were associated with worse participant and study-partner-reported daily functioning performance. This relationship underscores the importance of recognizing and treating NPS for improving daily functioning and quality of life, even prior to the onset of overt cognitive impairment, and considering source of report and methods of IADL measurement when utilizing the latter as clinical trial outcome measures.},
}

Humans
Female
Male
Aged
*Activities of Daily Living/psychology
Neuropsychological Tests
*Cognitive Dysfunction/psychology
Psychiatric Status Rating Scales
Middle Aged
Depression/psychology
Aged, 80 and over
Anxiety/psychology
Apathy
Independent Living

@article {pmid41444465,
year = {2025},
author = {Stockleben, LM and Woll, B and Atkinson, J},
title = {Dementia Care Research and Psychosocial Factors.},
journal = {Alzheimer's & dementia : the journal of the Alzheimer's Association},
volume = {21 Suppl 4},
number = {},
pages = {e097147},
doi = {10.1002/alz70858_097147},
pmid = {41444465},
issn = {1552-5279},
mesh = {Humans ; *Dementia/diagnosis/psychology ; Aged ; Female ; Male ; Middle Aged ; *Sign Language ; Aged, 80 and over ; *Neuropsychological Tests ; Reproducibility of Results ; Germany ; },
abstract = {BACKGROUND: Existing neurocognitive and language assessments provide normative data only for hearing or hard-of-hearing people (Brünecke et al., 2018; Völter et al., 2023) with inaccurate diagnosis and inadequate care for sign language using communities. The British Sign Language Cognitive Screening Test (BSL-CST) (Atkinson et al., 2015) is a sign language-based, normed, validated and clinically applied cognitive screening tool designed to identify dementia in BSL users. Several projects are currently working on adaptations into other sign languages (Tsatali et al., 2023). This paper presents the German sign language (DGS) adaptation.

METHOD: A culturally and linguistically appropriate DGS version (the KoDGS) was produced through an extensive adaptation process. The KoDGS assesses orientation, attention, memory, language, semantic verbal fluency, visual-spatial abilities and perception as well as executive functions. It was administered to 99 deaf individuals (age: 50 - 96 yrs; M = 64.33), together with social and neurological histories. Convergent measures were applied to check for test validity.

RESULT: The KoDGS significantly differentiates between normative (n = 86) and neurological (n = 13) samples, with a threshold for clinical test application. Positive correlations between convergent measures indicate robust test validity.

CONCLUSION: This paper presents the first cognitive screening tool in DGS, with potential to improve neuropsychological screening of signers in Germany. The study makes a significant contribution to research on diagnosing dementia in underserved minority communities, outlining a process for cultural and linguistic adaptation of cognitive screening tools, applicable to other sign languages and deaf communities. References 1. Atkinson, J., et al. (2015). Detecting Cognitive Impairment and Dementia in Deaf People: The British Sign Language Cognitive Screening Test. Arch Clin Neuropsych, 30(7), 649-711 2. Brünecke, I., Hölsken, S. & Kessler, J. (2018). Der DemTect Eye+Ear - Neues kognitives Screeningverfahren bei schwerhörigen Menschen mit Demenzverdacht. Zeitschrift für Audiologie, 57(3), 121. 3. Tsatali, M., et al. (2023). A Cognitive Screening Test for detecting Alzheimer's Disease Dementia in Deaf older adults in Austria and Greece: the De-Sign Erasmus+ project. 33[rd] Alzheimer Europe Conference, Helsinki. 4. Völter, C., et al. (2023). Validation of the German Montreal-Cognitive-Assessment-H for hearing-impaired. Front Aging Neurosci, 15, https://doi.org/10.3389/fnagi.2023.1209385.},
}

Humans
*Dementia/diagnosis/psychology
Aged
Female
Male
Middle Aged
*Sign Language
Aged, 80 and over
*Neuropsychological Tests
Reproducibility of Results
Germany

@article {pmid41444461,
year = {2025},
author = {Duijkers, S and Ramakers, IHGB and Massloh, K and van Gils, V and van der Velden, J and Oomens, JE and Vos, SJB and Visser, PJ and Jansen, WJ and , },
title = {Biomarkers.},
journal = {Alzheimer's & dementia : the journal of the Alzheimer's Association},
volume = {21 Suppl 2},
number = {},
pages = {e099639},
doi = {10.1002/alz70856_099639},
pmid = {41444461},
issn = {1552-5279},
mesh = {Humans ; *Biomarkers/cerebrospinal fluid ; Male ; Female ; *tau Proteins/cerebrospinal fluid ; *Amyloid beta-Peptides/cerebrospinal fluid ; *Cognitive Dysfunction/cerebrospinal fluid/epidemiology ; Aged ; *Alzheimer Disease/cerebrospinal fluid/epidemiology ; *Diabetes Mellitus/cerebrospinal fluid/epidemiology ; Comorbidity ; *Hypercholesterolemia/epidemiology/cerebrospinal fluid ; *Hypertension/epidemiology/cerebrospinal fluid ; Aged, 80 and over ; *Peptide Fragments/cerebrospinal fluid ; },
abstract = {BACKGROUND: With an aging global population, incidence of Alzheimer's disease (AD) and age-related comorbid conditions are increasing. Hypertension (HT), diabetes mellitus (DM) and hypercholesterolemia (HCHOL) are related to dementia, it remains unclear if (a combination of) these are associated with AD pathology. Our current study investigates associations between combinations of HT, DM and HCHOL and amyloid-β-42 and p-tau pathology in cerebrospinal fluid.

METHOD: 2479 participants with normal cognition (NC) and 1618 participants with Mild Cognitive Impairment (MCI) from 41 studies with data on presence of HT, DM or HCHOL were included from the Amyloid Biomarker Study. Four AT-biomarker profiles were created, with normal or abnormal amyloid-β-42 (A) or phosphorylated tau (T) (using data-driven cut-offs). Participants were classified as having no, one, or two or more comorbidities. We compared frequencies of AT profiles across comorbidity groups and presence of separate comorbidities with independent samples t-tests.

RESULT: In the NC group, those with one or two or more comorbidities more often were A+T- (Table 1, p = 0.005 and p =  0.014), and less often A-T- (p = 0.002; p =  0.005), compared to no comorbidities. Presence of HT and HCHOL were related to higher frequency of A+T- (Table 2, p = 0.003; p =  0.014), only presence of HT was related to lower frequency A-T- (p = 0.001). In the MCI group, those with one or two or more comorbidities more often were A-T+ (p = 0.023; p =  0.005), those with one comorbidity were less frequently A-T- (p = 0.008, p =  0.011) and those with 2 or more comorbidities were less frequently A+T+ (p = 0.018; p = 0.002). Presence of HT and HCHOL were related to higher A-T+ (p = 0.01; p =  0.027), presence of HCHOL was related to lower A+T+ (p = 0.003).

CONCLUSION: In NC, presence of comorbidities is related to A+T-, while in MCI, comorbidities were associated to A-T+ and reversely to A+T+. HT and HCHOL but not DM were differentially related to AT profiles. The current results may have implications for diagnostics in memory clinics.},
}

Humans
*Biomarkers/cerebrospinal fluid
Male
Female
*tau Proteins/cerebrospinal fluid
*Amyloid beta-Peptides/cerebrospinal fluid
*Cognitive Dysfunction/cerebrospinal fluid/epidemiology
Aged
*Alzheimer Disease/cerebrospinal fluid/epidemiology
*Diabetes Mellitus/cerebrospinal fluid/epidemiology
Comorbidity
*Hypercholesterolemia/epidemiology/cerebrospinal fluid
*Hypertension/epidemiology/cerebrospinal fluid
Aged, 80 and over
*Peptide Fragments/cerebrospinal fluid

@article {pmid41444446,
year = {2025},
author = {Lipnicki, DM and Valentí, M and Valeriano-Lorenzo, E and Vella, AS and Zea-Sevilla, M and Ricciardi, M and Frades, B and Martinez, M and Wagner, S and Sachdev, PS and Del Ser, T and Sanchez-Juan, P},
title = {Clinical Manifestations.},
journal = {Alzheimer's & dementia : the journal of the Alzheimer's Association},
volume = {21 Suppl 3},
number = {},
pages = {e097922},
doi = {10.1002/alz70857_097922},
pmid = {41444446},
issn = {1552-5279},
mesh = {Humans ; Female ; Male ; Aged ; *tau Proteins/blood ; Apolipoprotein E4/genetics ; *Cognitive Dysfunction/genetics ; *Dreams/physiology/psychology ; Neuropsychological Tests ; Alzheimer Disease/genetics ; *Mental Recall/physiology ; Aged, 80 and over ; },
abstract = {BACKGROUND: Evidence suggests that dreaming is subserved by the default mode network (DMN) (Domhoff, 2022. The Neurocognitive Theory of Dreaming). β-amyloid plaques and phosphorylated tau (p-tau) protein tangles accumulate and contribute to abnormal functionality in the DMN long before clinical Alzheimer's disease, and similarly early abnormal DMN functionality is shown by apolipoprotein E (APOE) gene ε4 allele carriers. Given this, we reasoned that dream recall in cognitively normal older adults may be associated with blood p-tau levels, APOE ε4 carriage, and future cognitive decline.

METHOD: Data were for 1049 cognitively unimpaired individuals (mean age=74.7 years; 64% women) in the Spanish Vallecas Project. Dream recall was ascertained by asking "Do you remember your dreams?" (yes/no). Blood p-tau217 levels >0.247 pg/mL were considered high, and ≥1 ε4 alleles indicated APOE ε4 carriage. Cognition was assessed with a modified Preclinical Alzheimer Cognitive Composite (PACCm) annually over 10 years, with z-scores <-1 considered relatively low baseline cognition. Our analyses used general linear models, as well as a linear mixed-effect model to compare the longitudinal cognitive trajectories of dream recallers and non-recallers. Analyses were controlled for factors including sleep characteristics, medications, depression, and memory test scores.

RESULT: Thirty-one percent of participants did not remember dreams. Higher p-tau217 levels and APOE ε4 carriage were both associated with a lower likelihood of remembering dreams (OR=0.52, 95%CI=0.35-0.79, p = .002 and OR=0.61, 95%CI=0.43-0.86, p = .006, respectively), independently of memory test scores. Further, individuals who did not remember dreams at baseline showed faster decline in PACCm scores (βnon-DR=-0.03) over 10 years than dream recallers (βDR=-0.02; βAge*Dream Recall=0.011, SE=0.005, p = .036), despite dream recall status not being associated with relatively low cognition at baseline (OR=0.94, 95%CI=0-60-1.48, p = .788).

CONCLUSION: Dream recall status was associated with blood p-tau217 levels, APOE ε4 carriage, and future cognitive decline among older individuals cognitively healthy at baseline. Not remembering dreams in later life may be an early indicator of neurodegeneration in the DMN. This would help explain an unexpected and overlooked finding more than 30 years ago that lower dream recall frequency predicted incident dementia (Persson & Skoog, J Geriatr Psychiatry Neurol 1992;5:172-178), a decade before the DMN was discovered.},
}

Humans
Female
Male
Aged
*tau Proteins/blood
Apolipoprotein E4/genetics
*Cognitive Dysfunction/genetics
*Dreams/physiology/psychology
Neuropsychological Tests
Alzheimer Disease/genetics
*Mental Recall/physiology
Aged, 80 and over

@article {pmid41444444,
year = {2025},
author = {Chatterjee, P and Kalinowski, P and Roberts, AM and Roberts, BR and Tijms, BM and Teunissen, CE and Bush, AI and Ayton, S},
title = {Biomarkers.},
journal = {Alzheimer's & dementia : the journal of the Alzheimer's Association},
volume = {21 Suppl 2},
number = {},
pages = {e099406},
doi = {10.1002/alz70856_099406},
pmid = {41444444},
issn = {1552-5279},
mesh = {Humans ; *Biomarkers/cerebrospinal fluid ; *Alzheimer Disease/cerebrospinal fluid/diagnosis ; *tau Proteins/cerebrospinal fluid ; Male ; Female ; Amyloid beta-Peptides/cerebrospinal fluid ; *Amyloid beta-Protein Precursor/cerebrospinal fluid ; Aged ; Cohort Studies ; Aged, 80 and over ; Cognitive Dysfunction/cerebrospinal fluid ; Peptide Fragments/cerebrospinal fluid ; },
abstract = {BACKGROUND: The integration of biomarkers for amyloid-β (A+) and phosphorylated tau (T+) pathology has transformed Alzheimer's disease (AD) diagnosis from being solely based on clinical assessment to a more accurate, biologically-driven approach. However, this biomarker framework also exposes cases that deviate from the expected AD pattern, wherein 15-20% of clinically diagnosed AD cases exhibit atypical biomarker profiles (e.g. A+/T- dementia). This group presents a diagnostic challenge and here we investigate alternative pathophysiological mechanisms for their AD-like symptoms.

METHODS: CSF amyloid precursor protein (APP) was analysed across two cohorts: ADNI (N = 384) and ADC (N = 419).

RESULTS: Concentrations of CSF APP were significantly lower in T- compared to T+ individuals across all clinical diagnostic groups across cohorts, regardless of A± status (Figure 1). Concentrations of APP showed a positive correlation with those of CSF p-tau181 but were not associated with the Aβ42/Aβ40 ratio. APP reductions were most pronounced in T- cases clinically diagnosed with AD (AUC [95% CI]: 0.81 [0.70-0.92]). Lower CSF APP levels were associated with elevated NfL, worse Mini-Mental State Examination scores, and higher Clinical Dementia Rating-Sum of Boxes scores. In T+ individuals, APP was initially elevated in cognitively unimpaired participants but declined with disease progression, albeit from a higher baseline (Figure 2). Stratifying participants by low/high APP and p-tau revealed the highest frequency of clinical AD diagnoses in individuals with low APP and high p-tau. This group exhibited the most severe cognitive and functional impairments compared to those with high APP and/or low p-tau profiles (Figure 3).

CONCLUSIONS: Individuals with low APP levels (APP positive) or elevated p-tau181 (p-tau181 positive) had the highest prevalence of AD-like dementia, with the risk being greatest in those positive for both markers. These results reveal a unique biological profile for T- status in clinically diagnosed AD, who are a complex and under-explored patient group, and highlight opportunities for enhancing diagnostic refinement. Given that APP influences neuronal plasticity, memory, synaptogenesis, and maintenance of neuronal iron homeostasis, our findings suggest that disruptions in APP production and processing may contribute to disease progression.},
}

Humans
*Biomarkers/cerebrospinal fluid
*Alzheimer Disease/cerebrospinal fluid/diagnosis
*tau Proteins/cerebrospinal fluid
Male
Female
Amyloid beta-Peptides/cerebrospinal fluid
*Amyloid beta-Protein Precursor/cerebrospinal fluid
Aged
Cohort Studies
Aged, 80 and over
Cognitive Dysfunction/cerebrospinal fluid
Peptide Fragments/cerebrospinal fluid

@article {pmid41444408,
year = {2025},
author = {Sandau, US and Wiedrick, JT and McFarland, TJ and Chen, S and Quinn, JF and Saugstad, JA},
title = {Comparison of multi-miRNA models from donor-matched plasma and cerebrospinal fluid as candidate biomarkers for Alzheimer's disease prediction.},
journal = {Scientific reports},
volume = {},
number = {},
pages = {},
doi = {10.1038/s41598-025-33589-0},
pmid = {41444408},
issn = {2045-2322},
abstract = {We discovered and validated miRNA biomarkers for Alzheimer's disease (AD) in human cerebrospinal fluid (CSF). However, as more easily accessible biofluids are preferred for clinical assays, we compared the performance of the AD miRNAs in CSF to plasma to determine their potential use as AD biomarkers in this readily available biofluid. We obtained 320 donor- and date-matched normal control (NC) and AD CSF and plasma samples from the AD Neuroimaging Initiative, then analyzed 57 candidate AD miRNAs in both biofluids by RT-qPCR. For analysis, we divided the sample sets into 80% for discovery and 20% for validation. We then used predictive modeling of the 57 candidate AD miRNAs in the discovery phase to develop AD classifiers for each biofluid that showed similar performance in both CSF and plasma. However, in the validation phase AD classification performance was only maintained for the plasma models. When the plasma miRNA models were combined with clinical predictors (APOE genotype, age, sex, years of education) there was a boost in classification performance to a level comparable to the CSF proteins (Aβ42, t-tau, p-tau181) alone, which suggests that plasma miRNA assays combined with clinical information could serve as an alternative to more invasive CSF-based measurements. We also developed a parsimonious model based on two miRNAs that were top ranked and had increased (miR-23a-3p) and decreased (miR-423-5p) expression in AD. The ratio of these top two miRNAs classified AD with similar performance to all 57 miRNAs jointly and was sensitive to changes in cognitive score. These results support that an assay consisting of only two plasma miRNAs can classify AD from NC, and is informative about the disease stage reflected in cognitive scores.},
}

@article {pmid41444206,
year = {2025},
author = {Ortega, A},
title = {Clinical Manifestations.},
journal = {Alzheimer's & dementia : the journal of the Alzheimer's Association},
volume = {21 Suppl 3},
number = {},
pages = {e098431},
doi = {10.1002/alz70857_098431},
pmid = {41444206},
issn = {1552-5279},
mesh = {Humans ; *Alzheimer Disease/diagnosis ; *Neuropsychological Tests ; Semantics ; Early Diagnosis ; tau Proteins ; },
abstract = {BACKGROUND: Early detection of Alzheimer's disease (AD) and related dementias (ADRD) is critical as this is when emerging therapies are most effective. Traditional cognitive assessments often lack sensitivity to detect subtle early deficits, and specificity required to identify ADRD. To address these limitations, our lab has developed and continuously refined the Loewenstein-Acevedo Scales for Semantic Interference and Learning (LASSI-L), a novel cognitive challenge test (CCT) that targets cognitive vulnerabilities associated with AD.

METHOD: Core components include the assessment of proactive semantic interference (PSI) and the failure to recover from proactive semantic interference (frPSI), aspects associated with deficits in semantic processing. The LASSI-L employs semantic category cues during encoding and retrieval to facilitate learning, reduce reliance on individualized learning strategies and enhance recall. Early executive and inhibitory control deficits can be assessed using the Percent Intrusion Errors (PIE) metric. This metric represents the ratio of semantic intrusion errors (SIEs), which occur when individuals fail to suppress irrelevant, competing information in favor of identifying correct targets. The addition of a delayed semantic source memory recognition task was designed to evaluate deficits in source memory and enhance detection of SIEs. This CCT has been fully digitized featuring a Cloud-based software using voice recognition technology and is available in English and Spanish. Integration with amyloid PET imaging and plasma-based biomarkers (e.g., p-tau181, p-tau217), to improve diagnostic precision and validate its use in identifying AD-specific cognitive deficits.

RESULTS: Delayed semantic source memory recognition task resulted in increased identification of SIEs linked to executive function and source memory deficits. SIEs have been found to be highly discriminative between those with amnestic Mild Cognitive Impairment (aMCI) with amyloid PET positivity. SIEs also differentiate between aMCI who are plasma p-tau181+ versus p-tau181-and those who are p-tau217+ versus p-tau217-. Deficits have been correlated with amyloid load and hippocampal atrophy. PIE has shown high sensitivity and specificity, distinguishing preclinical AD from cognitively unimpaired individuals.

CONCLUSION: This presentation will discuss the innovative modifications to the LASSI-L. This CCT holds promise as an accessible tool for early AD/ADRD detection, particularly in diverse and underserved populations, and complements emerging biomarker-based approaches to diagnosis.},
}

Humans
*Alzheimer Disease/diagnosis
*Neuropsychological Tests
Semantics
Early Diagnosis
tau Proteins

@article {pmid41444205,
year = {2025},
author = {Li, Q and Köhler, S and König, A and Dyrba, M and Alexopoulou, ZS and Mallick, E and Linz, N and Schneider, A and Spottke, A and Falkenburger, B and Laske, C and Düzel, E and Jessen, F and Zerr, I and Wiltfang, J and Priller, J and Kleineidam, L and Stark, M and Wagner, M and Petzold, GC and Levin, F and Teipel, S},
title = {Clinical Manifestations.},
journal = {Alzheimer's & dementia : the journal of the Alzheimer's Association},
volume = {21 Suppl 3},
number = {},
pages = {e098534},
doi = {10.1002/alz70857_098534},
pmid = {41444205},
issn = {1552-5279},
mesh = {Humans ; Male ; Female ; *Cognitive Dysfunction/diagnosis/pathology/physiopathology ; Aged ; Magnetic Resonance Imaging ; *Alzheimer Disease/diagnosis/pathology ; Neuropsychological Tests/statistics & numerical data ; *Brain/pathology/diagnostic imaging/physiopathology ; Longitudinal Studies ; Atrophy/pathology ; Cross-Sectional Studies ; *Speech ; Middle Aged ; },
abstract = {BACKGROUND: Speech features extracted from automated remote cognitive assessments correlate with performance on traditional cognitive tasks in individuals at risk of Alzheimer's Disease (AD), demonstrating their potential to support early diagnosis. However, the capability of these features to signal early AD-related brain changes remains less explored.

METHOD: Within the PROSPECT-AD study, 234 participants ranging from cognitively normal to mild cognitive impairment were recruited from the German DZNE longitudinal cohorts DELCODE and DESCRIBE. At home, all participants completed the phone-based and chatbot-guided Semantic Verbal Fluency task (SVF) and the Rey Auditory Verbal Learning Test (RAVLT). Linguistic and acoustic features were automatically extracted from phone call recordings using an AI model to calculate task-specific and composite cognitive scores. Structural MRI, functional MRI, and various paper-and-pencil cognitive scores were collected during cohort visits. We employed multiple linear regression, mixed-effects models, and independent component analysis (ICA), followed by voxel-wise post hoc analyses, to assess associations between digital speech-based indicators and: (1) cross-sectional brain atrophy (n = 108), (2) longitudinal brain atrophy (n = 90), (3) cross-sectional resting-state functional connectivity (n = 86), and additionally (4) trajectories of cognitive decline (n = 146).

RESULT: SVF correct counts were positively associated with brain volumes in the left temporal pole, left inferior, middle, and superior temporal gyri (The t(100) values ranged from 4.48 to 4.96) in voxel-wise analyses (Figure 1a). Longitudinal analyses indicated that higher SVF correct counts were linked to slower rates of hippocampal and anterior cingulate atrophy (Figure 1b). Functional connectivity analyses suggested that SVF features, such as word frequency, were associated with rsFC areas within the default mode network (The t(71) values ranged from 3.65 to 3.85) (Figure 1c). Higher composite cognitive scores, along with SVF and RAVLT features, were associated with slower cognitive decline, as measured by established paper-and-pencil cognitive assessments, including the Preclinical Alzheimer Cognitive Composite (PACC) 5, SVF, and RAVLT delayed recall (Figure 2).

CONCLUSION: Phone-based cognitive assessments hold promise as a remote and scalable tool for identifying AD-related structural and functional brain changes. They offer predictive value for cognitive trajectories in pre-dementia populations. This approach could aid in identifying individuals at risk while guiding further evaluation, broadening their utility beyond cognitive screening.},
}

Humans
Male
Female
*Cognitive Dysfunction/diagnosis/pathology/physiopathology
Aged
Magnetic Resonance Imaging
*Alzheimer Disease/diagnosis/pathology
Neuropsychological Tests/statistics & numerical data
*Brain/pathology/diagnostic imaging/physiopathology
Longitudinal Studies
Atrophy/pathology
Cross-Sectional Studies
*Speech
Middle Aged

@article {pmid41444204,
year = {2025},
author = {Brutman, JN and Kaufman, EJ and Nizamis, E and Busald, T and Smukowski, S and de Leon, MJ and Johnson, CSC and Latimer, CS and Child, DD and Bird, TD and Prater, KE and Jayadev, S and Valdmanis, PN},
title = {Basic Science and Pathogenesis.},
journal = {Alzheimer's & dementia : the journal of the Alzheimer's Association},
volume = {21 Suppl 1},
number = {},
pages = {e105919},
doi = {10.1002/alz70855_105919},
pmid = {41444204},
issn = {1552-5279},
mesh = {Humans ; *Alzheimer Disease/genetics/pathology ; *DNA Breaks, Double-Stranded ; *Apolipoproteins E/genetics ; Male ; Microglia/metabolism ; Female ; Genotype ; Prefrontal Cortex/pathology/metabolism ; Aged ; Sequence Analysis, RNA ; },
abstract = {BACKGROUND: APOE genotype status is the strongest common risk factor for Alzheimer's disease (AD), yet the biological mechanisms that underlie this pathogenesis are still unclear. Under normal circumstances, neuronal double-stranded breaks (DSBs) facilitate memory formation. However, DSBs also occur in early AD pathology, though a consistent pattern or pathological mechanism has not been observed.

METHODS: We performed analysis of single-nuclei RNA sequencing (snRNAseq) data from published unsorted and PU.1 sorted microglia from human post-mortem dorsolateral prefrontal cortex. We further analyzed ∼36,000 DNA samples from the Alzheimer's Disease Sequencing Project to confirm presence of reads with gaps in DNA sequence.

RESULTS: We found 1,999 sequence reads from ∼36,000 samples from the Alzheimer's Disease Sequencing Project exhibit DNA double-strand break and repair events specifically at APOE. These DSBs removed an average of 334bp of sequence and were primarily located in the last exon of APOE. Several DSBs originated or terminated at APOE-ε4, APOE-ε2, or APOE-Christchurch variants, or removed these variants entirely. Curiously, DSBs present in the coding region of APOE preserved the protein reading frame 96% of the time (n = 1,816 reads spread across 56 different breakpoints) compared to 22% of reads that extended past the 3'UTR (p <2.2×10[-16] by chi-square test). Amazingly, these DSB events are also transcribed: we detected 1,223 sequence reads from 22 individuals from snRNAseq data with the same breakpoints and loss of the APOE sequence, averaging 337bp. Split-reads lacked canonical splice donor and acceptor sites suggesting they originated at the DNA level. Split-reads were present most frequently in astrocytes, followed by microglia with only rare instances detected in neurons. Importantly, 7 of 12 AD samples and 0 of 10 controls had split-reads that originated from a 13bp segment immediately after the APOE-ε4 SNP rs429358 (p = 0.0053 by Fisher's exact test).

CONCLUSION: Our data reveal that APOE is subject to widespread double-strand break and repair events excising key APOE risk variants in the process. These data have profound implications for APOE function and our understanding of the mechanism underlying APOE risk.},
}

Humans
*Alzheimer Disease/genetics/pathology
*DNA Breaks, Double-Stranded
*Apolipoproteins E/genetics
Male
Microglia/metabolism
Female
Genotype
Prefrontal Cortex/pathology/metabolism
Aged
Sequence Analysis, RNA

@article {pmid41444203,
year = {2025},
author = {Miller, MJ and Saito, N and Conti, CC and Flenniken, D and Fockler, J and Truran-Sacrey, D and Diaz, A and Weston, J and Fristed, E and Farias, ST and Harvey, DJ and Beckett, L and Okonkwo, OC and Mindt, MGR and Weiner, MSW and Nosheny, RL},
title = {Clinical Manifestations.},
journal = {Alzheimer's & dementia : the journal of the Alzheimer's Association},
volume = {21 Suppl 3},
number = {},
pages = {e099537},
doi = {10.1002/alz70857_099537},
pmid = {41444203},
issn = {1552-5279},
mesh = {Humans ; Male ; Female ; *Cognitive Dysfunction/diagnosis ; Aged ; *Alzheimer Disease/diagnosis ; Neuropsychological Tests ; Aged, 80 and over ; Cohort Studies ; Neuroimaging ; Self Report ; },
abstract = {BACKGROUND: Scalable, efficient methods are needed to enroll older adults, especially those with Mild Cognitive Impairment (MCI), into AD observational studies and clinical trials. We evaluated feasibility of a novel, digital approach to recruit and screen participants for the Alzheimer's Disease Neuroimaging Initiative (ADNI4).

METHOD: Digital advertising tailored towards older adults residing near clinical ADNI sites directed potential participants to a recruitment website to enroll in a Digital Cohort (Figure 1). They completed remote, unsupervised, digital surveys (demographics, ADNI exclusion criteria, memory concerns and changes, self-report cognitive impairment, and the Everyday Cognition Scale (ECog)-12 item); and the Novoic Storyteller self-administered speech-based cognitive test. Digital assessment results were used to prioritize those with possible MCI or dementia (based on self-report cognitive impairment, ECog, and/or Novoic Storyteller scores), to ADNI sites for screening into in-clinic ADNI. For those screened at ADNI sites, associations between ECog12 or Storyteller score and cognitive impairment assessed using the Clinical Dementia Rating global score were estimated using logistic regression.

RESULT: Since June 2023, 8103 participants enrolled in the Digital Cohort (Table 1). Of those, 26% indicated ADNI4 exclusions (such as metal precluding MRI), 93% completed ECog12,16% had study partners who completed ECog12, and 60% completed Storyteller. For referral to clinical sites, 693 were invited, 313 accepted the invitation and were referred to a site, and 54 were screened at one of 44 ADNI sites (Table 1). In a subset with CDR screening data, more report of subjective cognitive decline on ECog12 and worse performance on Storyteller were associated with greater odds of cognitive impairment (CDR global >0) (Table 2).

