Polsinelli, Angelina J.

Abstract INTRODUCTION : Despite expanding use of plasma biomarkers for Alzheimer's disease (AD), minimal examination has been undertaken in early‐onset AD (EOAD). Prior analyses assessed criterion and convergent validity of common plasma biomarkers in a well‐characterized sample with sporadic EOAD. METHODS : Plasma amyloid beta (Aβ) 42/40, tau phosphorylated at threonine 231 (p‐tau231), glial fibrillary acidic protein (GFAP), and neurofilament light change (NfL) levels were obtained for 189 EOAD, 52 early‐onset non‐AD (EOnonAD), and 83 cognitively normal (CN) participants. Diagnostic group differences, convergence with imaging biomarkers, and the capacity to predict specific cognitive domains were investigated. RESULTS : After controlling for cognitive status, EOAD participants exhibited more pathologic levels of Aβ42/40, p‐tau231, and GFAP relative to EOnonAD participants. However, NfL displayed the greatest sensitivity to non‐amnestic cognitive impairment across the sample. DISCUSSION : These results establish criterion and convergent validity of plasma biomarkers in sporadic EOAD and highlight complementary roles that AD‐specific and non‐specific plasma markers may play across the course of AD care.

Importance Tau positron emission tomography (PET) allows in vivo detection of neurofibrillary tangles, a core neuropathologic feature of Alzheimer disease (AD). Objective To provide estimates of the frequency of tau PET positivity and its associated risk of clinical outcomes. Design, Setting, and Participants Longitudinal study using data pooled from 21 cohorts, comprising a convenience sample of 6514 participants from 13 countries, collected between January 2013 and June 2024. Cognitively unimpaired individuals and patients with a clinical diagnosis of mild cognitive impairment (MCI), AD dementia, or other neurodegenerative disorders were included. Exposures Tau PET with flortaucipir F 18, amyloid-β (Aβ) PET, and clinical examinations. Tau PET scans were visually rated as positive according to a US Food and Drug Administration– and European Medicines Agency–approved method, designed to indicate the presence of advanced neurofibrillary tangle pathology (Braak stages V-VI). Main Outcomes and Measures Frequency of tau PET positivity and absolute risk of clinical progression (eg, progression to MCI or dementia). Results Among the 6514 participants (mean age, 69.5 years; 50.5% female), median follow-up time ranged from 1.5 to 4.0 years. Of 3487 cognitively unimpaired participants, 349 (9.8%) were tau PET positive; the estimated frequency of tau PET positivity was less than 1% in those aged younger than 50 years, and increased from 3% (95% CI, 2%-4%) at 60 years to 19% (95% CI, 16%-24%) at 90 years. Tau PET positivity frequency estimates increased across MCI and AD dementia clinical diagnoses (43% [95% CI, 41%-46%] and 79% [95% CI, 77%-82%] at 75 years, respectively). Most tau PET–positive individuals (92%) were also Aβ PET positive. Cognitively unimpaired participants who were positive for both Aβ PET and tau PET had a higher absolute risk of progression to MCI or dementia over the following 5 years (57% [95% CI, 45%-71%]) compared with both Aβ PET–positive/tau PET–negative (17% [95% CI, 13%-22%]) and Aβ PET–negative/tau PET–negative (6% [95% CI, 5%-8%]) individuals. Among participants with MCI at the time of the tau PET scan, an Aβ PET–positive/tau PET–positive profile was associated with a 5-year absolute risk of progression to dementia of 70% (95% CI, 59%-81%). Conclusions and Relevance In a large convenience sample, a positive tau PET scan occurred at a nonnegligible rate among cognitively unimpaired individuals, and the combination of Aβ PET positivity and tau PET positivity was associated with a high risk of clinical progression in both preclinical and symptomatic stages of AD. These findings underscore the potential of tau PET as a biomarker for staging AD pathology.

