Objectives Fewer than half of dementia cases are identified and diagnosed. Barriers to timely diagnosis include lack of accurate, efficient screening tools for mild cognitive impairment (MCI), a frequent antecedent to dementia. While many screening tools are available, robust screeners (e.g., montreal cognitive assessment [MoCA]) take more time than primary care teams have available, and briefer tools (e.g., the Mini-Cog) aren’t robust enough. We describe the development and validation of the Virginia Mason Cognitive Screener (VMCS), which meets the competing needs of efficiency and accuracy in screening for MCI and dementia. Participants One hundred fifty older adults volunteered to participate in a quality improvement effort. Participants were recruited from a primary care practice being seen for their Medicare annual wellness visits (MAWV), chronic disease management care, or neurology consultation in an urban multispecialty group practice. All participants completed the MoCA and a measure of semantic verbal fluency. The VMCS score was determined by extracting the clock draw and 5-word recall scores from the MoCA and incorporating the semantic fluency score. Subsequent diagnostic evaluation included neuroimaging, neurological evaluation, blood work, and neuropsychological testing. Diagnoses were determined after detailed chart review by a clinical neuropsychologist. Results The MoCA and VMCS were significantly correlated (Pearson r = 0.85, p <0.01, N = 150) with receiver operating characteristic (ROC) curve analyses indicating nondistinguishable sensitivity and specificity in MCI, Alzheimer’s disease (AD), all dementias, and all-cognitive-impairment, including MCI. Conclusions With significant reduction in administration time, the VMCS sufficiently detects MCI and dementia and provides the opportunity for improved early detection in primary care settings.

OBJECTIVE:The Strong Heart Study, a large cohort of American Indians from three U.S. regions, collected standardized neuropsychological assessments from participants aged 65-95 years at two visits (2010-2019), with prior documentation of lower overall score distributions and higher prevalence of cognitive impairment and dementia. This report aims to define expected score ranges for impaired and unimpaired as well as typical error patterns across this multidomain battery. METHOD:Participants were assessed as cognitive unimpaired (normal) or impaired through case review by a panel of clinicians-experts. Cognitive test score distributions were summarized and regression-normalized by age, sex, education, baseline cognition, bilingual status, and depression. RESULTS:The strongest determinants of variability explained in test scores were age, education, and baseline cognition; depression was also associated with some tests. Error patterns were similar between overall group and intact group. Subitem analyses suggested that some tasks did not contribute to overall scores because most participants either correctly or incorrectly responded to the item. Common item analyses between similar tests suggested that interference may change score interpretability for similar tasks when repeated on different tests. CONCLUSIONS:These data represent the best estimates of expected cognitive test performance for older American Indians and may be useful to clinicians and researchers hoping to contextualize individual performance for patients within this sociodemographic. These results suggest that more research is needed among other Tribal groups, other Indigenous peoples, other socioeconomic contexts, younger ages, and with longitudinal evaluation. (PsycInfo Database Record (c) 2026 APA, all rights reserved).

INTRODUCTION:Previous works implicate 14 modifiable risk factors as underlying 45% of dementia cases. Population attributable fraction (PAF) is population-specific, limiting generalizability. Little is known about the risk and PAF of dementia in American Indians. METHODS:American Indians from the Southwest, Southern Plains, and Northern Plains made multiple visits from mid- to late-life (1989 to 2019). Cognitive status was adjudicated by panel consensus (ages 70 to 95). Logistic regression models assessed relative risk and PAF for dementia. RESULTS:American Indians had distinctive patterns of factor prevalence. The proportion with limited education and social isolation was similar. Mid-life depression, head injury, smoking, hypertension, obesity, and diabetes were more common. High low-density lipoprotein levels, sedentary/inactivity, and consumption of ≥21 units of alcohol/week were less common. We did not assess hearing loss, vision loss, or air pollution. Significant risk factors for dementia with PAF percentage were as follows: education (19%), hypertension (11%), isolation (13%), and depression (60%). DISCUSSION:Important, unique risk patterns were detected for American Indians, in contrast to prior models.

