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Biomarkers / Alzheimer Disease · Journal article
Neurology · August 5, 2026
Reinforces what was already believed, rather than introducing something new.
This retrospective analysis of 184 patients with biomarker-confirmed atypical Alzheimer disease phenotypes shows that 70–85% would fail to meet eligibility criteria for anti-amyloid therapies based on published trial standards. Cognitive thresholds (MMSE-based cutoffs) are the primary exclusion driver, affecting 50–67% of ineligible patients, despite most having early symptomatic disease; imaging and severity criteria account for secondary exclusions.
Retrospective cohort study with retrospective eligibility analysis. 184 patients (61.4% female) with biomarker-confirmed atypical AD phenotypes: PCA (n = 98), lvPPA (n = 42), dAD (n = 37), and CBS-AD (n = 7), evaluated at Mayo Clinic.. Intervention: Theoretical eligibility for anti-amyloid therapies (lecanemab or donanemab) assessed at initial clinical evaluation.. Compared with: Published trial eligibility criteria (CLARITY-AD and TRAILBLAZER-ALZ2) and appropriate use criteria for anti-amyloid therapies.. n = 184. Mayo Clinic (single center).
70%–85% of atypical AD patients would not meet eligibility criteria depending on the framework applied Bedside cognitive thresholds (MMSE-based) drove 50%–67% of exclusions despite 82% of patients having global CDR 0.5–1 (early symptomatic disease) Imaging-based exclusions occurred in 22%–27% and severity thresholds (moderate or severe dementia) in 19%–23% of cases
No prospective treatment outcome data; study assesses theoretical eligibility only, not treatment efficacy or safety in these phenotypes.
These findings suggest that current anti-amyloid therapy eligibility criteria, derived from trials enrolling amnestic-predominant early AD, are poorly calibrated for atypical presentations despite biomarker confirmation. Clinicians should recognize that MMSE-based cognitive cutoffs may inappropriately exclude early-stage atypical AD patients; phenotype-sensitive staging and revised selection criteria are needed to expand access to effective therapies for atypical populations.
Retrospective eligibility analysis demonstrating that 70–85% of biomarker-confirmed atypical AD patients would be ineligible for anti-amyloid therapies, primarily due to cognitive thresholds misaligned with disease severity.
As stated by the source record.
Quoted from the source exactly as published.
These findings suggest that current anti-amyloid therapy eligibility criteria, derived from trials enrolling amnestic-predominant early AD, are poorly calibrated for atypical presentations despite biomarker confirmation. Clinicians should recognize that MMSE-based cognitive cutoffs may inappropriately exclude early-stage atypical AD patients; phenotype-sensitive staging and revised selection criteria are needed to expand access to effective therapies for atypical populations.
Graded across the dimensions that decide whether you should act, each from what the source actually supports. There is no single score, and where a dimension was not assessed it says so.
Clinical trials of anti-amyloid therapies (AATs) for Alzheimer disease (AD) primarily enrolled patients with mildly symptomatic, amnestic predominant presentations. The applicability of eligibility criteria to atypical AD phenotypes, including posterior cortical atrophy (PCA), logopenic variant primary progressive aphasia (lvPPA), dysexecutive AD (dAD), and corticobasal syndrome because of AD (CBS-AD), is unknown. We conducted a retrospective eligibility analysis of patients with atypical AD evaluated at Mayo Clinic. Theoretical eligibility for AAT was assessed at initial clinical evaluation by applying inclusion and exclusion criteria from landmark clinical trials (Study to Confirm Safety and Efficacy of Lecanemab in Participants With Early Alzheimer's Disease [CLARITY-AD] and the Study of LY3002813 (Donanemab) in Participants With Early Symptomatic Alzheimer's Disease [TRAILBLAZER-ALZ2]) and appropriate use criteria for lecanemab and donanemab. Eligibility percentages and reasons for exclusion were compared across phenotypes. The cohort included 184 patients (61.4% female) with biomarker-confirmed atypical AD: PCA (n = 98, 53.3%), lvPPA (n = 42, 22.8%), dAD (n = 37, 20.1%), and CBS-AD (n = 7, 3.8%). Age at onset (p = 0.039) and presentation (p < 0.001) differed, with patients with lvPPA oldest (median age at onset, presentation: 63.1, 66.9 years) and patients with dAD youngest (onset, presentation: 55.1, 57.3). Functional impairment differed by phenotype (p = 0.005), with lvPPA more often diagnosed at the mild cognitive impairment/very mild stage (Clinical Dementia Rating [CDR] 0.5; 71.4%), whereas PCA and dAD more frequently presented with mild dementia, although time from symptom onset to diagnosis did not differ (p = 0.634). Mini-Mental State Examination (MMSE) scores differed (p = 0.036), with lower scores in PCA and lvPPA (median 21 and 21, respectively) compared with CBS-AD (median 27). Depending on the eligibility framework applied, 70%-85% of patients would not meet treatment criteria. Bedside cognitive thresholds were the primary drivers of ineligibility (50%-67% of exclusions), despite most patients having early symptomatic disease (global CDR 0.5-1; 82%). Imaging-based exclusions (22%-27%) and severity thresholds (moderate or severe dementia, 19%-23%) were also frequent. Reasons for ineligibility were similar across phenotypes. Most patients with atypical AD would not meet eligibility criteria for AAT, typically because of MMSE-based exclusion rather than measures of cognitive function. Eligibility rates are broadly similar across atypical phenotypes. These findings highlight the need for phenotype-sensitive staging and patient selection for treatment in atypical AD.
Taken from the source record, never inferred. Follow any of these and new work involving them reaches your briefing.