Background
Recruitment for preclinical Alzheimer’s disease clinical trials and observational studies in the Latino population continues to increase as researchers aim to diversify their samples. The ...Telephone Interview for Cognitive Status modified version (TICS‐m) is a pre‐screening tool that has shown to have high diagnostic validity for identification of dementia in mostly Caucasian samples. The TICS‐m cut‐off currently used for screening out cognitive impairment in older individuals is ≥26. We aimed to 1) determine whether currently used TICS‐m cut‐offs are appropriate for pre‐screening clinically normal older Latinos, and 2) assess the relationships among the TICS‐m score and outcome measures typically used in clinical trials, such as Mini Mental State Exam (MMSE), Logical Memory Delayed Recall, and Clinical Dementia Rating (CDR).
Methods
Twenty‐nine older Latino adults (mean age= 68.7, mean education=15.6, and mean TICS‐m= 33.4/40) from the Harvard Aging Brain Study (HABS) were included in this study. Participants completed the pre‐screening TICS‐m over the phone, followed by an in‐clinic screening neuropsychological battery, which included the MMSE, Logical Memory Delayed Recall, and CDR, administered in Spanish. Linear regression models controlling for age, sex, and education were used to assess the relationships between TICS‐m score and performance on the neuropsychological measures.
Results
TICS‐m scores were positively correlated with years of education (r=0.54, p=0.002). No significant associations were observed among TICS‐m scores and other cognitive measures, after adjusting by age, sex, and education (MMSE: r=0.04, p=0.82; Logical Memory Delayed: r=0.10, p=0.62; and CDR sum of boxes: r=‐0.03, p=0.86).
Conclusion
Preliminary results suggest that in this sample of largely cognitively normal Latino adults, TICS‐m score is not associated with performance in other cognitive outcome measures typically used in clinical and observational trials for preclinical Alzheimer’s disease. These findings also suggest that the TICS‐m may not accurately reflect actual cognitive function in older Latino participants. However, we do not know if we are inadvertently screen‐failing participants using TICS‐m as a pre‐screening tool. Further research is needed to assess whether this pre‐screening tool is adequate in the pre‐screening process for preclinical Alzheimer’s disease in older Latino adults.
Background
Understanding the extent to which vascular and lifestyle factors operate independently and synergistically with Alzheimer’s disease pathology is critical to designing optimized clinical ...trials and to assessing the efficacy of interventions to delay cognitive impairment. We examined this question by leveraging data from a longitudinal cohort study with detailed cognitive and multi‐modal imaging data (the Harvard Aging Brain Study; HABS).
Method
We used cross‐sectional and longitudinal data from HABS (n = 223; mean age at entry: 72y; mean follow‐up of 5.9y), including 11C‐Pittsburgh‐Compound‐B (PiB) amyloid PET, 18F‐Flortaucipir (FTP) tau PET, MRI, pedometer‐measured physical activity data, cognitive testing (Preclinical Alzheimer Cognitive Composite; PACC), and the Framingham Heart Study Cardiovascular Disease Risk Score (FHS‐CVD). Using linear mixed effects models, we examined the interplay of vascular risk factors, imaging measures of cerebrovascular injury, and physical activity with PET measures of b‐amyloid burden as they relate to longitudinal cognitive performance, neurodegeneration, and tau pathology.
Result
We observed that higher FHS‐CVD at study entry was predictive of poorer longitudinal cognitive performance on the PACC, alone and interactively with PiB‐PET (both p<0.001). Greater baseline physical activity (mean steps) was predictive of better longitudinal cognitive performance when interacted with PiB‐PET (p <0.001). Lower FHS‐CVD and greater physical activity were both predictive of less neurodegeneration (longitudinal MRI measures of hippocampal and gray matter volumes) when interacted with PiB‐PET (all p < 0.01). In the subset of participants with available tau PET, FHS‐CVD but not physical activity interacted with PiB‐PET to significantly predict cross‐sectional and longitudinal tau accumulation (p < 0.05). Diffusion but not FLAIR measures of white matter disruption added to FHS‐CVD in predicting cognitive decline.