The Lancet Commission estimated 45% of dementia cases are collectively attributable to 14 modifiable risk factors (education, hearing loss, head injury, hypertension, heavy alcohol use, obesity, smoking, depression, social isolation, inactivity, diabetes, and air pollution), with assumption that this population attributable fraction (PAF) effect is consistent across populations. However, structural, environmental, cultural, and health contexts may modify factor prevalence, timing of effect, and cross-factor interactions, especially for heavily-burdened groups such as American Indians. The Strong Heart Study recruited middle-aged American Indians from 13 Tribes in the Southwest, Southern Plains, and Northern Plains in 1989-91 ( N =3516). In 2010-13 ( N =818) and again in 2017-19 ( N =403), an ancillary study recruited surviving participants (85% and 76%, respectively) for detailed neurology examinations. Mild cognitive impairment (MCI) and dementia was adjudicated by consensus panel based on change in cognitive performance over time, according to clinical standards. Logistic regression models supplemented by Gordis method calculated PAF for 10 of the 14 original Lancet factors for cognitive outcomes. American Indian populations have very different patterns of risk factor prevalence than the populations in the Lancet report, with lower prevalence of dyslipidemia, physical inactivity, heavy alcohol use, social isolation; and higher prevalence of depression, head injury, diabetes, smoking, hypertension, and obesity. Significant PAF findings for MCI and dementia included early-life education (PAF 12%); mid-life diabetes (9%), hypertension (11%); late-life isolation (PAF 11%), depression (17%). Other Lancet Model factors had no risk association. These findings collectively demonstrate important differences across populations in PAF for dementia. In the Lancet report, 45% of PAF for dementia was attributable to 14 factors; in this study of older American Indians, education, diabetes, hypertension, depression, and isolation alone accounted for 60% of PAF, with other factors not associated. However, more research is needed to understand these unique patterns: especially timing of risk exposure, risk factor burden and interactions, and likelihood to survive to older-age. Meanwhile, public health programs to address these institutional or structural early-life exposures, vascular risks at mid-life, and psychological health in later-life may provide appropriate targets for reducing risk in American Indian communities.

Abstract Cognitive reserve, a component of resilience, may be conceptualized as the ability to overcome accumulating neuropathology and maintain healthy aging and function. However, research measuring and evaluating it in American Indians is needed. We recruited American Indians from 3 regional centers for longitudinal examinations (2010-13, n = 818; 2017-19, n = 403) including MRI, cognitive, clinical, and questionnaire data. We defined cognitive reserve by measuring the residual from individual regressions of cognitive tests over imaged brain volumes, adjusted for age and sex. Analyses examined three different metrics of cognitive reserve against sociodemographic, clinical, and longitudinal cognitive data in causal mediation models. Better cognitive reserve was significantly associated with more education, higher income, lower prevalence of depression, lower prevalence of diabetes, and lower prevalence of kidney disease, but we found no statistically significant evidence for an association with plasma biomarkers for Alzheimer’s disease and related dementias, APOE e4 carrier status, alcohol use, body mass, or hypertension. Better cognitive reserve was associated with better cognitive function over mean 6.7 years follow-up (range 4-9 years); and the association for education with cognition over time was mediated in part (15-24%) by cognitive reserve. Cognitive reserve, although challenging to measure, appears important for understanding the range of cognitive aging in American Indians.

