Aims

With the advent of disease-modifying therapeutic trials in early stages of Alzheimer’s disease (AD), disentangling normal age-related biomarker changes from AD-related pathological changes will be crucial to unravel therapy effectiveness in trial populations. Here, we aim to investigate the effects of age, the greatest risk factor of AD, on markers of amyloid-β (Aβ), tau, and neuroinflammation PET in late-onset AD.

Methods

238 participants (120 amyloid- and tau-negative [A-] and 118 amyloid-positive [A+]) from the TRIAD cohort underwent ¹⁸F-AZD4694 amyloid-PET and ¹⁸F-MK620 tau-PET. A subset also underwent ¹¹C-PBR28 neuroinflammation-PET, plasma Ptau181 and Aβ_1-42/Aβ_1-40 concentration measures, and 1-year follow-up tau-PET. We investigated the association between age and all PET modalities as well as between age and plasma concentrations using linear regression models, adjusting for sex, education, APOE-ε4, and the remaining PET or plasma variables. In addition, we investigated whether there is a significant difference in these associations between the A- and A+ groups (i.e., interaction-effect age*Aβ-status on PET/plasma biomarkers).

Results

Younger A+ subjects showed increased plasma Ptau181 and tau-PET in Braak3and4 predominant areas at baseline as well as increased tau-PET SUVR changes in Braak1and2 predominant areas after 1-year follow-up compared to older A+ individuals, while there was no age-effect on tau-PET in A-. Second, while we detected a significant main effect of age on neocortical Aβ and orbitofrontal neuroinflammation SUVR, the effect of age on both markers did not significantly differ between A+ and A-.

Conclusions

Future clinical trials should consider age as an important stratification factor particularly when targeting tau in late-onset AD.

Aims

To assess anxiety and its relationship to tau pathology and COVID-19 induced subjective stress in the participants of a biomarker observational study during the COVID-19 pandemic.

Methods

Participants of the Translational Biomarker of Aging and Dementia (TRIAD) cohort who had baseline measures of cognition (MMSE, MoCA), anxiety (GAD-7) and the tau tracer [18F]MK-6240, were assessed during the COVID-19 lockdown period, to evaluate their individual change in anxiety and cognitive decline. A measurement of COVID-19 induced subjective stress was included at the follow-up time point as well.

Results

244 TRIAD participants (cognitively healthy, N=178; cognitively impaired, N=66, of which 16 had dementia due to Alzheimer’s disease) were assessed in between March and May 2020. While increased on average in the cognitively healthy group, both anxiety and subjective stress due to COVID-19 were lower in the cognitively impaired group. Furthermore, the strong correlation in cognitively healthy individuals between anxiety and subjective stress due to COVID-19 was not present in the cognitively impaired individuals (fig 1). A negative association between [18F]MK-6240 tracer binding and the difference in GAD score between the two timepoints was found in cognitively impaired individuals (fig 2). Cognitive decline was observed only in symptomatic individuals.

Figure 1:

Figure 2:

Conclusions

Cognitive impairment differentially affected anxiety among participants of this longitudinal observational study during the lockdown period. The presence of tau negatively affected the difference in GAD scores between the two time points. Further studies should determine whether these effects can impact the outcomes of clinical trials.

Abstract Body

It is expected that tau imaging will provide a framework for staging and estimate Alzheimer’s disease (AD) progression. However, the off-target binding typically present in the first generation of tau imaging agents and the low tissue concentrations of tau typical from early Braak stages constitute a challenge for quantification of early pathophysiological phases AD. In fact, post-mortem Braak staging proposes that tau neurofibrillary tangle accumulation follows a stereotypical sequential pattern, beginning in the transentorhinal, spreading through the temporal, and then extra-temporal association and primary sensory cortices. Here we showed that high-sub-nanomolar imaging agents, due to their kinetic properties, identify individuals in the early stages of tau accumulation. We demonstrated these properties in a cohort of 301 individuals. Participants had imaging amyloid-beta PET with [¹⁸F]NAV4694, neurofibrillary tangles PET with [¹⁸F]MK-6240, magnetic resonance imaging, and clinical assessments. [¹⁸F]MK-6240 standardized uptake value ratio was quantified from 90-110 min. recapitulated the 6 hierarchical stages proposed by Braak in 98% of our population. No single region-of-interest accurately segregated individuals into the 6 Braak stages. [¹⁸F]MK-6240 SUVRs discriminated Alzheimer's disease from frontotemporal dementia patients (area under the curve = ~95-100%) with the highest accuracy in the transentorhinal, entorhinal, and hippocampal cortices. These results support that [¹⁸F]MK-6240 is suitable for staging preclinical and symptomatic AD. Tau positron emission tomography Braak staging using sub-nanomolar affinity tracers has the potential to be incorporated in the diagnosis and staging of living patients with AD.