Abstract INTRODUCTION Early‐onset and late‐onset Alzheimer's disease (EOAD and LOAD, respectively) have distinct clinical manifestations, with prior work based on small samples suggesting unique patterns of neurodegeneration. The current study performed a head‐to‐head comparison of cortical atrophy in EOAD and LOAD, using two large and well‐characterized cohorts (LEADS and ADNI). METHODS We analyzed brain structural magnetic resonance imaging (MRI) data acquired from 377 sporadic EOAD patients and 317 sporadicLOAD patients who were amyloid positive and had mild cognitive impairment (MCI) or mild dementia (i.e., early‐stage AD), along with cognitively unimpaired participants. RESULTS After controlling for the level of cognitive impairment, we found a double dissociation between AD clinical phenotype and localization/magnitude of atrophy, characterized by predominant neocortical involvement in EOAD and more focal anterior medial temporal involvement in LOAD. DISCUSSION Our findings point to the clinical utility of MRI‐based biomarkers of atrophy in differentiating between EOAD and LOAD, which may be useful for diagnosis, prognostication, and treatment. Highlights Early‐onset Alzheimer's disease (EOAD) and late‐onset AD (LOAD) patients showed distinct and overlapping cortical atrophy patterns. EOAD patients showed prominent atrophy in widespread neocortical regions. LOAD patients showed prominent atrophy in the anterior medial temporal lobe. Regional atrophy was correlated with the severity of global cognitive impairment. Results were comparable when the sample was stratified for mild cognitive impairment (MCI) and dementia.

Abstract INTRODUCTION Early‐onset Alzheimer's disease (EOAD) manifests prior to the age of 65, and affects 4%–8% of patients with Alzheimer's disease (AD). The current analyses sought to examine longitudinal cognitive trajectories of participants with early‐onset dementia. METHODS Data from 307 cognitively normal (CN) volunteer participants and those with amyloid‐positive EOAD or amyloid‐negative cognitive impairment (EOnonAD) were compared. Cognitive trajectories across a comprehensive cognitive battery spanning 42 months were examined using mixed‐effects modeling. RESULTS The EOAD group displayed worse cognition at baseline relative to EOnonAD and CN groups, and more aggressive declines in cognition over time. The largest effects were observed on measures of executive functioning domains, while memory declines were blunted in EOAD. DISCUSSION EOAD declined 2–4× faster than EOnonAD, and EOAD pathology is not restricted to memory networks. Early identification of deficits is critical to ensure that individuals with sporadic EOAD can be considered for treatment using disease‐modifying medications. Highlights Represents the most comprehensive longitudinal characterization of sporadic EOAD to date. The trajectory of cognitive declines was steep for EOAD participants and worse than for other groups. Executive functioning measures exhibited the greatest declines over time in EOAD.

Abstract INTRODUCTION Early‐onset Alzheimer's disease (EOAD) and late‐onset Alzheimer's disease (LOAD) share similar amyloid etiology, but evidence from smaller‐scale studies suggests that they manifest differently clinically. Current analyses sought to contrast the cognitive profiles of EOAD and LOAD. METHODS Z‐ score cognitive‐domain composites for 311 amyloid‐positive sporadic EOAD and 314 amyloid‐positive LOAD participants were calculated from baseline data from age‐appropriate control cohorts. Z‐ score composites were compared between AD groups for each domain. RESULTS After controlling for cognitive status, EOAD displayed worse visuospatial, executive functioning, and processing speed/attention skills relative to LOAD, and LOAD displayed worse language, episodic immediate memory, and episodic delayed memory. DISCUSSION Sporadic EOAD possesses distinct cognitive profiles relative to LOAD. Clinicians should be alert for non‐amnestic impairments in younger patients to ensure proper identification and intervention using disease‐modifying treatments. Highlights Both early‐onset Alzheimer's disease (EOAD) and late‐onset Alzheimer's disease (LOAD) participants displayed widespread cognitive impairments relative to their same‐aged peers. Cognitive impairments were more severe for EOAD than for LOAD participants in visuospatial and executive domains. Memory and language impairments were more severe for LOAD than for EOAD participants Results were comparable after removing clinical phenotypes of posterior cortical atrophy (PCA), primary progressive aphasia (lv‐PPA), and frontal‐variant AD.