CONCLUSION: Recruitment and assessment of older adults, including those with possible cognitive impairment, is feasible using tailored digital advertising and remote, unsupervised digital assessment. Remote assessments can be used to enrich for cognitive impairment. This approach can be adapted to facilitate recruitment and longitudinal assessment in other AD studies and trials.},
}

Humans
Male
Female
*Cognitive Dysfunction/diagnosis
Aged
*Alzheimer Disease/diagnosis
Neuropsychological Tests
Aged, 80 and over
Cohort Studies
Neuroimaging
Self Report

@article {pmid41444200,
year = {2025},
author = {Thorwald, MA and Godoy-Lugo, JA and Vermulst, M and Forman, HJ and Head, E and Finch, CE},
title = {Basic Science and Pathogenesis.},
journal = {Alzheimer's & dementia : the journal of the Alzheimer's Association},
volume = {21 Suppl 1},
number = {},
pages = {e105930},
doi = {10.1002/alz70855_105930},
pmid = {41444200},
issn = {1552-5279},
mesh = {Humans ; *Alzheimer Disease/metabolism/pathology ; *Iron/metabolism ; Lipid Peroxidation/physiology ; Male ; *Down Syndrome/metabolism/pathology ; Female ; Aged ; Amyloid beta-Protein Precursor/metabolism/genetics ; *Prefrontal Cortex/metabolism/pathology ; *Cerebellum/metabolism/pathology ; *Brain/metabolism/pathology ; Amyloid beta-Peptides/metabolism ; Middle Aged ; },
abstract = {BACKGROUND: Increased brain iron is associated with sporadic Alzheimer Disease (AD) and Down Syndrome with AD (DSAD), which may involve iron from cerebral microhemorrhages (MBs). The prevalence of MBs is higher in DSAD, possibly from the triplication of the amyloid precursor protein on chromosome 21. Increased MB iron could cause oxidative damage through Fenton chemistry and subsequent lipid peroxidation. We hypothesize that iron and APP are intrinsically linked, and that triplication of APP would result in more tissue iron and lipid peroxidation than observed in sporadic AD.

METHOD: Prefrontal cortex and cerebellum of cognitively normal, AD, and DSAD(n = 8/group) were examined for iron metabolism, antioxidant response, and amyloid peptides by immunoblot, inductively coupled mass spectrometry, and enzymatic assay.

RESULT: Iron was 2-fold higher in DSAD. Iron storage proteins and lipid peroxidation were increased in prefrontal cortex, but not in the cerebellum. The glutathione synthesis protein GCLM was decreased by 50% in both AD and DSAD. Activity of lipid raft GPx4, responsible for membrane repair, was decreased by at least 30% in AD and DSAD. These decreases in GPx4 activity were paralleled by reduced α-secretase activity while β-secretase activity increased.

CONCLUSION: DSAD shows greater lipid peroxidation than AD consistent with greater MBs and iron load. DSAD also shares similar and more pronounced features of AD such as decreased protein levels of critical GSH producing enzyme GCLM and other protective mechanisms against lipid peroxidation. The extensive increase of iron and lipid peroxidation suggests their linkage to APP gene dosage. The impairment of these key mechanisms asserts ferroptosis as a key feature during AD.},
}

Humans
*Alzheimer Disease/metabolism/pathology
*Iron/metabolism
Lipid Peroxidation/physiology
Male
*Down Syndrome/metabolism/pathology
Female
Aged
Amyloid beta-Protein Precursor/metabolism/genetics
*Prefrontal Cortex/metabolism/pathology
*Cerebellum/metabolism/pathology
*Brain/metabolism/pathology
Amyloid beta-Peptides/metabolism
Middle Aged

@article {pmid41444199,
year = {2025},
author = {Lorenz, AS and Sathe, A and Yang, Y and Durant, A and Wu, Y and Kim, ME and Gao, C and Newlin, NR and Ramadass, K and Kanakaraj, P and Khairi, NM and Li, Z and Yao, T and Huo, Y and Dumitrescu, L and Shashikumar, N and Pechman, KR and Risacher, S and Beason-Held, LL and An, Y and Arfanakis, K and Erus, G and Davatzikos, C and Habes, M and Wang, D and Tosun, D and Toga, AW and Thompson, PM and Mormino, EC and Zhang, P and Schilling, K and Albert, MSS and Kukull, WW and Biber, S and Landman, BA and Johnson, SC and Bendlin, BB and Schneider, JA and Barnes, LL and Bennett, DAA and Jefferson, AL and Resnick, SM and Saykin, AJ and Hohman, TJ and Archer, D and , },
title = {Biomarkers.},
journal = {Alzheimer's & dementia : the journal of the Alzheimer's Association},
volume = {21 Suppl 2},
number = {},
pages = {e098641},
doi = {10.1002/alz70856_098641},
pmid = {41444199},
issn = {1552-5279},
mesh = {Humans ; Male ; *White Matter/diagnostic imaging/pathology ; Female ; Aged ; *Alzheimer Disease/genetics/diagnostic imaging/pathology ; Biomarkers ; Polymorphism, Single Nucleotide ; Diffusion Magnetic Resonance Imaging ; Genome-Wide Association Study ; Aged, 80 and over ; Diffusion Tensor Imaging ; },
abstract = {BACKGROUND: Limbic white matter (WM) abnormalities are strongly elevated along the Alzheimer's Disease (AD) diagnostic continuum, but the underlying biological mechanisms remain unclear. This study aims to conduct a large-scale genetic analysis of WM microstructure in older adults.

METHOD: WM was assessed in seven limbic tracts, including the cingulum, fornix, inferior longitudinal fasciculus (ILF), uncinate fasciculus (UF), and transcallosal tracts of the inferior, middle, and superior temporal gyri (ITG, MTG, STG) using advanced diffusion MRI metrics corrected for free-water (FW) (fractional anisotropy [FAFWcorr], axial diffusivity [AxDFWcorr], mean diffusivity [MDFWcorr], radial diffusivity [RDFWcorr]). Genetic associations with WM microstructure were investigated using harmonized data from seven aging cohorts, comprising 2,614 non-Hispanic white older adults (mean age = 73.66 ± 9.76; 42.65% male), through SNP-heritability estimation, genome-wide association studies (GWAS), and post-GWAS analyses (genetic correlation, gene-level, and pathway analysis). Bulk RNA-seq brain data were used to evaluate the relationship between expression of genes identified in the GWAS with cognition and AD pathologies.

RESULT: WM microstructure is heritable, with 16 of 35 metrics exhibiting estimates between 0.26 and 0.60 (pFDR<0.05). Genome-wide associations (p <5×10[-8]) were observed for fornix AxDFWcorr (chr3, rs78407651), ILF FAFWcorr (chr15, rs8026709) and AxDFWcorr (chr15, rs8026709), STG RDFWcorr (chr10, rs11542181), and cingulum RDFWcorr (chr6, rs56017587). A locus with 38 genome-wide significant SNPs (chr18, rs12959877) was associated with FAFWcorr and RDFWcorr (Figure 1). These SNPs are eQTLs for CDH19, a gene highly expressed in oligodendrocytes with a role in cell adhesion. Among the genes identified in the GWAS, RORA, FAM107 and KC6 expression in brain tissues was linked to cognitive decline and AD pathologies (pFDR<.05). Gene-level analysis highlighted SERPINA12 (z=4.60, pFDR=.03), a gene implicated in type 2 diabetes and atherosclerosis. Pathway analysis revealed associations with insulin, immune response, and neurotrophic signaling. Genetic correlations were identified with lipid profiles, cardiovascular traits, and neuropsychiatric conditions (pFDR<.05).

CONCLUSION: This study identified genetic factors related to cognition, vascular health, and inflammation as contributors to WM microstructure changes in aging and AD. These findings open avenues for future research on AD's molecular mechanisms and therapeutic targets for improving vascular and metabolic health in aging populations.},
}

Humans
Male
*White Matter/diagnostic imaging/pathology
Female
Aged
*Alzheimer Disease/genetics/diagnostic imaging/pathology
Biomarkers
Polymorphism, Single Nucleotide
Diffusion Magnetic Resonance Imaging
Genome-Wide Association Study
Aged, 80 and over
Diffusion Tensor Imaging

@article {pmid41444196,
year = {2025},
author = {Ballotta, D and Maramotti, R and Parr, T and Carbone, C and Iacovino, N and Tondelli, M and Pagnoni, G and Zamboni, G},
title = {Clinical Manifestations.},
journal = {Alzheimer's & dementia : the journal of the Alzheimer's Association},
volume = {21 Suppl 3},
number = {},
pages = {e103031},
doi = {10.1002/alz70857_103031},
pmid = {41444196},
issn = {1552-5279},
mesh = {Humans ; Female ; Male ; Aged ; *Alzheimer Disease/psychology/physiopathology/complications ; Stroop Test ; Reaction Time/physiology ; Emotions/physiology ; Neuropsychological Tests ; *Agnosia/psychology/physiopathology ; Middle Aged ; },
abstract = {BACKGROUND: Anosognosia (i.e. lack of illness awareness) is common in neurodegenerative diseases and involves an inability to recognize cognitive, emotional, and behavioral impairments. Despite this, implicit knowledge may still influence behavior at a preconscious level (Mograbi & Morris, 2013). This can be investigated using the Emotional Stroop task, a color-naming test that assesses interference from emotionally charged words (Martyr et al., 2011). Our previous study (Tondelli et al., 2022) showed that Alzheimer's Disease (AD) patients lacking explicit awareness exhibited distinct activation patterns in the Posterior Cingulate Cortex when processing dementia-related words. However, reaction times varied widely, limiting traditional statistical analyses. To address this, we employed a generative model based on Active Inference, which integrates perception and action as an inferential process (Parr et al., 2022). Here, we present predictive simulations assessing the model's validity.

METHOD: A computerized Emotional Stroop task was administered to 37 healthy controls (age 65.4 ± 6.6) and 40 AD patients (age 72.3 ± 6.7). Participants viewed neutral, negative, and disease-related words in different colors and identified the color via button press. The experiment included 216 randomized trials, with a maximum response time of 1400 ms and a 600 ms intertrial interval. We developed a Partially Observable Markov Decision Process (POMDP) model within the Active Inference framework, incorporating four hidden state factors: word meaning, color, mental action, and task sequence (Figure 1). Four subject-specific parameters were included: one for learning effects, a temperature term for random variability, and two for the salience of negative and disease-related words.

RESULT: Simulated reaction times were non-normally distributed, mirroring the observed data. A specific slowing of reaction times for disease-related words compared to negative words, which we assume indicate implicit knowledge of the disease, could be obtained by coupling a high value for the parameter associated with the salience of disease-related words with a low value of the salience of negative words (Figure 2).

CONCLUSION: Thus, the model successfully reproduced behavioral patterns, and its estimates could be linked to MRI and neuropsychological measures, potentially enabling an implicit metacognitive assessment of anosognosia.},
}

Humans
Female
Male
Aged
*Alzheimer Disease/psychology/physiopathology/complications
Stroop Test
Reaction Time/physiology
Emotions/physiology
Neuropsychological Tests
*Agnosia/psychology/physiopathology
Middle Aged

@article {pmid41444195,
year = {2025},
author = {Kirste, I and Caley, D and Rubio, CQ and Carboni, M},
title = {Biomarkers.},
journal = {Alzheimer's & dementia : the journal of the Alzheimer's Association},
volume = {21 Suppl 2},
number = {},
pages = {e102804},
doi = {10.1002/alz70856_102804},
pmid = {41444195},
issn = {1552-5279},
mesh = {Humans ; *Biomarkers/blood ; *Alzheimer Disease/diagnosis/blood ; Female ; Male ; Patient Selection ; Aged ; Ethnicity ; Comorbidity ; },
abstract = {BACKGROUND: Access to healthcare is unbalanced across different populations with disparities in the availability of diagnostic tests. Additionally, test development currently relies on studies with limited representation of minorities and comorbidities present in the real clinical population. In order to develop diagnostic tests that can bring medical value to a broad population, clinical trial design needs to take these aspects into consideration.

METHOD: As part of the development of a novel blood-based biomarker for patients with suspected early progression towards Alzheimer's disease Roche is currently running a clinical study aiming to include racial and ethnic minorities as well as subjects with comorbidities. Our approach includes the use of mobile units for patient recruitment, multilingual study materials, outreach events, study site selection based on geographic location and proven capability of diverse enrollment. The current clinical trial has a goal of enrollment of 1500 patients into two arms: cut-off determination and validation.

RESULT: This approach led to a significant representation of racial and ethnic minorities as well as inclusion of patients with multiple comorbidities, potentially better reflecting the true patient population. Out of 600 enrolled patients in the cut-off determination arm, 387 (64.5%) are non-hispanic caucasian. African Americans reflect 12.5% (n = 75) of the study population with the remaining minorities including Multiracial and Asian-Americans. Nearly all of our patients have more than one comorbidity reflective of the target clinical population including cardiovascular, metabolic, neurological, renal, oncological, and immunological conditions as well as other age and non-age related diseases. Recruitment into the pivotal trial arm for cut-off validation is still ongoing but shows an even slightly better diversity profile.

CONCLUSION: A carefully designed clinical trial can achieve valid reflection of real-world disease population leading to more accurate results and better reflection of post-launch usage.},
}

Humans
*Biomarkers/blood
*Alzheimer Disease/diagnosis/blood
Female
Male
Patient Selection
Aged
Ethnicity
Comorbidity

@article {pmid41444184,
year = {2025},
author = {Zajac, DJ and Carling, GK and Fan, L and Xu, J and Gan, L and Cheng, F},
title = {Basic Science and Pathogenesis.},
journal = {Alzheimer's & dementia : the journal of the Alzheimer's Association},
volume = {21 Suppl 1},
number = {},
pages = {e106895},
doi = {10.1002/alz70855_106895},
pmid = {41444184},
issn = {1552-5279},
mesh = {Animals ; Humans ; *Alzheimer Disease/genetics/pathology/metabolism ; *Oligodendroglia/metabolism ; Male ; Apolipoprotein E4/genetics ; *Membrane Glycoproteins/genetics/metabolism ; Female ; *Receptors, Immunologic/genetics/metabolism ; Mice ; Mice, Transgenic ; Disease Models, Animal ; tau Proteins/metabolism/genetics ; Microglia/metabolism ; Genotype ; Aged ; },
abstract = {BACKGROUND: Alzheimer's Disease (AD) risk variants APOE4 and TREM2-R47H are known to impact glial cell functions and transcriptional profiles. TREM2-mediated oligodendrocyte-microglial crosstalk has not been revealed in previous research studies. Here, we present novel findings suggesting a TREM2-dependent mediation of oligodendrocyte transcriptional profiles.

METHODS: We investigated cell-type specific transcriptional changes associated with humanized APOE4 and TREM2-R47H genotypes in P301S+ mice versus background controls via single-nuclei RNA-sequencing of the frontal cortex. We investigated cell type subcluster abundance in association with genotype, sex and tau-positivity. We classified subclusters through differentially expressed gene network modules and gene set enrichment analysis. We compared our findings in mice to a human cohort. The mouse cohort consisted of 52 humanized APOExTREM2 mice, with six-to-eight mice per genotype-tau group, evenly split on sex. The human cohort consisted of 55 AD and control humans: APOE4-carrier TREM2-R47H (E4-R47H) (n = 18), nonE4-R47H (nonE4-R47H) (n = 6), APOE4-carrier TREM2-common variant (E4-CV) (n = 16), nonE4-CV (n = 6).

RESULTS: We found that APOE-TREM2 status had sex- and tau-independent TREM2-R47H-specific effects, and APOE4-R47H synergistic effects on cell abundance in oligodendrocytes, oligodendrocyte progenitor cells (OPCs), and a subgroup of inhibitory neurons. Specifically, we identified OPC and oligodendrocyte subclusters that strongly associate with TREM2-R47H in a tau-independent manner, further exacerbated by APOE genotype. Of note, the human cohort also showed a strong synergistic effect of APOE4 and TREM2-R47H on an oligodendrocyte subcluster that may be related to the TREM2-R47H-dependent oligodendrocyte subclusters identified in the mice. This finding of TREM2-specific effects on oligodendrocyte transcriptional states in both mice and humans suggests possible TREM2-mediated microglia-oligodendrocyte crosstalk, or the presence of TREM2-oligodendrocyte cell-ligand interactions that merits further investigation.

CONCLUSION: In summary, this study suggests possible synergistic effects of APOE4-carrier and TREM2-R47H-carrier status on OPC, oligodendrocyte, and inhibitory neuron abundance and transcriptional profiles. Specifically, OPCs and oligodendrocytes show a strong association with TREM2-R47H that is exacerbated by APOE genotype, a finding that is reflected in the human cohort. Hence, further classification of differences between joint APOE-TREM2 genotypes will improve our understanding of glial cell alterations in AD, and could lead to novel cell type-specific therapeutic interventions for AD and other AD-related dementia if broadly applied.},
}

Animals
Humans
*Alzheimer Disease/genetics/pathology/metabolism
*Oligodendroglia/metabolism
Male
Apolipoprotein E4/genetics
*Membrane Glycoproteins/genetics/metabolism
Female
*Receptors, Immunologic/genetics/metabolism
Mice
Mice, Transgenic
Disease Models, Animal
tau Proteins/metabolism/genetics
Microglia/metabolism
Genotype
Aged

@article {pmid41444183,
year = {2025},
author = {Hoyo, LD and Sandkühler, K and Videla, L and Benejam, B and Carmona-Iragui, M and Wlasich, E and Barroeta, I and Vaqué-Alcázar, L and Rodríguez-Baz, Í and Bejanin, A and Fernandez, S and Arranz, J and Arriola-Infante, JE and Maure-Blesa, L and Hernandez, AS and Nübling, G and Wagemann, O and Stockbauer, A and Hassenstab, JJ and Levin, J and Fortea, J},
title = {Clinical Manifestations.},
journal = {Alzheimer's & dementia : the journal of the Alzheimer's Association},
volume = {21 Suppl 3},
number = {},
pages = {e099293},
doi = {10.1002/alz70857_099293},
pmid = {41444183},
issn = {1552-5279},
mesh = {Humans ; Male ; Female ; *Alzheimer Disease/diagnosis ; Neuropsychological Tests ; Cohort Studies ; Middle Aged ; Aged ; *Down Syndrome/complications/diagnosis ; *Intellectual Disability/diagnosis/classification ; },
abstract = {BACKGROUND: Cut-offs derived from baseline cognitive assessments, stratified by intellectual disability (ID) level, have been proposed to diagnose symptomatic Alzheimer's disease (AD) in Down syndrome (DS). However, discrepancies in ID classification risk misclassification when applying cut-offs across sites.

METHOD: This dual-center cohort study included 673 adults with mild to moderate ID at different AD stages. We assessed ID classification discrepancies across sites and its impact on CAMCOG-DS cut-offs for AD dementia diagnosis derived from ROC analysis.

RESULT: Inter-rater agreement for ID level classification was 95% within sites but 60% between sites. While CAMCOG-DS score distributions in the whole cohort were similar across sites, ID classification discrepancies caused higher cut-offs in Barcelona for mild and moderate ID compared to Munich. Applying site-specific cut-offs to another cohort reduced sensitivity and specificity.

CONCLUSION: Standardizing ID classification is critical for generalizable cut-offs to accurately diagnose AD dementia based on neuropsychological assessments in DS.},
}

Humans
Male
Female
*Alzheimer Disease/diagnosis
Neuropsychological Tests
Cohort Studies
Middle Aged
Aged
*Down Syndrome/complications/diagnosis
*Intellectual Disability/diagnosis/classification

@article {pmid41444182,
year = {2025},
author = {Olayinka, OA and Farrell, JJ and Zhu, C and Khurshid, Z and , and Martin, ER and Bush, WS and Pericak-Vance, M and Wang, LS and Schellenberg, GD and Haines, JL and Lunetta, KL and Zhang, X and Farrer, LA},
title = {Basic Science and Pathogenesis.},
journal = {Alzheimer's & dementia : the journal of the Alzheimer's Association},
volume = {21 Suppl 1},
number = {},
pages = {e106998},
doi = {10.1002/alz70855_106998},
pmid = {41444182},
issn = {1552-5279},
mesh = {Humans ; *Alzheimer Disease/genetics ; Genome-Wide Association Study ; Female ; Male ; *Genetic Predisposition to Disease/genetics ; *Multifactorial Inheritance/genetics ; Aged ; White People/genetics ; Polymorphism, Single Nucleotide ; Risk Factors ; },
abstract = {BACKGROUND: Polygenic risk scores (PRS) are measures of an individual's aggregate genetic risk of disease and are typically calculated using common variants. Rare variants (RV), though not captured by PRS, have been shown to play an important role in AD. We utilized an AD PRS to discover associations with novel RVs.

METHOD: PRS for non-Hispanic white (NHW) samples (n = 11,409; AD=6630, controls=4779) from the Alzheimer's Disease Sequencing Project (ADSP) R4 dataset were calculated using published GWAS summary statistics of NHW subjects, excluding the APOE region. Participants were classified into high (n = 5,442) and low (n = 5,967) PRS groups based on the median PRS. After quality control, 11,485,531 low frequency variants (LV) (1% < MAF < 5%) and RVs with a MAC>5 were included in the analysis. The association of each variant was evaluated in low and high PRS groups separately using a regression model including covariates for age, sex, and principal components of ancestry implemented in GENESIS.

RESULT: Genome-wide significant (GWS) associations of RVs and LVs with AD were identified in both the low and high PRS groups. Risk variants were disproportionately enriched in the low group while protective ones were disproportionately enriched in the high group. Among the GWS, RVs in the coding region of NYNRIN (rs570910195) (β=4.06, p = 4.37x10[-10]) and 52 kb upstream of LOC105373398 (rs572619714, β=1.67, p = 2.20x10[-8]) increased AD risk in the low PRS group. A rare deletion located 27 kb downstream of SDHC (chr1:161390036) was associated with decreased AD risk (β=-2.33, p = 7.45x10[-9]) and a low frequency variant 20 kb downstream of SMNDC1 (rs150913764, MAF=0.02) was associated with increased AD risk (β=0.96, p = 3.13x10[-8]) in the high PRS group. These variants were not associated with AD in the other respective PRS group.

CONCLUSION: Stratifying individuals into those with lower and higher risk for AD based on aggregated effects of common variants enhanced the detection of RV and LV associations. Our results suggest that a PRS calculated from common variants may not necessarily correspond to an individual's genetic relative risk for AD. These findings also provide unique opportunities to study RVs whose effects are opposite to the risk conferred by the genetic background.},
}

Humans
*Alzheimer Disease/genetics
Genome-Wide Association Study
Female
Male
*Genetic Predisposition to Disease/genetics
*Multifactorial Inheritance/genetics
Aged
White People/genetics
Polymorphism, Single Nucleotide
Risk Factors

@article {pmid41444181,
year = {2025},
author = {Zhang, F and Petersen, M and Johnson, LA and Hall, J and O'Bryant, SE},
title = {Biomarkers.},
journal = {Alzheimer's & dementia : the journal of the Alzheimer's Association},
volume = {21 Suppl 2},
number = {},
pages = {e099869},
doi = {10.1002/alz70856_099869},
pmid = {41444181},
issn = {1552-5279},
mesh = {Humans ; *Biomarkers/blood ; Male ; Female ; *Alzheimer Disease/blood/diagnosis ; Aged ; *Brain/pathology ; *Aging ; Middle Aged ; Machine Learning ; Aged, 80 and over ; },
abstract = {BACKGROUND: Brain age prediction is a valuable tool for identifying deviations from normal aging and detecting neurological disorders such as Alzheimer's disease (AD) at an early stage. With the advent of multimodal databases like HABS-HD, leveraging multilevel and multiscale AD datasets may enhance the precision of brain age prediction. This study aimed to investigate whether combining serum and plasma biomarkers with feature selection could improve brain age prediction.

METHODS: The study included 150 normal controls for serum testing and 100 normal controls for plasma testing, with 65 overlapping normal participants. A 10-times repeated 5-fold cross-validation model was employed to compare performance and reduce overfitting. Feature selection methods were applied to enhance prediction performance by combining serum and plasma biomarkers in brain age prediction.

RESULTS: Predictive performance was evaluated using Root Mean Square Error (RMSE) and the coefficient of determination (R[2]). The "Serum only" model achieved an RMSE of 5.07 and an R[2] of 0.746, indicating moderate accuracy. The "Plasma only" model improved performance with an RMSE of 4.48 and an R[2] of 0.786. Combining "Serum + Plasma" further enhanced results, achieving an RMSE of 4.12 and an R[2] of 0.816, underscoring the synergistic benefits of multimodal integration. The highest performance was observed with "Serum + Plasma + Feature Elimination," which achieved the lowest RMSE of 2.77 and the highest R[2] of 0.917, indicating superior predictive accuracy and model fit.

CONCLUSION: Leveraging machine learning (ML) techniques with comprehensive AD datasets holds significant potential to improve brain age prediction.},
}

Humans
*Biomarkers/blood
Male
Female
*Alzheimer Disease/blood/diagnosis
Aged
*Brain/pathology
*Aging
Middle Aged
Machine Learning
Aged, 80 and over

@article {pmid41444180,
year = {2025},
author = {Gaugler, J},
title = {Dementia Care Research and Psychosocial Factors.},
journal = {Alzheimer's & dementia : the journal of the Alzheimer's Association},
volume = {21 Suppl 4},
number = {},
pages = {e096546},
doi = {10.1002/alz70858_096546},
pmid = {41444180},
issn = {1552-5279},
mesh = {Humans ; *Dementia/therapy/psychology ; United States ; National Institute on Aging (U.S.) ; *Biomedical Research ; },
abstract = {BACKGROUND: With the passage of the National Alzheimer's Project Act (NAPA) in 2011 and the National Plan to Address Alzheimer's Disease in the U.S., federal funding support for dementia care science increased exponentially. The National Institute on Aging (NIA), in keeping with National Plan's goal of effectively treating and preventing Alzheimer's disease and Alzheimer's Disease Related Dementias (AD/ADRD) by 2025, created a series of research milestones to track success. One of these is research milestone 13.H: Create research programs to evaluate novel and innovative dissemination and implementation methods to scale up promising practices in dementia care across settings and across the disease severity spectrum. The objective of this presentation is to summarize scientific advancements in the dissemination and implementation of dementia care innovations.

METHOD: This presentation uses narrative review and case study methods to assess the state-of-the-science of dementia care implementation and dissemination and to identify recommendations to continue to propel the field forward so that the ultimate goal of ensuring people living with dementia and their carers can benefit from evidence-based programs, services, and innovations are more readily achieved.

RESULT: Although a range of efforts exist documenting dissemination and implementation efforts of dementia care interventions, a range of barriers have been identified in the literature, including staff training requirements, length, complexity, little alignment with operations and daily workflow, and lack of incentivization/reimbursement. Within the framework of the NIH Stage Model of Behavioral Intervention Development, several methodological strategies could be applied to dementia care intervention design, testing, and dissemination/implementation to expedite the translation of evidence into real-world contexts.

CONCLUSION: Designing dementia care interventions with the intent of implementation at the earliest stages of development is critical. Key methodological strategies to expedite the translational "pipeline" of dementia care science include the identification, measurement, and testing of mechanisms of action; use of process evaluations; application of advanced intervention design methodologies such as the Multiphase Optimization Strategy, Sequential Multiple Assignment Randomized Trials, and hybrid-effectiveness studies; and incorporation of person-centered outcome measures.},
}

Humans
*Dementia/therapy/psychology
United States
National Institute on Aging (U.S.)
*Biomedical Research

@article {pmid41444179,
year = {2025},
author = {Kim, JS and Farahmand, G and Corona, MG and Nan, B and Zou, A and Sajjadi, SA},
title = {Clinical Manifestations.},
journal = {Alzheimer's & dementia : the journal of the Alzheimer's Association},
volume = {21 Suppl 3},
number = {},
pages = {e107659},
doi = {10.1002/alz70857_107659},
pmid = {41444179},
issn = {1552-5279},
mesh = {Humans ; Male ; Female ; *Cognitive Dysfunction/diagnosis/psychology ; Aged ; Disease Progression ; Neuropsychological Tests ; Aged, 80 and over ; *Dementia/diagnosis ; Self Report ; },
abstract = {BACKGROUND: Subjective cognitive decline (SCD) has been linked to an increased risk of progression to mild cognitive impairment (MCI) and dementia. Furthermore, informant confirmation of SCD has been associated with a higher likelihood of future decline than participant-reported SCD alone. Objectively-defined subtle cognitive impairment (sOCI), reflecting cognitive deficits that do not meet MCI criteria, has also been associated with increased risk for future cognitive impairment. Whether sOCI or SCD is a better predictor of future cognitive decline remains unknown. This study aims to (1) examine the combined impact of sOCI and SCD on future risk of MCI or dementia, (2) determine whether informant-reported SCD (as opposed to patient-reported SCD) is associated with higher risk, and (3) assess whether sOCI provides predictive value beyond SCD.

METHODS: Participants in UC Irvine Alzheimer's Disease Research Center (ADRC) who were free from MCI or dementia at baseline were included. SCD was determined using responses from the Uniform Data Set (UDS) Form B9, assessing both self- and informant-reported cognitive decline. sOCI was defined by scores at least one standard deviation the mean (z ≤ -1.00) on both story memory and list learning delayed recall tests. Cox proportional-hazards models, Kaplan-Meier survival curves, and generalized mixed models were employed to evaluate the relationship between sOCI and SCD (patient and informant reported), and progression to MCI or dementia.

RESULTS: The mean age of the participants was 66.7 ±7.4 (Table 1). Participants with both sOCI and SCD had the highest risk of progression to MCI or dementia. SCD alone was associated with a slightly higher risk than sOCI alone (Figure 1). Informant-reported SCD had the highest OR for prediction of future MCI/dementia (HR=2.97, p <0.0001) followed by sOCI (HR=2.61, p = 0.02) and self-reported SCD (HR=1.85, p = 0.04) (Table 2).

CONCLUSIONS: The combination of sOCI and SCD confers the highest risk for progression, underscoring the importance of close monitoring of individuals with both indicators. The observation that sOCI adds unique prognostic value beyond self-reported SCD suggests that integrating objective measures with subjective complaints may enhance early detection of cognitive impairment. Furthermore, Informant-reported SCD could be a separate predictor of cognitive impairment.},
}

Humans
Male
Female
*Cognitive Dysfunction/diagnosis/psychology
Aged
Disease Progression
Neuropsychological Tests
Aged, 80 and over
*Dementia/diagnosis
Self Report

@article {pmid41444176,
year = {2025},
author = {Shim, Y and Hong, YJ and Ku, BD and Jang, JW and Na, S},
title = {Clinical Manifestations.},
journal = {Alzheimer's & dementia : the journal of the Alzheimer's Association},
volume = {21 Suppl 3},
number = {},
pages = {e101232},
doi = {10.1002/alz70857_101232},
pmid = {41444176},
issn = {1552-5279},
mesh = {Humans ; Male ; Female ; Aged ; *Cognitive Dysfunction/etiology/diagnostic imaging ; Prospective Studies ; Positron-Emission Tomography ; Neuropsychological Tests/statistics & numerical data ; *Plaque, Amyloid/diagnostic imaging ; Middle Aged ; *Stroke/complications ; Donepezil/therapeutic use ; },
abstract = {BACKGROUND: Post-stroke cognitive impairment (PSCI) frequently occurs, with a prevalence ranging from 20% to 80%. Amyloid deposition, a hallmark of Alzheimer's disease (AD), is hypothesized to exacerbate cognitive decline in PSCI. This study investigates the impact of amyloid plaques on cognitive deterioration in stroke patients.

