Luchsinger, Jose Alejandro

Abstract Background Sex, education and race/ethnicity are all associated with risk of Alzheimer's disease dementia. Here, we assess the effects of self‐reported sex, educational attainment and race/ethnicity on amyloid‐positivity, and tau‐PET‐positivity in 12,048 (7,394 cognitively unimpaired [CU], 2,177 MCI, and 2,477 dementia) individuals from 42 cohorts worldwide. Method Logistic generalized estimating equations were used to estimate frequency of amyloid‐positivity (using cohort‐specific thresholds for amyloid‐PET [84%] or CSF) and tau‐PET‐positivity (cohort‐specific thresholds of 2SD above mean temporal uptake in amyloid‐negative controls). We assessed: i) sex and APOEε4 ( N = 10,098) associations, to complement earlier findings of a higher frequency of tau‐positivity in females, ii) effects of lower/higher education ( N = 10,970; cohort‐specific median‐split), and iii) effects of race/ethnicity (non‐Hispanic White [hereafter: White], N = 4880; Asian, N = 116; Black or African‐American [hereafter: Black], N = 353; Hispanic, N = 356, only from Northern‐American cohorts). Outcomes were frequency of amyloid‐positivity in CU individuals only, and tau‐PET‐positivity in both amyloid‐positive (AB+) CU and cognitively impaired (CI, i.e. MCI and dementia) individuals. Interaction effects on the relationship between age and amyloid/tau‐positivity were assessed and only retained in the models when significant. Result Female sex was associated with an APOEε4 ‐independent increased frequency of amyloid‐positivity (β=0.51[0.22], p = 0.02) in CU and increase of tau‐positivity in both AB+CU (β=0.27[0.08]) and AB+CI (β=0.37[0.08], both p <0.01). Remarkably, tau‐positivity frequencies of female APOEε4 non‐carriers were equivalent to male APOEε4 carriers in AB+CI (Figure 1). No significant sex* APOE interactions were observed. In CU, higher education was associated with lower amyloid‐positivity frequency (β=‐0.12[0.05], p = 0.02). In contrast, among AB+CU, there was an age*education interaction effect that indicated more pronounced age effects on tau‐positivity in individuals with higher education (age*education:β interaction =0.03[0.01], p <0.01). There were no education effects in AB+CI (Figure 2). In CU, an age*race/ethnicity interaction effect was observed across all non‐White groups compared to White (Hispanic:β interaction =‐0.05[0.01], p <0.01; Black:‐0.04[0.01], p <0.01; Asian:‐0.02[0.01], p = 0.04). This suggests that the impact of age on amyloid‐positivity was less pronounced in non‐White groups. Furthermore, in AB+CI, Hispanic ethnicity was related to higher tau‐positivity frequency than White (β=0.51[0.22], p = 0.02; Figure 3). Conclusion In this multi‐center initiative comprised of clinical and community‐based cohorts, we observed that self‐reported sex, educational attainment and race/ethnicity were related to positivity‐frequencies of Alzheimer's disease pathology.