INTRODUCTION:Accurate epidemiologic estimates for dementia are lacking for American Indians, despite substantive social and health disparities. METHODS:The Strong Heart Study, a population-based cohort of 11 American Indian tribes, conducted detailed cognitive testing and examinations over two visits approximately 7 years apart. An expert panel reviewed case materials for consensus adjudication of cognitive status (intact; mild cognitive impairment [MCI]; dementia; other impaired/not MCI) and probable etiology (Alzheimer's disease [AD], vascular bain injury [VBI], traumatic brain injury [TBI], other). RESULTS:American Indians aged 70-95 years had 54% cognitive impairment including 10% dementia. VBI and AD were primary etiology approximately equal proportions (>40%). Apolipoprotein (APO) Eε4 carriers were more common among those with dementia (p = 0.040). Plasma pTau, glial fibrillary acidic protein (GFAP), and neurofilament light chain (NfL) were higher among those with cognitive impairment, but not amyloid beta (Aβ). Cognitive intact had mean 3MSE 92.2 (SD 6.4) and mean Montreal Cognitive Assessment (MoCA) score of 21.3 (SD 3.2). DISCUSSION:This is the first population-based study to estimate the prevalence of vascular and Alzheimer's dementias in a population-based study of American Indians. HIGHLIGHTS:The Strong Heart Study is a population-based cohort of American Indian tribes, conducted over 30+ years and three US geographic regions (Northern Plains, Southern Plains, Southwest). Our teams conducted detailed cognitive testing, neurological examination, and brain imaging over two visits approximately 7 years apart. An expert panel reviewed collected materials for consensus-based adjudication of cognitive status (intact; MCI; dementia; other impaired/not MCI) and probable underlying etiology (AD; VBI; TBI; other). In this cohort of American Indians aged 70-95, 54% were adjudicated with cognitive impairment, including approximately 35% MCI and 10% dementia. These data expand on prior reports from studies using electronic health records, which had suggested prevalence, and incidence of dementia in American Indians to be more comparable to the majority population or non-Hispanic White individuals, perhaps due to latent case undercounts in clinical settings. Vascular and neurodegenerative injuries were approximately equally responsible for cognitive impairment, suggesting that reduction of cardiovascular disease is needed for primary prevention. Traumatic injury was more prevalent than in other populations, and common among those in the "other/not MCI" cognitive impairment category. Mean scores for common dementia screening instruments-even among those adjudicated as unimpaired-were relatively low compared to other populations (mean unimpaired 3MSE 92.2, SD 6.4; mean unimpaired MoCA 21.3, SD 3.2), suggesting the need for cultural and environmental adaptation of common screening and evaluation instruments.

INTRODUCTION:Identification of Alzheimer's disease (AD) needs inexpensive, noninvasive biomarkers, with validation in all populations. METHODS:We collected plasma markers in older American Indian individuals: phosphorylated-tau181 (pTau181); amyloid-beta (Aβ) 40,42; glial fibrillary acidic protein (GFAP); and neurofilament light chain (NfL). Plasma markers were analyzed for discriminant properties with cognitive status and etiology using receiver operating characteristic (ROC) analysis. RESULTS:PTau181, GFAP, NfL plasma values were significantly associated with cognition, but Aβ were not. Discriminant performance was moderate for individual markers, with pTau181, GFAP, NfL performing best, but an empirically selected panel of markers (age, sex, education, pTau181, GFAP, NfL, Aβ4240 ratio) had excellent discriminant performance (AUC > 0.8). DISCUSSION:In American Indian individuals, pTau181 and Aβ values suggested more common pathology than in majority populations. Aβ was less informative than in other populations; however, all four markers were needed for a best-performing dementia diagnostic model. These data validate utility of AD plasma markers, while suggesting population-specific diagnostic characteristics.

BACKGROUND Cognitive resilience may be conceptualized as the ability to overcome the influence of accumulating pathology, to maintain healthy aging and function. However cognitive resilience has not been measured or evaluated in American Indian elders. METHODS We recruited American Indians from 3 regional centers for two examinations (2010-13, n=818; repeated 2017-19, n=403) including MRI, cognitive, clinical, and questionnaire. We defined cognitive reserve by measuring the residual from individual regressions of Weschler Adult Intelligence Scale digit symbol coding test scores over MRI brain volumes, adjusted for age and sex. Analyses examined residuals of cogntiive reserve against sociodemographic, clinical, and longitudinal cognitive data in causal mediation models. RESULTS Better cognitive reserve was significantly associated with more education (P<0.0001), higher income (P<0.0001), better quality of life (P<0.0001), lower prevalence of diabetes (P=0.001), fewer symptoms of depression (P=0.0007), and plasma biomarkers for Alzheimer’s disease and related dementias (P<0.0001), but not with APOE e4 status (P=0.50), alcohol use (P=0.38), obesity (P=0.06), hypertension (P=0.11), kidney disease (P=0.07). Better cognitive resilience was associated with better cognitive function over time. CONCLUSION Cognitive resilience, though challenging to measure, appears important for understanding the range of cognitive aging in American Indians.