METHOD: A multicenter prospective observational cohort study was conducted involving 192 patients with acute ischemic stroke and cognitive impairment. Participants were divided into amyloid-positive (n = 40) and amyloid-negative (n = 152) groups based on PET scan results. Cognitive function was assessed using MMSE, MoCA, and other neuropsychological tests over a 12-month period, with some patients receiving donepezil treatment.

RESULT: Amyloid (+) patients had significantly lower initial MMSE scores (19.03±6.30) compared to amyloid (-) patients (21.52±5.56, p = 0.016). After 12 months, the MMSE score in the amyloid (+) group was 19.48±6.70, showing a lesser improvement compared to the amyloid (-), which scored 23.28±5.47 (p = 0.032). Additionally, the CDR-SOB score worsened in the amyloid (+) group (4.31±3.46) compared to the amyloid (-) group (2.63±2.82, p = 0.051). Donepezil treatment led to temporary cognitive improvement in the amyloid-positive group during the first 6 months.

CONCLUSION: The presence of amyloid plaques in PSCI patients is associated with a faster cognitive decline, as evidenced by the lower MMSE and worsening CDR-SOB scores in the amyloid-positive group. Although donepezil shows short-term cognitive benefits, its impact diminishes over time. Early identification of amyloid deposition could be crucial in guiding personalized therapeutic strategies for managing PSCI effectively.},
}

Humans
Male
Female
Aged
*Cognitive Dysfunction/etiology/diagnostic imaging
Prospective Studies
Positron-Emission Tomography
Neuropsychological Tests/statistics & numerical data
*Plaque, Amyloid/diagnostic imaging
Middle Aged
*Stroke/complications
Donepezil/therapeutic use

@article {pmid41444175,
year = {2025},
author = {Martínez, NF and Val-Guardiola, A and Peña, M and Mayà, G and Pérez-Millan, A and Bosch, B and Fernandez-Villullas, G and Balasa, M and Gaig, C and Tort-Merino, A and Lladó, A and Muñoz-Moreno, E and Iranzo, Á and Grinberg, LT and Sánchez-Valle, R},
title = {Clinical Manifestations.},
journal = {Alzheimer's & dementia : the journal of the Alzheimer's Association},
volume = {21 Suppl 3},
number = {},
pages = {e099055},
doi = {10.1002/alz70857_099055},
pmid = {41444175},
issn = {1552-5279},
mesh = {Humans ; Male ; Female ; *Alzheimer Disease/pathology/diagnostic imaging/physiopathology/complications ; Aged ; Magnetic Resonance Imaging ; *Cognitive Dysfunction/diagnostic imaging/physiopathology/pathology ; Sleep/physiology ; Neuropsychological Tests ; Middle Aged ; *Sleep Wake Disorders/etiology ; *Locus Coeruleus/pathology/diagnostic imaging ; Age of Onset ; Aged, 80 and over ; },
abstract = {BACKGROUND: Atypical variants of sporadic Alzheimer's disease (AD) are characterized by earlier onset (EOAD, before age 65), non-amnestic cognitive patterns, and distinctive neuropsychiatric and sleep-related traits. Earlier onset has been linked to greater severity of neuropsychiatric symptoms and increased use of antidepressants or sleep medications. Furthermore, atypical variants such as Posterior Cortical Atrophy and the logopenic variant of Primary Progressive Aphasia exhibit pronounced REM sleep dysfunction. The mechanisms driving these behavioral and sleep differences, influenced by age at onset and atypical disease features, remain unclear. Emerging evidence suggests that a differential pattern of degeneration within the neuromodulatory subcortical systems (NSS), including the locus coeruleus (LC), may contribute to these distinct profiles. This study compared sleep-wake patterns and volumes of NSS in EOAD and late-onset AD (LOAD).

METHOD: The study included 113 biomarker-confirmed AD participants (37 EOAD, 76 LOAD) in the early stages (mild cognitive impairment or mild dementia). All participants underwent MRI with quantification of subcortical nucleus volumes. A subset of 66 participants (23 EOAD, 43 LOAD) completed the Pittsburgh Sleep Quality Index (PSQI), Epworth Sleepiness Scale (ESS), and two weeks of actigraphy monitoring using the Motion Watch8 device. Sleep-wake patterns and circadian rhythms were analyzed using MotionWare software.

RESULT: EOAD and LOAD participants had similar functional status (GDS3: 57% vs 55%), neuropsychiatric medication use (46% vs 42%), and subjective sleep assessments (PSQI: 6.55±4.33 vs 6.98±3.89; ESS: 6.45±4.35 vs 5.48±4.01). However, actigraphy revealed shorter total sleep time (384.07±67.06 vs. 425.00±58.09 min, p < 0.05) and more fragmented, unstable sleep patterns (384.13±68.57 vs. 419.33±57.17 min, p < 0.05) in EOAD compared to LOAD. Unlike other subcortical nuclei, LC volume was significantly smaller in EOAD than in LOAD (26.32±8.51 vs. 32.02±9.83 mm[3]) (see Table 1).

CONCLUSIONS: While subjective sleep measures were similar between EOAD and LOAD, actigraphy revealed more significant sleep disruption in EOAD. Notably, LC volume was uniquely reduced in EOAD, whereas other subcortical nuclei showed larger volumes than LOAD. These findings highlight the need to explore the role of subcortical degeneration in sleep disturbances in early-onset AD.},
}

Humans
Male
Female
*Alzheimer Disease/pathology/diagnostic imaging/physiopathology/complications
Aged
Magnetic Resonance Imaging
*Cognitive Dysfunction/diagnostic imaging/physiopathology/pathology
Sleep/physiology
Neuropsychological Tests
Middle Aged
*Sleep Wake Disorders/etiology
*Locus Coeruleus/pathology/diagnostic imaging
Age of Onset
Aged, 80 and over

@article {pmid41444173,
year = {2025},
author = {Alex, GS and Chinagorom, I and , },
title = {Dementia Care Research and Psychosocial Factors.},
journal = {Alzheimer's & dementia : the journal of the Alzheimer's Association},
volume = {21 Suppl 4},
number = {},
pages = {e096925},
doi = {10.1002/alz70858_096925},
pmid = {41444173},
issn = {1552-5279},
mesh = {Humans ; *Alzheimer Disease/psychology/diagnostic imaging ; Magnetic Resonance Imaging ; *Machine Learning ; Disease Progression ; *Cognitive Dysfunction/diagnostic imaging/psychology ; Neuroimaging/methods ; Aged ; *Dementia/psychology/diagnostic imaging ; Male ; Female ; },
abstract = {BACKGROUND: Alzheimer's disease is the most common form of dementia, a significant contributor to the global burden of disability and death globally. Early diagnosis and accurate prediction of disease progression are crucial for effective management and treatment plan.

METHOD: We utilized publicly available neuroimaging dataset comprising 2D axial MRI scans from three classes: Alzheimer's disease, Cognitive Impaired and Cognitive normal. Preprocessing of data was performed using OpenCV (Open source computer vision library). The models employed were ResNet50 and DenseNet121. Model performance was evaluated using accuracy, loss, AUC and confusion matrices RESULT: Our results showed that both ResNet50 and DenseNet121 achieved exceptional accuracy of 99.8% and 100% respectivly. Confusion matrices of both models showed excellent performance in classifying images with AUC value exceeding 0.99.

CONCLUSION: The study demonstrates the potential of machine learning in predicting the progression of Alzheimer's disease. Our finding suggest that machine learning models can help clinicians and healthcare professionals.},
}

Humans
*Alzheimer Disease/psychology/diagnostic imaging
Magnetic Resonance Imaging
*Machine Learning
Disease Progression
*Cognitive Dysfunction/diagnostic imaging/psychology
Neuroimaging/methods
Aged
*Dementia/psychology/diagnostic imaging
Male
Female

@article {pmid41444171,
year = {2025},
author = {Düzel, E and Cikrikcili, U and Schott, BH and Jockschat, TN and Berron, D and Soch, J and Krohn, F},
title = {Basic Science and Pathogenesis.},
journal = {Alzheimer's & dementia : the journal of the Alzheimer's Association},
volume = {21 Suppl 1},
number = {},
pages = {e107337},
doi = {10.1002/alz70855_107337},
pmid = {41444171},
issn = {1552-5279},
mesh = {Humans ; Male ; Female ; *Amygdala/physiopathology/diagnostic imaging ; Magnetic Resonance Imaging ; *tau Proteins/cerebrospinal fluid ; Aged ; *Depression/physiopathology ; *Cognitive Dysfunction/physiopathology/diagnostic imaging ; *Alzheimer Disease ; Middle Aged ; },
abstract = {BACKGROUND: Late-life depression (LLD) is a well-established risk factor for Alzheimer's disease (AD) and has been linked to cognitive decline. The amygdala, an important region for emotional regulation and novelty detection, is one of the earliest sites of tau accumulation in AD. However, it remains unclear how depressive symptoms and tau burden interact with amygdala function in preclinical AD stages. This study examines the relationship between amygdala novelty responses, depressive symptoms.

METHOD: A total of 190 participants (HC = 58, SCD = 88, MCI = 44) underwent functional MRI (fMRI) to assess amygdala novelty responses. Depression severity was measured using the GDS, and tau pathology was classified based on CSF phosphorylated tau (p-Tau) and total tau (t-Tau) levels. Participants were further categorized based on depressive symptoms (GDS = 0 vs. GDS ≥1) and tau status (Tau (-) vs. Tau (+)) for statistical analyses.

RESULT: Group comparisons revealed significantly higher GDS scores in SCD and MCI groups compared to HC (p < 0.05), reflecting increased depressive symptoms in individuals with cognitive complaints. However, no significant correlation was observed between amygdala novelty responses and GDS scores across diagnostic groups. Additionally, CSF tau levels (p-Tau and t-Tau) did not significantly interact with depressive symptoms in predicting amygdala responses. The lack of significant findings in amygdala response may be attributed to the relatively low overall severity of depressive symptoms in the sample, which could limit detectability of neural alterations.

CONCLUSION: Although prior studies have indicated that late-life depression and tau pathology are associated with the progression of Alzheimer's disease (AD), our findings suggest that subclinical depressive symptoms do not significantly impact amygdala novelty responses in preclinical AD. The observed increase in depressive symptoms in SCD and MCI groups suggests that affective changes may still be an important factor in disease progression, but their relationship with amygdala function remains unclear. Future research should explore clinically significant depression, longitudinal changes in affective symptoms, and other neurobiological mechanisms, such as amyloid burden and neuroinflammation, to better understand the early neural changes associated with AD.},
}

Humans
Male
Female
*Amygdala/physiopathology/diagnostic imaging
Magnetic Resonance Imaging
*tau Proteins/cerebrospinal fluid
Aged
*Depression/physiopathology
*Cognitive Dysfunction/physiopathology/diagnostic imaging
*Alzheimer Disease
Middle Aged

@article {pmid41444167,
year = {2025},
author = {Sanchez-Juan, P and Arcelay, EG and Almagro, M and Balasa, M and Piñol-Ripoll, G and Boada, M and Landete, L and Abellán, I and Berbel, A and Espejo, B and Baquero, M and Marin, J and Franco-Macías, E and Galende, AV and Fernandez, FV and Vilar, IF and Pérez-Vieitez, C and Rodriguez-Espinosa, N and Puig-Pijoan, A and Pizarro, EB and Rodríguez, ER and Rodrígo, J and Mauriño, J and Manzano, MS},
title = {Dementia Care Research and Psychosocial Factors.},
journal = {Alzheimer's & dementia : the journal of the Alzheimer's Association},
volume = {21 Suppl 4},
number = {},
pages = {e096377},
doi = {10.1002/alz70858_096377},
pmid = {41444167},
issn = {1552-5279},
mesh = {Humans ; *Caregivers/psychology ; Female ; Male ; Cross-Sectional Studies ; Aged ; Middle Aged ; *Cognitive Dysfunction/nursing/psychology ; *Dementia/psychology/nursing ; Aged, 80 and over ; Quality of Life ; },
abstract = {BACKGROUND: The quality of the caregiver-patient relationship is essential for both parties, as it significantly influences the emotional well-being of patients, and the satisfaction and burden of caregivers. This study aimed to assess the quality of caregiver-patient relationships in informal caregivers of patients with mild cognitive impairment (MCI) and to identify associated factors.

METHOD: A non-interventional, cross-sectional study was conducted at 19 memory clinics in collaboration with the Spanish Confederation of Alzheimer's Disease (CEAFA). Informal caregivers of patients with MCI (NIA-AA criteria) and a Global Deterioration Scale score of 3 were included. The quality of the patient-caregiver relationship was measured using the Quality of Carer-Patient Relationship Scale (QCPR). A score >56 indicates a good-quality relationship. Associations between QCPR scores and caregiver demographic, psychological, and behavioral factors, as well as patient characteristics, were analyzed through logistic regression.

RESULT: A total of 196 caregivers were studied (mean age: 63.5 ± 13.1 years; 63% female). Of these, 68.4% were spouses of patients (mean age: 72.9 ± 7.0 years) with a median disease duration of 2 years (IQR 1.0-4.0) and a median MMSE score of 26.0 (IQR 23.0-27.0). Over half of the participants reported a good relationship with the patient (53.6%, mean QCPR score: 26.1 ± 6.1). Higher QCPR scores were associated with lower caregiving burden, greater care competence, better quality of life, stronger social support, greater resilience, and higher levels of anxiety and depression. Younger caregivers, employed, and living separately from the patient reported having better relationships with them. In multivariate analysis, a good patient-caregiver relationship was independently associated with higher MMSE score (OR=1.165, 95% CI 1.034-1.312, p = 0.012), fewer neuropsychiatric symptoms (OR=0.865, 95% CI 0.795-0.942, p = 0.001), lower use of avoidant coping strategies (OR=0.424, 95% CI 0.182-0.987, p = 0.047), and lower perception of stigma (OR=0.048, 95% CI 0.048-0.007, p = 0.002).

CONCLUSION: The quality of the relationship is influenced by demographic, psychological, and behavioral factors relating to both the caregiver and the patient. Specific interventions on these factors could be useful in enhancing caregiver-patient relationships.},
}

Humans
*Caregivers/psychology
Female
Male
Cross-Sectional Studies
Aged
Middle Aged
*Cognitive Dysfunction/nursing/psychology
*Dementia/psychology/nursing
Aged, 80 and over
Quality of Life

@article {pmid41444166,
year = {2025},
author = {Skampardoni, I and Erus, G and Nasrallah, IM and Yang, Z and Baik, K and Shou, H and Nikita, K and Davatzikos, C},
title = {Biomarkers.},
journal = {Alzheimer's & dementia : the journal of the Alzheimer's Association},
volume = {21 Suppl 2},
number = {},
pages = {e101668},
doi = {10.1002/alz70856_101668},
pmid = {41444166},
issn = {1552-5279},
mesh = {Humans ; Magnetic Resonance Imaging ; *Biomarkers ; *Brain/pathology/diagnostic imaging ; Male ; Cross-Sectional Studies ; Female ; Atrophy/pathology ; Aged ; *Aging/pathology ; Middle Aged ; Machine Learning ; Neuroimaging ; Longitudinal Studies ; },
abstract = {BACKGROUND: Understanding brain aging heterogeneity is critical for early detection of neurodegeneration related to underlying neuropathologies and effective recruitment for clinical trials. Machine learning techniques have shown potential in this domain but often rely on cross-sectional data, neglecting dynamic observations of pathological changes. This study applies Coupled Cross-sectional and Longitudinal Non-negative Matrix Factorization (CCL-NMF), a novel framework integrating static and dynamic brain changes, to analyze aging-related brain atrophy heterogeneity in a large, diverse dataset from 12 neuroimaging studies consolidated by the iSTAGING consortium (Skampardoni et al., 2024).

METHOD: CCL-NMF uses a mutually constrained NMF framework to identify brain aging components, combining population-level aging effects from cross-sectional data with individual-specific dynamics from longitudinal data. Individual expression levels (loadings) for each component are estimated, optimizing the reconstruction of both data types to capture the interplay between static and dynamic aspects of brain alterations. Structural MRI data from 48,949 individuals ≥50 years were analyzed. Comparative analyses were conducted against a weakly-supervised generative adversarial network model, Surreal-GAN (Yang et al., 2024), which relies solely on cross-sectional data. Predictive performance for biomarkers, clinical variables, and disease progression was assessed using regression and Cox proportional hazards models with 5-fold stratified cross-validation. To facilitate application to external datasets without retraining or harmonization, out-of-sample regression-based estimation of CCL-NMF loadings was implemented via NiChart (https://cbica.github.io/NiChart_Project/) with reliability validated through Pearson correlations with original loadings.

RESULT: CCL-NMF identified seven distinct brain atrophy components associated with Alzheimer's disease (AD), cognitive decline, and cardiovascular risk factors. Comparative analyses with the five Surreal-GAN components revealed consistent representations between the two models, elucidating well-reproducible brain atrophy components (Figure 1A). Importantly, CCL-NMF provided a richer representation and demonstrated improved predictive performance across various outcomes, including AD, cardiovascular disease markers, and disease progression (Figure 1B). Furthermore, Spearman correlations between original and approximated CCL-NMF loadings demonstrated high reliability, enabling seamless out-of-sample usage (Figure 2).

CONCLUSION: CCL-NMF offers a robust, interpretable framework for understanding brain aging and neurodegeneration by integrating cross-sectional and longitudinal data. It outperforms cross-sectional approaches, delivering richer representations with superior predictive accuracy, and supports easy application to external datasets through regression-based loadings estimation under a web-accessible server (neuroimagingchart.com).},
}

Humans
Magnetic Resonance Imaging
*Biomarkers
*Brain/pathology/diagnostic imaging
Male
Cross-Sectional Studies
Female
Atrophy/pathology
Aged
*Aging/pathology
Middle Aged
Machine Learning
Neuroimaging
Longitudinal Studies

@article {pmid41444165,
year = {2025},
author = {Zhu, Y and Zhang, B},
title = {Clinical Manifestations.},
journal = {Alzheimer's & dementia : the journal of the Alzheimer's Association},
volume = {21 Suppl 3},
number = {},
pages = {e101542},
doi = {10.1002/alz70857_101542},
pmid = {41444165},
issn = {1552-5279},
mesh = {Humans ; Male ; Female ; Magnetic Resonance Imaging ; Aged ; *Cognitive Dysfunction/physiopathology/diagnostic imaging ; Middle Aged ; *Alzheimer Disease/physiopathology/complications/diagnostic imaging ; *Olfaction Disorders/etiology/physiopathology ; Neuropsychological Tests ; *Brain/physiopathology/diagnostic imaging ; },
abstract = {BACKGROUND: Patients with Alzheimer's disease (AD) exhibit olfactory impairments in the early stages of the disease. Individuals with subjective cognitive decline (SCD) are at high risk of preclinical AD. However, it is unclear whether individuals with SCD have impaired olfactory function, and the underlying neural mechanisms remain unknown.

METHOD: A total of 61 normal controls (NC) and 63 individuals with SCD were included. All participants were assessed with cognitive scale assessments, olfactory behavioral tests, and olfactory task-based functional magnetic resonance imaging (fMRI) examinations. Based on the literature, two olfactory brain networks were defined: the primary olfactory brain network and the advanced olfactory brain network. The primary olfactory brain network included the bilateral piriform cortex, amygdala, and entorhinal cortex. The advanced olfactory brain network included bilateral hippocampus, insula cortex, and orbitofrontal cortex. A general linear model was used to calculate functional connectivity within and between networks under odor stimulation. Additionally, correlations between functional connectivity and cognitive performance as well as olfactory behavioral performance were calculated, using gender, age, and years of education as covariates.

RESULT: The olfactory identification scores and SCD-Q scale scores of the SCD group were significantly higher than those of the NC group. Under odor stimulation, the SCD group showed significantly lower connectivity between the right entorhinal cortex and the left insular cortex compared to the NC group, while connectivity between the left piriform cortex and the left amygdala, the left piriform cortex and the right hippocampus, and the right insular cortex and the left orbitofrontal cortex were significantly higher in the SCD group than in the NC group (FDR corrected, p < 0.05). The altered functional connectivity in the SCD group was significantly positively correlated with olfactory thresholds, identification, and memory functions.

CONCLUSION: The results indicate that in response to odor stimulation, individuals with SCD primarily exhibit enhanced functional connectivity in key regions within the olfactory brain network, which may represent a potential neural mechanism for maintaining normal olfactory perception.},
}

Humans
Male
Female
Magnetic Resonance Imaging
Aged
*Cognitive Dysfunction/physiopathology/diagnostic imaging
Middle Aged
*Alzheimer Disease/physiopathology/complications/diagnostic imaging
*Olfaction Disorders/etiology/physiopathology
Neuropsychological Tests
*Brain/physiopathology/diagnostic imaging

@article {pmid41444164,
year = {2025},
author = {Sidhu, G and Guan, DX and Ghahremani, M and Ismail, Z},
title = {Clinical Manifestations.},
journal = {Alzheimer's & dementia : the journal of the Alzheimer's Association},
volume = {21 Suppl 3},
number = {},
pages = {e097686},
doi = {10.1002/alz70857_097686},
pmid = {41444164},
issn = {1552-5279},
mesh = {Humans ; Male ; Female ; Aged ; Atrophy/pathology ; *Cognitive Dysfunction/pathology/psychology ; *Hippocampus/pathology/diagnostic imaging ; Magnetic Resonance Imaging ; *Cognitive Reserve/physiology ; *Entorhinal Cortex/pathology/diagnostic imaging ; Neuropsychological Tests ; Alzheimer Disease/pathology ; Mental Status and Dementia Tests/statistics & numerical data ; Aged, 80 and over ; },
abstract = {BACKGROUND: Cognitive reserve (CR) can serve as a buffer against the clinical manifestations of neurodegenerative disease pathology. For example, greater CR can mitigate cognitive decline in the presence of Alzheimer disease (AD). However, less is known about the associations between CR and neuropsychiatric symptoms (NPS), which also manifest in neurodegenerative disease. AD-related cortical atrophy has previously been linked to NPS. Here, we investigated the moderation effect of CR on the relationship between atrophy in the entorhinal cortex and hippocampus, and NPS in older adults.

METHOD: Data were from 455 participants with normal cognition, mild cognitive impairment, or dementia in the Comprehensive Assessment of Neurodegeneration and Dementia (COMPASS-ND). Composite CR score (CRS) was derived from established pro-cognitive proxies across three domains: education, occupation, and personal activities. Convergent validity of the CRS was assessed by modelling association with Montreal Cognitive Assessment (MoCA) score. Logistic regression modelled the relationship between hippocampal/entorhinal atrophy and NPS. A volume/thickness*CRS interaction term was used to assess effect modification, i.e., whether the association between volume/thickness and NPS differed between the levels of CRS. Marginal effects of hippocampal volume and entorhinal thickness were reported across CRS strata (low[-1SD], average, high[+]). All models adjusted for age and sex; NPS models adjusted for MoCA.

RESULT: Sample characteristics are shown in Table 1. CRS was associated with higher MoCA score (B=8.48, 95%CI: 5.26-11.71, p <0.001) as well as NPS+ status (OR=0.13, 95%CI: 0.02-0.65, p = 0.01). The association between hippocampal atrophy and NPS+ status was weaker at higher CRS strata (p < 0.05), suggesting a protective effect of CR on behaviour. For the association between entorhinal atrophy and NPS+ status, magnitude and direction of the interaction effect were similar to the hippocampus, but the estimate was less precise, and non-significant [Table 2 for all models].

CONCLUSION: Findings indicate that greater CR mitigates NPS associated with hippocampal atrophy, independent of cognition, suggesting that CR may provide protective benefits that extend beyond cognition. Future research should explore outcomes longitudinally, consider domain-specific analyses, and explore whether these findings extend to functional imaging surrogates of CR.},
}

Humans
Male
Female
Aged
Atrophy/pathology
*Cognitive Dysfunction/pathology/psychology
*Hippocampus/pathology/diagnostic imaging
Magnetic Resonance Imaging
*Cognitive Reserve/physiology
*Entorhinal Cortex/pathology/diagnostic imaging
Neuropsychological Tests
Alzheimer Disease/pathology
Mental Status and Dementia Tests/statistics & numerical data
Aged, 80 and over

@article {pmid41444163,
year = {2025},
author = {Bruno, D and Zinkunegi, AJ and Mueller, KD and Lamar, M},
title = {Clinical Manifestations.},
journal = {Alzheimer's & dementia : the journal of the Alzheimer's Association},
volume = {21 Suppl 3},
number = {},
pages = {e097981},
doi = {10.1002/alz70857_097981},
pmid = {41444163},
issn = {1552-5279},
mesh = {Humans ; Female ; Male ; *Alzheimer Disease/pathology/diagnosis/psychology ; Aged ; *Neuropsychological Tests ; *Mental Recall/physiology ; Bayes Theorem ; Aged, 80 and over ; Cohort Studies ; },
abstract = {BACKGROUND: The East Boston memory test (EBMT) is a short story recall test that compares favorably to longer story recall tests like the logical memory test. However, little is known as to how well EBMT predicts postmortem Alzheimer's disease (AD) pathology, and whether item-based serial position analysis is applicable to it for this purpose.

METHODS: Data from 1699 individuals participating in three different Rush University study cohorts were examined (age = 79.7, SD = 7.1). The majority of the sample was comprised of women (69%). All participants completed the test in English and were free of dementia at baseline. Analyses were carried out with Bayesian and Frequentist statistics. Regression analyses were applied to predict overall postmortem AD pathology longitudinally from baseline. Predictors were immediate EBMT recall, delayed EBMT recall, and serial position metrics, i.e., the order in which story items were learned. Control variables were age at baseline, gender, years of education, time between baseline and death, and APOE e4 status.

RESULTS: Inspection of q-q plots suggested the data were suitable for linear regressions. Results from the Bayesian analyses showed that the best fitting model included two predictors: immediate recall (BFinclusion = 4069) and delayed primacy recall (BFinclusion = 9), i.e., remembering the beginning of the story after a delay. The two predictors did not meaningfully interact. Frequentist tests confirmed that including either immediate recall (AIC = 2884; Figure 1) or delayed primacy (AIC = 2896; Figure 2) in the models improved fit over control variables (AIC = 2915). Further tests indicated that immediate and delayed primacy recalls predicted postmortem neuritic plaques and neurofibrillary tangles burdens, but not diffuse plaques burden.

CONCLUSION: In summary, EBMT is suitable to use for early prediction of AD pathology from a cognitively healthy baseline, despite its brevity. Additionally, immediate recall and delayed primacy performance are independent contributors to the prediction of post-mortem AD-related neuropathology.},
}

Humans
Female
Male
*Alzheimer Disease/pathology/diagnosis/psychology
Aged
*Neuropsychological Tests
*Mental Recall/physiology
Bayes Theorem
Aged, 80 and over
Cohort Studies

@article {pmid41444161,
year = {2025},
author = {Tirado, LAR and Cohen, AD and Shaaban, CE and Matan, C and Lopresti, BJ and Ikonomovic, MD and Karikari, TK and Villemagne, VL and Lopez, OL},
title = {Biomarkers.},
journal = {Alzheimer's & dementia : the journal of the Alzheimer's Association},
volume = {21 Suppl 2},
number = {},
pages = {e099147},
doi = {10.1002/alz70856_099147},
pmid = {41444161},
issn = {1552-5279},
mesh = {Humans ; Female ; *Biomarkers/blood/metabolism ; Male ; *Alzheimer Disease/diagnostic imaging/pathology/metabolism ; Amyloid beta-Peptides/metabolism ; Aged ; *Inflammation/metabolism ; Positron-Emission Tomography ; Glial Fibrillary Acidic Protein ; *Gliosis ; Aged, 80 and over ; White Matter/pathology/diagnostic imaging ; C-Reactive Protein/metabolism ; },
abstract = {BACKGROUND: Systemic inflammation and astrogliosis are relevant in Alzheimer's disease (AD). We evaluated whether peripheral inflammation has synergistic effects with astrogliosis on β-amyloid (Aβ), vascular, and neurodegeneration markers.

METHOD: In the Ginkgo Evaluation of Memory Study, we evaluated the relationship between peripheral inflammation (TNF-R1, TNF-R2, IL-6, IL-2, CRP and sCD14) and astrogliosis (GFAP
RESULT: 190 participants were included (mean age: 86±2.8 yrs., 40.8% women, 96.9% White). GFAP was higher among Aβ+ participants; it did not differ by levels of peripheral inflammation. Aβ accumulation was slower among those with high sCD14, particularly among Aβ+. There was a significant negative multiplicative interaction between GFAP and CRP on Aβ accumulation (RR;95%CI:0.61;.38-.99;p=0.047). WML were larger among GFAP+ individuals. There were significant additive and multiplicative interactions of GFAP with CRP (relative excess risk due to interaction (RERI);95%CI:0.47;0.12-0.83;p=0.008; RR;95%CI:1.76;1.11-2.81;p=0.016, respectively), with TNFR1 (RERI;95%CI:0.63;0.29-0.97;p<.001; RR;95%CI:1.93;1.24-3.01;p=0.004, respectively), and with TNFR2 (RERI;95%CI:0.52;0.22-0.82;p=0.001; RR;95%CI:1.82;1.18-2.82;p=0.006, respectively) on WML. Regarding neurodegeneration, there were significant joint effects of GFAP with CRP, sCD14 and/or TNFR1; and significant additive and/or multiplicative interactions of GFAP with CRP (RERI;95%CI:0.35;0.07-0.62;p=0.012, RR;95%CI:1.37;1.04-1.81;p=0.023, respectively) with TNFR1 (RERI;95%CI:0.29;0.08-0.50;p=.007, RR;95%CI:1.30;1.03-1.63;p=0.023, respectively) and with TNFR2 (RERI;95%CI:0.22;0.005-0.45;p=.045).