Conclusion
Together with many prior studies, these data indicate strong additive and/or synergistic effects of vascular risk and physical activity with b‐amyloid in prediction of longitudinal cognition, neurodegeneration, and tau accumulation. These results suggest interventions targeting physical activity and vascular risk in order to delay cognitive decline may be particularly effective in people with elevated β‐amyloid burden. Similarly, consideration of vascular and lifestyle factors may improve our understanding of the potential clinical effectiveness of anti‐amyloid and tau therapies currently in testing.
Abstract
Background
Understanding the extent to which vascular and lifestyle factors operate independently and synergistically with Alzheimer’s disease pathology is critical to designing optimized ...clinical trials and to assessing the efficacy of interventions to delay cognitive impairment. We examined this question by leveraging data from a longitudinal cohort study with detailed cognitive and multi‐modal imaging data (the Harvard Aging Brain Study; HABS).
Method
We used cross‐sectional and longitudinal data from HABS (n = 223; mean age at entry: 72y; mean follow‐up of 5.9y), including 11C‐Pittsburgh‐Compound‐B (PiB) amyloid PET, 18F‐Flortaucipir (FTP) tau PET, MRI, pedometer‐measured physical activity data, cognitive testing (Preclinical Alzheimer Cognitive Composite; PACC), and the Framingham Heart Study Cardiovascular Disease Risk Score (FHS‐CVD). Using linear mixed effects models, we examined the interplay of vascular risk factors, imaging measures of cerebrovascular injury, and physical activity with PET measures of b‐amyloid burden as they relate to longitudinal cognitive performance, neurodegeneration, and tau pathology.
Result
We observed that higher FHS‐CVD at study entry was predictive of poorer longitudinal cognitive performance on the PACC, alone and interactively with PiB‐PET (both p<0.001). Greater baseline physical activity (mean steps) was predictive of better longitudinal cognitive performance when interacted with PiB‐PET (p <0.001). Lower FHS‐CVD and greater physical activity were both predictive of less neurodegeneration (longitudinal MRI measures of hippocampal and gray matter volumes) when interacted with PiB‐PET (all p < 0.01). In the subset of participants with available tau PET, FHS‐CVD but not physical activity interacted with PiB‐PET to significantly predict cross‐sectional and longitudinal tau accumulation (p < 0.05). Diffusion but not FLAIR measures of white matter disruption added to FHS‐CVD in predicting cognitive decline.
Conclusion
Together with many prior studies, these data indicate strong additive and/or synergistic effects of vascular risk and physical activity with b‐amyloid in prediction of longitudinal cognition, neurodegeneration, and tau accumulation. These results suggest interventions targeting physical activity and vascular risk in order to delay cognitive decline may be particularly effective in people with elevated β‐amyloid burden. Similarly, consideration of vascular and lifestyle factors may improve our understanding of the potential clinical effectiveness of anti‐amyloid and tau therapies currently in testing.
Background
APOE‐ε4 allele (APOE4) increases the risk for sporadic Alzheimer’s disease (AD) and is associated with an earlier onset of AD dementia. However, previous studies have shown conflicting ...results on the association of APOE4 with the age of dementia onset in individuals with autosomal dominant AD (ADAD). Here, we examined the impact of APOE4 genotype on the age‐related trajectory of global cognitive function in mutation carriers and non‐carriers from the Colombian ADAD kindred.
Method
Data were obtained from a retrospective cohort of individuals from the largest known early‐onset ADAD kindred, residing in Antioquia, Colombia. Analyses included 675 PSEN1 E280A carriers (ages 18 to 75; 141 with an APOE4 allele: APOE4+, and 534 without an APOE4 allele: APOE4‐) and 594 non‐carriers. The Mini‐Mental State Examination (MMSE) was used to assess global cognitive functioning. Age‐related trajectories were derived from cross‐sectional log‐transformed MMSE scores modeled using a restricted cubic spline model. Model parameters were estimated using a Hamiltonian Markov chain Monte Carlo method to compare APOE4+ versus APOE4‐ trajectories in the mutation carrier and non‐carrier groups and estimate the age at onset of differences in global cognitive functioning.
