INTRODUCTION: Subjective cognitive decline (SCD) may be an early marker of Alzheimers disease (AD) pathology. Until recently, it was impossible to measure biomarkers specific for α-synuclein pathology; therefore, its association with subjective reports of cognitive decline is unknown. METHODS: Alzheimers Disease Neuroimaging Initiative participants without dementia (n = 918) were classified as positive or negative for amyloid beta (Aβ+ or Aβ-) and α-synuclein (α-syn+ or α-syn-) biomarkers. Self- and study partner-reported cognitive decline was measured with the Everyday Cognition (ECog) questionnaire. RESULTS: Per self-report, Aβ+/α-syn+ had the greatest cognitive decline. Aβ-/α-syn+ did not differ from Aβ-/α-syn- across ECog scores. Study partner-reported results had a similar pattern, but Aβ+/α-syn- and Aβ+/α-syn+ did not differ across ECog scores. Mild cognitive impairment classification moderated the study partner-reported memory score. DISCUSSION: While α-syn+ alone did not increase subjective reports of cognitive decline, Aβ+/α-syn+ had the most self- and study partner-rated cognitive decline. Therefore, the presence of multiple pathologies was associated with greater SCD. HIGHLIGHTS: Cerebrospinal fluid α-synuclein (α-syn) seed amplification assay was used to determine α-syn positivity. Amyloid beta (Aβ)-/α-syn-, Aβ-/α-syn+, Aβ+/α-syn-, and Aβ+/α-syn+ biomarker groups were created. Aβ+/α-syn+ had greater subjective cognitive decline (SCD) than the other biomarker groups. Aβ-/α-syn+ did not differ from Aβ-/α-syn- across self- or study-partner reported SCD scores. Study partner-reported subjective memory results were largely driven by participants with mild cognitive impairment.

BACKGROUND: Within older Veterans, multiple factors may contribute to cognitive difficulties. Beyond Alzheimers disease (AD), psychiatric (e.g., PTSD) and health comorbidities (e.g., TBI) may also impact cognition. OBJECTIVE: This study aimed to derive subgroups based on objective cognition, subjective cognitive decline (SCD), and amyloid burden, and then compare subgroups on clinical characteristics, biomarkers, and longitudinal change in functioning and global cognition. METHODS: Cluster analysis of neuropsychological measures, SCD, and amyloid PET was conducted on 228 predominately male Vietnam-Era Veterans from the Department of Defense-Alzheimers Disease Neuroimaging Initiative. Cluster-derived subgroups were compared on baseline characteristics as well as 1-year changes in everyday functioning and global cognition. RESULTS: The cluster analysis identified 3 groups. Group 1 (n = 128) had average-to-above average cognition with low amyloid burden. Group 2 (n = 72) had the lowest memory and language, highest SCD, and average amyloid burden; they also had the most severe PTSD, pain, and worst sleep quality. Group 3 (n = 28) had the lowest attention/executive functioning, slightly low memory and language, elevated amyloid and the worst AD biomarkers, and the fastest rate of everyday functioning and cognitive decline. CONCLUSIONS: Psychiatric and health factors likely contributed to Group 2s low memory and language performance. Group 3 was most consistent with biological AD, yet attention/executive function was the lowest score. The complexity of older Veterans co-morbid conditions may interact with AD pathology to show attention/executive dysfunction (rather than memory) as a prominent early symptom. These results could have important implications for the implementation of AD-modifying drugs in older Veterans.

INTRODUCTION: White matter hyperintensities (WMHs) are magnetic resonance imaging markers of small vessel cerebrovascular disease that are associated with cognitive decline and clinical Alzheimer disease. Previous studies have often focused on global or total WMH; less is known about associations of regional WMHs and cognitive abilities among older adults without dementia. METHODS: A total of 610 older adults with normal cognition (n=302) or mild cognitive impairment (n=308) from the Alzheimers Disease Neuroimaging Initiative underwent neuropsychological testing and magnetic resonance imaging. Linear regression models examined associations between regional WMH volumes and cognition, adjusting for age, sex, education, apolipoprotein E ε4 allele frequency, and pulse pressure. RESULTS: Among all participants, greater regional WMH volume in all lobes was associated with poorer performance on memory and speed/executive functioning. Among participants with normal cognition, greater temporal and occipital WMH volumes were associated with poorer memory, whereas no regional WMH volumes were associated with speed/executive function. DISCUSSION: Results show that greater regional WMH volume relates to poorer cognitive functioning-even among those with normal cognition. Together with results from previous studies, our findings raise the possibility that WMH may be a useful therapeutic target and/or important effect modifier in treatment or prevention dementia trials.