CONCLUSION: In this 85+ population, with expected high levels of inflammation and more co-pathology; peripheral inflammation (CRP, TNFR1 and/or TNFR2) showed additive/multiplicative synergistic effects with astrogliosis resulting in less amyloid accumulation, greater vascular burden, and more neurodegeneration, particularly in Aβ+ participants. More inflammation may relate with more pathogenesis, bringing participants closer to the amyloid asymptote, slowing Aβ accumulation.},
}

Humans
Female
*Biomarkers/blood/metabolism
Male
*Alzheimer Disease/diagnostic imaging/pathology/metabolism
Amyloid beta-Peptides/metabolism
Aged
*Inflammation/metabolism
Positron-Emission Tomography
Glial Fibrillary Acidic Protein
*Gliosis
Aged, 80 and over
White Matter/pathology/diagnostic imaging
C-Reactive Protein/metabolism

@article {pmid41444157,
year = {2025},
author = {Williams, S and Siddiqi, S and Liu, S and Patel, R and Melgosa-Ecenarro, L and Radulescu, C and Barnes, SJ and Matthews, PM and Jackson, JS},
title = {Biomarkers.},
journal = {Alzheimer's & dementia : the journal of the Alzheimer's Association},
volume = {21 Suppl 2},
number = {},
pages = {e099018},
doi = {10.1002/alz70856_099018},
pmid = {41444157},
issn = {1552-5279},
mesh = {Humans ; *Alzheimer Disease/pathology/metabolism ; Biomarkers/metabolism ; Male ; Aged ; Female ; *Nerve Tissue Proteins/metabolism ; *Membrane Glycoproteins/metabolism ; Aged, 80 and over ; *Synapses/metabolism/pathology ; Synaptophysin/metabolism ; Vesicular Glutamate Transport Protein 1/metabolism ; Disks Large Homolog 4 Protein/metabolism ; Middle Aged ; Membrane Proteins/metabolism ; Vesicular Inhibitory Amino Acid Transport Proteins/metabolism ; },
abstract = {BACKGROUND: Synapse loss is a key component of Alzheimer's Disease (AD) and correlates with cognitive impairment. PET tracer, UCB-J, binds to pre-synaptic protein SV2a and is a potential biomarker of synapse density. SV2a is reportedly ubiquitously expressed at synapses but has been found in other locations making the origin of the PET signal difficult to interpret. Here, we determined the cellular and sub-cellular distribution of SV2a.

METHOD: Prefrontal and mid-temporal gyral non-diseased control (n = 14, Braak 0-II) and AD (n = 14, Braak III-VI) human post-mortem tissue sections were stained with SV2a, synaptophysin, VGLUT1, VGAT, PSD-95 and gephyrin to determine synaptic colocalisation. Further staining used MAP2, NfL, Iba1 and GFAP to map the distribution at non-synaptic sites. Confocal imaging and Imaris were used for all analyses.

RESULT: ∼18% SV2a puncta colocalised with synaptophysin with no regional or disease-state differences but a greater propensity to colocalise with VGLUT1 excitatory protein (∼11%) vs VGAT inhibitory protein (∼8%), similar to mouse models. The proportion of inhibitory and excitatory synapses with SV2a was ∼45% and 58% respectively. SV2a was found in axons (∼23%), and in somato-dendritic compartments (∼7%) which was positively correlated with amyloid pathology. SV2a was observed in astrocytes and significantly increased in AD cortical layer 1 (∼24-25%) vs controls (∼10-16%) however only ∼2% was found in microglia throughout.

CONCLUSION: We show that SV2a is not expressed at all synapses, with a substantial proportion found elsewhere in neurons and glia. Therefore, SV2a as a biomarker may not reveal the true extent of synapse loss in AD.},
}

Humans
*Alzheimer Disease/pathology/metabolism
Biomarkers/metabolism
Male
Aged
Female
*Nerve Tissue Proteins/metabolism
*Membrane Glycoproteins/metabolism
Aged, 80 and over
*Synapses/metabolism/pathology
Synaptophysin/metabolism
Vesicular Glutamate Transport Protein 1/metabolism
Disks Large Homolog 4 Protein/metabolism
Middle Aged
Membrane Proteins/metabolism
Vesicular Inhibitory Amino Acid Transport Proteins/metabolism

@article {pmid41444156,
year = {2025},
author = {Contreras, PR and Alay, NS and Henriquez, F and Migeot, J and Aguillon, D and Bruno, MA and Takada, LT and de Paula, E and Resende, F and Matallana, DL and Funes, JAÁ and Behrens, MI and Custodio, N and Miller, BL and Ibanez, A and Valcour, V and Chonchol, AS},
title = {Clinical Manifestations.},
journal = {Alzheimer's & dementia : the journal of the Alzheimer's Association},
volume = {21 Suppl 3},
number = {},
pages = {e098024},
doi = {10.1002/alz70857_098024},
pmid = {41444156},
issn = {1552-5279},
mesh = {Humans ; *Activities of Daily Living ; Male ; Female ; *Alzheimer Disease/diagnosis/physiopathology/psychology ; *Frontotemporal Dementia/physiopathology/diagnosis/psychology ; Aged ; Neuropsychological Tests/statistics & numerical data ; Middle Aged ; Latin America ; },
abstract = {BACKGROUND: Functional impairment (FI) in activities of daily living (ADL) is a critical criterion for diagnosing dementia that could be categorized into its three dimensions: basic (BADL), instrumental (IADL) and advanced activities (aADL). While FI has been well studied in Alzheimer's disease (AD), this characterization has been underexplored in frontotemporal dementia (FTD) and even more in Latin American countries, where genetic and exposome diversity defines variability in its clinical presentation.

METHOD: We evaluated 547 individuals from RedLat consortium for dementia research in Latin America (262 controls, 236 AD and 49 FTD) from 5 Latin American countries (Argentina, Brazil, Chile, Colombia and Mexico). We performed descriptive statistics for sociodemographic variables. Functional performance was evaluated through the Tecnology-Activities of Daily Living (T-ADLQ) global score and subscores for BADL, IADL, and aADL. Kruskal-Wallis and Dunn post-hoc tests were performed to compare T-ADLQ scores between the three groups.

RESULT: AD participants showed poor global cognitive performance compared to FTD, and FTD presented higher scores in NPI than AD. In total, basic, instrumental, and advanced T-ADLQ scores, FTD showed higher scores than AD participants, which means poor functional performance in FTD participants; however, these differences only showed significance in the basic domain.

CONCLUSION: In Latin American individuals, FTD showed poorer functional performance than AD patients, statistically significant in the basic domain. Further research would be oriented toward exploring the relationship between this functional performance and cognitive and clinical symptoms to determine the functional profile in FTD, compared with AD.},
}

Humans
*Activities of Daily Living
Male
Female
*Alzheimer Disease/diagnosis/physiopathology/psychology
*Frontotemporal Dementia/physiopathology/diagnosis/psychology
Aged
Neuropsychological Tests/statistics & numerical data
Middle Aged
Latin America

@article {pmid41444154,
year = {2025},
author = {Cukier, HN and Song, YE and Coombs, LE and Tang, E and Gu, T and DeRosa, BA and Dykxhoorn, DM and Haines, JL and Pericak-Vance, M and Bush, WS and Griswold, AJ},
title = {Basic Science and Pathogenesis.},
journal = {Alzheimer's & dementia : the journal of the Alzheimer's Association},
volume = {21 Suppl 1},
number = {},
pages = {e106554},
doi = {10.1002/alz70855_106554},
pmid = {41444154},
issn = {1552-5279},
mesh = {Humans ; Male ; *Alzheimer Disease/genetics ; Genome-Wide Association Study ; *Chromosomes, Human, Y/genetics ; Induced Pluripotent Stem Cells ; Leukocytes, Mononuclear ; Aged ; Genotype ; *Mosaicism ; Female ; Middle Aged ; },
abstract = {BACKGROUND: Mosaic loss of the Y chromosome (LOY) is a somatic, age-related phenomenon associated with an increased risk of developing Alzheimer's disease (AD) by our group and others. While the underlying biological mechanism driving this risk remains unknown, genome wide association studies (GWAS) of LOY outcomes identified ∼150 loci involved in cell cycle regulation, mitotic pathways, and DNA damage response. These variants also predict X chromosome loss in women, suggesting that LOY is a marker of genomic instability in males that precedes the AD clinical phenotype.

METHOD: To understand the mechanism by which LOY may contribute to AD risk, we sought to identify both affected and neurologically normal individuals with LOY from genotyping data using the MADloy program. We reprogrammed peripheral blood mononuclear cells (PBMCs) from three of these individuals and used the CytoTune iPS 2.0 Sendai Reprogramming Kit to create induced pluripotent stem cells (iPSCs) lines.

RESULT: 1,068 males with genotyping data were screened for loss of the Y chromosome; 41 (3.83%) had detectable LOY in the blood. As expected, LOY was positively correlated with the age of the individual at the time of sample collection. Three LOY samples (2 cognitively normal individuals and 1 individual with Alzheimer's disease) were chosen for iPSC reprogramming. Samples were independently shown to have LOY through either CNV TaqMan assays or whole genome sequencing data analyzed via the Control-FREEC software. iPSC reprogramming was performed using Sendai virus. Clones were identified from each sample that either carried or were missing the Y chromosome, thereby generating isogenic pairs of cell lines.

CONCLUSION: We have generated paired iPSC cell lines derived from AD and cognitively normal individuals that allow for explicit examination of the impact of LOY on AD-relevant cell types.},
}

Humans
Male
*Alzheimer Disease/genetics
Genome-Wide Association Study
*Chromosomes, Human, Y/genetics
Induced Pluripotent Stem Cells
Leukocytes, Mononuclear
Aged
Genotype
*Mosaicism
Female
Middle Aged

@article {pmid41444152,
year = {2025},
author = {Ge, J and Ling, Y and Luo, B},
title = {Clinical Manifestations.},
journal = {Alzheimer's & dementia : the journal of the Alzheimer's Association},
volume = {21 Suppl 3},
number = {},
pages = {e098945},
doi = {10.1002/alz70857_098945},
pmid = {41444152},
issn = {1552-5279},
mesh = {Humans ; *Alzheimer Disease/therapy/physiopathology/diagnostic imaging ; Magnetic Resonance Imaging ; Electroencephalography ; *Brain/physiopathology/diagnostic imaging ; Neuropsychological Tests ; Male ; Cognitive Dysfunction/therapy ; Female ; *Ultrasonic Therapy/methods ; },
abstract = {BACKGROUND: Alzheimer's disease (AD) is a progressive neurodegenerative disorder characterized by cognitive decline, memory loss, and behavioral changes. Current treatment options are limited in their ability to halt or reverse disease progression, leading to a growing interest in non-invasive neuromodulation techniques. Transcranial focused ultrasound (tFUS) has emerged as a promising therapeutic approach due to its ability to modulate neural activity, enhance drug delivery across the blood-brain barrier, and promote neuroplasticity. Recent studies suggest that tFUS may help alleviate AD symptoms by targeting specific brain regions involved in cognitive function, offering a potential avenue for non-pharmacological intervention.

METHOD: Using tFUS to treat AD patients continuously for two weeks. Neuropsychological assessments, resting-state electroencephalography (EEG), resting-state functional magnetic resonance imaging (fMRI), graph theory analysis, and edge analysis will be used to evaluate changes in cognitive function, brain network connectivity, EEG power spectral density, and functional connectivity before and after tFUS treatment in AD patients.

RESULT: After two weeks of tFUS treatment for Alzheimer's disease patients, significant improvements were observed in MMSE and MOCA scores in the active stimulation group. Edge analysis revealed a significant enhancement in intra-network connectivity within the default mode network (DMN) in the active stimulation group. DTI results showed a significant increase in the rich-club coefficient in the active stimulation group. Resting-state EEG indicated a significant reduction in delta band power spectral density in the frontal region of the scalp.

CONCLUSION: TFUS stimulation has shown promising potential in improving cognitive impairment in Alzheimer's disease patients by enhancing the connectivity and functionality of the DMN. Additionally, neuroimaging findings have demonstrated that tFUS enhances structural and functional connectivity in key DMN regions, potentially slowing disease progression and offering a non-invasive therapeutic strategy for managing cognitive decline in AD patients.},
}

Humans
*Alzheimer Disease/therapy/physiopathology/diagnostic imaging
Magnetic Resonance Imaging
Electroencephalography
*Brain/physiopathology/diagnostic imaging
Neuropsychological Tests
Male
Cognitive Dysfunction/therapy
Female
*Ultrasonic Therapy/methods

@article {pmid41444151,
year = {2025},
author = {Zammit, MD},
title = {Biomarkers.},
journal = {Alzheimer's & dementia : the journal of the Alzheimer's Association},
volume = {21 Suppl 2},
number = {},
pages = {e099359},
doi = {10.1002/alz70856_099359},
pmid = {41444151},
issn = {1552-5279},
mesh = {Humans ; *tau Proteins/blood/metabolism ; *Biomarkers/blood ; Male ; Female ; Positron-Emission Tomography ; *Amyloid beta-Peptides/metabolism ; *Alzheimer Disease/diagnostic imaging ; Adult ; Middle Aged ; *Down Syndrome/diagnostic imaging/metabolism ; Longitudinal Studies ; Disease Progression ; Brain/diagnostic imaging/metabolism ; Aged ; },
abstract = {BACKGROUND: Characterizing the timing and progression of Alzheimer's disease (AD) biomarker positivity in Down syndrome (DS) and contrasting potential timing differences with neurotypical (NT) adults is needed to identify optimal anti-amyloid treatment windows in DS. This work uses temporal modeling to characterize tau accumulation using plasma pTau217 and Tau PET relative to amyloid accumulation using amyloid PET for DS and NT.

METHOD: 198 adults with DS from the ABC-DS and 172 NT adults from WRAP with available longitudinal Aβ PET, Tau PET and plasma pTau217 Lilly-Mesoscale immunoassay were included (Table 1). Aβ was quantified using Centiloids. Tau PET SUVRs were obtained from the Mesial Temporal and Universal CenTauR ROIs. A+ time was estimated using sampled iterative local approximation applied to longitudinal CL data. A Cox proportional hazards model was used to test differences in A+ onset age between DS/NT groups with A- participants right-censored at their last observation. Linear mixed-effects models (considering up to cubic polynomials) with random person-level intercepts were performed between estimated A+ time (predictor) and pTau217 and Tau PET for all participants. pTau217+ and Tau PET T+ onset times were extracted using inverse estimation of the LMEs.

RESULT: Following A+, DS revealed earlier pTau217 and Tau PET increases relative to NT (Figure 1). The Cox PH model indicated a significant difference in A+ risk between groups (p <0.001) with DS having 21.25[13.89, 32.51]-fold higher risk of becoming A+ over 5.5 years of follow-up (Table 1). pTau217+ and T+ in DS occurred nearly simultaneously (∼3-5 years after A+), while NT had greater time to pTau217+ and T+ and exhibited temporal latency between pTau217 and Tau PET onset (Figure 2).

CONCLUSION: Individuals with DS have earlier pTau217 and Tau PET progression following PET A+ compared to neurotypical adults. The early and simultaneous onset of these biomarkers in DS highlight the necessity for early AD interventions in this population. This work, combined with the upcoming DSAD clinical trials will help identify optimal treatment windows for these individuals.},
}

Humans
*tau Proteins/blood/metabolism
*Biomarkers/blood
Male
Female
Positron-Emission Tomography
*Amyloid beta-Peptides/metabolism
*Alzheimer Disease/diagnostic imaging
Adult
Middle Aged
*Down Syndrome/diagnostic imaging/metabolism
Longitudinal Studies
Disease Progression
Brain/diagnostic imaging/metabolism
Aged

@article {pmid41444147,
year = {2025},
author = {Elia, A and Rullan, RMP and Vazquez-Torres, R and Carey, AM and Fossati, S},
title = {Basic Science and Pathogenesis.},
journal = {Alzheimer's & dementia : the journal of the Alzheimer's Association},
volume = {21 Suppl 1},
number = {},
pages = {e106732},
doi = {10.1002/alz70855_106732},
pmid = {41444147},
issn = {1552-5279},
mesh = {Animals ; Humans ; *Alzheimer Disease/pathology/metabolism ; Brain-Derived Neurotrophic Factor/metabolism ; Mice ; Myocytes, Cardiac/metabolism/pathology ; Amyloid beta-Peptides/metabolism ; Mice, Transgenic ; Disease Models, Animal ; Myocardium/pathology/metabolism ; Brain/pathology/metabolism ; Fibrosis ; Male ; },
abstract = {BACKGROUND: Alzheimer's disease (AD) profoundly disrupts neurotrophic factors (NTFs) signaling in the brain, including key players like NGF and BDNF, which are essential for maintaining healthy neuronal homeostasis. A loss of NTFs may also instigate peripheral nervous system dysfunction, potentially predisposing AD patients to develop cardiovascular disorders of different etiology. Despite the growing recognition of cardiac abnormalities in AD, the mechanisms through which AD pathology impairs the brain-heart axis and affects myocardial innervation and function have remained poorly understood.

METHODS: This study comprehensively analyzes cardiac physiology, amyloid pathology, neurotrophic factor depletion, and cardiac neuronal fiber degeneration in Tg2576-AD mice, human cardiomyocytes, and human AD postmortem left ventricular (LV) heart tissue.

RESULTS: Our results demonstrate that AD pathology leads to increased myocardial fibrosis, amyloid β (Aβ) deposition, and significant remodeling of the brain-heart axis neuro-signaling pathway, culminating in myocardial denervation and impaired cardiac function. Notably, Aβ oligomers were found to reduce BDNF expression in human cardiomyocytes by disrupting CREB function, the key transcription factor for BDNF expression. Postmortem analysis of human LV tissue from AD patients confirmed the animal and cell findings.

CONCLUSION: Collectively, our research unveils a previously unrecognized mechanism by which Aβ dysregulates cardiac neurotrophic signaling, emphasizing the relevance of cardiac degeneration in AD. Our findings highlight the importance of addressing cardiac complications in AD management, thus opening novel translational avenues for future precision medicine investigations that may help to reevaluate the clinical approaches to AD therapy.},
}

Animals
Humans
*Alzheimer Disease/pathology/metabolism
Brain-Derived Neurotrophic Factor/metabolism
Mice
Myocytes, Cardiac/metabolism/pathology
Amyloid beta-Peptides/metabolism
Mice, Transgenic
Disease Models, Animal
Myocardium/pathology/metabolism
Brain/pathology/metabolism
Fibrosis
Male

@article {pmid41444146,
year = {2025},
author = {Gerards, M and Hübner, C and Baumeister, A and Ribaldi, F and Cantero-Fortiz, Y and Braun, J and Boada, M and Frisoni, GB and Schmitz-Luhn, B and Schwegler, C and Woopen, C and Jessen, F and Rostamzadeh, A},
title = {Clinical Manifestations.},
journal = {Alzheimer's & dementia : the journal of the Alzheimer's Association},
volume = {21 Suppl 3},
number = {},
pages = {e098147},
doi = {10.1002/alz70857_098147},
pmid = {41444146},
issn = {1552-5279},
mesh = {Humans ; Male ; Female ; Aged ; *Alzheimer Disease/diagnosis/psychology ; Germany ; Spain ; Switzerland ; *Cognitive Dysfunction/diagnosis/psychology ; Aged, 80 and over ; Surveys and Questionnaires ; Middle Aged ; Risk Assessment ; },
abstract = {BACKGROUND: Advances in disease-modifying treatments and blood-based biomarkers for Alzheimer's disease (AD) have increased the importance of early diagnosis and dementia risk estimation before symptom onset. Autonomous decisions about AD risk estimation are complex and should align with individual needs and preferences. The PreTAD study (Predictive Turn in Alzheimer's Disease: Ethical, Clinical, Linguistic, and Legal Aspects) evaluates and compares attitudes on dementia risk estimation among first-degree relatives of individuals with dementia and patients with subjective cognitive decline to improve counseling for preclinical predictive AD diagnostics in the future.

METHOD: PreTAD assesses risk perception, attitudes and views on AD dementia risk estimation, along with influencing psychosocial factors (living situation, loneliness, resilience, anxiety, and depression). The risk perception survey assessed participants' opinions on two aspects: (1) what percentage they consider to represent a high general risk of developing AD dementia (perceived high general dementia risk), and (2) their perceived personal risk of developing AD dementia within 10 years (personal dementia risk).

RESULT: Results from 390 participants in Germany, Switzerland, and Spain are presented. The perceived high general dementia risk assessed by participants ranged from >0%-100%. Around 30% perceived their personal dementia risk as 0-10%, while 70% rated their personal dementia risk as higher than 10%. Higher estimated personal dementia risk was associated with a greater estimated impact of biomarker-based early dementia risk estimation and clinical trial participation on the decision to estimate one's own dementia risk. Perceived high general dementia risk correlated with a higher influence of income, belief in the impact of lifestyle changes, and preference for high test accuracy over low invasiveness on the decision to estimate dementia risk. Higher perceived personal dementia risk correlated with lower resilience and higher anxiety.

CONCLUSION: Risk perception is highly individual and may influence the process of AD dementia risk estimation. While psychosocial factors appear to have a limited impact on the decision to pursue dementia risk estimation in a hypothetical scenario, their impact in the subsequent process remains unclear. PreTAD findings highlight the need for personalized counseling that considers emotional and cognitive profiles to support informed decision-making in preclinical predictive AD diagnostics.},
}

Humans
Male
Female
Aged
*Alzheimer Disease/diagnosis/psychology
Germany
Spain
Switzerland
*Cognitive Dysfunction/diagnosis/psychology
Aged, 80 and over
Surveys and Questionnaires
Middle Aged
Risk Assessment

@article {pmid41444145,
year = {2025},
author = {AlQahtani, BG},
title = {Clinical Manifestations.},
journal = {Alzheimer's & dementia : the journal of the Alzheimer's Association},
volume = {21 Suppl 3},
number = {},
pages = {e097105},
doi = {10.1002/alz70857_097105},
pmid = {41444145},
issn = {1552-5279},
mesh = {Humans ; *Cognitive Dysfunction/physiopathology/diagnosis ; *Alzheimer Disease/diagnosis/physiopathology/complications ; *Motion Perception/physiology ; Contrast Sensitivity/physiology ; *Visual Perception/physiology ; Attention/physiology ; },
abstract = {BACKGROUND: Research indicates that Alzheimer's disease (AD) significantly affects visual processing capabilities, which can be linked to cognitive performance. Individuals with AD exhibit visual attention, contrast sensitivity, and motion perception impairments, all of which are crucial for cognitive tasks. Furthermore, studies have shown that visual deficits may precede cognitive decline, suggesting that assessing visual processing could provide early indicators of Alzheimer's disease.

OBJECTIVE: This systematic review aims to evaluate the evidence linking visual processing deficits to early cognitive decline in Alzheimer's disease and to identify neuro-ophthalmological tools that assess these deficits and their potential role in early diagnosis.

METHODS: A systematic search was conducted across PubMed, Scopus, Embase, and Web of Science for studies published between January 2010 and December 2024. The inclusion criteria encompassed studies that examined visual processing metrics (e.g., contrast sensitivity, motion perception) in individuals diagnosed with AD or mild cognitive impairment (MCI). The selected studies were critically appraised for their quality and relevance to the research question.

RESULTS: Twenty-four studies met the inclusion criteria, comprising 10,211 participants. Significant deficits were observed in AD patients compared to controls: Motion Perception: The Standardized Mean Difference (SMD) was found to be -0.89 (95% CI: -1.12 to -0.66), indicating a significant difference in motion perception between AD patients and controls. Saccadic Eye Movements: SMD = -0.76 (95% CI: -0.94 to -0.58), Contrast Sensitivity: SMD = -0.82 (95% CI: -1.03 to -0.61), MCI patients exhibited intermediate impairments in these metrics. Importantly, visual processing deficits were found to strongly correlate with cognitive scores (r = 0.52 to 0.63, p < 0.001), providing robust evidence for the strong relationship between visual deficits and cognitive decline.

CONCLUSION: Visual processing deficits are consistently associated with early cognitive decline in AD and may serve as non-invasive biomarkers for early detection. Understanding this link can aid in developing diagnostic tools for timely intervention. The need for further investigation into their clinical utility is clear, and this area of research promises to be both challenging and rewarding.},
}

Humans
*Cognitive Dysfunction/physiopathology/diagnosis
*Alzheimer Disease/diagnosis/physiopathology/complications
*Motion Perception/physiology
Contrast Sensitivity/physiology
*Visual Perception/physiology
Attention/physiology

@article {pmid41444144,
year = {2025},
author = {Ospina, P and Vasquez, D and Baena, AY and Ramirez, S and Tirado, V and Henao, E and Zubiri, V and Aponte, C and Guerrero, A and Martinez, JE and Carmo, SD and Niño, DFA and Cuello, AC and Quiroz, YT},
title = {Clinical Manifestations.},
journal = {Alzheimer's & dementia : the journal of the Alzheimer's Association},
volume = {21 Suppl 3},
number = {},
pages = {e107606},
doi = {10.1002/alz70857_107606},
pmid = {41444144},
issn = {1552-5279},
mesh = {Humans ; Male ; Female ; *Social Support ; Adult ; *Presenilin-1/genetics ; Neuropsychological Tests ; *Alzheimer Disease/genetics/psychology ; Colombia ; Mutation/genetics ; *Cognitive Dysfunction/genetics/psychology ; Middle Aged ; Depression/psychology ; Cohort Studies ; Cognition ; },
abstract = {BACKGROUND: Perceived social support is an individual's sense of available emotional support from family and social networks. In neurodegenerative diseases, it has been explored as a potential protective factor against cognitive decline. Identifying modifiable factors is especially crucial for high-risk populations. Individuals with autosomal dominant Alzheimer's disease (ADAD) typically develop early-onset dementia, with research suggesting that certain factors may influence the timing of clinical onset. This study investigated the effects of perceived social support on cognitive performance in members of the Colombian kindred with the PSEN1 E280A mutation.

METHOD: This study included 144 cognitively-unimpaired individuals from the PSEN1 E280A cohort (64 carriers, 80 non-carriers) from the Rita/NGF biomarker study. The mean age was 30.33(SD5.74) years for carriers and 34.38(SD9.23) for non-carriers. Cognitive function was assessed using the MMSE and CERAD Word List Delayed Recall, while depression was measured with the Geriatric Depression Scale (GDS). Perceived social support was evaluated using the Multidimensional Scale of Perceived Social Support (MSPSS), which captures support from three sources: family, friends, and significant others. Group comparisons and associations were analyzed using the Mann-Whitney-Wilcoxon test and Spearman correlations.

RESULTS: Carriers had lower MMSE scores than non-carriers (carriers: 26.3, SD 1.4; non-carriers: 28.8, SD 1.3; p =  0.033) and reported more depressive symptoms (carriers: 2.8, SD 3.4; non-carriers: 1.6, SD 2.2; p =  0.039). Additionally, carriers perceived lower overall social support (5.1 SD 1.3) compared to non-carriers (5.6 SD 1.2; p =  0.014), with the difference largely driven by reduced support from family and significant others. These differences remained statistically significant even after controlling for depressive symptoms. However, perceived social support was not linked to cognition, age, or education.

CONCLUSION: This study found significant differences in overall perceived social support between carriers and non-carriers in individuals with autosomal dominant AD. Longitudinal follow-up of this population is essential to further explore the relationship between perceived social support and other cognitive functions, such as executive function. Evaluating perceived support may help identify modifiable risk factors for dementia and inform interventions aimed at enhancing mental and brain health in individuals at high risk for AD.},
}

Humans
Male
Female
*Social Support
Adult
*Presenilin-1/genetics
Neuropsychological Tests
*Alzheimer Disease/genetics/psychology
Colombia
Mutation/genetics
*Cognitive Dysfunction/genetics/psychology
Middle Aged
Depression/psychology
Cohort Studies
Cognition

@article {pmid41444142,
year = {2025},
author = {Jutten, RJ and Soberanes, D and Kim, H and Dubbelman, MA and D'Aquila, L and Yang, HS and Blacker, D and Rentz, DM and Marshall, GA and Johnson, KA and Sperling, RA and Amariglio, RE and Papp, KV},
title = {Clinical Manifestations.},
journal = {Alzheimer's & dementia : the journal of the Alzheimer's Association},
volume = {21 Suppl 3},
number = {},
pages = {e106782},
doi = {10.1002/alz70857_106782},
pmid = {41444142},
issn = {1552-5279},
mesh = {Humans ; Female ; Male ; Aged ; *Alzheimer Disease/diagnosis/blood ; *tau Proteins/blood ; Neuropsychological Tests ; Biomarkers/blood ; *Cognitive Dysfunction/diagnosis/blood ; Cohort Studies ; Aged, 80 and over ; },
abstract = {BACKGROUND: Timely identification of individuals at-risk for Alzheimer's disease (AD) is pivotal for secondary prevention and requires innovative approaches. Combining remote smartphone-based cognitive assessments with blood-based biomarkers holds promise for both sensitive and scalable detection of early AD-related cognitive changes. Here, we aimed to investigate whether the Boston Remote Cognitive Assessment of NeuroCognitive Health (BRANCH) captures cognitive changes associated with early AD pathophysiology as measured by plasma p-tau217.

METHOD: N = 254 cognitively unimpaired older adults (age=74.5±8.6, 68% female, 16.6±2.4 years of education) from four well-characterized cohorts completed multi-day BRANCH on their personal device. Multiday BRANCH includes two associative memory tests (Face Name and Groceries Prices) and a processing speed test with an associative memory component (Digit Signs) with identical stimuli repeated for seven consecutive days. For each test, an MDLC score was computed using an area under the curve method combining day 1 performance with a non-linear learning trajectory over the subsequent six days. MDLCs for each individual test were averaged into a BRANCH Composite MDLC. All cohorts had standardized in-clinic cognitive test data available, from which a Preclinical Alzheimer's Cognitive Composite (PACC-5) score was derived. Concentrations of plasma p-tau217 were measured using the Meso Scale Discovery platform. Linear regression models adjusting for age, sex, years of education and study cohort were used to investigate the association between p-tau217 (log-transformed values) and BRANCH MDLC scores. For comparison, similar analyses were run with PACC-5 scores and p-tau217.