Background: Conventional normative samples include individuals with undetected Alzheimer’s disease neuropathology, lowering test sensitivity for cognitive impairment. Objective: We developed Mayo Normative Studies (MNS) norms limited to individuals without elevated amyloid or neurodegeneration (A–N–) for Rey’s Auditory Verbal Learning Test (AVLT). We compared these MNS A–N– norms in female, male, and total samples to conventional MNS norms with varying levels of demographic adjustments. Methods: The A–N– sample included 1,059 Mayo Clinic Study of Aging cognitively unimpaired (CU) participants living in Olmsted County, MN, who are predominantly non-Hispanic White. Using a regression-based approach correcting for age, sex, and education, we derived fully-adjusted T-score formulas for AVLT variables. We validated these A–N– norms in two independent samples of CU ( n = 261) and mild cognitive impairment (MCI)/dementia participants ( n = 392) > 55 years of age. Results: Variability associated with age decreased by almost half in the A–N– norm sample relative to the conventional norm sample. Fully-adjusted MNS A–N– norms showed approximately 7– 9% higher sensitivity to MCI/dementia compared to fully-adjusted MNS conventional norms for trials 1– 5 total and sum of trials. Among women, sensitivity to MCI/dementia increased with each normative data refinement. In contrast, age-adjusted conventional MNS norms showed greatest sensitivity to MCI/dementia in men. Conclusions: A–N– norms show some benefits over conventional normative approaches to MCI/dementia sensitivity, especially for women. We recommend using these MNS A–N– norms alongside MNS conventional norms. Future work is needed to determine if normative samples that are not well characterized clinically show greater benefit from biomarker-refined approaches.

AbstractBackgroundWe examined neuropsychiatric symptoms (NPS) and psychotropic medication use at the midway point of data collection of the Longitudinal Early‐onset Alzheimer’s Disease Study (LEADS). We compared amyloid‐positive early‐onset Alzheimer’s disease (EOAD) participants and amyloid‐negative early‐onset non‐Alzheimer’s disease [EOnonAD]) participants across NPS domains and psychotropic medication categories.Method282 participants enrolled in LEADS were compared across diagnostic groups – amyloid‐positive EOAD (n = 212) and amyloid‐negative EOnonAD (n = 70). All participants were between ages 40 and 64 at baseline. NPS were measured with the Neuropsychiatric Inventory – Questionnaire (NPI‐Q) and Geriatric Depression Scale – Short Form (GDS‐SF). Medications were categorized into psychotropic category (e.g., antidepressants, antipsychotics, benzodiazepines). Groups were compared on NPI‐Q using binary logistic regression adjusting for sex and disease severity, on GDS‐SF using linear regression adjusting for sex and disease severity, and on psychotropic medication use using Chi square or Fisher’s exact test.ResultDemographic data are presented in Table 1. Average total NPI‐Q score was higher in EOnonAD than EOAD (p = .002, ŋp 2 = .03). Regardless of diagnostic group, informants endorsed Affective behaviors most frequently (76.2%). EOAD informants endorsed fewer Distress‐Tension behaviors (p = .02, OR = .498) and Impulse Control behaviors (p = .01, OR = .438). EOAD informants also endorsed apathy (p < .001, OR = .316), irritability (p = .02, OR = .498), and disinhibition (p = .04, OR = .476) at lower frequency than EOnonAD. GDS‐SF showed that the EOnonAD participants self‐reported more symptoms of depression than the EOAD group (p = .002, ŋp 2 = .03). (Table 2A). A minority of participants, regardless of diagnostic group, reported psychotropic medication use (35%). There was higher use in EOnonAD (38%) than EOAD (24%) (p = .03, Cohen W = .14) (Table 2B).ConclusionNPS burden and psychotropic medication use were higher in EOnonAD than EOAD participants, despite EOnonAD being less severely impaired. LEADS continues to collect data. Future studies will examine etiologies that may be larger drivers of NPS than AD neuropathology, mediators (e.g., race, ethnicity) in the association between NPS and diagnostic group classication, compare NPS in EOAD vs. LOAD, and examine longitudinal changes in neuropsychiatric profiles.