Objective: Assessment of cognition in American Indians poses challenges, including barriers to healthcare, unvalidated clinical standards, and confounding social determinants of health. Alternative strategies for case identification include algorithmic methods, which can outperform clinical judgment in some circumstances. Method: Algorithmic methods can be maximized using single-domain tests with multiple-serial trial tasks, such as the California Verbal Learning Test II-Short Form (CVLT-SF). We collected CVLT-SF and detailed clinical data, including dementia gold standard by consensus adjudication, in 818 American Indians aged 65-95 in 2010-2013 and repeated in 403 returning participants in 2017-2019 (mean follow-up 6.7 years, range: 4-9). Our algorithm categorized CVLT-SF scores into four memory deficit categories: none, encoding, storage, and retrieval. Results: At Visit 1, 75.4% had no memory deficit, 15.6% encoding deficit, 3.5% storage deficit, and 5.5% retrieval deficit. At Visit 2, comparable percentages were 68.7%, 10.6%, 6.5%, and 14.2% (respectively). The majority with any deficit at Visit 1-especially encoding-were lost to follow-up by Visit 2. Most with deficits at Visit 2 were newly categorized from those previously intact. The performance of our memory algorithm, compared with adjudication for dementia, was moderately good: correct classification 69%, sensitivity 51%, and specificity 91%. Conclusions: These descriptive findings encompass a novel contribution in defining memory impairment among American Indians from a single cognitive test. However, more work is needed to improve the sensitivity of this algorithm and maximize its utility for case identification over conventional methods. Altogether, these data provide an important step toward better cognitive characterization and dementia care for an understudied, underserved population.

American Indians have the highest mortality and hospitalizations from head injury of all US groups; however, little is known about prevalence, risk, or outcomes in this population. The Strong Heart Study recruited American Indians representing 11 tribes and communities across three regions for two sequential examinations in 2010–2019. Participants were asked to self-report prior head injury, loss of consciousness (LOC), cause, sociodemographics, and behaviors (age, sex, education, bilingual, smoking, alcohol use, stroke). Cognitive testing covered executive function, phonemic fluency, processing speed, and memory. Analyses tabulated summaries and multivariate logistic regressions estimated risk associations. This older cohort of American Indians (visit 1 N = 818, follow-up visit 2 N = 403) was mean age 73 at intake, with mean 6.7 years between exams. At visit 1, 40

Standardized neuropsychological instruments are used to evaluate cognitive impairment, but few have been psychometrically evaluated in American Indians. We collected Montreal Cognitive Assessment (MoCA) in 403 American Indians 70 to 95 years, as well as age, sex, education, bilingual status, depression symptoms, and other neuropsychological instruments. We evaluated inferences of psychometric validity, including scoring inference using confirmatory factor analysis and structural equation modeling, generalizability inference using reliability coefficient, and extrapolation inference by examining performance across different contexts and substrata. The unidimensional (total score) model had good fit criteria. Internal consistency reliability was high. MoCA scores were positively associated with crystallized cognition (ρ = 0.48, p < .001) and inversely with depression symptoms (ρ = −0.27, p < .001). Significant differences were found by education ( d = 0.79, p < .05) depression ( d = 0.484, p < .05), and adjudicated cognitive status ( p = .0001) strata; however, MoCA was not sensitive or specific in discriminating cognitive impairment from normal cognition (area under the curve <0.5). MoCA scores had psychometric validity in older American Indians, but education and depression are important contextual features for score interpretability. Future research should evaluate cultural or community-specific adaptations, to improve test discriminability in this underserved population.

The Controlled Oral Word Association (COWA) test is used to assess phonemic fluency and executive function. Formal validation of test scores is important for accurate cognitive evaluation. However, there is a dearth of psychometric validation among American Indian adults. Given high burden of dementia risk and key contextual factors associated with cognitive assessments, this represents a critical oversight. In a large, longitudinal population-based cohort study of adult American Indians, we examined several validity inferences for COWA, including scoring, generalization, and extrapolation inferences, by investigation of factor structure, internal consistency, test-retest reliability, and differential test functioning. We found adequate unidimensional model fit, with high factor loadings. Internal consistency reliability and test-retest reliability were 0.88 and 0.77, respectively, for the full group. COWA scores were lowest among the oldest, lowest education, bilingual speakers; group effects for sex and bilingual status were small; age effect was medium; and education effect was largest. However, Wide Range Achievement Test (WRAT) score effect was stronger than education effect, suggesting better contextualization may be needed. These results support interpretation of total COWA score, including across sex, age, or language use strata.