RESULT: Lower BRANCH Composite MDLC scores were associated with higher p-tau217 levels (corrected std. β = -0.23, 95%CI [-0.44 - -0.02], p = 0.031) (Figure 1), which was primarily driven by the Digit Signs test (corrected std. β = -0.22, 95%CI [-0.42 - -0.02], p = 0.031). In contrast, we did not find an association between the PACC-5 and p-tau217 (corrected std. β = -0.15, 95%CI [-0.37 - 0.07], p = 0.187).

CONCLUSION: These results complement our previous work that multi-day BRANCH may improve the detection of very subtle memory deficits that are associated with early AD pathophysiology. Combining a remote and sensitive cognitive paradigm like BRANCH with plasma biomarkers may facilitate scalable detection of those at risk for AD-related cognitive decline.},
}

Humans
Female
Male
Aged
*Alzheimer Disease/diagnosis/blood
*tau Proteins/blood
Neuropsychological Tests
Biomarkers/blood
*Cognitive Dysfunction/diagnosis/blood
Cohort Studies
Aged, 80 and over

@article {pmid41444141,
year = {2025},
author = {Tanner, JA and Valdespino, R and Kautz, TF and Masette, G and Hromas, G and Wang, CP and Himali, JJ and Paul, R and Nakasujja, N and Reynolds, Z and Atwine, F and Tindimwebwa, E and Greene, M and Passell, E and Ritchie, CS and Hoeppner, SS and Tsai, AC and Janet, S and VandeVrede, L and Werry, A and Tsoy, E and Possin, KL and Seshadri, S and Okello, S and Asiimwe, S and Saylor, D and Siedner, MJ},
title = {Clinical Manifestations.},
journal = {Alzheimer's & dementia : the journal of the Alzheimer's Association},
volume = {21 Suppl 3},
number = {},
pages = {e098870},
doi = {10.1002/alz70857_098870},
pmid = {41444141},
issn = {1552-5279},
mesh = {Humans ; Female ; Male ; *HIV Infections/drug therapy/psychology/complications/epidemiology ; Middle Aged ; Neuropsychological Tests/statistics & numerical data ; Uganda/epidemiology ; Prospective Studies ; Amyloid beta-Peptides/blood ; *Cognitive Dysfunction ; Aged ; Cohort Studies ; tau Proteins/blood/cerebrospinal fluid ; *Alzheimer Disease/epidemiology ; *Aging ; Biomarkers/blood ; },
abstract = {BACKGROUND: Sub-Saharan Africa (sSA) is projected to have the fastest population growth in older adults globally, a >250% increase in Alzheimer's Disease (AD), and rapid growth in older people living with HIV (PLWH) well-treated on antiretroviral therapies (ARTs) in the coming decades. In the Global North, HIV infection has been associated with neuroinflammation, accelerated brain aging, cognitive impairment, and AD pathology. In sSA, data about the intersections of aging, AD, and HIV are lacking.

METHOD: The Uganda Aging Cohort Study (UACS) is a prospective cohort study of PLWH well-treated on ARTs, and age- and sex-matched community-dwelling people without HIV enrolled with population-based sampling. Participants completed cognitive testing with the locally normed Ugandan Neuropsychological Battery and tablet-based Cognitive Assessment Tool (TabCAT). Z-scores for each test were created using a regression-based normative approach with adjustment for age, sex, and education. Composite scores were created from mean Z-scores for global cognition, TabCAT, and each cognitive domain. The presence/absence of cognitive impairment was defined using Jak/Bondi criteria. Plasma p-tau217 and Aβ42/40 were measured on the Fujirebio Lumipulse platform. GFAP and NfL were measured on the Quanterix Simoa HD-X. Chi-squared and t-tests were used to compare cognitive performance and natural log-transformed plasma biomarker levels between groups.

RESULT: A total of 576 UACS participants (mean age 60±6.5 years, age range 48-82, 50% female, 51% with less than a primary school education) completed study measures. PLWH had higher scores on animal fluency, but otherwise cognitive performance was comparable between groups including composite scores, cognitive domains, and individual tests (Table 1, Figure 1). There was a trend towards higher frequency of cognitive impairment and elevated p-tau217 among PLWH. There were no statistically significant differences in p-tau217/Aβ42, Aβ42/40, GFAP, or NfL by HIV serostatus (Table 1, Figure 2).

CONCLUSION: Older PLWH well-treated on ART in Uganda have cognitive performance and plasma ADRD biomarker levels comparable to demographically-matched people without HIV, consistent with recent studies showing cognitive impairment is less common among PLWH with viral suppression. Ongoing studies will further assess trends in increased cognitive impairment and p-tau217 in PLWH, and evaluate differences in ADRD prevalence and cognitive trajectories in this cohort.},
}

Humans
Female
Male
*HIV Infections/drug therapy/psychology/complications/epidemiology
Middle Aged
Neuropsychological Tests/statistics & numerical data
Uganda/epidemiology
Prospective Studies
Amyloid beta-Peptides/blood
*Cognitive Dysfunction
Aged
Cohort Studies
tau Proteins/blood/cerebrospinal fluid
*Alzheimer Disease/epidemiology
*Aging
Biomarkers/blood

@article {pmid41444140,
year = {2025},
author = {Katragadda, HV and Ghaseminejad-Bandpey, A and Keating, M and Alhneif, M and Mojtabai, M and Habes, M and Seshadri, S and Flanagan, ME and Bieniek, KF},
title = {Basic Science and Pathogenesis.},
journal = {Alzheimer's & dementia : the journal of the Alzheimer's Association},
volume = {21 Suppl 1},
number = {},
pages = {e106144},
doi = {10.1002/alz70855_106144},
pmid = {41444140},
issn = {1552-5279},
mesh = {Humans ; Female ; Aged ; *Frontotemporal Dementia/pathology/genetics ; *Amyotrophic Lateral Sclerosis/pathology/genetics/complications ; Neuropsychological Tests ; Magnetic Resonance Imaging ; Cognitive Dysfunction/pathology ; Brain/pathology/diagnostic imaging ; },
abstract = {BACKGROUND: Amyotrophic lateral sclerosis (ALS) with frontotemporal dementia (FTD) is a neurodegenerative disorder characterized by an admixture of motor and cognitive/behavioral impairments (either concurrent or sequential). The predominant pathological hallmark is TDP-43 proteinopathy, but it encompasses multiple frontotemporal lobar degeneration (FTLD) TDP-43 subtypes, complicating both diagnosis and classification. The case report herein details a 69-year-old female with a history of cognitive decline, dysarthria, and behavioral changes, ultimately diagnosed with ALS-FTD.

METHOD: A 69-year-old right-handed Caucasian female presented with decreased short-term memory. Initial neuropsychological testing in 2019 revealed superior performance on the Dementia Rating Scale (DRS; 143/144) and Mini-Mental State Exam (MMSE; 30/30), with mild impairment in visuospatial construction, visual-motor organization, and visual memory, consistent with mild cognitive impairment (MCI). MRI revealed mild ischemic changes, more pronounced in the pons and left basal ganglia. No significant frontal or temporal lobar atrophy was observed, consistent with findings from 2017 MRI. Follow-up testing in 2020 revealed mild to moderate impairments across multiple visuospatial cognitive domains, which were consistent with MCI. By late 2021, the patient developed progressive dysarthria, executive dysfunction, and behavioral changes (inappropriate), and pseudobulbar affect resulting in an antemortem diagnosis of ALS with FTD. While delusions are typically present in most cases, they were notably absent in this case.

RESULTS: At the age of 72, Postmortem neuropathology revealed changes consistent with mild cerebrovascular disease and Intermediate-level Alzheimer's disease neuropathological changes (ADNC). Immunohistochemical analysis for phosphorylated TDP-43 demonstrated skein-like inclusions in the spinal cord as well as neocortical glial cytoplasmic inclusions, neuronal cytoplasmic inclusions, and dystrophic neurites, consistent with mixed FTLD-TDP and ALS as the primary pathological findings. TDP-43 pathology was not specific to a single FTLD-TDP subtype, rather features of both Type A and Type B were present. Additionally, p62-immunohistochemistry indicates possible C9ORF72 repeat expansion (with genetic testing pending).

CONCLUSION: Mixed Type A+B cases are typically associated with C9ORF72 repeat expansions and prominent delusions. In contrast, the case presented here lacked delusions, with early disease features predominantly characterized by visuospatial deficits. The clinical presentation, along with overlapping pathological features of FTLD-TDP subtypes A and B, underscores the atypical nature of this case relative to previously reported series.},
}

Humans
Female
Aged
*Frontotemporal Dementia/pathology/genetics
*Amyotrophic Lateral Sclerosis/pathology/genetics/complications
Neuropsychological Tests
Magnetic Resonance Imaging
Cognitive Dysfunction/pathology
Brain/pathology/diagnostic imaging

@article {pmid41444139,
year = {2025},
author = {Vellone, DA and Guan, DX and Ismail, Z},
title = {Clinical Manifestations.},
journal = {Alzheimer's & dementia : the journal of the Alzheimer's Association},
volume = {21 Suppl 3},
number = {},
pages = {e099159},
doi = {10.1002/alz70857_099159},
pmid = {41444139},
issn = {1552-5279},
mesh = {Humans ; Female ; Male ; Aged ; Magnetic Resonance Imaging ; Cross-Sectional Studies ; *Apathy/physiology ; *Cognitive Dysfunction/pathology/diagnostic imaging ; *Brain/pathology/diagnostic imaging ; Neuropsychological Tests ; Middle Aged ; Aged, 80 and over ; },
abstract = {BACKGROUND: Mild Behavioral Impairment (MBI) is a pre-dementia syndrome defined by persistent late-life-onset behavioural changes and serves as a risk marker for cognitive decline and incident dementia. The apathy MBI domain is hypothesized to be associated with regional brain changes, but it is unclear if these are the same regions described for apathy in dementia. This study investigates volumetric differences between dementia-free individuals with MBI-apathy and those without neuropsychiatric symptoms (No NPS).

METHOD: This study included 446 participants (mean age = 69.6 years; 79.8% cognitively normal; 62.8% female) from the National Alzheimer's Coordinating Center. Participants were grouped into No NPS (n = 387) and MBI-apathy (n = 59). Cross-sectional linear regression models examined the association between NPS status and regional brain measures. Outcomes included AD-related region composite measures of cortical thickness (entorhinal cortex, inferior temporal gyrus, middle temporal gyrus, inferior parietal lobule, fusiform gyrus, and precuneus) and volume (hippocampus, entorhinal cortex, amygdala, middle temporal gyrus, inferior parietal lobule, and precuneus). Additionally, cortical thickness and volume measures for four apathy-related regions (anterior cingulate cortex [ACC], orbitofrontal cortex [OFC], dorsolateral prefrontal cortex [dlPFC], and ventrolateral prefrontal cortex [vlPFC]) were included. Models adjusted for age, sex, education, APOE4 carrier status, and Mini-Mental State Examination score.

RESULT: Compared to the No NPS group, MBI-apathy status was significantly associated with lower average AD composite thickness score (β = -0.40; 95% CI = -0.74-(-0.05); p = 0.024), total AD composite volume (β = -3.33; 95% CI = -4.66-(-2.00); p < 0.001), dlPFC thickness (β = -0.35; 95% CI = -0.69-(-0.004); p = 0.048), OFC volume (β = -0.34; 95% CI = -0.64-(-0.04); p = 0.028), and dlPFC volume (β = -0.27; 95% CI = -0.54-(-0.01); p = 0.040).

CONCLUSION: MBI-apathy shows stronger stronger associations with atrophy in regions affected early in the course of AD. This finding suggests that at the CN and MCI stages, MBI-apathy may reflect brain changes characteristic of early AD. These findings suggest that MBI-apathy is associated with early-stage AD and that regions typically linked to apathy are likely affected later in the disease, with stronger associations emerging as AD progresses.},
}

Humans
Female
Male
Aged
Magnetic Resonance Imaging
Cross-Sectional Studies
*Apathy/physiology
*Cognitive Dysfunction/pathology/diagnostic imaging
*Brain/pathology/diagnostic imaging
Neuropsychological Tests
Middle Aged
Aged, 80 and over

@article {pmid41444138,
year = {2025},
author = {Bose, C and Hindle, A and Baker, A and Smith, S and Singh, SP and Lawrence, JJ},
title = {Basic Science and Pathogenesis.},
journal = {Alzheimer's & dementia : the journal of the Alzheimer's Association},
volume = {21 Suppl 1},
number = {},
pages = {e106950},
doi = {10.1002/alz70855_106950},
pmid = {41444138},
issn = {1552-5279},
mesh = {Animals ; *Tretinoin/pharmacology ; Mice ; Vorinostat ; NF-E2-Related Factor 2/metabolism ; *Hippocampus/drug effects/pathology/metabolism/cytology ; *Oxidative Stress/drug effects/physiology ; *Neurons/drug effects/metabolism/pathology ; Hydroxamic Acids/pharmacology ; Apoptosis/drug effects ; Hydrogen Peroxide/pharmacology ; Cell Line ; Histone Deacetylase Inhibitors/pharmacology ; Lipid Peroxidation/drug effects ; Antioxidants/pharmacology ; },
abstract = {BACKGROUND: A key feature of Alzheimer's disease (AD) is the accumulation of reactive oxygen species (ROS), which causes oxidative damage and mitochondrial dysfunction. Diet-derived antioxidants such as all-trans retinoic acid (ATRA) and oxidative stress (OS)-responsive regulatory factors, such as nuclear factor erythroid 2-related factor 2 (Nrf2), support exogenous and endogenous antioxidant defenses in neurons. Evidence suggests that ATRA and Nrf2 levels are decreased in the hippocampus of AD patients. Additionally, histone acetylation/deacetylation homeostasis is disrupted in AD. The present study seeks to determine whether the histone deacetylase inhibitor vorinostat and ATRA can synergistically or differentially regulate redox homeostasis to protect neuronal cells from OS METHOD: Mouse hippocampal neurons (HT22 cells) were pre-treated with non-cytotoxic doses of ATRA (5µM) and/or vorinostat (VOR; 0.5µM). After 24h, cells were challenged with 50µM H2O2 for 24h. Lipid peroxidation, mitochondrial oxidation, apoptosis, DNA fragmentation, Nrf2 expression, and antioxidant response enzymes were examined via colorimetric ELISAs, comet assay, TUNEL assay, flow cytometry, immunocytochemistry, and Western blots.

RESULT: Pre-treatment of HT22 cells with ATRA and VOR in combination was protective against 150 µM H2O2. 4-HNE protein adducts, and apoptosis/necrosis were significantly attenuated by ATRA or VOR pretreatments (p <0.001). H2O2 showed numerous DNA strand breaks with an average of 94.8±4.7% of DNA in comet tails. However, pretreatments of ATRA and VOR significantly (p <0.001) decreased DNA breaks (9.4±0.3%-17.1±0.61%). Pretreatments of either ATRA or VOR alone significantly increased Nrf2 protein levels (p <0.05) and led to increased downstream antioxidant enzymes HO-1 and SOD. Although H2O2 alone induced Nrf2 protein expression, nuclear Nrf2 binding activity was significantly lower than in cells pre-treated with ATRA (p <0.05, and p <0.001, respectively). Thus, nuclear Nrf2 activity does not result from generalized loss of total Nrf2 protein but may reflect impaired nuclear trafficking and transcription factor activity. Our observations suggest that the Nrf2 pathway is likely dysfunctional in hippocampal neurons after OS.

CONCLUSION: It is evident that ATRA and VOR, alone or in combination, protect neuronal cells from OS via independent pathways. However, both pathways are important to initiate protection and could be useful to reduce OS during early disease pathogenesis and progression.},
}

Animals
*Tretinoin/pharmacology
Mice
Vorinostat
NF-E2-Related Factor 2/metabolism
*Hippocampus/drug effects/pathology/metabolism/cytology
*Oxidative Stress/drug effects/physiology
*Neurons/drug effects/metabolism/pathology
Hydroxamic Acids/pharmacology
Apoptosis/drug effects
Hydrogen Peroxide/pharmacology
Cell Line
Histone Deacetylase Inhibitors/pharmacology
Lipid Peroxidation/drug effects
Antioxidants/pharmacology

@article {pmid41444137,
year = {2025},
author = {Custodio, N and Malaga, M and Bustamante-Paytan, D and Huilca, JC and Aguero, K and Verastegui, G and Bartolo, P and Bendezu, D and Yauri, Z and Montesinos, R},
title = {Clinical Manifestations.},
journal = {Alzheimer's & dementia : the journal of the Alzheimer's Association},
volume = {21 Suppl 3},
number = {},
pages = {e099298},
doi = {10.1002/alz70857_099298},
pmid = {41444137},
issn = {1552-5279},
mesh = {Humans ; Male ; Female ; Aged ; Retrospective Studies ; *Lewy Body Disease/diagnosis/physiopathology/psychology/complications ; Neuropsychological Tests ; Disease Progression ; *Alzheimer Disease/diagnosis/physiopathology/psychology ; Aged, 80 and over ; Middle Aged ; Peru ; Cognitive Dysfunction ; },
abstract = {BACKGROUND: Dementia with Lewy Bodies (DLB) is a specific type of dementia associated with the accumulation of alpha-synuclein protein in the brain. The disease often presents heterogeneously in its early stages, and little is known about how this variability affects its progression. We investigated the initial clinical presentation of DLB among Peruvian patients and its impact on the clinical course.

METHOD: We conducted a retrospective study of patients with DLB and Alzheimer's disease (AD). Participants were diagnosed using established clinical criteria. Neuropsychological assessments, including the MMSE, IFS, and UDS, were administered to evaluate cognitive function. We compared the clinical characteristics and neuropsychological profiles of DLB patients based on their initial presenting symptoms (hallucinations or parkinsonism). Statistical analyses, including ANOVA, chi-squared tests, Wilcoxon tests, and multinomial linear regression, were performed to identify differences between groups and to investigate the impact of initial symptoms on disease progression and cognitive decline.

RESULT: A total of 46 patients with probable DLB were included in the study. The median time from symptom onset to DLB diagnosis was approximately five years. Cognitive symptoms were the most common initial presentation, followed by motor and behavioral symptoms. However, no significant differences were observed in clinical or neuropsychological characteristics between groups at the time of evaluation. Compared to AD patients, DLB patients scored higher on measures of cognitive function (MMSE, RUDAS) and behavioral symptoms (NPI). Neuropsychological testing revealed distinct profiles between the two groups, with DLB patients demonstrating greater impairment in visuospatial and executive functions.

CONCLUSION: DLB patients with initial cognitive symptoms developed dementia earlier compared to those with initial motor or behavioral symptoms. However, the initial presenting symptoms did not result in worse severity across specific cognitive or behavioral domains.},
}

Humans
Male
Female
Aged
Retrospective Studies
*Lewy Body Disease/diagnosis/physiopathology/psychology/complications
Neuropsychological Tests
Disease Progression
*Alzheimer Disease/diagnosis/physiopathology/psychology
Aged, 80 and over
Middle Aged
Peru
Cognitive Dysfunction

@article {pmid41444135,
year = {2025},
author = {Wu, X and Zhang, B},
title = {Biomarkers.},
journal = {Alzheimer's & dementia : the journal of the Alzheimer's Association},
volume = {21 Suppl 2},
number = {},
pages = {e098565},
doi = {10.1002/alz70856_098565},
pmid = {41444135},
issn = {1552-5279},
mesh = {Humans ; Male ; Female ; *Cognitive Dysfunction/physiopathology/blood ; Biomarkers/blood ; Magnetic Resonance Imaging ; Aged ; *Alzheimer Disease/physiopathology/blood ; *Olfactory Cortex/physiopathology/diagnostic imaging ; Middle Aged ; *Smell/physiology ; *Olfactory Perception/physiology ; },
abstract = {BACKGROUND: Previous studies have shown that Alzheimer's disease (AD) is linked to specific activation patterns in the primary olfactory cortex (POC) as observed through functional MRI (fMRI). As the stimulus concentration increases, both mild cognitive impairment (MCI) and AD patients exhibit sustained activation, suggesting impaired olfactory habituation in these groups. However, current research on olfactory adaptation has not yet explored its effects in the subjective cognitive decline (SCD) population.

METHOD: A total of 181 right-handed participants were enrolled, including 60 NCs, 69 individuals with SCD, and 52 with MCI. The activation changes of POC were analyzed across four odor concentrations (0.032%, 0.1%, 0.32%, 1.0%) and phases (114s, 222s, 330s, 438s) to identify distinct olfactory adaptation patterns. Plasma biomarker levels were compared between the normal and abnormal olfactory adaptation groups.

RESULT: The number of POC activated β×voxels in the SCD and MCI groups was significantly lower compared to the NC group. When re-grouping the participants into three groups (NC, SCD, MCI) based on the normality of the POC olfactory adaptation pattern, chi-square tests revealed that NC participants were predominantly in the normal olfactory adaptation group, while SCD and MCI participants were primarily in the abnormal POC olfactory adaptation group. Mediation analysis indicated that the number of POC activated voxels fully mediated the relationship between olfactory identification ability and memory cognition domains. Additionally, mean plasma levels of p-tau217 and NfL were significantly higher in the abnormal olfactory adaptation group compared to the normal group.

CONCLUSION: The study demonstrated the role of olfactory adaptation patterns in the early stages of AD, especially in SCD.},
}

Humans
Male
Female
*Cognitive Dysfunction/physiopathology/blood
Biomarkers/blood
Magnetic Resonance Imaging
Aged
*Alzheimer Disease/physiopathology/blood
*Olfactory Cortex/physiopathology/diagnostic imaging
Middle Aged
*Smell/physiology
*Olfactory Perception/physiology

@article {pmid41444134,
year = {2025},
author = {Belbin, O and Iulita, F and Videla, L and Barroeta, I and Benejam, B and Altuna, M and Maure-Blesa, L and Rodríguez-Baz, Í and Hernandez, AS and Del Hoyo, L and Valle-Tamayo, N and Dols-Icardo, O and Bejanin, A and Alcolea, D and Lleó, A and Fortea, J and Carmona-Iragui, M},
title = {Biomarkers.},
journal = {Alzheimer's & dementia : the journal of the Alzheimer's Association},
volume = {21 Suppl 2},
number = {},
pages = {e099361},
doi = {10.1002/alz70856_099361},
pmid = {41444134},
issn = {1552-5279},
mesh = {Humans ; *Biomarkers/cerebrospinal fluid/blood ; *Down Syndrome/cerebrospinal fluid/blood ; Female ; Male ; *Alzheimer Disease/cerebrospinal fluid/blood ; Middle Aged ; *Inflammation/cerebrospinal fluid/blood ; Aged ; Adult ; Amyloid beta-Peptides/cerebrospinal fluid ; },
abstract = {BACKGROUND: Down syndrome (DS) is a genetic form of Alzheimer's disease (AD) and is associated with inflammation both dependent and independent of AD. This study aims to determine the contribution of DS and AD pathology to inflammation profiles in CSF and blood.

METHOD: We applied the Olink Target 96 Inflammation panel to paired blood plasma and CSF from non-trisomic cognitively unimpaired controls (n = 38), adults with DS with AD biomarkers within the normal range (DS; n = 39, all asymptomatic AD), DS with abnormal AD biomarkers (DSAD; n = 149, including asymptomatic and symptomatic AD), and patients with sporadic AD (sAD; n = 130) shown in Table 1. We used the first principal component of inflammation markers in plasma and CSF to generate peripheral and central inflammation scores, linear regression for group comparisons adjusting for covariates, Spearman test for correlation analyses and controlled the false discovery rate (FDR) using the Benjamini-Hochberg method.

RESULT: Trisomy 21 (DS versus controls) was associated with higher peripheral inflammation scores (p = 0.04), higher individual plasma markers (17 p <0.05, 3 FDR p <0.05), lower CNS inflammation scores (p = 0.01) and lower individual CSF markers (23 p <0.05, 10 FDR<0.05). Peripheral (rho=0.43) and CNS scores (rho=0.38) correlated with age in controls but not DS (rho<0.06). Compared to DS, DSAD showed higher peripheral scores (p = 0.04), higher individual plasma markers (14 p <0.05, 7 FDR p <0.05), higher CNS scores (p <0.0001) and higher individual CSF markers (37 p <0.05, 10 FDR p <0.05). sAD showed comparable peripheral scores (p = 0.16), individual plasma markers (30 p <0.05, 0 FDR>0.05) and CNS scores (p = 0.84), while individual CSF markers were elevated (39 p <0<05, 1 FDR>0.05) compared to controls. CNS but not peripheral scores correlated with age in DSAD (rho=0.24, rho=0.03) and sAD (rho=0.28, rho=0.03). CNS scores correlated with CSF pTau181 and NfL but not Aβ42:40 in DS and sAD and with all three biomarkers in DSAD (Table 2). Plasma scores did not correlate with CSF biomarkers in DS, DSAD or sAD (p >0.10).

CONCLUSION: Inflammation was detectable in plasma and CSF in adults with DS prior to AD onset and over the AD continuum. Inflammation scores in the CSF reflect AD pathophysiological changes in DSAD even prior to AD onset.},
}

Humans
*Biomarkers/cerebrospinal fluid/blood
*Down Syndrome/cerebrospinal fluid/blood
Female
Male
*Alzheimer Disease/cerebrospinal fluid/blood
Middle Aged
*Inflammation/cerebrospinal fluid/blood
Aged
Adult
Amyloid beta-Peptides/cerebrospinal fluid

@article {pmid41444133,
year = {2025},
author = {Vargas-González, JC and Ingelsson, M and Tang-Wai, DF and Tartaglia, C},
title = {Clinical Manifestations.},
journal = {Alzheimer's & dementia : the journal of the Alzheimer's Association},
volume = {21 Suppl 3},
number = {},
pages = {e098603},
doi = {10.1002/alz70857_098603},
pmid = {41444133},
issn = {1552-5279},
mesh = {Humans ; Female ; Male ; Aged ; *Alzheimer Disease/diagnosis/psychology ; *Cognitive Dysfunction/diagnosis/psychology ; *Activities of Daily Living ; Surveys and Questionnaires ; Mental Status and Dementia Tests/statistics & numerical data ; Aged, 80 and over ; *Caregivers ; Neuropsychological Tests ; Middle Aged ; },
abstract = {BACKGROUND: The Functional Activities Questionnaire (FAQ) is one of the most frequently used functionality assessments in patients with Alzheimer's disease (AD). It is an informant-based assessment wherein informants are asked to rate daily instrumental activities performance in the patient. We have found that informant characteristics influence the Clinical Dementia Rating (CDR) in the National Alzheimer's Coordinating Center Uniform Data Set (NACC-UDS). We aimed to evaluate informant characteristics' effect on the FAQ in patients with mild cognitive impairment or dementia due to AD participating in the NACC-UDS.

METHOD: We included all participants from the NACC-UDS that had AD as the principal diagnosis, and the Mini-Mental State Examination or Montreal Cognitive Assessment scores, informant characteristics, CDR global score (CDR-GS) and the FAQ score. We performed a conditional growth model using multilevel linear regression analysis.

RESULT: We included 19863 participants, totalling 45596 visits with a median of 2 (1-4) visits. The patient's age at the initial visit was 74.1±9.4 years and 53.8% were females. Informants were 66.2±13.2 years, 69.2% were females, and the relationship was 61.0% spouse or partner, 26.7% children and 12.3% other. The FAQ scores were affected by informant characteristics. The FAQ scores were 0.48 (CI 95%:0.31 to 0.65) higher with female informants, 2.04 (CI 95%: 1.79 to 2.28) higher when informants were children, and 0.30 (CI 95%: 0.01 to 0.60) higher when informants were other family members, both compared with spouses or partners. The frequency of visits was associated with a FAQ score 0.57 lower (CI 95%:-0.89 to -0.26) when visiting daily, 1.54 lower (CI 95%:-1.78 to -1.29) when visiting at least once per week, and 2.50 lower (CI 95%:-2.80 to -2.20) when visiting less than once a week compared with living with the patient. As expected, FAQ scores increased with lower Z-standardized cognitive scores.

CONCLUSION: We found that the FAQ scores are modified by informant characteristics in the NACC-UDS patients with AD diagnosis. These results are clinically relevant because FAQ is often used to evaluate the severity of AD impact on instrumental activities of daily and monitor the functional decline in AD.},
}

Humans
Female
Male
Aged
*Alzheimer Disease/diagnosis/psychology
*Cognitive Dysfunction/diagnosis/psychology
*Activities of Daily Living
Surveys and Questionnaires
Mental Status and Dementia Tests/statistics & numerical data
Aged, 80 and over
*Caregivers
Neuropsychological Tests
Middle Aged

@article {pmid41444132,
year = {2025},
author = {Palma, LF and Bom, RC and Victoriano, PHM and de Sousa, DB and Garcia, MBB and Zucato, MCR and Pulgatti, KL and da Silva, VA and Grigoli, MM and de Oliveira, SD and Popolin, CP and Manzine, PR and Cominetti, MR and de Carvalho Pelegrini, LN},
title = {Clinical Manifestations.},
journal = {Alzheimer's & dementia : the journal of the Alzheimer's Association},
volume = {21 Suppl 3},
number = {},
pages = {e107243},
doi = {10.1002/alz70857_107243},
pmid = {41444132},
issn = {1552-5279},
mesh = {Humans ; Female ; Male ; Aged ; Cross-Sectional Studies ; *Alzheimer Disease/psychology/diagnosis/epidemiology ; Brazil/epidemiology ; Aged, 80 and over ; Neuropsychological Tests ; Educational Status ; Middle Aged ; Mental Status and Dementia Tests ; },
abstract = {BACKGROUND: Education is considered an important risk factor for neurocognitive disorders, especially among the Latin American population. It is also strongly associated with the cognitive performance of older adults and significantly correlated with cognitive reserve. This study aims to analyze the impact of education on cognitive performance of cognitively unimpaired older adults and people living with AD, and its relationship with the AD diagnosis in a Latin American sample living in Brazil.

