The association between Alzheimer’s disease blood‐based biomarkers and cognitive impairment and probable dementia in Look AHEAD MIND

Abstract

Background:The effect of an intensive lifestyle intervention (ILI) on Alzheimer's disease (AD) blood-based biomarker levels and cognitive outcomes among individuals with type 2 diabetes (T2D) is unknown. We examined AD biomarkers and cognitive outcomes in the Look AHEAD Study. Method: Participants aged 45-76 years were randomized at baseline to a 10-year ILI or a diabetes support and education (DSE) condition. Cognitive assessments at years 8-18 included measures of attention, executive function, global function, and memory. Mild cognitive impairment (MCI) and probable dementia were adjudicated by an expert panel. Stored baseline and end-of-intervention plasma samples were analyzed with the Quanterix Simoa HD-X Analyzer. Changes in Aβ 42 /Aβ 40, ptau181, neurofilament light chain (NfL), and glial fibrillary acidic protein (GFAP) were evaluated in relation to randomization status, demographic characteristics, and cognitive outcomes. Cognitive scores and biomarker levels were converted to z-scores. Cognitive trajectories were evaluated using mixed models to account for repeated measures; logistic regression was used for a composite outcome of MCI/dementia. Models were adjusted for baseline characteristics (age, sex, education, race/ethnicity, body mass index (BMI), CVD history, hypertension, diabetes duration, eGFR), APOE-ε4, randomization arm, time from randomization, and time between blood draw and cognitive testing. Result:The mean age of 779 participants was 61.4 years; 56% = female, 22.8% = APOE ε4+, mean BMI = 34.8, baseline diabetes duration >5 years = 57%, 16.7% Black, 12.5% Hispanic, 66.2% White, and 4.7% other racial and ethnic groups. There were no associations between the intervention and biomarker levels at baseline or biomarker change over time. Increases in NfL levels significantly predicted lower memory (-0.04 ±0.01; p = 0.002), global cognition scores (-0.05 ±0.02; p = 0.011), executive function (-0.04 ±0.01; p = 0.01), as well as increased risk of MCI/probable dementia (odds ratio [OR]

Biomarkers of Neurodegeneration and Alzheimer’s Disease Neuropathology in Adolescents and Young Adults with Youth-Onset Type 1 or Type 2 Diabetes: A Proof-of-Concept Study

“…NfL also significantly increased between adolescence and young adulthood in the Y-DM group. Again, these results are consistent with other, larger studies in adults with diabetes, where serum and plasma NfL are shown to be significantly higher, compared to nondiabetic reference groups, and increase with greater diabetes duration [45,49]. Despite this consistency, we exercise caution with the interpretation of our NfL results, given that NfL is a non-specific marker of neuron damage and could also indicate involvement from peripheral neuropathy in people with diabetes [50,51].…”

“…Interestingly, in this same study, serum GFAP levels followed a dose-response relationship where GFAP increased from cognitively unimpaired without T2D, to T2D only, to cognitively impaired only, and finally to T2D with cognitive impairment, suggesting that the presence of T2D confers added neuroimmune stress above and beyond that which underlies general cognitive impairment. Among our Y-DM group, the significant increase in plasma GFAP levels over the approximately 12-year follow-up period is also consistent with the Look AHEAD study, where they too observed significantly increased plasma GFAP levels in adults with T2D over an 8-to-13-year follow-up period [45].…”

“…Similar to the increase over time in Aβ40 and Aβ42 observed in our Y-DM group, Hayden et al (2024) also found an increase in these plasma biomarkers after 8 to 13 years of follow-up among middle age adults with T2D in the Look AHEAD trial [45]. However, despite using identical Quanterix platforms for plasma biomarker analysis, our Y-DM group had lower means of Aβ40 and Aβ42 (data not shown), compared to the means reported by Hayden et al in adults with T2D [45]. Hayden et al did not observe the nearly four-fold increase from baseline to follow-up in pTau181 among adults with T2D that we observed in the Y-DM group.…”

“…For example, in a matched case-control study in older adults with adult-onset T2D, Peters et al ( 2017) observed lower plasma Aβ40 and Aβ42 in those with diabetes, compared to controls [44]. Similar to the increase over time in Aβ40 and Aβ42 observed in our Y-DM group, Hayden et al (2024) also found an increase in these plasma biomarkers after 8 to 13 years of follow-up among middle age adults with T2D in the Look AHEAD trial [45]. However, despite using identical Quanterix platforms for plasma biomarker analysis, our Y-DM group had lower means of Aβ40 and Aβ42 (data not shown), compared to the means reported by Hayden et al in adults with T2D [45].…”