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IntroductionAlzheimer’s disease (AD) is highly heterogeneous, with substantial individual variabilities in clinical progression and neurobiology. Amyloid deposition has been thought to drive cognitive decline and thus a major contributor to the variations in cognitive deterioration in AD. However, the clinical heterogeneity of patients with early symptomatic AD (mild cognitive impairment or mild dementia due to AD) already with evidence of amyloid abnormality in the brain is still unknown.MethodsParticipants with a baseline diagnosis of mild cognitive impairment or mild dementia, a positive amyloid-PET scan, and more than one follow-up Alzheimer’s Disease Assessment Scale-Cognitive Subscale-13 (ADAS-Cog-13) administration within a period of 5-year follow-up were selected from the Alzheimer’s Disease Neuroimaging Initiative database (n = 421; age = 73±7; years of education = 16 ± 3; percentage of female gender = 43%; distribution of APOE4 carriers = 68%). A non-parametric k-means longitudinal clustering analysis in the context of the ADAS-Cog-13 data was performed to identify cognitive subtypes.ResultsWe found a highly variable profile of cognitive decline among patients with early AD and identified 4 clusters characterized by distinct rates of cognitive progression. Among the groups there were significant differences in the magnitude of rates of changes in other cognitive and functional outcomes, clinical progression from mild cognitive impairment to dementia, and changes in markers presumed to reflect neurodegeneration and neuronal injury. A nomogram based on a simplified logistic regression model predicted steep cognitive trajectory with an AUC of 0.912 (95% CI: 0.88 – 0.94). Simulation of clinical trials suggested that the incorporation of the nomogram into enrichment strategies would reduce the required sample sizes from 926.8 (95% CI: 822.6 – 1057.5) to 400.9 (95% CI: 306.9 – 516.8).DiscussionOur findings show usefulness in the stratification of patients in early AD and may thus increase the chances of finding a treatment for future AD clinical trials.

Abstract Background Given the complex and progressive nature of mild cognitive impairment (MCI), the ability to delineate and understand the heterogeneous cognitive trajectories is crucial for developing personalized medicine and informing trial design. The primary goals of this study were to examine whether different cognitive trajectories can be identified within subjects with MCI and, if present, to characterize each trajectory in relation to changes in all major Alzheimer’s disease (AD) biomarkers over time. Methods Individuals with a diagnosis of MCI at the first visit and ≥ 1 follow-up cognitive assessment were selected from the Alzheimer’s Disease Neuroimaging Initiative database (n = 936; age 73 ± 8; 40% female; 16 ± 3 years of education; 50% APOE4 carriers). Based on the Alzheimer’s Disease Assessment Scale-Cognitive Subscale-13 (ADAS-Cog-13) total scores from baseline up to 5 years follow-up, a non-parametric k-means longitudinal clustering method was performed to obtain clusters of individuals with similar patterns of cognitive decline. We further conducted a series of linear mixed-effects models to study the associations of cluster membership with longitudinal changes in other cognitive measures, neurodegeneration, and in vivo AD pathologies. Results Four distinct cognitive trajectories emerged. Cluster 1 consisted of 255 individuals (27%) with a nearly non-existent rate of change in the ADAS-Cog-13 over 5 years of follow-up and a healthy-looking biomarker profile. Individuals in the cluster 2 (n = 336, 35%) and 3 (n = 240, 26%) groups showed relatively mild and moderate cognitive decline trajectories, respectively. Cluster 4, comprising about 11% of our study sample (n = 105), exhibited an aggressive cognitive decline trajectory and was characterized by a pronouncedly abnormal biomarker profile. Conclusions Individuals with MCI show substantial heterogeneity in cognitive decline. Our findings may potentially contribute to improved trial design and patient stratification.

ObjectiveThere is growing evidence that testosterone may be implicated in the pathogenesis of Alzheimer’s disease (AD). We aimed to examine the relationship between plasma total testosterone levels and change in brain glucose metabolism over time among non-demented older people.MethodsThe association of plasma total testosterone levels with change in brain glucose metabolism among non-demented older people was investigated cross-sectionally and longitudinally. Given a significant difference in levels of plasma total testosterone between gender, we performed our analysis in a sex-stratified way. At baseline, 228 non-demented older people were included: 152 males and 76 females.ResultsIn the cross-sectional analysis, no significant relationship between plasma total testosterone levels and brain glucose metabolism was found in males or females. In the longitudinal analysis, we found a significant association of plasma total testosterone levels with change in brain glucose metabolism over time in males, but not in females. More specifically, in males, higher levels of total testosterone in plasma at baseline were associated with slower decline in brain glucose metabolism.ConclusionWe found that higher levels of total testosterone in plasma at baseline were associated with slower decline in brain glucose metabolism in males without dementia, indicating that testosterone may have beneficial effects on brain function.

Objective: To investigate whether APOE ε4 affects the association of verbal memory with neurodegeneration presented by the hippocampal volume/intracranial volume ratio (HpVR).Methods: The study sample included 371 individuals with normal cognition (NC), 725 subjects with amnestic mild cognitive impairment (aMCI), and 251 patients with mild Alzheimer’s disease (AD) from the Alzheimer’s Disease Neuroimaging Initiative (ADNI) who underwent the rey auditory verbal learning test (RAVLT). Multiple linear regression models were conducted to assess the effect of the APOE ε4∗HpVR interaction on RAVLT in all subjects and in each diagnostic group adjusting for age, gender and educational attainment, and global cognition.Results: In all subjects, there was no significant APOE ε4 × HpVR interaction for immediate recall or delayed recall (p > 0.05). However, in aMCI subjects, there was a significant APOE ε4 × HpVR interaction for delayed recall (p = 0.008), but not immediate recall (p = 0.15). More specifically, the detrimental effect of APOE ε4 on delayed recall altered by HpVR such that this effect was most evident among subjects with small to moderate HpVR, but this disadvantage was absent or even reversed among subjects with larger HpVR. No significant interaction was observed in the NC or AD group.Conclusion: These findings highlight a potential role of APOE ε4 status in affecting the association of hippocampus size with delayed recall memory in the early stage of AD.