Type 2 diabetes mellitus is associated with cognitive impairment and greater Alzheimer's disease risk, with cross-sectional studies suggesting that this is driven by neurodegeneration and vascular changes. Longitudinal studies, however, report similar rates of total brain atrophy over time in diabetic and non-diabetic adults. We recently showed that diabetes-related neurodegeneration in cognitively unimpaired adults is regional and may not be evident in longitudinal studies of global brain atrophy. The mechanisms driving diabetes-related neurodegeneration are unknown; glycemic control may play an important role but the relative influence of Alzheimer's and cerebrovascular pathology is unclear. Here, we longitudinally examined regional patterns of cortical thinning associated with diabetes and glycemic control over nearly 3 years. We controlled for Alzheimer's disease neuropathology and white matter hyperintensity burden. We also examined whether subsequent changes in hemoglobin A1c (HbA1c) levels correlated with rates of cortical thinning in diabetes-associated regions and tested whether faster cortical thinning in diabetes-relevant regions mediated a relationship between diabetes and decline in cognitive performance. Among 1,298 cognitively unimpaired participants (mean age=65.0 years, 305 diabetic, 869 female) from the Health and Aging Brain Study-Health Disparities cohort who completed baseline and follow-up MRI scans, we used linear mixed-effects models to examine the relationship between diabetes and cortical thickness changes across 34 brain regions, controlling for socioeconomic factors and comorbidities. We further adjusted for amyloid-PET, tau-PET, white matter hyperintensities, and APOE ε4 carrier status. We also examined associations between baseline and longitudinal HbA1c levels and cortical thinning rates in diabetes-related regions in the whole sample and separately in diabetic and non-diabetic participants. P-values were corrected using the false discovery rate method. Path analysis tested whether diabetes-related cortical thinning mediated the relationship between diabetes and decline in cognitive performance. Diabetic participants exhibited faster cortical thinning in seven frontal, parietal, and occipital regions (-0.060≤βs≤-0.046, corrected Ps<0.017). Associations remained unchanged after accounting for socioeconomic factors, comorbidities, amyloid, tau, white matter hyperintensities, and APOE ε4. Higher baseline HbA1c predicted faster thinning in diabetes-vulnerable regions (corrected Ps<0.032), independent of subsequent HbA1c changes. Diabetes was associated with faster decline in processing speed (β=-0.022, P=0.033), with cortical thinning in diabetes-related regions mediating approximately 13% of this effect (indirect effect β=-0.034, P=0.019). Diabetes-related cortical thinning in cognitively unimpaired older adults follows a regional pattern independent of Alzheimer's and cerebrovascular pathology and partially mediates accelerated decline in processing speed. Chronic hyperglycemia may contribute to diabetes-related neurodegeneration, regardless of subsequent short-term changes in glycemic control.
A. Tsiknia, Victoria R. Tennant, Marylan Davison et al.· Brain : a journal of neurolo...· 1 citation
Importance
Blood-based biomarkers for Alzheimer disease, particularly plasma phosphorylated tau 217 (p-tau217), accurately reflect early Alzheimer disease brain pathology in cognitively unimpaired individuals, but estimates of absolute risk of progression to cognitive impairment across multiple cohorts are needed.
Objective
To estimate absolute risk of progression to cognitive impairment and rates of cognitive decline based on plasma p-tau217 across cognitively unimpaired older adults.
Design, Setting, and Participants
Longitudinal cohort study using harmonized data from 2684 cognitively unimpaired older adults (defined within cohort) across 6 observational and clinical trial cohorts based in North America, Japan, and Australia. The earliest enrollment was in 2004, with most recent follow-up in 2025.
Exposure
Baseline plasma p-tau217.
Main Outcomes and Measures
The primary outcome was time to progression to cognitive impairment (mild cognitive impairment, dementia, or 2 consecutive global Clinical Dementia Rating scores ≥0.5). The secondary outcome was longitudinal change on the latent Preclinical Alzheimer Cognitive Composite (PACC; higher values indicate better performance).
Results
Among the 2684 participants (median [IQR] age, 69.6 [66.2-74.2] years; 1697 [63%] female), there were 478 events of progression to cognitive impairment over a median follow-up of 5.4 years (maximum follow-up of 13.5 years). Each 1-SD increase in baseline p-tau217 level was associated with an increased risk of progression to cognitive impairment (hazard ratio, 1.38 [95% CI, 1.30-1.46]), and the association remained significant after adjustment, including β-amyloid positron emission tomography scan Centiloids (hazard ratio, 1.32 [95% CI, 1.24-1.41]). Participants with high (1.1-2.4 SD) and very high (>2.5 SD) baseline p-tau217 had 24% (95% CI, 20%-28%) and 38% (95% CI, 33%-43%) absolute risk of progression over 5 years, respectively, and risk was markedly higher over 10 years, although longer-term estimates were constrained by limited data. Elevated p-tau217 was also associated with faster cognitive decline based on change in latent PACC score. Among the overall sample, baseline latent PACC scores ranged from -0.8 to 2.7. The 5-year annualized decline for the very high p-tau217 group was -0.07 latent PACC units/y (95% CI, -0.10 to -0.05), relative to 0.03 units/y (95% CI, 0.02-0.04) in the low p-tau217 group.
Conclusions and Relevance
In a pooled sample of multiple selected cohorts of cognitively unimpaired older adults, higher plasma p-tau217 levels were consistently associated with increased risk of clinical progression and accelerated cognitive decline. By providing time-specific absolute risk estimates, these findings support the potential of p-tau217 for prognostic model development, with direct implications for future trial design. Further validation in unselected populations is needed to inform individual prognosis and clinical decision-making in cognitively unimpaired individuals.
R. Buckley, D. Townsend, C. Birkenbihl et al.· Journal of the American Medi...· 1 citation
A double-cutoff analysis suggest that scans in the 11 to 26 Centiloid range should be interpreted with caution depending on the context of use, and positivity cutoffs converged around 18 Centiloids (data-driven) and 27 Centiloids (visual reads).
G. Blazhenets, D. Soleimani-Meigooni, Konstantinos Chiotis et al.· Journal of the American Medi...· 5 citations
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