Neurology · 2026
Neuropsychological Profile and Cognitive Trajectories of Patients With Biomarker Evidence of Alzheimer Disease or Dementia With Lewy bodies.
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Tort-Merino Adrià, Esteller-Gauxax Diana, Pérez-Millan Agnès, Castellví Magda, Bosch Bea, Sánchez-Rodríguez Marta M, Rigol Axel, Rubio Georgina, Morante-Serra Claudia, Mir-Sala Laura, Patricio Víctor, Juncà-Parella Jordi, Torres-Coll Jaume, Guillén Núria, Martín-Sobrino Isabel, Massons Miquel, Canasto Paula, Alcón Desirée, Fernández-Villullas Guadalupe, Puey Roger, Comas-Albertí Aina, Antonell Anna, Borrego-Écija Sergi, Falgàs Neus, Sánchez-Valle Raquel, Lladó Albert, Balasa Mircea
Аннотация
BACKGROUND AND OBJECTIVES: Alzheimer disease (AD) and dementia with Lewy bodies (DLB) often coexist, yet the cognitive effect of mixed AD and α-synuclein pathology in vivo remains unclear. We aimed to (1) characterize baseline neuropsychological profiles, (2) assess plasma biomarker associations, and (3) examine longitudinal cognitive trajectories in patients with AD, DLB, and mixed pathology in a memory clinic cohort.
METHODS: This was a retrospective longitudinal study including participants from an academic memory clinic cohort with available CSF and blood samples at baseline who completed a comprehensive cognitive assessment. Baseline neuropsychological performance was compared between groups using analysis of covariance controlling for age, sex, and education. Associations between plasma biomarkers and cognition were examined using multiple linear regression models. Linear mixed-effects models examined longitudinal change across groups, with time from baseline, diagnosis, the diagnosis-by-time interaction, baseline age, sex, and years of education as fixed effects, and intercept as a random effect.
RESULTS: A total of 350 participants (mean age 70.1 ± 6.6 years; 48.6% female) were included: AD alone (n = 249), AD with α-synuclein pathology (n = 31), DLB alone (n = 33), and DLB with AD pathology (n = 37). At baseline, patients with AD showed greater impairment than those with DLB in memory and language (all p < 0.01). Compared with AD alone, patients with AD and α-synuclein pathology showed poorer performance in visual attention/processing speed (F[1,259] = 7.71, p < 0.01) and ideomotor apraxia (F[1,244] = 4.02, p < 0.05). Conversely, patients with DLB and AD pathology performed worse than those with isolated DLB in visual memory (F[1,38] = 5.38, p < 0.05), constructional praxis (F[1,59] = 6.26, p < 0.01), and executive function (F[1,40] = 5.68, p < 0.05). Memory (p < 0.01) and language (p < 0.05) best differentiated groups with mixed pathology. Plasma phosphorylated tau at threonine 217 was broadly associated with worse performance across cognitive domains in patients with AD (p < 0.05). Longitudinally, patients with AD showed steeper decline than those with DLB in memory (β = 0.184, SE = 0.069, p < 0.01) and language (β = 0.206, SE = 0.074, p < 0.01). Within AD, those with α-synuclein pathology exhibited steeper decline in encoding (β = -0.186, SE = 0.075, p < 0.05) and delayed total recall (β = -0.178, SE = 0.082, p < 0.05). Among mixed-pathology patients, those with primary AD diagnosis showed greater decline across memory (β = -0.324, SE = 0.104, p < 0.01), language (β = -0.359, SE = 0.109, p < 0.01), and visuospatial function (β = -0.356, SE = 0.175, p < 0.05).
DISCUSSION: Distinct neuropsychological profiles and trajectories emerge in AD and DLB depending on underlying pathology. Identifying mixed pathology in vivo is clinically relevant for accurate diagnosis and prognosis and has implications for outcome measures and patient stratification in clinical trials.
METHODS: This was a retrospective longitudinal study including participants from an academic memory clinic cohort with available CSF and blood samples at baseline who completed a comprehensive cognitive assessment. Baseline neuropsychological performance was compared between groups using analysis of covariance controlling for age, sex, and education. Associations between plasma biomarkers and cognition were examined using multiple linear regression models. Linear mixed-effects models examined longitudinal change across groups, with time from baseline, diagnosis, the diagnosis-by-time interaction, baseline age, sex, and years of education as fixed effects, and intercept as a random effect.
RESULTS: A total of 350 participants (mean age 70.1 ± 6.6 years; 48.6% female) were included: AD alone (n = 249), AD with α-synuclein pathology (n = 31), DLB alone (n = 33), and DLB with AD pathology (n = 37). At baseline, patients with AD showed greater impairment than those with DLB in memory and language (all p < 0.01). Compared with AD alone, patients with AD and α-synuclein pathology showed poorer performance in visual attention/processing speed (F[1,259] = 7.71, p < 0.01) and ideomotor apraxia (F[1,244] = 4.02, p < 0.05). Conversely, patients with DLB and AD pathology performed worse than those with isolated DLB in visual memory (F[1,38] = 5.38, p < 0.05), constructional praxis (F[1,59] = 6.26, p < 0.01), and executive function (F[1,40] = 5.68, p < 0.05). Memory (p < 0.01) and language (p < 0.05) best differentiated groups with mixed pathology. Plasma phosphorylated tau at threonine 217 was broadly associated with worse performance across cognitive domains in patients with AD (p < 0.05). Longitudinally, patients with AD showed steeper decline than those with DLB in memory (β = 0.184, SE = 0.069, p < 0.01) and language (β = 0.206, SE = 0.074, p < 0.01). Within AD, those with α-synuclein pathology exhibited steeper decline in encoding (β = -0.186, SE = 0.075, p < 0.05) and delayed total recall (β = -0.178, SE = 0.082, p < 0.05). Among mixed-pathology patients, those with primary AD diagnosis showed greater decline across memory (β = -0.324, SE = 0.104, p < 0.01), language (β = -0.359, SE = 0.109, p < 0.01), and visuospatial function (β = -0.356, SE = 0.175, p < 0.05).
DISCUSSION: Distinct neuropsychological profiles and trajectories emerge in AD and DLB depending on underlying pathology. Identifying mixed pathology in vivo is clinically relevant for accurate diagnosis and prognosis and has implications for outcome measures and patient stratification in clinical trials.