AbstractBackgroundInexpensive, non‐invasive tests may improve the identification of persons at increased risk for cognitive decline and dementia. We compared impairment in odor identification and global cognition with neuro‐imaging biomarkers to predict cognitive decline and dementia in the population‐based Mayo Clinic Study of Aging (MCSA).MethodAt the 2008 assessment, 647 participants who were ≥ 55 years old with at least one follow‐up had the following procedures: modified Blessed Information‐Memory‐Concentration Test (BIMCT), 12‐item Brief Smell Identification Test (BSIT), brain magnetic resonance imaging (MRI), and Positron Emission Tomography (PET) amyloid imaging with 11C‐Pittsburgh compound B (11C‐PiB). A subsample (n=556) also had 18F‐fluorodeoxyglucose (18F‐FDG) PET scans. The utility of these baseline measures to predict cognitive decline (cognitively unimpaired to mild cognitive impairment [MCI] or dementia, or MCI to dementia) was examined during follow‐up (mean 8.1 SD 3.4 years). Transition to dementia was a secondary outcome.ResultAmong 647 participants without dementia (mean age 74.0 SD 8.1 years; 54.4% male) at baseline, 102 participants manifested cognitive decline and 34 participants transitioned to dementia. In Cox regression survival analyses for cognitive decline, PiB PET showed the strongest predictive utility (hazard ratio HR 5.05, 95% CI = 3.32‐7.69, p<.001). Impaired BSIT (HR 3.46, 95% CI = 2.34‐5.11, p<.001), impaired BIMCT (HR 3.63, 95% CI 2.46‐5.36, p<.001), MRI and FDG measures were also significant predictors. After adjusting for age, sex and education, these predictors remained significant with attenuated effects (PiB HR 3.89, 95% CI 2.54‐5.95, p<.001; BSIT HR 2.77, 95% CI 1.85‐4.14, p<.001; BIMCT HR 3.3, 95% CI 2.21‐4.95, p<.001). After adding these demographic variables in the model, the combination of BSIT and BIMCT showed strong predictive utility (C‐index=0.85), similar to PiB PET (C‐index=0.84). Combining all predictors showed a C‐index of 0.89. These measures showed similar but stronger results for dementia transition.ConclusionTests of global cognition and odor identification provide a brief, non‐invasive, inexpensive method comparable to PET amyloid imaging for identifying community‐dwelling persons likely to decline cognitively or transition to dementia. Other potential uses for this combination include identification of persons likely to benefit from disease‐modifying medications and determination of eligibility for prevention trials.

AbstractINTRODUCTIONWe evaluated impaired odor identification and global cognition as simple, cost‐effective alternatives to neuroimaging biomarkers to predict cognitive decline and dementia in the Mayo Clinic Study of Aging.METHODSSix hundred forty‐seven participants (mean 8.1, standard deviation 3.4 years’ follow‐up) had the following baseline procedures: modified Blessed Information Memory Concentration Test (BIMCT), 12‐item Brief Smell Identification Test (BSIT), structural brain magnetic resonance imaging (MRI), and positron emission tomography (PET) imaging with 11C‐Pittsburgh compound B (11C‐PiB) and fluorodeoxyglucose (FDG; subset).RESULTSCognitive decline developed in 102 participants and dementia in 34 participants. In survival analyses, PiB PET showed robust prediction for cognitive decline. Impaired BSIT, impaired BIMCT, MRI, and FDG measures were also significant predictors. The combination of demographics + BSIT + BIMCT showed strong predictive utility (C‐index 0.81), similar to demographics + PiB PET (C‐index 0.80). Similar but stronger results were obtained for prediction of dementia.DISCUSSIONImpairment in both odor identification test and global cognition was comparable to PiB PET for predicting cognitive decline and dementia.Highlights In 647 participants in the population‐based Mayo Clinic Study of Aging, several clinical markers and biomarkers each predicted cognitive decline or dementia during an average 8 years of follow‐up. The combination of the demographic variables of age, sex, and education with a brief odor identification test (BSIT) and a global cognitive test (Blessed Information Memory Concentration Test) showed strong predictive utility (C‐index 0.81) for cognitive decline that was similar to the demographic variables combined with Pittsburgh Compound B amyloid imaging (C‐index 0.80). Combining a brief odor identification test with a brief cognitive test needs consideration as a simple, cost‐effective option in the clinical assessment of individuals at risk of cognitive decline and dementia, as well as a potential tool to identify individuals who may benefit from disease‐modifying treatments and to screen participants for prevention trials.

AbstractBackgroundThe 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.MethodParticipants 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 Aβ42/Aβ40, 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.ResultThe 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] 1.10, 95% CI 1.02‐1.19). Increases in GFAP predicted lower memory (‐0.10 ±0.03; p = 0.0001), global cognition (‐0.09 ±0.03; p = 0.009), executive function scores (‐0.12 ±0.03; p<0.0001), and increased risk of MCI/probable dementia (OR 1.24, 95% CI 1.09‐1.41).ConclusionThere was no association between the intervention and changes in biomarker levels. Increasing levels of NfL and GFAP over the ∼10 year period were associated with reduced cognitive performance and increased risk of MCI/probable dementia.