Alzheimer’s disease (AD) is best defined in vivo using quantifiable, objective markers reflecting amyloid deposition (A), pathologic tau (T), and neurodegeneration (N). However, gold standards for ATN (imaging or cerebrospinal proteins) are expensive, invasive, and/or impractical in low resource settings. Circulating proteins offer a practical alternative. Candidate plasma markers include amyloid-β (Aβ40&42), phosphorylated tau-181 (ptau), glial fibrillary protein (GFAP), and neurofilament light chain (NfL). However, no such markers have been evaluated in American Indians. The Strong Heart Study recruited 401 American Indians over 3 states in 2017-2019 for MRI, cognitive testing, and clinical examination. MRI included T1 sequences, which were processed using FreeSurfer to quantify structural volumes. Neuropsychological testing incuded California Verbal Learning Test, which was operationalized into categories of memory impairment using indices of learning and recall. Plasma samples were sent to University of Gothenburg for Simoa Quanterix assay. Statistics included descriptive summary; multivariate regression; and receiver operating characteristic analysis. The study population was mean age 78 (SD 4.7, range 70-95); majority female (71%); and 21% APOE ε4 allele carriers. An estimated 31% had any memory impairment (13.8% retrieval, 6.5% storage, 10.7% encoding). Median plasma marker values were: ptau 5.0pg/mL (range: 1.5-442), Aβ 40 128pg/mL (116-175), Aβ 42 8.2pg/mL (6.7-9.7), GFAP 150pg/mL (0-651), and NfL 31.6pg/mL (9.7-343); median Aβ 42:40 ratio 0.06. Comparing APOEε4 carriers to non-carriers (Table1), ptau was +12%, Aβ 40 -0.8%, Aβ 42 -8.4%, Aβ 4240 -16.7% (P = 0.006), GFAP +16.1%, NfL +3.2%, but only Aβ 4240 was significant. Linear regressions with brain volumes identified significant associations for Aβ 42 , Aβ 40 , GFAP, and NfL (but not ptau) with ventricle, cortical, and overall volume; NfL was also associated with entorhinal and hippocampal volume. GFAP and ptau were significantly higher in those with memory encoding deficit; NfL higher with encoding or retrieval deficit (Table2). Although not significant, Aβ 40 was lower with storage deficit, and Aβ 42 with encoding or storage deficit. AUC range for plasma markers to discriminate memory impaired from intact: 0.4-0.6. These data are a first look at ATN plasma markers in a population-based cohort of American Indians, an underrepresented group in AD research. Future research should address generalizability and measurement validity.

Background and ObjectivesLittle is known about incidence of vascular and Alzheimer dementias in American Indians.MethodsWe conducted a large, heterogeneous, population-based, longitudinal cohort study of brain aging in community-dwelling American Indians aged 64-95 years from 11 tribes across 3 states, with neurologic examinations, 1.5T MRI, and extensive cognitive testing. Visit 1 in 2010-2013 (n = 817) and visit 2 in 2017-2019 (n = 403) included all willing, surviving participants. Standardized cognitive tests at both visits included Modified Mini-Mental Status Examination (MMSE), Wechsler Adult Intelligence Scale digit symbol coding (WAIS), Controlled Oral Word Association (COWA), and California Verbal Learning Test short form (CVLT). Test materials added at follow-up included Wide Range Achievement (reading) Test (WRAT) and National Alzheimer Coordinating Center Uniform Data Set cognitive battery (v3 form C2), including Montreal Cognitive Assessment (MoCA). MRI neuroradiologists coded infarcts, hemorrhages, white matter hyperintensities, sulcal atrophy, and ventricle enlargement.ResultsThe mean time between examinations was 6.7 years (SD 1.1, range 3.8-9.1 years). Years of formal education had modest correlation with WRAT reading score (r = 0.45). Prevalence and incidence (respectively) of infarcts were 32% and 12.8/1,000 person-years (PYs) hemorrhages 6% and 4.4/1000 PY worsening sulci 74% and 19.0/1000 PY worsening ventricle 79% and 30.1/1000 PY worsening leukoaraiosis 44% and 26.1/1000 PY. Linear losses per year in cognitive scores were 0.6% MMSE, 1.2% WAIS, 0.6% COWA, and 2.2% CVLT. The mean MoCA scores were 18.9 (SD 4.3).DiscussionThese are the first data on longitudinal cognitive and imaging changes in American Indians and first reports of Alzheimer disease-related features. The mean scores in MoCA were similar or lower than standard cutoffs used to diagnose dementia in other racial/ethnic groups, suggesting that standardized cognitive tests may not perform well in this population. Test validation, adaptation, and score adjustment are warranted. Years of education were a poor proxy for premorbid function, suggesting novel methods for cognitive score contextualization is also needed in this population. Evaluation of selective survival suggests attrition from death, and frailty should be accounted for in causal analyses. Overall, these data represent a unique opportunity to examine neurology topics of critical importance to an understudied population.

