INTRODUCTIONAmnestic mild cognitive impairment (aMCI) is emerging as a heterogeneous condition.METHODSWe looked at a cohort of N = 207 aMCI subjects, with baseline fluorodeoxyglucose positron emission tomography (FDG‐PET), T1 magnetic resonance imaging, cerebrospinal fluid (CSF), apolipoprotein E (APOE), and neuropsychological assessment. An algorithm based on FDG‐PET hypometabolism classified each subject into subtypes, then compared biomarker measures and clinical progression.RESULTSThree subtypes emerged: hippocampal sparing–cortical hypometabolism, associated with younger age and the highest level of Alzheimer's disease (AD)‐CSF pathology; hippocampal/cortical hypometabolism, associated with a high percentage of APOE ε3/ε4 or ε4/ε4 carriers; medial–temporal hypometabolism, characterized by older age, the lowest AD‐CSF pathology, the most severe hippocampal atrophy, and a benign course. Within the whole cohort, the severity of temporo‐parietal hypometabolism, correlated with AD‐CSF pathology and marked the rate of progression of cognitive decline.DISCUSSIONFDG‐PET can distinguish clinically comparable aMCI at single‐subject level with different risk of progression to AD dementia or stability. The obtained results can be useful for the optimization of pharmacological trials and automated‐classification models.Highlights Algorithm based on FDG‐PET hypometabolism demonstrates distinct subtypes across aMCI; Three different subtypes show heterogeneous biological profiles and risk of progression; The cortical hypometabolism is associated with AD pathology and cognitive decline; MTL hypometabolism is associated with the lowest conversion rate and CSF‐AD pathology.

No abstract

INTRODUCTIONAccumulating evidence suggests that α‐synuclein (αSyn) can modulate Alzheimer's disease (AD) pathology. The aim of this study was to evaluate the prevalence and clinical features associated with cerebrospinal fluid (CSF) αSyn detected by seed amplification assay (SAA) in AD.METHODSEighty AD patients with CSF AT(N) biomarker positivity (mean age 70.3 ± 7.3 years) and 28 non‐AD age‐matched controls were included. All subjects underwent standardized clinical assessment; CSF αSyn aggregates were detected by SAA.RESULTSCSF was αSyn‐SAA positive (αSyn+) in 36/80 AD patients (45%) and in 2/28 controls (7.1%). AD αSyn+ and αSyn− patients were comparable for age, disease severity, comorbidity profile, and CSF core biomarkers. AD αSyn+ presented a higher prevalence of atypical phenotypes and symptoms.CONCLUSIONSOur findings demonstrate that concomitant CSF αSyn pathology is present in a significant proportion of AD patients starting in the early stages and can affect clinical presentation. Longitudinal studies are warranted to evaluate the significance for the disease course.