Result
Lower MMSE scores distinguished PSEN1 E280A mutation carriers from non‐carriers at age 31.4, approximately 14 years before the average age of mild cognitive impairment (MCI) onset in this cohort. Among PSEN1 E280A mutation carriers, lower scores in MMSE began to significantly differentiate APOE4+ from APOE4‐ at age 45, the estimated average age of MCI onset in this kindred (figure 1). MMSE scores did not differentiate APOE4+ from APOE4‐ in those without the PSEN1 E280A mutation.
Conclusion
Our findings suggest that age‐related changes in cognitive function, as measured by the MMSE, are accelerated in ADAD mutation carriers who are APOE4+, compared to those who are APOE4‐. Future longitudinal studies of PSEN1 mutation carriers are needed to further clarify the impact of APOE4 genotype on rates of cognitive decline, heterogeneity of clinical presentation, and clinical progression in the preclinical, MCI, and dementia stages.
Abstract
Background
The immune system plays a critical role in Alzheimer’s disease (AD) pathophysiology, and altered peripheral cytokine levels have been reported in AD dementia. However, it remains ...unclear whether and how plasma cytokines in cognitively normal (CN) older adults predict cognitive decline.
Method
We studied 298 CN Harvard Aging Brain Study (HABS) participants with baseline amyloid‐β (Aβ) measure (Pittsburgh Compound B PET neocortical distribution volume ratio (DVR)), baseline plasma collection, and longitudinal cognitive measures (Preclinical Alzheimer Cognitive Composite 5 (PACC5)). We measured nine plasma cytokines (IFN‐γ, IL‐1b, IL‐4, IL‐6, IL‐8, IL‐10, IL‐12p70, IL‐13, TNF‐α) using the Meso‐Scale Discovery V‐PLEX platform, and the cytokine levels were log‐transformed and normalized. We first screened for the cytokines that modify the association between baseline Aβ and longitudinal PACC5 (linear mixed effect models). We then screened the remaining cytokines for their Aβ‐independent association with longitudinal PACC5 (linear mixed effect models). The identified cytokines’ association with Aβ (“A”), neocortical tau (“T”) (inferior temporal cortex flortaucipir PET standardized uptake value ratio (SUVR) at Year 4), and neurodegeneration (longitudinal hippocampal volume (HV)) (“N”) were tested.
Result
Higher baseline plasma IL‐12p70 modified the association between baseline Aβ and longitudinal cognition, whereby higher IL‐12p70 predicted less cognitive decline especially in the setting of higher Aβ (IL‐12p70*Aβ*time: β=0.17, p=3.6×10
‐5
, FDR=3.2×10
‐4
): higher IL‐12p70 predicted less cognitive decline in the Aβ+ subgroup (n=72; β=0.085, p=4.0×10
‐4
), but not in the Aβ‐ subgroup (n=221; p=0.33). IL‐12p70 was not associated with baseline Ab (p=0.79), but its interaction term with baseline Ab predicted lower neocortical tau burden at Year 4 (n=118; β=‐0.15, p=0.040), and less longitudinal hippocampal volume loss (n=244; β=42, p=0.035). On the other hand, higher IFN‐γ was associated with less cognitive decline independent of Aβ (IFN‐γ*time: β=0.026, p=1.5×10
‐3
, FDR=0.011). IFN‐γ was not associated with Aβ, tau, or longitudinal hippocampal volume.
Conclusion
Plasma IL‐12/IFN‐γ axis predicted a favorable cognitive trajectory in CN older adults, and plasma IL‐12p70 captured a process that modifies the association of Aβ with neocortical tau and longitudinal neurodegeneration. Our results showing protective effect of upregulated peripheral IL‐12/IFN‐γ axis illustrate complex roles the immune system plays in the progression of AD.
