Cerebrospinal fluid biomarkers and cerebral atrophy in distinct clinical variants of probable Alzheimer's disease

No abstract

SYNOPSIS Early-onset Alzheimer’s disease (EOAD) with onset <65 years of age, while overshadowed by the more common late-onset AD (LOAD), differs significantly from LOAD. EOAD comprises about 5% of AD and is associated with delays in diagnosis, an aggressive course, and age-related psychosocial needs. One source of confusion is that a substantial percentage of EOAD are phenotypic variants that differ from the usual memory-disordered presentation of typical AD. Patients with EOAD overall have greater parietal atrophy, more white matter abnormalities, and less hippocampal volume loss, compared to those with LOAD. The phenotypic variants also have atrophy and white matter changes corresponding anatomically to the cognitive changes and appear to involve alternate neural networks relative to typical AD. The management of EOAD is similar to that for LOAD but special emphasis should be placed on targeting the specific cognitive areas involved and more age-appropriate psychosocial support and education.

Introduction Patients with Alzheimer’s disease (AD) show heterogeneity in profile of cognitive impairment. We aimed to identify cognitive subtypes in four large AD cohorts using a data-driven clustering approach. Methods We included probable AD dementia patients from the Amsterdam Dementia Cohort (n = 496), Alzheimer’s Disease Neuroimaging Initiative (n = 376), German Dementia Competence Network (n = 521), and University of California, San Francisco (n = 589). Neuropsychological data were clustered using nonnegative matrix factorization. We explored clinical and neurobiological characteristics of identified clusters. Results In each cohort, a two-clusters solution best fitted the data (cophenetic correlation >0.9): one cluster was memory-impaired and the other relatively memory spared. Pooled analyses showed that the memory-spared clusters (29%–52% of patients) were younger, more often apolipoprotein E (APOE) ε4 negative, and had more severe posterior atrophy compared with the memory-impaired clusters (all P < .05). Conclusions We could identify two robust cognitive clusters in four independent large cohorts with distinct clinical characteristics.