METHOD: This is a quantitative, cross-sectional, descriptive, and correlational study involving 135 participants divided into two groups: cognitively unimpaired (n = 86) and individuals with Alzheimer's Disease (AD, n = 49). Assessments included a sociodemographic questionnaire, the Addenbrooke's Cognitive Examination-Revised (ACE-R), the Mini-Mental State Examination (MMSE), and the word list from the CERAD battery. Data analysis was conducted using descriptive statistics, Student's t-test, chi-square test, and Pearson's correlation, with SPSS v.29.0.0 and a significance level of p ≤0.05.

RESULT: Most participants were female (65.7%), married (60.4%), retired (72.9%), and physically active (53.7%). The group comparison analysis revealed the AD group was older (79.6 ± 7.6 years; t=-8.59; p <0.001), had lower educational levels (6.7 ± 4.7 years; t=5.93; p <0.001), and performed worse on ACE-R (42.3 ± 19.1; t=15.04; p <0.001), MMSE (16.5 ± 5.7; t=13.64; p <0.001), and the CERAD word list (immediate recall: 7.6 ± 4.4; t=12.23; p <0.001; delayed recall: 0.7 ± 1.6; t=6.08; p <0.001; recognition: 6.3 ± 3.1; t=5.69; p = 0.002). Considering the variability in education, groups were then stratified into low education (≤8 years) and high education (>8 years). The lower education group (≤8 years) had more individuals with AD (X[2] = 24.95; p <0.001), lower family income (X[2] = 27.95; p <0.001), and practice less physical activity (X[2] = 14.68; p <0.001). Correlation analysis indicated a negative relationship between cognitive assessment performance and both age and educational level.

CONCLUSION: Our findings highlight the influence of education on cognitive performance and its association with cognitive reserve in older adults. Lower education levels were linked to poorer cognitive outcomes and a higher prevalence of AD, emphasizing the need for lifelong educational opportunities to mitigate cognitive decline, especially in the Latin American context. Future studies should further explore targeted interventions for individuals with limited education.},
}

Humans
Female
Male
Aged
Cross-Sectional Studies
*Alzheimer Disease/psychology/diagnosis/epidemiology
Brazil/epidemiology
Aged, 80 and over
Neuropsychological Tests
Educational Status
Middle Aged
Mental Status and Dementia Tests

@article {pmid41444130,
year = {2025},
author = {Inagawa, Y and Miyagi, Y and Inagawa, S and Takenoshita, N and Sato, T and Yoshimura, M and Saito, K and Hanyu, H and Shimizu, S},
title = {Biomarkers.},
journal = {Alzheimer's & dementia : the journal of the Alzheimer's Association},
volume = {21 Suppl 2},
number = {},
pages = {e098835},
doi = {10.1002/alz70856_098835},
pmid = {41444130},
issn = {1552-5279},
mesh = {Humans ; *Alzheimer Disease/pathology/drug therapy/diagnostic imaging/cerebrospinal fluid ; Male ; Female ; Atrophy/pathology ; Magnetic Resonance Imaging ; Aged ; Biomarkers/cerebrospinal fluid ; Positron-Emission Tomography ; *Brain/pathology/drug effects/diagnostic imaging ; Amyloid beta-Peptides/cerebrospinal fluid ; Middle Aged ; Hippocampus/pathology ; Aged, 80 and over ; },
abstract = {BACKGROUND: The voxel-based specific regional analysis system for Alzheimer's disease (VSRAD) is a cutting-edge imaging tool used to assess and diagnose Alzheimer's disease (AD), by analyzing structural changes in the brain using MRI. In this study, we aimed to evaluate the effects of lecanemab on hippocampal and overall brain atrophy, by examining changes using VSRAD.

METHOD: This study included 16 patients. All patients were diagnosed as having probable AD based on the National Institute on Aging and Alzheimer's Association diagnostic criteria in 2011. Aβ pathology was confirmed either by amyloid positron emission tomography or cerebrospinal fluid analysis, and lecanemab treatment was initiated. For VSRAD analysis, three dimensions sagittal T1-weighted spin-echo images were obtained. VSRAD Advance 2 software was used to assess the severity of atrophy. The volume of interest (VOI) to be used as a reference in the assessment of brain atrophy in patients with AD was the medial temporal cortex (hippocampus, amygdala, and most of the olfactory cortex). The severity of VOI atrophy was assessed by comparing scores obtained before the first lecanemab administration, and scores obtained before the fifth administration. Additionally, the proportion of atrophy within the VOI relative to whole brain atrophy was evaluated.

RESULT: Mean severity of VOI atrophy before the first administration was 1.61 ± 0.76, whereas that before the fifth administration was 1.38 ± 0.66, demonstrating a statistically significant difference (p < 0.001). In terms of the VOI/whole brain atrophy ratio, the mean ratio before the first administration was 6.76 ± 6.44, whereas that before the fifth administration was 4.92 ± 4.83, also showing a statistically significant difference (p < 0.05).

CONCLUSION: Our results demonstrated that the severity of VOI atrophy measured using VSRAD was significantly decreased in patients treated with lecanemab in actual clinical practice.},
}

Humans
*Alzheimer Disease/pathology/drug therapy/diagnostic imaging/cerebrospinal fluid
Male
Female
Atrophy/pathology
Magnetic Resonance Imaging
Aged
Biomarkers/cerebrospinal fluid
Positron-Emission Tomography
*Brain/pathology/drug effects/diagnostic imaging
Amyloid beta-Peptides/cerebrospinal fluid
Middle Aged
Hippocampus/pathology
Aged, 80 and over

@article {pmid41444129,
year = {2025},
author = {Ross, D and Split, M and Kunicki, ZJ and Keszycki, RM and Prieto, S and Manoochehri, M and Huey, ED and Barker, MS},
title = {Clinical Manifestations.},
journal = {Alzheimer's & dementia : the journal of the Alzheimer's Association},
volume = {21 Suppl 3},
number = {},
pages = {e097441},
doi = {10.1002/alz70857_097441},
pmid = {41444129},
issn = {1552-5279},
mesh = {Humans ; Female ; Male ; Aged ; *Alzheimer Disease/pathology/epidemiology/psychology ; *Frontotemporal Lobar Degeneration/pathology/epidemiology/psychology ; Comorbidity ; Aged, 80 and over ; tau Proteins ; Neuropsychological Tests ; },
abstract = {BACKGROUND: Neurodegenerative diseases often co-occur; however, little is known about the clinical presentation of comorbid Alzheimer's disease neuropathologic change (ADNC) and frontotemporal lobar degeneration (FTLD) neuropathology despite frequent comorbidity on autopsy. We examined neuropsychiatric symptoms in comorbid FTLD (tau or TDP-43) and AD, compared to FTLD and AD pathology alone.

METHOD: National Alzheimer's Coordinating Center data from 29 Alzheimer's Disease Research Centers (as of September 2024) was used to compare antemortem neuropsychiatric data in 919 people with intermediate to high ADNC, FTLD-tau and/or FTLD-TDP-43 neuropathology and clinical data at their last visit. Neuropsychiatric symptoms were identified via clinician-rated presence or absence of apathy/withdrawal, depressed mood, visual/auditory hallucinations, abnormal/false/delusional beliefs, disinhibition, irritability, agitation, personality change, REM sleep behavior disorder, and anxiety at the final visit before death. We ran logistic regression models to examine odds of expressing each neuropsychiatric symptom by pathology, controlling for age, sex, race, ethnicity, education, and time between visit and death.

RESULT: 94 people (mean age=84, SD = 10, 46% female) had comorbid ADNC and FTLD pathology, 590 people had ADNC only, and 235 people had FTLD pathology (65% tau, 29% TDP-43, 7% both types) only. Compared to the comorbid ADNC and FTLD group, the FTLD-only group was less likely to present with delusions (O.R. = 0.38, p = .021), irritability (O.R. = 0.54, p = .028), and anxiety (O.R. = 0.33, p = .004). Conversely, the ADNC-only group was less likely to present with disinhibition (O.R. = 0.50, p = .017) and personality change (O.R. = 0.32, p < .001). Likelihood of presenting with apathy, depression, hallucinations, agitation, and REM sleep behavior did not differ in the comorbid group compared to either single pathology group (ps > .05).

CONCLUSION: Comorbid presence of ADNC and FTLD neuropathology was associated with greater likelihood of presenting with known neuropsychiatric symptoms of the other disease, irrespective of clinical syndrome. Disinhibition and personality change differentiated comorbid ADNC and FTLD from ADNC alone, while delusions, irritability, and anxiety differentiated comorbid ADNC and FTLD from FTLD alone. These findings highlight the diagnostic value of antemortem behavioral symptoms in comorbid pathology. Moreover, findings are consistent with well-established neuropsychiatric phenotypes of ADNC and FTLD, emphasizing the importance of clinical phenotypes in precision medicine.},
}

Humans
Female
Male
Aged
*Alzheimer Disease/pathology/epidemiology/psychology
*Frontotemporal Lobar Degeneration/pathology/epidemiology/psychology
Comorbidity
Aged, 80 and over
tau Proteins
Neuropsychological Tests

@article {pmid41444128,
year = {2025},
author = {Walach, G and Kennedy, K and Dimick, M and Zai, C and MacIntosh, B and Goldstein, B},
title = {Biomarkers.},
journal = {Alzheimer's & dementia : the journal of the Alzheimer's Association},
volume = {21 Suppl 2},
number = {},
pages = {e099327},
doi = {10.1002/alz70856_099327},
pmid = {41444128},
issn = {1552-5279},
mesh = {Humans ; Female ; Male ; Adolescent ; Magnetic Resonance Imaging ; *Bipolar Disorder/diagnostic imaging/genetics/pathology ; Young Adult ; *Alzheimer Disease/genetics/diagnostic imaging/pathology ; *Brain/diagnostic imaging/pathology ; Biomarkers ; Gyrus Cinguli/diagnostic imaging/pathology ; Genetic Predisposition to Disease ; },
abstract = {BACKGROUND: Bipolar disorder (BD) is linked to an increased risk of Alzheimer's disease (AD). It is well established that the AD process long precedes onset of clinical symptoms, highlighting the importance of understanding the early genesis of AD. Evaluating genetic risk for AD in relation to brain structure in youth may provide insights regarding regional neurostructural susceptibility to AD. The anterior cingulate cortex has been implicated in both BD and in relation to polygenic risk scores (PRS) for AD in healthy children.

METHODS: This study investigated AD-PRS derived from adult studies, both as main effect and interaction with diagnosis, on brain structure using T1-weighted magnetic resonance imaging data. Participants included 112 youth aged 13-20 years (n = 67 BD; n = 45 healthy controls [HC]). AD-PRS were calculated using PRS-CS-auto. General linear models assessed the association between AD-PRS and regional brain structure, controlling for age, sex, intracranial volume, and the first two genetic principal components. Vertex-wise analyses and an anterior cingulate cortex region of interest analyses were conducted, as well as sex-stratified analyses.

RESULTS: In the whole sample, higher AD-PRS was associated with lower superior temporal gyrus volume (p = 0.03). In interaction analyses, higher AD-PRS was associated with lower regional structure to a greater extent in the BD vs. HC group, including: superior temporal gyrus (p = 0.008) and precuneus (p = 0.01) volume, and rostral middle frontal (L: p <0.001; R: p = 0.03), caudal middle frontal (p = 0.001), superior frontal (p = 0.005), precentral (p = 0.049) gyri, and superior parietal lobule (p = 0.04) thickness. In sex-stratified analyses, higher AD-PRS was associated with lower superior parietal lobule surface area (p = 0.03) and volume (p <0.001) in females. In males, higher AD-PRS was associated with higher cortical thickness and volume in the supramarginal and rostral middle frontal gyri, respectively (p <0.001; p = 0.004). Region of interest analyses were not significant.

CONCLUSION: Higher AD-PRS is associated with smaller brain structure metrics in youth with BD compared to HC. Findings also highlight potential sex differences. Future longitudinal studies should be conducted to investigate dynamic changes in the association between AD-PRS and brain structure across development.},
}

Humans
Female
Male
Adolescent
Magnetic Resonance Imaging
*Bipolar Disorder/diagnostic imaging/genetics/pathology
Young Adult
*Alzheimer Disease/genetics/diagnostic imaging/pathology
*Brain/diagnostic imaging/pathology
Biomarkers
Gyrus Cinguli/diagnostic imaging/pathology
Genetic Predisposition to Disease

@article {pmid41444127,
year = {2025},
author = {Mitra, S and Gera, R and Tambaro, S and Nilsson, P and Linderoth, B and Behbahani, H and Darreh-Shori, T and Eriksdotter, M},
title = {Basic Science and Pathogenesis.},
journal = {Alzheimer's & dementia : the journal of the Alzheimer's Association},
volume = {21 Suppl 1},
number = {},
pages = {e106449},
doi = {10.1002/alz70855_106449},
pmid = {41444127},
issn = {1552-5279},
mesh = {Animals ; *Hippocampus/pathology/metabolism ; *Alzheimer Disease/pathology/metabolism/genetics ; Mice, Transgenic ; Disease Models, Animal ; Amyloid beta-Protein Precursor/genetics/metabolism ; Nerve Growth Factor/metabolism ; Brain-Derived Neurotrophic Factor/metabolism ; Mice ; Mice, Inbred C57BL ; Humans ; Acetylcholinesterase/metabolism ; Choline O-Acetyltransferase/metabolism ; Butyrylcholinesterase/metabolism ; Amyloid beta-Peptides/metabolism ; Male ; },
abstract = {BACKGROUND: The hippocampal region of the brain is a crucial site of neurotrophic factor production like nerve growth factor (NGF) - the master regulator of cholinergic pathways and brain derived neurotrophic factor (BDNF). Hippocampus coordinates memory and cognition and is found affected with amyloid-beta (Aβ) pathology in AD. Altered cholinergic pathways and memory dysfunction are well-known changes during Alzheimer's disease (AD). Til date, a clear connection between Aβ pathology in modulating hippocampal cholinergic pathways has not been proven.

METHOD: Humanized APP-knock-in mouse model of AD (App[NL-G-F]) was utilized, and hippocampus tissue was isolated at 2-month age (pre-plaque stage), 7-month age (plaques present + initiation of cognitive deficits), and 12-month age (advanced amyloid pathology), and from age-matched wildtype control mice (C57BL/6JRj) respectively. Total protein was isolated by extracting hippocampal samples in various buffers (soluble, ionic, and detergent soluble fractions) and pooled together. Enzyme assays for acetylcholinesterase (AChE), butyrylcholinesterase (BuChE) and choline acetyltransferase (ChAT) were performed, along with ELISA for the estimation of total NGF and BDNF levels, respectively.

RESULT: Age-dependent changes were observed in App[NL-G-F] mice compared to wild-type controls. Cholinesterase activity in the App[NL-G-F] mice was increased for AChE in 7 months, while BuChE activity was higher during all time points, with respect to wildtype control mice. ChAT levels were nominally altered while the cholinergic index (ChAT/AChE) was significantly increased at 2-months in App[NL-G-F] mice. NGF levels remained unchanged, but BDNF levels increased in an age-dependent manner in App[NL-G-F] mice as compared to control mice.

CONCLUSION: Significant age-dependent alterations in cholinergic activity and neurotrophic factors were evident in hippocampus tissue of App[NL-G-F] mice, when compared to wild-type counterparts, underlining the importance of the cholinergic activity in relation to amyloid pathology.},
}

Animals
*Hippocampus/pathology/metabolism
*Alzheimer Disease/pathology/metabolism/genetics
Mice, Transgenic
Disease Models, Animal
Amyloid beta-Protein Precursor/genetics/metabolism
Nerve Growth Factor/metabolism
Brain-Derived Neurotrophic Factor/metabolism
Mice
Mice, Inbred C57BL
Humans
Acetylcholinesterase/metabolism
Choline O-Acetyltransferase/metabolism
Butyrylcholinesterase/metabolism
Amyloid beta-Peptides/metabolism
Male

@article {pmid41444126,
year = {2025},
author = {Ryan, NS and Farrell, C and Willumsen, N and Rice, H and Nasir, M and Zhang, X and Burdon, C and Ocal, D and Weston, PS and Wiseman, FK and Lashley, T and Fox, NC},
title = {Clinical Manifestations.},
journal = {Alzheimer's & dementia : the journal of the Alzheimer's Association},
volume = {21 Suppl 3},
number = {},
pages = {e098875},
doi = {10.1002/alz70857_098875},
pmid = {41444126},
issn = {1552-5279},
mesh = {Humans ; Female ; Male ; *Alzheimer Disease/genetics/pathology ; Middle Aged ; Aged ; Amyloid beta-Protein Precursor/genetics ; Presenilin-1/genetics ; Mutation/genetics ; Amyloid beta-Peptides/metabolism ; Cerebral Amyloid Angiopathy/pathology/genetics ; Aged, 80 and over ; *Brain/pathology/metabolism ; Presenilin-2/genetics ; Adult ; Phenotype ; },
abstract = {BACKGROUND: Autosomal dominant familial Alzheimer's disease (ADAD), caused by APP, PSEN1 and PSEN2 mutations, is clinically and pathologically similar to sporadic AD, with both typically presenting with memory impairment. However as in sporadic AD, atypical phenotypes and neuropathological heterogeneity occur, including variability in the type of amyloid-β plaque pathology, and in the degree of vascular amyloid-β deposition as cerebral amyloid angiopathy (CAA). Investigating relationships between clinical, neuropathological and genetic heterogeneity in ADAD may provide insights into underlying pathophysiological and molecular mechanisms and inform strategies for targeting them therapeutically.

METHODS: We analyzed clinical phenotype data from over 250 symptomatic individuals from ADAD families seen at our Centre since the first mutation was identified over 30 years ago. 50 of these individuals underwent post-mortem brain donation to the Institute of Psychiatry or Queen Square Brain Bank (QSBB); 37 with mutations in PSEN1, 13 in APP. Frontal cortex sections were stained immunohistochemically with a pan amyloid-β antibody and vessel counts were used to determine the frequency and severity of CAA in leptomeninges and parenchyma. In the 29 cases donated to QSBB, patterns of amyloid-β40, amyloid-β42 and amyloid-β43 antibody binding were also examined.

RESULTS: Age at onset was strongly influenced by the specific mutation but survival was influenced by mutation to a much lesser extent. Atypical (non-amnestic) cognitive presentations with initial behavioral, language, dyscalculic or dysexecutive symptoms, and atypical clinical features (pyramidal, extrapyramidal and cerebellar signs) were more common in PSEN1 than APP cases, particularly those with mutations post-codon 200. In the post-mortem cohort, 21 different mutations in PSEN1, four in APP and one APP duplication were represented. All cases demonstrated end-stage AD pathology, however the frequency and severity of CAA varied considerably. Amyloid-β43 deposition was seen in some individuals with PSEN1 but not with APP mutations. Relationships between clinical and neuropathological features and patterns of amyloid-β isoform binding were explored.

CONCLUSIONS: Phenotypic heterogeneity in ADAD is influenced by causative gene and mutation type. Examining how mutation-specific patterns of amyloid-β peptide deposition relate to variability in CAA and clinical manifestations might inform the development of more personalised treatment approaches for individuals with ADAD mutations.},
}

Humans
Female
Male
*Alzheimer Disease/genetics/pathology
Middle Aged
Aged
Amyloid beta-Protein Precursor/genetics
Presenilin-1/genetics
Mutation/genetics
Amyloid beta-Peptides/metabolism
Cerebral Amyloid Angiopathy/pathology/genetics
Aged, 80 and over
*Brain/pathology/metabolism
Presenilin-2/genetics
Adult
Phenotype

@article {pmid41444124,
year = {2025},
author = {Cui, M and Jin, Z and Wang, Y and Dong, Q and , },
title = {Biomarkers.},
journal = {Alzheimer's & dementia : the journal of the Alzheimer's Association},
volume = {21 Suppl 2},
number = {},
pages = {e101954},
doi = {10.1002/alz70856_101954},
pmid = {41444124},
issn = {1552-5279},
mesh = {Humans ; *Biomarkers/blood ; Female ; Male ; Aged ; *Cognitive Dysfunction/blood/etiology ; Middle Aged ; China ; tau Proteins/blood ; *Stroke/complications/blood ; Alzheimer Disease/blood ; Amyloid beta-Peptides/blood ; Glial Fibrillary Acidic Protein/blood ; Diffusion Magnetic Resonance Imaging ; },
abstract = {BACKGROUND: The Global Burden of Disease Study 2019 reports that China has the highest number of stroke patients globally, with one-third developing post-stroke cognitive impairment (PSCI), making stroke-related dementia the most prevalent form in China. Understanding the overlap between cerebrovascular pathology and Alzheimer's disease (AD) pathology is crucial in comprehending their joint contribution to cognitive decline post-stroke.

METHOD: This study, conducted within the Vascular, Imaging, and Cognition Association of China (VICA), included 350 patients enrolled within 14 days of ischemic infarction/TIA. Baseline blood samples were collected, and patients were followed up for six months for cognitive assessments. Of these, 274 patients completed the follow-up and were divided into PSCI and PSNCI groups. Infarct lesions were quantitatively analyzed using diffusion-weighted imaging (DWI), and several peripheral blood biomarkers were measured using a single-molecule immunoarray, including, Aβ, pTau217, neurofilament light (NFL), glial fibrillary acidic protein (GFAP), monocyte chemoattractant protein-1 (MCP-1), matrix metalloproteinases (MMPs), interleukin-6 (IL-6), brain-derived neurotrophic factor (BDNF), vascular endothelial growth factor (VEGF), and placental growth factor (PLGF).

RESULT: Machine learning identified pTau217, GFAP, NFL, and IL-6 most strongly associated with the occurrence of PSCI, which reflect neurodegeneration, inflammatory responses, and neuronal injury. After adjusting for factors such as infarct volume and NIHSS score, only pTau217 remained significantly associated with PSCI. In predicting the occurrence of PSCI, the area under the ROC curve (AUC) for pTau217 was 0.70, which was comparable to the AUC of 0.71 for infarct characteristics (including volume and location). However, the combination of pTau217 and infarct characteristics improved the prediction, achieving an AUC of 0.86. Notably, pTau217 demonstrated superior predictive performance for PSCI caused by smaller infarcts (lesion volume < 5 cm[3]). To further explore whether pTau217 reflects neurodegenerative pathology, we conducted amyloid PET imaging in a subset of patients with elevated pTau217 levels. The results confirmed that elevated pTau217 levels are associated with amyloid pathology.

CONCLUSION: Pre-stroke AD pathology may contribute to the development of PSCI. pTau217 serves as a valuable biomarker for detecting underlying amyloid pathology and holds promise in predicting PSCI.},
}

Humans
*Biomarkers/blood
Female
Male
Aged
*Cognitive Dysfunction/blood/etiology
Middle Aged
China
tau Proteins/blood
*Stroke/complications/blood
Alzheimer Disease/blood
Amyloid beta-Peptides/blood
Glial Fibrillary Acidic Protein/blood
Diffusion Magnetic Resonance Imaging

@article {pmid41444122,
year = {2025},
author = {Gopinath, G and Yep, R and Marawi, T and Kumar, R and Malhotra, S and Zhang, A and Alexander, MW and Nyman, AJ and Boshmaf, SZ and Vandeloo, KL and Black, SE and Goubran, M and Rabin, JS},
title = {Clinical Manifestations.},
journal = {Alzheimer's & dementia : the journal of the Alzheimer's Association},
volume = {21 Suppl 3},
number = {},
pages = {e098783},
doi = {10.1002/alz70857_098783},
pmid = {41444122},
issn = {1552-5279},
mesh = {Humans ; Female ; Male ; Aged ; *Cognitive Dysfunction/ethnology/psychology/diagnosis ; Middle Aged ; Aged, 80 and over ; Canada/epidemiology ; Cohort Studies ; *Depression/ethnology/psychology ; White People/psychology ; Asian People ; *Anxiety/ethnology/psychology ; Neuropsychological Tests ; Psychiatric Status Rating Scales ; },
abstract = {BACKGROUND: Subjective cognitive decline (SCD) may represent one of the earliest symptoms of Alzheimer's disease. However, SCD remains understudied in diverse ethnoracial groups, particularly among individuals of Asian descent. Leveraging data from a cohort study of Canadian South Asian, Chinese, and White older adults, this study investigated ethnic differences in: (1) SCD burden, (2) the association between self- and study partner-reported SCD, and (3) the demographic and neuropsychiatric factors associated with SCD.

METHODS: Participants were South Asian, Chinese, and White adults aged 55-85 enrolled in the observational cohort study, Canadian Multi-Ethnic Research on Aging (CAMERA). Participants were classified as cognitively unimpaired based on a Clinical Dementia Rating global score of 0. SCD was assessed using the self- and study partner-reported Cognitive Functioning Index (CFI). Depression and anxiety symptoms were measured using the Geriatric Depression Scale and Generalized Anxiety Disorder-7 Scale, respectively. Linear regression models were used to examine associations of interest, adjusting for age, sex, years of education, as well as depression and anxiety symptoms.

RESULTS: We included 140 participants (mean age=65.8±6.4, 69.3% female) who self-identified as South Asian (n = 38), Chinese (n = 52) or White (n = 50). Self-reported CFI scores were significantly higher in South Asian (β=0.9, p = 0.02) and Chinese participants (β=1.4, p < 0.001) compared to White participants, and did not significantly differ between South Asian and Chinese participants (β=0.5, p = 0.2). Self- and study partner-reported CFI scores were significantly associated across the whole sample (β=0.3, p = 0.01), with no moderation by ethnicity (p>0.05). However, the associations between symptoms of depression and anxiety with self-reported CFI scores were stronger in South Asian and Chinese participants compared to White participants (p < 0.05). The associations between depression and anxiety with CFI did not significantly differ between South Asian and Chinese participants (p>0.05).

CONCLUSIONS: In a sample of cognitively unimpaired older adults, self- and study partner-reported SCD were associated, and the strength of the association did not differ across ethnic groups. However, among South Asian and Chinese participants, SCD burden was greater and more strongly associated with depression and anxiety symptoms. These findings underscore the importance of considering ethnoracial differences and neuropsychiatric symptoms when assessing SCD in diverse populations.},
}

Humans
Female
Male
Aged
*Cognitive Dysfunction/ethnology/psychology/diagnosis
Middle Aged
Aged, 80 and over
Canada/epidemiology
Cohort Studies
*Depression/ethnology/psychology
White People/psychology
Asian People
*Anxiety/ethnology/psychology
Neuropsychological Tests
Psychiatric Status Rating Scales

@article {pmid41444121,
year = {2025},
author = {Ribaldi, F and Chicherio, C and Mendes, AJ and Frisoni, G},
title = {Clinical Manifestations.},
journal = {Alzheimer's & dementia : the journal of the Alzheimer's Association},
volume = {21 Suppl 3},
number = {},
pages = {e098967},
doi = {10.1002/alz70857_098967},
pmid = {41444121},
issn = {1552-5279},
mesh = {Humans ; *Cognitive Dysfunction/classification/diagnosis/psychology ; Neuropsychological Tests ; Male ; Female ; Aged ; Alzheimer Disease/diagnosis ; Risk Factors ; },
abstract = {BACKGROUND: Subjective cognitive decline (SCD) is recognized as a potential early risk factor for Alzheimer's disease (AD) and other dementias, but standardized approaches to assess and address the concerns of individuals with SCD remain limited. Moreover, its prevalence is increasing in memory clinics, highlighting an unmet clinical need for tailored protocols and evidence-based guidance. A recent work proposed a taxonomy for SCD, categorizing individuals into three subgroups based on psychological factors (e.g., anxiety, depression, neuroticism), comorbidities (e.g., vascular risk factors, neurological or somatic comorbidities), and no apparent cause. This taxonomy provides a structured framework for interpreting SCD and guiding management strategies. However, its clinical applicability requires validation in independent cohorts.

METHOD: The SCD taxonomy was initially tested on a small subset of individuals from the Geneva Memory Center, classifying individuals into the three previously introduced subgroups using detailed clinical reports (Ribaldi et al., 2024). Currently, the taxonomy is being applied to a larger retrospective cohort. All participants underwent comprehensive neuropsychological assessments and clinical evaluations, with a subset also featuring biomarker data. To streamline its application, the taxonomy has been converted into an automated algorithm that assigns individuals to subgroups based on available clinical data. The ongoing effort focuses on validating the accuracy of this automated classification by comparing it with expert clinical judgments. Once this step is complete, baseline differences among the subgroups will be analyzed, followed by an assessment of longitudinal cognitive trajectories.

RESULT: We will present the taxonomy structure and preliminary findings from the validation cohort. Initial findings from the original cohort demonstrated the taxonomy's ability to stratify individuals based on psychological factors and somatic comorbidities, revealing significant differences in demographics, clinical features, and cognitive trajectories across subgroups. Specifically, the SCD group with no apparent cause exhibited faster cognitive decline and an AD-like biomarker profile. Ongoing analyses aim to confirm these findings in the larger cohort.

CONCLUSION: Preliminary findings support the applicability of the SCD taxonomy, underscoring its potential as a clinical tool for risk stratification and personalized intervention. This validation represents a critical step toward integrating the taxonomy into routine clinical workflows, addressing the growing needs of individuals with SCD.},
}

Humans
*Cognitive Dysfunction/classification/diagnosis/psychology
Neuropsychological Tests
Male
Female
Aged
Alzheimer Disease/diagnosis
Risk Factors

@article {pmid41444118,
year = {2025},
author = {Saul, E and Lasserve, J and Chauveau, L and Landeau, B and Poisnel, G and Chételat, G and de Flores, R and , },
title = {Biomarkers.},
journal = {Alzheimer's & dementia : the journal of the Alzheimer's Association},
volume = {21 Suppl 2},
number = {},
pages = {e098529},
doi = {10.1002/alz70856_098529},
pmid = {41444118},
issn = {1552-5279},
mesh = {Humans ; Male ; Female ; Aged ; *White Matter/diagnostic imaging ; Magnetic Resonance Imaging ; *Amyloid beta-Peptides/metabolism ; Biomarkers/metabolism ; Positron-Emission Tomography ; *Temporal Lobe/diagnostic imaging/metabolism ; Alzheimer Disease ; Neural Pathways/diagnostic imaging ; Middle Aged ; Longitudinal Studies ; },
abstract = {BACKGROUND: Two networks within the medial temporal lobe (MTL)-the anterior-temporal (AT) and posterior-medial (PM)-are known to be functionally impaired in aging and Alzheimer's disease (AD). While our previous work suggested that AT hyperconnectivity is a pivotal mechanism in AD, and PM hypoconnectivity is canonical to aging, their structural connectivity is not fully understood. This study leverages longitudinal data to (i) identify the white matter fibers supporting the AT and PM networks, (ii) explore the effects of amyloid-β (Aβ) accumulation on these fibers, and (iii) examine the link between fiber integrity and functional connectivity.