Background
The immune system plays a critical role in Alzheimer’s disease (AD) pathophysiology, and altered peripheral cytokine levels have been reported in AD dementia. However, it remains unclear ...whether and how plasma cytokines in cognitively normal (CN) older adults predict cognitive decline.
Method
We studied 298 CN Harvard Aging Brain Study (HABS) participants with baseline amyloid‐β (Aβ) measure (Pittsburgh Compound B PET neocortical distribution volume ratio (DVR)), baseline plasma collection, and longitudinal cognitive measures (Preclinical Alzheimer Cognitive Composite 5 (PACC5)). We measured nine plasma cytokines (IFN‐γ, IL‐1b, IL‐4, IL‐6, IL‐8, IL‐10, IL‐12p70, IL‐13, TNF‐α) using the Meso‐Scale Discovery V‐PLEX platform, and the cytokine levels were log‐transformed and normalized. We first screened for the cytokines that modify the association between baseline Aβ and longitudinal PACC5 (linear mixed effect models). We then screened the remaining cytokines for their Aβ‐independent association with longitudinal PACC5 (linear mixed effect models). The identified cytokines’ association with Aβ (“A”), neocortical tau (“T”) (inferior temporal cortex flortaucipir PET standardized uptake value ratio (SUVR) at Year 4), and neurodegeneration (longitudinal hippocampal volume (HV)) (“N”) were tested.
Result
Higher baseline plasma IL‐12p70 modified the association between baseline Aβ and longitudinal cognition, whereby higher IL‐12p70 predicted less cognitive decline especially in the setting of higher Aβ (IL‐12p70*Aβ*time: β=0.17, p=3.6×10‐5, FDR=3.2×10‐4): higher IL‐12p70 predicted less cognitive decline in the Aβ+ subgroup (n=72; β=0.085, p=4.0×10‐4), but not in the Aβ‐ subgroup (n=221; p=0.33). IL‐12p70 was not associated with baseline Ab (p=0.79), but its interaction term with baseline Ab predicted lower neocortical tau burden at Year 4 (n=118; β=‐0.15, p=0.040), and less longitudinal hippocampal volume loss (n=244; β=42, p=0.035). On the other hand, higher IFN‐γ was associated with less cognitive decline independent of Aβ (IFN‐γ*time: β=0.026, p=1.5×10‐3, FDR=0.011). IFN‐γ was not associated with Aβ, tau, or longitudinal hippocampal volume.
Conclusion
Plasma IL‐12/IFN‐γ axis predicted a favorable cognitive trajectory in CN older adults, and plasma IL‐12p70 captured a process that modifies the association of Aβ with neocortical tau and longitudinal neurodegeneration. Our results showing protective effect of upregulated peripheral IL‐12/IFN‐γ axis illustrate complex roles the immune system plays in the progression of AD.
The shared role of amyloid-β (Aβ) deposition in cerebral amyloid angiopathy (CAA) and Alzheimer disease (AD) is arguably the clearest instance of crosstalk between neurodegenerative and ...cerebrovascular processes. The pathogenic pathways of CAA and AD intersect at the levels of Aβ generation, its circulation within the interstitial fluid and perivascular drainage pathways and its brain clearance, but diverge in their mechanisms of brain injury and disease presentation. Here, we review the evidence for and the pathogenic implications of interactions between CAA and AD. Both pathologies seem to be driven by impaired Aβ clearance, creating conditions for a self-reinforcing cycle of increased vascular Aβ, reduced perivascular clearance and further CAA and AD progression. Despite the close relationship between vascular and plaque Aβ deposition, several factors favour one or the other, such as the carboxy-terminal site of the peptide and specific co-deposited proteins. Amyloid-related imaging abnormalities that have been seen in trials of anti-Aβ immunotherapy are another probable intersection between CAA and AD, representing overload of perivascular clearance pathways and the effects of removing Aβ from CAA-positive vessels. The intersections between CAA and AD point to a crucial role for improving vascular function in the treatment of both diseases and indicate the next steps necessary for identifying therapies.
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