Aims

Elucidating sex-dependent mechanisms resulting in greater vulnerability in females in Alzheimer’s disease (AD) is important for therapeutic strategy and personalized medicine. Here, we aimed to elucidate the sex-dependent microglial effect on neurodegeneration and cognition using multimodal imaging biomarkers.

Methods

A total of 143 participants (50 males, 93 females; 92 CN, 32 MCI, 19 AD) from the TRIAD cohort underwent T1, 3 PET, and CDR-SB procedures. VBM was generated using the DARTEL pipeline while static [¹¹C]PBR28, [¹⁸F]AZD4694, and [¹⁸F]MK6240 SUVR images were generated using an in-house pipeline. Then, all images were normalized to the ADNI template with 8 mm smoothing. A multiple linear regression model was used to evaluate the effect of sex on VBM, [¹¹C]PBR28, or the relationship between VBM and [¹¹C]PBR28. Then, the effect of VBM and [¹¹C]PBR28 on cognition was evaluated using mediation analysis. All analyses included age, education, APOEε4, amyloid-beta, tau, and diagnosis as covariates.

Results

Females showed a significantly lower VBM while they also showed a significantly greater [¹¹C]PBR28 SUVR in medial temporal regions compared to males. Also, there was a substantial positive association between VBM and [¹¹C]PBR28 in the medial temporal regions only in males. Consequently, the effect of [¹¹C]PBR28 on CDR-SB was significantly mediated by VBM in the medial temporal lobe only in males but not in females.

Conclusions

This study highlights a sex-dependent disease mechanism in medial temporal regions; males showed lower activated microglia, greater VBM, and a protective relationship between VBM and microglia on cognition after adjusting for the AD hallmarks compared to females.

Aims

Elucidating sex-dependent mechanisms resulting in greater vulnerability in females in Alzheimer’s disease (AD) is important for therapeutic strategy and personalized medicine. Here, we aimed to elucidate the sex-dependent microglial effect on neurodegeneration and cognition using multimodal imaging biomarkers.

Methods

A total of 143 participants (50 males, 93 females; 92 CN, 32 MCI, 19 AD) from the TRIAD cohort underwent T1, 3 PET, and CDR-SB procedures. VBM was generated using the DARTEL pipeline while static [¹¹C]PBR28, [¹⁸F]AZD4694, and [¹⁸F]MK6240 SUVR images were generated using an in-house pipeline. Then, all images were normalized to the ADNI template with 8 mm smoothing. A multiple linear regression model was used to evaluate the effect of sex on VBM, [¹¹C]PBR28, or the relationship between VBM and [¹¹C]PBR28. Then, the effect of VBM and [¹¹C]PBR28 on cognition was evaluated using mediation analysis. All analyses included age, education, APOEε4, amyloid-beta, tau, and diagnosis as covariates.

Results

Females showed a significantly lower VBM while they also showed a significantly greater [¹¹C]PBR28 SUVR in medial temporal regions compared to males. Also, there was a substantial positive association between VBM and [¹¹C]PBR28 in the medial temporal regions only in males. Consequently, the effect of [¹¹C]PBR28 on CDR-SB was significantly mediated by VBM in the medial temporal lobe only in males but not in females.

Conclusions

This study highlights a sex-dependent disease mechanism in medial temporal regions; males showed lower activated microglia, greater VBM, and a protective relationship between VBM and microglia on cognition after adjusting for the AD hallmarks compared to females.