METHOD: Eighty-nine cognitively healthy older adults (68.96 ± 3.89 years) were included. Structural and functional connectivity within the AT and PM networks were assessed using resting-state fMRI and DKI, respectively, using the perirhinal and parahippocampal cortices as seeds for correlation or tractography analyses. Amyloid-β deposition was quantified with Florbetapir-PET imaging.

RESULT: The hippocampal cingulum and inferior longitudinal fasciculus were identified as independent components of both networks. Additionally, the AT network is supported by the thalamic radiations and corpus callosum, while the PM network is underpinned by the cingulum and inferior fronto-occipital fasciculus. An inverted U-shaped relationship was found between Aβ burden and white matter fiber integrity. Although no direct association was observed between fiber integrity and AT or PM functional connectivity, significant interactions with Aβ load were found: individuals with high Aβ levels showed a negative association between AT structural and functional connectivity, while those with low Aβ levels showed a positive correlation.

CONCLUSION: These findings underscore the impact of Aβ on MTL structural connectivity and its association with increased AT functional connectivity, providing new insights into the complex relationship between connectivity and Aβ.},
}

Humans
Male
Female
Aged
*White Matter/diagnostic imaging
Magnetic Resonance Imaging
*Amyloid beta-Peptides/metabolism
Biomarkers/metabolism
Positron-Emission Tomography
*Temporal Lobe/diagnostic imaging/metabolism
Alzheimer Disease
Neural Pathways/diagnostic imaging
Middle Aged
Longitudinal Studies

@article {pmid41444117,
year = {2025},
author = {Akgun, B and Cornejo-Olivas, M and Mena, PR and Adams, LD and Celis, K and Whitehead, PG and Hamilton-Nelson, KL and Rios-Pinto, J and Medina-Colque, A and Dalgard, CL and Martin, ER and Cornejo-Herrera, I and Illanes-Manrique, M and Ochoa-Valle, E and Sarapura-Castro, E and Mejia-Rojas, K and Marca-Ysabel, V and Castro-Suarez, S and Griswold, AJ and Isasi, R and McInerney, KF and Cuccaro, ML and Vance, JM and Rajabli, F and Pericak-Vance, M and , },
title = {Basic Science and Pathogenesis.},
journal = {Alzheimer's & dementia : the journal of the Alzheimer's Association},
volume = {21 Suppl 1},
number = {},
pages = {e105970},
doi = {10.1002/alz70855_105970},
pmid = {41444117},
issn = {1552-5279},
mesh = {Humans ; Genome-Wide Association Study ; *Alzheimer Disease/genetics ; Male ; Peru ; Female ; Polymorphism, Single Nucleotide/genetics ; *Genetic Predisposition to Disease/genetics ; Aged ; Linkage Disequilibrium ; },
abstract = {BACKGROUND: Increasing ethnic/ancestral diversity in genetic studies is critical for defining the genetic architecture of Alzheimer disease (AD) and maximizing the opportunities for identifying genetic protective and risk alleles. The Peruvian population, with up to ∼80% of Amerindian ancestry, provides a unique opportunity to leverage Amerindian ancestry for deeper insights into AD mechanism. We performed the genome-wide association study (GWAS) in the Peruvian population to characterize known AD genetic risk loci.

METHOD: 567 individuals (215 AD; 352 cognitively unimpaired) were included in these analyses. We performed GWAS on the Whole Genome Sequencing (WGS) dataset using a generalized linear mixed model, adjusting for sex, age, and population substructure as fixed effects and the genetic relationship matrix as a random effect. For follow-up analysis, we extracted all nominal significant known AD variants and calculated linkage disequilibrium (LD) with surrounding SNPs. Variants with an R[2] ≥ 0.8 with the index SNP were annotated and further evaluated. To assess whether the associations were ancestry-specific, we calculated the local ancestry of the regions corresponding to these variants.

RESULT: We replicated two known AD loci APOE4 allele and TREML2 marker (rs60755019). Fine-mapping analysis at the TREML2 loci identified a TREM2 missense exonic marker (p.H157Y, OR=3.3 [1.9-5.9], p = 4x10[-5], CADD=23.2) having strong LD with the TREML2 risk marker in Peruvians. LA analysis showed that p.H157Y is located on an Amerindian ancestral background. p.H157Y is extremely rare across frequency databases (gnomAD, HGDP, and 1000 Genomes) except in Admixed American population ∼0.02. Additionally, APOE showed a strong association with AD, with an effect size (OR=4.3 [3.0-6.1], p = 4x10[-15]) higher that was observed in non-Hispanic White populations.

CONCLUSION: Peruvian GWAS identified Amerindian ancestry specific exonic AD susceptibility variant p.H157Y. This variant has been previously reported as AD marker in Han Chinese populations with extreme effect size, but its rarity and contradictory findings in other groups suggest a potential ancestry-specific effect. Functional studies indicate that it may enhance TREM2 shedding, impacting microglial function and contributing to AD pathogenesis. These observations highlight the power of examining diverse populations to gain a more comprehensive view of the genetic architecture of AD.},
}

Humans
Genome-Wide Association Study
*Alzheimer Disease/genetics
Male
Peru
Female
Polymorphism, Single Nucleotide/genetics
*Genetic Predisposition to Disease/genetics
Aged
Linkage Disequilibrium

@article {pmid41444112,
year = {2025},
author = {Song, X and Vecchi, T and Widmann, J and Fierli, F and Ruf, V and Tang, Q and Arzberger, T and Roeber, S and Köglsperger, T and Windl, O and Haass, C and Winkelmann, J and Herms, J and Strübing, F},
title = {Basic Science and Pathogenesis.},
journal = {Alzheimer's & dementia : the journal of the Alzheimer's Association},
volume = {21 Suppl 1},
number = {},
pages = {e106193},
doi = {10.1002/alz70855_106193},
pmid = {41444112},
issn = {1552-5279},
mesh = {Humans ; *alpha-Synuclein/genetics/metabolism ; *tau Proteins/metabolism/genetics ; *Alzheimer Disease/genetics/pathology/metabolism ; Male ; Female ; Aged ; Neurons/metabolism/pathology ; Brain/pathology/metabolism ; Whole Genome Sequencing ; Parkinson Disease/genetics/pathology ; Aged, 80 and over ; },
abstract = {BACKGROUND: The molecular basis for accelerated cognitive decline seen in Alzheimer's Disease (AD) cases presenting with cortical alpha-Synuclein co-pathology is not well understood. Mouse experiments have shown adverse interactions between tau (encoded by MAPT) and alpha-Synuclein (encoded by SNCA), but how this finding translates to humans from a genome-centered point of view remains unknown.

METHOD: Whole genome sequencing was performed on 137 neuropathologically defined AD cases, 36 of which presented with neocortical alpha-Synuclein co-pathology (Braak stage 6). Polygenic risk scores were calculated. Single-nucleus RNA sequencing and Western Blot data were collected from post-mortem tissue. Transcriptomic and proteomic results were validated in the MSBB cohort (n >300). Cellular, molecular and epigenetic consequences were assessed in isogenic iPSCs-derived neurons carrying a triplication of SNCA (AST) or a normal SNCA copy number (CAS).

RESULT: AD brains with alpha-Synuclein co-pathology had significantly higher polygenic risk scores for Parkinson's Disease, which could be partially explained by variants associated with higher expression of SNCA. Single-nucleus RNA sequencing and immunoblot analysis revealed a higher expression of MAPT and phosphorylated tau in alpha-Synuclein co-pathology cases. Protein and mRNA expression of MAPT and SNCA were positively correlated in the MSBB cohort. The employed iPSCs differentiation protocol accelerated neuronal maturation due to transient inhibition of EZH2. Day50 AST neurons exhibited significantly increased pathological tau and alpha-Synuclein at both the RNA and protein levels compared to CAS neurons. AST neurons also showed highly activated GSK3β and decreased PSD95 (post-synaptic protein) in the immunofluorescence and immunoblot analyses. ATAC profiles identified dysregulated accessibility in the cAMP signaling pathway, as well as pathways related to axon guidance, postsynaptic density, and calcium signaling, among others.

CONCLUSION: We demonstrate that alpha-Synuclein co-pathology in AD is characterized by higher phosphorylated tau levels in patients and iPSC-derived neurons. Our results provide insights into the complex molecular processes through which alpha-Synuclein and tau synergistically drive dementia-related pathology.},
}

Humans
*alpha-Synuclein/genetics/metabolism
*tau Proteins/metabolism/genetics
*Alzheimer Disease/genetics/pathology/metabolism
Male
Female
Aged
Neurons/metabolism/pathology
Brain/pathology/metabolism
Whole Genome Sequencing
Parkinson Disease/genetics/pathology
Aged, 80 and over

@article {pmid41444111,
year = {2025},
author = {Rosenberg, PB and Manning, CA and Porsteinsson, AP and Lyketsos, KG and Baksh, S and Spira, AP and Wanigatunga, SK and Burhan, AM},
title = {Clinical Manifestations.},
journal = {Alzheimer's & dementia : the journal of the Alzheimer's Association},
volume = {21 Suppl 3},
number = {},
pages = {e106843},
doi = {10.1002/alz70857_106843},
pmid = {41444111},
issn = {1552-5279},
mesh = {Humans ; Female ; Male ; Aged ; Actigraphy ; *Psychomotor Agitation/drug therapy/etiology ; Aged, 80 and over ; *Alzheimer Disease/complications/drug therapy ; *Sleep Wake Disorders/drug therapy/etiology ; *Escitalopram/therapeutic use ; Citalopram/therapeutic use ; Selective Serotonin Reuptake Inhibitors/therapeutic use ; Sleep/drug effects ; },
abstract = {BACKGROUND: Sleep commonly is disturbed in Alzheimer's disease (AD) and poor sleep may accelerate AD progression. Disturbed sleep may contribute to neuropsychiatric symptoms (NPS) of AD, including agitation. We examined associations between actigraphic sleep parameters with baseline agitation and changes in agitation with escitalopram treatment among participants in the S-CitAD trial.

METHOD: S-CitAD was a 12-week randomized controlled trial of escitalopram for agitation in AD. Of 173 S-CitAD participants, 32 (age = 79 +/-9.93 years, 43.7 % female, 12.5 % non-White) had actigraphic sleep data (median 13 nights at baseline). Agitation was measured with the NPI-C Agitation and Aggression (NPI-C-A+A) domains. We measured standard sleep variables (awakening length, number of awakenings, efficiency, fragmentation index, latency, total activity counts during sleep, total minutes in bed, total sleep time, wake after sleep onset).

RESULT: Of the 32 participants with baseline actigraphy data, 9 had follow-up at week 12. The actigraphy subset had mean age of 79 +/-9.9 years, were 56% male, had Mini-Mental State Exam (MMSE) scores of 18.5 +/-8.2 and baseline NPI-C A/A scores of 16.0+/-6.2 (Table 1). There were no significant associations of sleep variables with baseline agitation or with change in agitation at 12 weeks. Escitalopram responders, defined by a decrease in NPI-C A/A of ≥ 4 at 12 weeks, had a smaller decline in sleep latency than placebo responders at 12 weeks (p = 0.002) Escitalopram participants (responders and nonresponders) had a smaller reduction in sleep latency (0.60 min vs. 2.81) and total minutes in bed (8 min increase vs. 35 min decrease on placebo) relative to people on placebo (Table 2). Although not significant, there was a trend for participants with worse baseline sleep efficiency to have greater 12-week improvement in agitation. (Figure 1) CONCLUSION: We observed no association of sleep variables with baseline agitation or change in agitation with treatment. Escitalopram exposure was associated with modest changes in selected sleep parameters. These findings may inform future studies of agitation in AD as well as targets for future treatments.},
}

Humans
Female
Male
Aged
Actigraphy
*Psychomotor Agitation/drug therapy/etiology
Aged, 80 and over
*Alzheimer Disease/complications/drug therapy
*Sleep Wake Disorders/drug therapy/etiology
*Escitalopram/therapeutic use
Citalopram/therapeutic use
Selective Serotonin Reuptake Inhibitors/therapeutic use
Sleep/drug effects

@article {pmid41444109,
year = {2025},
author = {Smith, PJ and Johnson, KG and Roth, HL and Potter, GG and Patillo, S and Lin, WJ and Song, AJ and Berger, M and O'Brien, RJ and Liu, A and Lutz, MW and Luo, S and Bozoki, A and Welsh-Bohmer, KA and Garden, GA and Whitson, H},
title = {Biomarkers.},
journal = {Alzheimer's & dementia : the journal of the Alzheimer's Association},
volume = {21 Suppl 2},
number = {},
pages = {e098671},
doi = {10.1002/alz70856_098671},
pmid = {41444109},
issn = {1552-5279},
mesh = {Humans ; *Biomarkers/cerebrospinal fluid ; Female ; Male ; Middle Aged ; tau Proteins/cerebrospinal fluid ; Aged ; Amyloid beta-Peptides/cerebrospinal fluid ; Adult ; *Alzheimer Disease/cerebrospinal fluid/psychology ; Neuropsychological Tests ; Depression/cerebrospinal fluid ; Neurofilament Proteins/cerebrospinal fluid ; Cohort Studies ; Peptide Fragments/cerebrospinal fluid ; },
abstract = {BACKGROUND: Psychosocial factors, including mood function and residential status (urban vs. rural), have been suggested to affect the risk of Alzheimer's Disease and Related Dementias (ADRD). Few studies, however, have attempted to examine the associations between these psychosocial factors and ADRD cerebrospinal fluid (CSF) biomarkers, which provide unique information on prodromal ADRD risk prior to the onset of clinical impairments in neuropsychological function.

METHOD: We examined the associations between psychosocial functioning with cognitive function and ADRD biomarker profiles among young, middle-aged, and older adults participating in the Duke-UNC ADRC cohort. Among the 243 enrolled participants, 162 underwent CSF biomarker assessments. Depressive symptoms were assessed using the Geriatric Depression Scale (GDS). Residential status was indexed as either Urban or Rural using the 2010 United States urban maps from ArcGIS. CSF markers included Aβ42/40, phosphorylated tau (p-tau181) and neurofilament light (NfL). Cognitive function was assessed from the National Alzheimer's Coordinating Center Uniform Data Set. Factor analysis was used to aggregate individual cognitive subtests into two unit-weighted cognitive domain scores: Executive, Language, and Visuospatial Function (ELVF) and Memory. General linear models were used to examine the associations between psychosocial functioning with cognitive function and ADRD biomarkers, controlling for age, education, gender, race, comorbidities, and APOE genotype.

RESULT: Participants ranged from 28 to 80 years of age (mean = 59.8 years [SD = 11]), were mostly female (69%) and white (20%), and nearly half had ≥ one APOE risk allele. Levels of depressive symptoms were minimal, with only 27 (11%) exhibiting clinically elevated levels. The majority of participants resided in urban areas (74%). Greater depressive symptoms associated with worse Memory performance (p = .005) and higher p-tau181 levels (p = .026; Figure 1). The association between depressive symptoms and p-tau181 also varied by age (p = .034 for interaction), such that the age and p-tau181 association was stronger in the presence of elevated depressive symptoms (Figure 2). Individuals who resided in rural vs. urban areas showed lower ELVF performance (p = .033) and higher NfL levels (p = .048; Figure 3).

CONCLUSION: Psychosocial characteristics associate with cognitive function and ADRD biomarkers among middle-aged adults.},
}

Humans
*Biomarkers/cerebrospinal fluid
Female
Male
Middle Aged
tau Proteins/cerebrospinal fluid
Aged
Amyloid beta-Peptides/cerebrospinal fluid
Adult
*Alzheimer Disease/cerebrospinal fluid/psychology
Neuropsychological Tests
Depression/cerebrospinal fluid
Neurofilament Proteins/cerebrospinal fluid
Cohort Studies
Peptide Fragments/cerebrospinal fluid

@article {pmid41444108,
year = {2025},
author = {Pham, A and Garai, S and Zhai, T and Shen, L},
title = {Basic Science and Pathogenesis.},
journal = {Alzheimer's & dementia : the journal of the Alzheimer's Association},
volume = {21 Suppl 1},
number = {},
pages = {e106783},
doi = {10.1002/alz70855_106783},
pmid = {41444108},
issn = {1552-5279},
mesh = {*Alzheimer Disease/genetics/metabolism ; Humans ; *Tripartite Motif Proteins/genetics/metabolism ; *Ubiquitin-Protein Ligases/genetics ; Bayes Theorem ; Algorithms ; Animals ; Mice ; },
abstract = {BACKGROUND: It has been found that the Tripartite motif-containing protein 11 (TRIM11) is downregulated in Alzheimer's Disease (AD). When overexpressed in AD mouse models, this gene is associated with the degradation of the amyloid tau protein and improving cognitive functions. The finding poses a promising pathway for potentially new targets that can upregulate TRIM11 expression and control AD symptoms. In this research, we employ single-nucleus RNA sequencing (snRNA-seq) data, Bayesian Networks, and Causal DAGs using the NOTEARS algorithm to identify potential genetic expression regulators of TRIM11, aiming to upregulate this gene in AD.

METHOD: The snRNA-seq dataset GSE173731 was obtained from the National Center for Biotechnology Information Gene Expression Omnibus (NCBI GEO), a publicly accessible database. This study focused on the control samples, consisting of 33,538 genes (coding and non-coding) across 171,520 nuclei. Raw gene counts were processed in RStudio using the SingleCellExperiment and normalized via Relative Log Expression (RLE). Gene-gene interactions were analyzed using a three-step framework: Pearson correlation assessed linear associations of other genes with TRIM11, Bayesian analysis identified probabilistic dependencies, and the NOTEARS algorithm refined causal inference with a sparse, acyclic network.

RESULT: After calculating the Pearson correlation of all other genes to TRIM11, 1,088 genes were found to be positively correlated to TRIM11, with a significant-adjusted p-value threshold of 1.47x10-6, determined by the Bonferroni Correction. Applying the Bayesian framework to those 1,088 genes, we identified 219 genes positively influencing TRIM11. The NOTEARS algorithm was then applied to these 219 genes, of which 16 genes were found to have a direct, positive causal relationship with TRIM11, suggesting their potential regulatory or functional roles in its expression. Examples of these genes include ATRIP (plays a key role in DNA damage response), NDST2 (involved in heparan sulfate biosynthesis), and SLC7A7 (critical for amino acid transport).

CONCLUSION: By integrating Pearson correlation analysis, Bayesian framework, and NOTEARS causal network modeling, we identified key genes that may influence TRIM11 expression. Future studies can focus on experimental validation of these genes and exploring their functional roles in pathways associated with TRIM11 to uncover potential therapeutic targets.},
}

*Alzheimer Disease/genetics/metabolism
Humans
*Tripartite Motif Proteins/genetics/metabolism
*Ubiquitin-Protein Ligases/genetics
Bayes Theorem
Algorithms
Animals
Mice

@article {pmid41444105,
year = {2025},
author = {Wu, F and Dirani, A and Lavoie, M and Hébert, M and Laforce, R},
title = {Biomarkers.},
journal = {Alzheimer's & dementia : the journal of the Alzheimer's Association},
volume = {21 Suppl 2},
number = {},
pages = {e098816},
doi = {10.1002/alz70856_098816},
pmid = {41444105},
issn = {1552-5279},
mesh = {Humans ; Tomography, Optical Coherence ; Male ; Female ; Cross-Sectional Studies ; Biomarkers ; Aged ; *Aphasia, Primary Progressive/pathology/diagnostic imaging ; Middle Aged ; *Retina/pathology/diagnostic imaging ; },
abstract = {BACKGROUND: The logopenic variant of Primary Progressive Aphasia (lvPPA) is a neurodegenerative disorder affecting primarily language functions. In 86% of lvPPA cases, the underlying pathology is amyloidopathy, as seen in Alzheimer's disease (AD). Since the retina is considered an extension of the brain, recent research has explored optical coherence tomography (OCT) and OCT-angiography (OCT-A) as non-invasive biomarkers in AD. However, their potential in lvPPA remains unexplored. The aim of this study was to compare retinal findings in lvPPA patients and healthy controls using OCT and OCT-A.

METHODS: We conducted a cross-sectional study recruiting participants with lvPPA (diagnostic criteria by Gorno-Tempini, 2011) and healthy controls matched for sex and age. Participants were excluded if they had preexisting neurological or eye conditions. An extensive ophthalmological assessment was conducted to rule out eye diseases. OCT/OCTA imaging was then performed for all participants. For lvPPA patients, the Clinical Dementia Rating scale and a lumbar puncture were performed to assess disease stage and underlying pathology.

RESULTS: Ten lvPPA patients and eleven controls were enrolled. All lvPPA patients had amyloidopathy confirmed by lumbar puncture. Mean CDR global score was 0.55 ± 0.16 (indicating mild dementia). Retinal nerve fiber layer (RNFL) in the temporal region was significantly thinner in the lvPPA group compared to controls (63.1 ± 3.3 μm vs 75.6 ± 3.2 μm, p = 0.013). Foveal avascular zone (FAZ) circularity was also significantly lower in the lvPPA group (0.69 ± 0.02 vs 0.77 ± 0.02, p = 0.002).

CONCLUSIONS: Our findings suggest decreased RNFL thickness and reduced FAZ circularity in lvPPA. Decreased RNFL thickness reflects neuronal degeneration and its underlying mechanisms include retinal amyloid accumulation or retrograde degeneration. This suggests that amyloid-induced brain atrophy leads to a lack of trophic factors, resulting in thinning of the RNFL while reduced FAZ circularity could signal early vascular alterations induced by amyloid. Altogether, these findings suggest that OCT and OCT-A could serve as valuable biomarkers for lvPPA, thus enhancing early diagnosis.},
}

Humans
Tomography, Optical Coherence
Male
Female
Cross-Sectional Studies
Biomarkers
Aged
*Aphasia, Primary Progressive/pathology/diagnostic imaging
Middle Aged
*Retina/pathology/diagnostic imaging

@article {pmid41444104,
year = {2025},
author = {Chen, Y and Wu, Y and Wang, D and Yang, Y and Guo, Q and Qiu, Q and Wan, C and Li, X},
title = {Clinical Manifestations.},
journal = {Alzheimer's & dementia : the journal of the Alzheimer's Association},
volume = {21 Suppl 3},
number = {},
pages = {e097465},
doi = {10.1002/alz70857_097465},
pmid = {41444104},
issn = {1552-5279},
mesh = {Humans ; Male ; Female ; *Cognitive Dysfunction/diagnosis ; Aged ; *Alzheimer Disease/diagnosis ; *Niacin/adverse effects ; *Flushing/chemically induced ; Middle Aged ; *Depression/complications ; Mental Status and Dementia Tests ; Neuropsychological Tests ; },
abstract = {BACKGROUND: Late-life depression (LLD) with cognitive impairment (CI), as a potential subtype of LLD, carries an elevated risk of progressing to Alzheimer's disease (AD), yet the underlying mechanisms remain elusive. While anomalies in niacin skin flushing response (NSFR) have been observed in various neuropsychiatric disorders, there is a paucity of research examining these phenomena in LLD patients. This study aims to elucidate the potential value of the NSFR in predicting CI in LLD patients.

METHOD: This study included 86 patients of LLD (46 LLD with CI and 40 LLD without CI), 20 AD and 32 Healthy Controls (HCs). Cognitive functions were estimated through the Chinese version of Montreal Cognitive Assessment (MoCA). NSFR tests were conducted with a modified method. LogEC50 is utilized to indicate the rate of NSFR. MoCA was retested after six months of treatment. Multivariate analysis of variance (MANOVA) was conducted with demographic variables that differed statistically among the groups to assess differences in NSFR and clinical indexes among groups. Logistic regression models based on NSFR were constructed, and receiver-operating characteristic (ROC) curve analysis was calculated to evaluate the performance of models.

RESULT: The LogEC50 levels were significantly elevated in LLD with CI group compared to both the LLD without CI (p <0.05) and HCs (p <0.05). However, no significant differences were observed between the LLD without CI and the HCs group, nor between the LLD with CI and AD. ROC analysis demonstrated that Log EC50 can effectively distinguish between LLD with CI and LLD without CI. Six-month follow-up data revealed that the baseline LogEC50 can also effectively predict cognitive outcomes in LLD.

CONCLUSION: LLD with CI exhibited a delayed NSFR. Delayed NSFR proved effective in distinguishing cognitive impairment in LLD, suggesting that NSFR could serve as a potential biomarker for LLD with CI. Furthermore, in patients with LLD, a delayed NSFR at baseline predicts poorer cognitive outcomes. These insights open new avenues for research into the mechanisms underlying CI in LLD and offer fresh perspectives on potential therapeutic targets.},
}

Humans
Male
Female
*Cognitive Dysfunction/diagnosis
Aged
*Alzheimer Disease/diagnosis
*Niacin/adverse effects
*Flushing/chemically induced
Middle Aged
*Depression/complications
Mental Status and Dementia Tests
Neuropsychological Tests

@article {pmid41444101,
year = {2025},
author = {Santiago, JA and Gutierrez-Silva, JC and Hsu, WC and Sanchez, K and Almanza, C and Ramos, W and Haq, IU and Rundek, T},
title = {GLP-1 agonists in neurodegeneration: a multimodal biomarker-guided approach.},
journal = {Trends in molecular medicine},
volume = {},
number = {},
pages = {},
doi = {10.1016/j.molmed.2025.12.001},
pmid = {41444101},
issn = {1471-499X},
abstract = {Glucagon-like peptide-1 receptor agonists (GLP1-RAs), widely used for type 2 diabetes mellitus, are emerging as promising neuroprotective therapies in Alzheimer's disease (AD) and Parkinson's disease (PD). Agents such as exenatide, lixisenatide, and liraglutide have demonstrated disease-modifying potential in preclinical and clinical studies. However, translation remains hindered by the absence of validated biomarkers to guide patient selection, track target engagement, and monitor progression. Here, we review the mechanistic links between GLP1-RA signaling and neurodegeneration, summarize the evolving clinical evidence, and highlight emerging blood-based and molecular biomarkers, including those tied to insulin signaling, neurodegeneration, and metabolic and cardiovascular dysfunction, that may accelerate therapeutic development. Integrating these biomarkers with digital phenotyping and artificial intelligence could enable precision approaches to advance GLP1-RA research and clinical use in neurodegeneration.},
}

@article {pmid41444088,
year = {2025},
author = {Lynch, S},
title = {Addressing Cognitive Dysfunction: Education, Diagnosis, and Practical Care.},
journal = {The Veterinary clinics of North America. Small animal practice},
volume = {},
number = {},
pages = {},
doi = {10.1016/j.cvsm.2025.09.030},
pmid = {41444088},
issn = {1878-1306},
abstract = {Cognitive dysfunction syndrome (CDS) is a common, yet underdiagnosed, neurobehavioral disease of domestic animals. Much like its human counterpart, Alzheimer's disease, CDS is the result of neuronal loss and inflammatory changes in the central nervous system; however, the specific pathophysiology of the disease continues to be researched in efforts to advance diagnostics, prognosis, and treatment. Diagnosis is typically conducted by ruling out possibilities and using assessment tools, including the Canine Dementia Scale and the Canine Cognitive Dysfunction Rating Scale. Treatment is often most successful when a tailored, multimodal approach is initiated early in the disease progression.},
}

@article {pmid41444017,
year = {2025},
author = {Farina, FR and Bennett, MP and Grill, JD and Sperling, RA and Lawlor, B and Griffith, JW},
title = {Clinical Manifestations.},
journal = {Alzheimer's & dementia : the journal of the Alzheimer's Association},
volume = {21 Suppl 3},
number = {},
pages = {e097819},
doi = {10.1002/alz70857_097819},
pmid = {41444017},
issn = {1552-5279},
mesh = {Humans ; Female ; Male ; Aged ; *Alzheimer Disease/psychology/diagnostic imaging/genetics ; Aged, 80 and over ; Positron-Emission Tomography ; Amyloid beta-Peptides/metabolism ; *Cognitive Dysfunction/psychology ; Mental Status and Dementia Tests ; Life Style ; Neuropsychological Tests ; Depression ; Anxiety/psychology ; },
abstract = {BACKGROUND: Concerns about developing Alzheimer's disease (AD) are common. AD concerns have been shown to indicate pathological changes like amyloid accumulation in individuals with subjective cognitive decline. However, the extent to which AD concerns relate to such changes in cognitively unimpaired populations is unclear. Our aim was to investigate if AD concerns are associated with amyloid burden in cognitively unimpaired older adults, and how these concerns relate to lifestyle behaviors.

METHOD: We analyzed screening data from the Anti-Amyloid Treatment in Asymptomatic Alzheimer (A4) study, which is a randomized clinical trial conducted across 67 sites. Data were collected between April 2014 and December 2017 and analyzed in October 2024. Participants were cognitively unimpaired older adults (65-85 years; Clinical Dementia Rating: 0 and/or Mini-Mental State Examination (MMSE) score: ≥25) who underwent positron emission tomography (PET) imaging to assess cortical amyloid beta levels. Measures were screening demographics, lifestyle variables, APOE genotyping, AD concerns (Concerns about Alzheimer's Disease Questionnaire; CADQ), anxiety (State-Trait Anxiety Inventory; STAI), depression (Geriatric Depression Scale; GDS), cognition (MMSE, Cognitive Function Index; CFI), and florbetapir amyloid PET. AD concerns were assessed prior to disclosure of amyloid or APOE status.