Primary care providers are on the front lines of dementia care and frequently the first point of contact for individuals and families concerned about changes in memory and thinking. In addition to the challenges of managing complex medical comorbidities, primary care providers in rural or lower-resource settings often lack access to specialists, interdisciplinary teams or other programs and services to aid in diagnosis and care of individuals with mild cognitive impairment and dementia. The current project extends an existing technology-based hub and spoke model virtual clinic, Project ECHO (Extension for Community Healthcare Outcomes, University of New Mexico), to improve diagnosis and care of dementia in primary care.The current project is an extension of work related to the Washington State Plan for Alzheimer's Disease and Other Dementias with implementation supported by legislative funding. The program includes an interdisciplinary expert panel ("hub") meeting with participants ("spokes") including primary and allied health care providers from healthcare systems, group practices, and solo practitioners. The twice-monthly virtual clinic sessions include a brief didactic followed by case-based learning in an "all-teach, all-learn" format emphasizing expertise and experience of spoke sites as well as the hub. Participants are provided with resources discussed during the clinic session, ongoing opportunities for consultation, and free continuing education credits.Launching amid the COVID-19 pandemic, the program has provided over 250 hours of education to more than 50 providers across 20 unique sites. Post session surveys indicate that the program is well-received with 2 in 3 providers indicating that they will change their practice based on learning. Surveys also demonstrate significant increases in both knowledge and confidence in dementia-specific diagnosis and care.The success of the current project demonstrates both the feasibility and benefit of leveraging technology to deliver dementia-related education to primary care providers in rural and under-resourced settings. While initially hampered by disruptions in care due to the COVID-19 pandemic, increased technological proficiency on the provider and systems level has appeared to be a benefit in terms of resources and comfort participating in a virtual education program to scale Dementia Capable Care in Primary Care.

Dementia and Alzheimer's disease (AD) are global health crises, with most affected individuals living in low- or middle-income countries. While research into diagnostics and therapeutics remains focused exclusively on high-income populations, recent technological breakthroughs suggest that low-cost AD diagnostics may soon be possible. However, as this disease shifts onto those with the least financial and structural ability to shoulder its burden, it is incumbent on high-income countries to develop accessible AD healthcare. We argue that there is a scientific and ethical mandate to develop low-cost diagnostics that will not only benefit patients in low-and middle-income countries but the AD field as a whole.

OBJECTIVE:Autosomal-dominant familial Alzheimer disease (AD) is caused by by variants in presenilin 1 (PSEN1), presenilin 2 (PSEN2), and amyloid precursor protein (APP). Previously, we reported a rare PSEN2 frameshift variant in an early-onset AD case (PSEN2 p.K115Efs*11). In this study, we characterize a second family with the same variant and analyze cellular transcripts from both patient fibroblasts and brain lysates. METHODS:We combined genomic, neuropathological, clinical, and molecular techniques to characterize the PSEN2 K115Efs*11 variant in two families. RESULTS:Neuropathological and clinical evaluation confirmed the AD diagnosis in two individuals carrying the PSEN2 K115Efs*11 variant. A truncated transcript from the variant allele is detectable in patient fibroblasts while levels of wild-type PSEN2 transcript and protein are reduced compared to controls. Functional studies to assess biological consequences of the variant demonstrated that PSEN2 K115Efs*11 fibroblasts secrete less Aβ 1-40 compared to controls, indicating abnormal γ-secretase activity. Analysis of PSEN2 transcript levels in brain tissue revealed alternatively spliced PSEN2 products in patient brain as well as in sporadic AD and age-matched control brain. INTERPRETATION:These data suggest that PSEN2 K115Efs*11 is a likely pathogenic variant associated with AD. We uncovered novel PSEN2 alternative transcripts in addition to previously reported PSEN2 splice isoforms associated with sporadic AD. In the context of a frameshift, these alternative transcripts return to the canonical reading frame with potential to generate deleterious protein products. Our findings suggest novel potential mechanisms by which PSEN variants may influence AD pathogenesis, highlighting the complexity underlying genetic contribution to disease risk.