Abstract INTRODUCTION Magnetic resonance imaging (MRI) research has advanced our understanding of neurodegeneration in sporadic early‐onset Alzheimer's disease (EOAD) but studies include small samples, mostly amnestic EOAD, and have not focused on developing an MRI biomarker. METHODS We analyzed MRI scans to define the sporadic EOAD‐signature atrophy in a small sample (n = 25) of Massachusetts General Hospital (MGH) EOAD patients, investigated its reproducibility in the large longitudinal early‐onset Alzheimer's disease study (LEADS) sample (n = 211), and investigated the relationship of the magnitude of atrophy with cognitive impairment. RESULTS The EOAD‐signature atrophy was replicated across the two cohorts, with prominent atrophy in the caudal lateral temporal cortex, inferior parietal lobule, and posterior cingulate and precuneus cortices, and with relative sparing of the medial temporal lobe. The magnitude of EOAD‐signature atrophy was associated with the severity of cognitive impairment. DISCUSSION The EOAD‐signature atrophy is a reliable and clinically valid biomarker of AD‐related neurodegeneration that could be used in clinical trials for EOAD. Highlights We developed an early‐onset Alzheimer's disease (EOAD)–signature of atrophy based on magnetic resonance imaging (MRI) scans. EOAD signature was robustly reproducible across two independent patient cohorts. EOAD signature included prominent atrophy in parietal and posterior temporal cortex. The EOAD‐signature atrophy was associated with the severity of cognitive impairment. EOAD signature is a reliable and clinically valid biomarker of neurodegeneration.

AbstractINTRODUCTIONWe used sex and apolipoprotein E ε4 (APOE ε4) carrier status as predictors of pathologic burden in early‐onset Alzheimer's disease (EOAD).METHODSWe included baseline data from 77 cognitively normal (CN), 230 EOAD, and 70 EO non‐Alzheimer's disease (EOnonAD) participants from the Longitudinal Early‐Onset Alzheimer's Disease Study (LEADS). We stratified each diagnostic group by males and females, then further subdivided each sex by APOE ε4 carrier status and compared imaging biomarkers in each stratification. Voxel‐wise multiple linear regressions yielded statistical brain maps of gray matter density, amyloid, and tau PET burden.RESULTSEOAD females had greater amyloid and tau PET burdens than males. EOAD female APOE ε4 non‐carriers had greater amyloid PET burdens and greater gray matter atrophy than female ε4 carriers. EOnonAD female ε4 non‐carriers also had greater gray matter atrophy than female ε4 carriers.DISCUSSIONThe effects of sex and APOE ε4 must be considered when studying these populations.HIGHLIGHTS Novel analysis examining the effects of biological sex and apolipoprotein E ε4 (APOE ε4) carrier status on neuroimaging biomarkers among early‐onset Alzheimer's disease (EOAD), early‐onset non‐AD (EOnonAD), and cognitively normal (CN) participants. Female sex is associated with greater pathology burden in the EOAD cohort compared to male sex. The effect of APOE ε4 carrier status on pathology burden was the most impactful in females across all cohorts.

AbstractIntroductionWe examined neuropsychiatric symptoms (NPS) and psychotropic medication use in a large sample of individuals with early‐onset Alzheimer's disease (EOAD; onset 40‐64 years) at the midway point of data collection for the Longitudinal Early‐onset Alzheimer's Disease Study (LEADS).MethodsBaseline NPS (Neuropsychiatric Inventory – Questionnaire; Geriatric Depression Scale) and psychotropic medication use from 282 participants enrolled in LEADS were compared across diagnostic groups – amyloid‐positive EOAD (n = 212) and amyloid negative early‐onset non‐Alzheimer's disease (EOnonAD; n = 70).ResultsAffective behaviors were the most common NPS in EOAD at similar frequencies to EOnonAD. Tension and impulse control behaviors were more common in EOnonAD. A minority of participants were using psychotropic medications, and use was higher in EOnonAD.DiscussionOverall NPS burden and psychotropic medication use were higher in EOnonAD than EOAD participants. Future research will investigate moderators and etiological drivers of NPS, and NPS differences in EOAD versus late‐onset AD.