RESULT: Of 4460 individuals (mean [SD] age, 71.29 [4.67] years, 59.4% female), AD concerns were elevated in: females compared to males (mean [SD] CADQ = 21.3 [4.62] vs. 20.34 [4.64]; p < .001), individuals with a parental history of dementia (21.71 [4.36] vs. 19.46 [4.83]; p < .001), APOEε4 carriers (21.56 [4.54] vs. 20.56 [4.68]; p < .001), and those who did not meet recommended guidelines for walking (21.16 [4.66] vs 20.83 [4.64]; p = 0.032) or sleep (21.14 [4.81] vs. 20.83 [4.59]; p = 0.039). AD concerns were associated with higher amyloid burden (p = 0.007) after adjusting for demographics, anxiety, depression, cognition, parental history and APOEε4. This model outperformed the reference model without AD concerns. The association between AD concerns and amyloid burden was stronger in APOEε4 carriers.

CONCLUSION: AD concerns were associated with elevated amyloid, a core diagnostic AD biomarker. Assessing AD concerns could inform future cohort and intervention recruitment strategies.},
}

Humans
Female
Male
Aged
*Alzheimer Disease/psychology/diagnostic imaging/genetics
Aged, 80 and over
Positron-Emission Tomography
Amyloid beta-Peptides/metabolism
*Cognitive Dysfunction/psychology
Mental Status and Dementia Tests
Life Style
Neuropsychological Tests
Depression
Anxiety/psychology

@article {pmid41444013,
year = {2025},
author = {Erani, F and Terao, CM and Cooper, S and Weigand, AJ and Bangen, KJ and Edmonds, EC and Thomas, KR},
title = {Clinical Manifestations.},
journal = {Alzheimer's & dementia : the journal of the Alzheimer's Association},
volume = {21 Suppl 3},
number = {},
pages = {e097877},
doi = {10.1002/alz70857_097877},
pmid = {41444013},
issn = {1552-5279},
mesh = {Humans ; Male ; Female ; *Cognitive Dysfunction/diagnosis/psychology ; Disease Progression ; Neuropsychological Tests/statistics & numerical data ; Aged ; *Alzheimer Disease/diagnosis ; Aged, 80 and over ; Depression ; Executive Function ; Phenotype ; },
abstract = {BACKGROUND: Data-driven analyses of neuropsychological measures have identified subtle cognitive decline phenotypes that demonstrate unique associations with Alzheimer's disease risk and progression. While early detection efforts traditionally focus on cognitive and biological markers, neuropsychiatric symptoms (NPS) have emerged as critical predictors of cognitive decline and dementia conversion. The current study examined whether distinct NPS phenotypes were associated with progression to mild cognitive impairment (MCI)/dementia and cognitive decline trajectories.

METHOD: A latent class analysis was conducted on 20,599 cognitively unimpaired (CU) older adults in the National Alzheimer's Coordinating Center Uniform Data Set identified NPS phenotypes using item-level variables from the Neuropsychiatric Inventory and Geriatric Depression Scale. Logistic regressions with Tukey-adjusted contrasts assessed odds of progression to MCI/dementia after adjusting for age, sex, education, and years since baseline. Linear mixed-effects models, adjusting for demographics, examined 6-year changes in cognitive composite scores (memory, attention, executive function, and language) by NPS phenotype.

RESULT: The best-fiting model had four NPS phenotypes: [1] Low-All; [2] High-Depression; [3] High-Agitation/Anxiety/Irritability, and [4] High-All (Table 1, Figure 1). The High-All group had the greatest progression risk to MCI/dementia, with 3x higher odds than Low-All (p < .001), 2.1x higher odds than High-Depression (p < .001), and 1.6x higher odds than High-Agitation/Anxiety/Irritability (p = .009). The High-Agitation/Anxiety/ Irritability group had 2x higher odds than Low-All (p < .001) and 1.4x higher odds than High-Depression, while the High-Depression group had 1.4x higher odds than Low-All. At baseline, the Low-All group outperformed others across cognitive domains (all ps < .001) except for memory, where High-Depression did not differ (Figure 2). The High-Depression group showed faster decline in attention than Low-All, while the High-All group declined faster in executive functioning (ps < .01). The High-Agitation/Anxiety/Irritability group showed slower memory improvement (p = .003) and faster decline across all other cognitive domains (ps < .01) compared to the Low-All group.

CONCLUSION: Distinct NPS phenotypes were observed among CU older adults and were associated with differing risks of MCI/dementia progression and cognitive trajectories. Phenotypes with high NPS, particularly agitation, anxiety, and irritability, showed higher odds of progression than depressive symptoms alone. These findings underscore the value and potential utility of early NPS patterns for predicting cognitive decline and early risk detection.},
}

Humans
Male
Female
*Cognitive Dysfunction/diagnosis/psychology
Disease Progression
Neuropsychological Tests/statistics & numerical data
Aged
*Alzheimer Disease/diagnosis
Aged, 80 and over
Depression
Executive Function
Phenotype

@article {pmid41444012,
year = {2025},
author = {Moreno, N and Shchankin, N and Bhatt, N and Haque, MA and Limon, A and Kayed, R},
title = {Basic Science and Pathogenesis.},
journal = {Alzheimer's & dementia : the journal of the Alzheimer's Association},
volume = {21 Suppl 1},
number = {},
pages = {e106052},
doi = {10.1002/alz70855_106052},
pmid = {41444012},
issn = {1552-5279},
mesh = {Humans ; *tau Proteins/metabolism/genetics ; *Alzheimer Disease/genetics/pathology/metabolism ; *Apolipoproteins E/genetics/metabolism ; *Brain/metabolism/pathology ; Protein Isoforms/metabolism/genetics ; Tandem Mass Spectrometry ; Male ; Female ; Chromatography, Liquid ; },
abstract = {BACKGROUND: Apolipoprotein E (APOE), the strongest genetic risk factor for late-onset Alzheimer's disease, exist as 3 isoforms (APOE2, 3, 4) which differentially influence Alzheimer's disease risk and tau pathology in disease. Recent studies have revealed the polymorphic nature of amyloidogenic proteins, including tau, across different diseases, yet there remains a gap in knowledge concerning tau polymorphism across genetic variants such as the APOE isoforms. Here, we address this gap in knowledge by characterizing tau oligomers associated with each APOE isoform.

METHOD: Brain-derived tau oligomers and fibrils were isolated from tissue of patients with various APOE genotypes. Tau oligomers were characterized using proteinase K (PK) digestion and liquid chromatography-tandem mass spectrometry (LC-MS/MS) to investigate proteolytic stability and cleavage site accessibility to PK. Electrophysiology was used to investigate synaptotoxicity of the tau oligomers.

RESULT: Tau oligomers differ in proteolytic stability and cleavage site profiles across the APOE isoforms, indicating conformationally-distinct tau oligomer polymorphs. The tau oligomer polymorphs differentially impair synaptic functioning in an APOE isoform-specific manner, with APOE4-relevant tau oligomers inducing the strongest impairment of synaptic functioning.

CONCLUSION: The APOE isoforms correspond with distinct tau oligomer polymorphs with varying synaptotoxicity. These findings highlight the need for APOE isoform to be considered when generating tau-based therapies for Alzheimer's disease. Specific targeting of APOE isoform-specific tau oligomer polymorphs could provide a novel method of mitigating Alzheimer's Disease pathology and combating disease progression.},
}

Humans
*tau Proteins/metabolism/genetics
*Alzheimer Disease/genetics/pathology/metabolism
*Apolipoproteins E/genetics/metabolism
*Brain/metabolism/pathology
Protein Isoforms/metabolism/genetics
Tandem Mass Spectrometry
Male
Female
Chromatography, Liquid

@article {pmid41444011,
year = {2025},
author = {Mohammadi, S and Rahmani, F and Dolatshahi, M and Schindler, SE and Raji, CA},
title = {Biomarkers.},
journal = {Alzheimer's & dementia : the journal of the Alzheimer's Association},
volume = {21 Suppl 2},
number = {},
pages = {e100022},
doi = {10.1002/alz70856_100022},
pmid = {41444011},
issn = {1552-5279},
mesh = {Humans ; Male ; Female ; Aged ; *Biomarkers/blood ; Positron-Emission Tomography ; *Alzheimer Disease/diagnostic imaging/blood/complications ; *Obesity/blood/complications/diagnostic imaging ; Body Mass Index ; Amyloid beta-Peptides/blood ; tau Proteins/blood ; Cross-Sectional Studies ; Aniline Compounds ; Aged, 80 and over ; Middle Aged ; Brain/diagnostic imaging/metabolism ; Thiazoles ; },
abstract = {BACKGROUND: Obesity is a risk factor for Alzheimer's disease (AD), but its impact on blood biomarkers (BBMs) trajectories of AD remains unclear. This study investigates how obesity influences changes in plasma biomarkers and amyloid burden in AD.

METHOD: BBM tests were performed on plasma samples from the Alzheimer's Disease Neuroimaging Initiative (ADNI) that were collected within six months of an amyloid positron emission tomography (PET) scan. Global amyloid burden was calculated as Centiloid values using (11)C-Pittsburgh Compound-B positron emission tomography. Spearman's partial correlation was used to assess the baseline cross-sectional association between body mass index (BMI) and BBM levels, with age, sex, and years of education as covariates and adjusted for multiple comparisons. Linear mixed-effects regression models were used to study three-way interaction between baseline BBM, obesity (BMI>30), and time.

RESULT: A total of 407 participants were included in the cohort, with a mean age of 72.92 years, 24.32% were classified as obese, 50.9% were male, and the mean Centiloid value was 25.16. At baseline, higher BMI was associated with lower amyloid burden as measured by PET as well as lower levels of plasma p-tau217, %p-tau217, GFAP and NFL. Obese participants had a faster increase in amyloid burden by PET and faster increases in plasma p-tau217 and %p-tau217 as compared to non-obese individuals. However, obesity was not consistently associated with the rate of changes in NfL or GFAP.

CONCLUSION: While obesity is mainly associated with lower baseline BBM levels, individuals with obesity tend to exhibit faster accumulation of amyloid burden by PET, as well as higher rates of changes in plasma p-tau217 and %p-tau217, compared to non-obese individuals. The findings of this study not only offer valuable insights for interpreting BBM levels in obese versus non-obese individuals but also provide insights on the effects of obesity on AD pathology over time.},
}

Humans
Male
Female
Aged
*Biomarkers/blood
Positron-Emission Tomography
*Alzheimer Disease/diagnostic imaging/blood/complications
*Obesity/blood/complications/diagnostic imaging
Body Mass Index
Amyloid beta-Peptides/blood
tau Proteins/blood
Cross-Sectional Studies
Aniline Compounds
Aged, 80 and over
Middle Aged
Brain/diagnostic imaging/metabolism
Thiazoles

@article {pmid41444000,
year = {2025},
author = {Boon, BDC and Piura, YD and Moloney, CM and Chalk, JL and Lincoln, SJ and Rutledge, MH and Johnson, DR and Dickson, DW and Nguyen, AT and Reichard, RR and Graff-Radford, J and Knopman, DS and Graff-Radford, NR and Murray, ME},
title = {Basic Science and Pathogenesis.},
journal = {Alzheimer's & dementia : the journal of the Alzheimer's Association},
volume = {21 Suppl 1},
number = {},
pages = {e105890},
doi = {10.1002/alz70855_105890},
pmid = {41444000},
issn = {1552-5279},
mesh = {Humans ; Male ; Female ; *Antibodies, Monoclonal, Humanized/therapeutic use ; *Alzheimer Disease/drug therapy/pathology/diagnostic imaging/genetics ; Aged ; Amyloid beta-Peptides/metabolism ; Positron-Emission Tomography ; *Brain/pathology/diagnostic imaging/metabolism ; Aged, 80 and over ; Middle Aged ; tau Proteins/metabolism ; },
abstract = {BACKGROUND: Monoclonal antibodies targeting amyloid-β (Aβ), including aducanumab, have been tested to treat Alzheimer's disease (AD). However, limited data exist on neuropathology following treatment and the effects of amyloid-related imaging abnormalities (ARIA). We report on such data from five aducanumab-treated study participants with AD of whom two experienced ARIA.

METHODS: Aducanumab-treated study participants who came to autopsy (n = 5) were matched to AD controls (n = 12) based on the presence/type of autosomal dominant AD mutation, APOE genotype, age at cognitive symptom onset, and sex. We assessed cognitive measures, [18]F-florbetapir PET centiloid, ARIA risk factors, and AD neuropathologic change. Using multiplex immunofluorescence, brain regions affected along Thal Aβ phases were stained for Aβ isoforms and phosphorylated tau, as well as for ARIA-associated markers, including Perls' Prussian blue to detect ferric iron, fibrinogen-α for blood brain barrier integrity, membrane attack complex (C5b-C9) for complement activation, and activated microglia (IBA1, CD68).

RESULTS: Study participants included four males and one female, all carrying at least one APOE ε4 allele. Two participants carried a PSEN1 NM_000021.4:c.817G>A, p.Glu273Lys mutation. Cumulative aducanumab dosage ranged between 5-241 mg/kg, with death occurring 5-41 months after the last infusion. Amyloid burden on PET declined in all participants (range 15-100 centiloids). Two participants experienced ARIA. Compared to AD controls, Aβaa1-8 and Aβ42 were selectively reduced in cortical layer I of aducanumab-treated study participants (p <0.05) but not in the total cortex, as shown for the middle frontal cortex in Figure 1. No differences were observed in phosphorylated tau burden. Prussian blue-stained hemosiderin was present in both treated and untreated AD cases. However, in participants with ARIA, hemosiderin accumulated in superficial cortical layers near CAA-laden meningeal and penetrating vessels, which also exhibited extensive complement and microglial activation (Figure 2).

CONCLUSIONS: Aβ clearance and ARIA-related findings were localized predominantly in superficial cortical layers, suggesting that aducanumab biodistribution is more pronounced in these regions rather than deeper cortical layers.},
}

Humans
Male
Female
*Antibodies, Monoclonal, Humanized/therapeutic use
*Alzheimer Disease/drug therapy/pathology/diagnostic imaging/genetics
Aged
Amyloid beta-Peptides/metabolism
Positron-Emission Tomography
*Brain/pathology/diagnostic imaging/metabolism
Aged, 80 and over
Middle Aged
tau Proteins/metabolism

@article {pmid41443999,
year = {2025},
author = {Khorsand, B and Ghanbarian, E and Andrews, HJ and Bodek, H and Cameron, JD and Moffitt, C and Lavin, R and Lipton, RB and Rabin, LA and Roque, NA and Sergeyev, N and Ezzati, A},
title = {Clinical Manifestations.},
journal = {Alzheimer's & dementia : the journal of the Alzheimer's Association},
volume = {21 Suppl 3},
number = {},
pages = {e105059},
doi = {10.1002/alz70857_105059},
pmid = {41443999},
issn = {1552-5279},
mesh = {Humans ; Male ; Female ; *Cognitive Dysfunction/diagnosis ; Aged ; *Neuropsychological Tests ; Cross-Sectional Studies ; Aged, 80 and over ; Self Report ; Surveys and Questionnaires ; Cognition ; },
abstract = {BACKGROUND: The Cognitive Function Index (CFI) and the Modified Telephone Interview for Cognitive Status (TICS-m) are widely used tools for cognitive screening in older adults. TICS-m is an examiner-administered, objective test, while the CFI is a self-reported, subjective questionnaire. Although subjective cognitive concerns are common among older adults and may portend progression to dementia, the cross-sectional relationship between subjective and objective cognition is inconsistent. This study examines the association between CFI and TICS-m to evaluate the utility of self-reported cognitive concerns in identifying cognitive impairment in older adults.

METHOD: The Remote Cognitive Aging and Alzheimer's Disease REsearch (R-CARE) study is an ongoing initiative aimed at validating a remote cognitive assessment toolbox for diverse, dementia-free older adults. As part of the screening for this cohort, 1496 individuals identified through the EHR system were contacted, 158 agreed to participate, and 128 participants completed both CFI and TICS-m assessments. Mild cognitive impairment (MCI) was defined as an education adjusted TICS-m cut-score (Knopman et al., 2010). Linear regression assessed the relationship between CFI and TICS-m scores, while logistic regression evaluated the ability of CFI items to classify cognitively unimpaired (CU) and MCI participants, defined by the TICS-m, adjusting for demographic covariates.

RESULTS: Participants had a mean age of 70.9±6.6 years, and 32% were categorized as MCI based on TICS-m scores. Higher CFI total scores were significantly associated with lower TICS-m scores in linear regression models (ß=-0.47±0.18, p = 0.009). Logistic regression models identified five CFI items significantly associated with MCI classification after adjusting for age, sex, education, and race: repeating questions (OR=1.88, p = 0.01), needing help to remember (OR=1.63, p = 0.04), difficulty managing money (OR=1.77, p = 0.03), difficulty in activities (OR=1.58, p = 0.04), and difficulty using household appliances (OR=2.48, p = 0.03).

CONCLUSION: The Cognitive Function Index (CFI) showed a significant association with TICS-m scores, highlighting its potential as a complementary tool for identifying cognitive impairment. Specific self-reported items, such as repeating questions and difficulties with activities of daily living, were predictive of MCI. These findings suggest that CFI, with its brevity and ease of administration, may prove valuable for remote cognitive screening and to enhance early detection efforts in diverse populations.},
}

Humans
Male
Female
*Cognitive Dysfunction/diagnosis
Aged
*Neuropsychological Tests
Cross-Sectional Studies
Aged, 80 and over
Self Report
Surveys and Questionnaires
Cognition

@article {pmid41443992,
year = {2025},
author = {Nair, AA and Wen, Z and Wang, Z and Yan, J and Saykin, AJ and Huang, H and Thompson, PM and Davatzikos, C and Shen, L},
title = {Biomarkers.},
journal = {Alzheimer's & dementia : the journal of the Alzheimer's Association},
volume = {21 Suppl 2},
number = {},
pages = {e098857},
doi = {10.1002/alz70856_098857},
pmid = {41443992},
issn = {1552-5279},
mesh = {Humans ; *Alzheimer Disease/diagnostic imaging/pathology ; *Biomarkers ; Positron-Emission Tomography ; Magnetic Resonance Imaging ; Disease Progression ; Male ; Female ; Aged ; Neuroimaging ; *Brain/diagnostic imaging/pathology ; Machine Learning ; tau Proteins/metabolism ; Algorithms ; Plaque, Amyloid/pathology/diagnostic imaging ; Aged, 80 and over ; },
abstract = {BACKGROUND: Alzheimer's disease (AD) is a progressive neurodegenerative disorder marked by amyloid-beta plaques (A), neurofibrillary tangles (T), and neuronal loss (N), commonly abbreviated A/T/N. Understanding the spatial progression of neurodegeneration is key to predicting disease trajectories and outcomes. Using Positron Emission Tomography (PET) and Magnetic Resonance Imaging (MRI) data from the Alzheimer's Disease Neuroimaging Initiative (ADNI), this study explores the staging and pseudotime of AD patients using A/T/N biomarkers.

METHOD: We collect cortical measurements from ADNI corresponding to A/T/N modalities (Table 1). For each of the three modalities, we apply PHATE, a dimensionality reduction technique for visualizing trajectories of disease progression. We translate PHATE embeddings into 1D pseudotime values using Slingshot, an algorithm that fits principal curves to the embeddings and orthogonally projects the points onto the fitted curves. We independently run SuStaIn, a machine learning algorithm that predicts patient stages and biomarker sequences underlying disease progression. Finally, we compare SuStaIn's stage predictions with pseudotime values from PHATE and Slingshot to test disease progression robustness and generate hypotheses for biomarker events driving underlying disease progression for each imaging modality.

RESULT: We observe that across all three modalities, the predicted SuStaIn stages are closely associated with the pseudotime values inferred by PHATE and Slingshot (Figure 1), with later stages corresponding to higher pseudotime values. Among the three modalities, amyloid PET and tau PET exhibit the strongest trajectory alignments, while MRI-based volume shows a slightly weaker alignment. We also observe agreement between predicted biomarker event sequences from SuStaIn and PHATE pseudotime-informed event-based models. Pseudotimes of amyloid and tau modalities are moderately correlated (r=0.55); however, SuStaIn suggests different biomarker events driving their progressions.

CONCLUSION: Integrative analysis of multiple computational methods allows for higher confidence in disease progression timings. Our results suggest that amyloid and tau-associated biomarkers follow distinct trajectories in the cortex, and that different computational approaches independently arrive at similar results. While this work generates sequences of staging events and pseudotime values of disease trajectories, future work is needed to validate the putative biomarker events and connect pseudotime to real-time disease progression.},
}

Humans
*Alzheimer Disease/diagnostic imaging/pathology
*Biomarkers
Positron-Emission Tomography
Magnetic Resonance Imaging
Disease Progression
Male
Female
Aged
Neuroimaging
*Brain/diagnostic imaging/pathology
Machine Learning
tau Proteins/metabolism
Algorithms
Plaque, Amyloid/pathology/diagnostic imaging
Aged, 80 and over

@article {pmid41443989,
year = {2025},
author = {Chang, JH and Hatch, M and Lynch, K and Phatak, VS and Murman, DL and Rizzo, M},
title = {Clinical Manifestations.},
journal = {Alzheimer's & dementia : the journal of the Alzheimer's Association},
volume = {21 Suppl 3},
number = {},
pages = {e098232},
doi = {10.1002/alz70857_098232},
pmid = {41443989},
issn = {1552-5279},
mesh = {Humans ; Male ; Female ; Aged ; *Cognitive Dysfunction/diagnosis/physiopathology ; Neuropsychological Tests/statistics & numerical data ; Aged, 80 and over ; Actigraphy ; *Sleep Wake Disorders ; Sleep/physiology ; Cognition ; },
abstract = {BACKGROUND: Mild cognitive impairment (MCI) can revert to normal cognitive function in 15-48 % of cases[1-3], suggesting that some initial MCI diagnosis reflect transient or context-dependent conditions. Sleep disruption is common in older adults, and even one night of poor sleep can adversely affect cognitive performance temporarily.[4,5] We hypothesized that the greater sleep disruption on the night preceding cognitive assessments would be associated with increased likelihood of MCI reversion at one-year follow-up.

METHOD: Sixty older adults (mean age = 75 years; 25 males), meeting Petersen's criteria[6] for MCI based on a battery of five cognitive-domain assessments (memory, attention, visuospatial, language, and executive function) at baseline year, participated in the study. Participants wore wrist- actigraphs to collect objective sleep data and completed sleep diaries to validate time to go to bed and out of bed on the night before the assessments. Sleep duration (hours) and efficiency (%) were standardized across individuals using Z-scores. A logistic regression model, adjusted for age and gender, estimated the odds of maintaining MCI classification versus reverting to normal cognitive status at a one-year follow-up using the same battery.

RESULT: At one-year follow-up, 45 (75%) maintained MCI status and 15 participants (25%) reverted to normal status (See details in Table 1). Shorter sleep duration the night before the baseline cognitive assessments was significantly associated with higher odds of reversion (b = -0.76, p =  0.049). Each standard deviation (1.27 hour) increases in sleep duration lowered the odds of reversion by approximately 53%. Sleep efficiency, age, and gender were not significant predictors (p > 0.10).

CONCLUSION: In this preliminary study, participants who slept shorter than the group average on the night before cognitive examination were more likely to revert from MCI to normal cognitive classification one year later. These findings underscore the need to consider acute sleep variation in MCI diagnoses. Incorporating short-term sleep measures into clinical care and trials[7] along with biological biomarkers may help refine diagnostic accuracy as prodromal Alzheimer's vs. potentially "reversible" causes, and guide targeted interventions for cognitive health.},
}

Humans
Male
Female
Aged
*Cognitive Dysfunction/diagnosis/physiopathology
Neuropsychological Tests/statistics & numerical data
Aged, 80 and over
Actigraphy
*Sleep Wake Disorders
Sleep/physiology
Cognition

@article {pmid41443988,
year = {2025},
author = {Rahmani, F and Ippolito, JE and Liu, J and Yifei, X and Benzinger, TLS},
title = {Biomarkers.},
journal = {Alzheimer's & dementia : the journal of the Alzheimer's Association},
volume = {21 Suppl 2},
number = {},
pages = {e098937},
doi = {10.1002/alz70856_098937},
pmid = {41443988},
issn = {1552-5279},
mesh = {Humans ; Male ; Female ; Aged ; *Alzheimer Disease/diagnostic imaging ; Biomarkers ; Magnetic Resonance Imaging ; Positron Emission Tomography Computed Tomography ; *Brain/diagnostic imaging/pathology ; Tomography, X-Ray Computed ; Aged, 80 and over ; Cohort Studies ; Middle Aged ; },
abstract = {BACKGROUND: Visceral adiposity, neck adiposity and sarcopenia are related to Alzheimer disease (AD) risk. Current amyloid confirmatory tests have the highest predictive value where there is high AD pretest probability. CT scan-derived adipose and fat quantification can provide insights into this probability. We investigated the relationship between head CT composition metrics and risk of AD.

METHOD: We selected participants with normal cognition (Clinical Dementia Rating Scale (CDRÒ=0) and negative amyloid PET at their baseline visit from the Knight Alzheimer Disease Research Center (Knight ADRC) cohort. Based on subsequent CDR measurements, we determined whether each participant: i) stably converted from normal cognition to early dementia (CDR>0) (dementia converters) or ii) remained cognitively normal throughout the follow up period (healthy non-converters). The PET/CT scan closest to the last CDR=0 date was then used to extract the low-dose attenuation correction CT scan necessary to perform CT composition analysis using the Data Analysis Facilitation Suite (DAFS, version 3) platform. Closest brain MRI within 1 year of this PET/CT scan was used for volumetric analyses through FreeSurfer 7.1.1. Survival and correlation analyses were used to test the relationship between head composition metrics and risk of conversion to early dementia and brain volumes, respectively.

RESULT: Total of 500 participants met the inclusion criteria (age: 69±8, 41.8% male, 13.2% African American). Over a median follow up of 123 months, 48(2.6%) stably converted to early dementia. Individuals with higher fraction of inter-intramuscular adipose tissue in the head have a 3-times increased risk of conversion from normal cognition to early dementia (Figure A). Males, but not females, with higher normalized temporalis muscle volume were protected against conversion to early dementia (HR(95%CI):0.3(0.1-0.8)), suggesting sex differences in this relationship (Figure B). Correlation analyses showed a direct relationship between the volume of the temporalis muscles and volume of the precuneus and entorhinal cortices that persisted even after correction for total intracranial volume (Figure C and D).

CONCLUSION: Head and neck composition metrics inform future risk of dementia and correlate with brain atrophy suggesting a potential role for automated CT-based screening paradigms based on this method.},
}

Humans
Male
Female
Aged
*Alzheimer Disease/diagnostic imaging
Biomarkers
Magnetic Resonance Imaging
Positron Emission Tomography Computed Tomography
*Brain/diagnostic imaging/pathology
Tomography, X-Ray Computed
Aged, 80 and over
Cohort Studies
Middle Aged

@article {pmid41443986,
year = {2025},
author = {Zawar, I and Zhu, SZ and Kapur, J and Quigg, MS and Manning, CA and Fletchet, PTZ},
title = {Clinical Manifestations.},
journal = {Alzheimer's & dementia : the journal of the Alzheimer's Association},
volume = {21 Suppl 3},
number = {},
pages = {e097534},
doi = {10.1002/alz70857_097534},
pmid = {41443986},
issn = {1552-5279},
mesh = {Humans ; Male ; Female ; Magnetic Resonance Imaging ; Aged ; *Alzheimer Disease/diagnostic imaging/complications/pathology ; *Hippocampus/pathology/diagnostic imaging ; *Amygdala/pathology/diagnostic imaging ; *Epilepsy/diagnostic imaging/pathology ; Middle Aged ; Neuroimaging ; *Dementia/diagnostic imaging/complications ; },
abstract = {BACKGROUND: Epilepsy is common in dementia. However, the neuroimaging correlates of epilepsy in AD and non-AD dementias remain unexplored. We investigated mesial temporal morphology and volumes in AD (AD+Epi) and non-AD dementias (non-AD+Epi) with epilepsy.

METHOD: Using multicenter data from 39 US Alzheimer's disease centers (9/2005-12/2021), participants were classified into Group 1 (dementia with epilepsy: AD+Epi, nonAD+Epi); Group 2 (dementia without epilepsy: AD-Epi, non-AD-Epi); and Group 3 (healthy controls, HC). Group 1 participants with available MRI scans were matched to Groups 2 and 3 (Figure 1) using fixed-ratio, optimal propensity score matching by age, sex, and dementia type (AD vs nonAD). Hippocampal and amygdalar segmentation from MRI was performed using FreeSurfer. Point distribution models created via ShapeWorks quantified morphological differences in the left and right hippocampi (512 points) and amygdalae (256 points). The volume of structure/Total intracranial volume yielded normalized volumes for hippocampi and amygdalae. Multivariate analysis of covariates (MANCOVA), adjusted for age, sex, intracranial volume, and dementia severity, identified statistically significant local morphological and normalized volume group differences. We compared AD+Epi vs AD-Epi, AD+Epi vs HC, AD-Epi vs HC, nonAD+Epi vs nonAD-Epi, nonAD+Epi vs HC and nonAD-Epi vs HC.

RESULT: Of 703 included participants (average age:70.78 years, 391 (55.62%) female), 35 had AD+Epi, 28 nonAD+Epi, 183 AD-Epi, 137 nonAD-Epi, and 320 HC. AD-Epi and NonAD-Epi exhibited uniform hippocampal and amygdalar morphological atrophy bilaterally. In contrast, AD+Epi demonstrated morphological atrophy in the hippocampal bodies and tails bilaterally with sparing of the hippocampal heads, more pronounced inward deviations on mesial and lateral surfaces, and outward deviations in the middle hippocampal body bilaterally on the superior surface (Figure 2). NonAD+Epi showed significant morphological atrophy in the right hippocampal head, tail, and amygdala (Figure 3). No group volume differences were found except for smaller left hippocampal volumes in AD-Epi than in HC.

CONCLUSION: We identified hippocampal body and tail atrophy in AD+Epi and right hippocampal head, tail, and amygdalar atrophy in nonAD+Epi demonstrating that mesial temporal morphology may serve as a neuroimaging correlate for epilepsy in ADRD. These lateralized and region-specific patterns highlight the possible role of epilepsy in altering the trajectory of neurodegeneration in ADRD, which warrants further investigation.},
}