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Abstract Background Alzheimer’s disease involves accumulating amyloid (A) and tau (T) pathology, and progressive neurodegeneration (N), leading to the development of the AD clinical syndrome. While several markers of N have been proposed, efforts to define normal vs. abnormal neurodegeneration based on neuroimaging have been limited. Sensitive markers that may account for or predict cognitive dysfunction for individuals in early disease stages are critical. Methods Participants (n = 296) defined on A and T status and spanning the AD-clinical continuum underwent multi-shell diffusion-weighted magnetic resonance imaging to generate Neurite Orientation Dispersion and Density Imaging (NODDI) metrics, which were tested as markers of N. To better define N, we developed age- and sex-adjusted robust z-score values to quantify normal and AD-associated (abnormal) neurodegeneration in both cortical gray matter and subcortical white matter regions of interest. We used general logistic regression with receiver operating characteristic (ROC) and area under the curve (AUC) analysis to test whether NODDI metrics improved diagnostic accuracy compared to models that only relied on cerebrospinal fluid (CSF) A and T status (alone and in combination). Results Using internal robust norms, we found that NODDI metrics correlate with worsening cognitive status and that NODDI captures early, AD neurodegenerative pathology in the gray matter of cognitively unimpaired, but A/T biomarker-positive, individuals. NODDI metrics utilized together with A and T status improved diagnostic prediction accuracy of AD clinical status, compared with models using CSF A and T status alone. Conclusion Using a robust norms approach, we show that abnormal AD-related neurodegeneration can be detected among cognitively unimpaired individuals. Metrics derived from diffusion-weighted imaging are potential sensitive markers of N and could be considered for trial enrichment and as outcomes in clinical trials. However, given the small sample sizes, the exploratory nature of the work must be acknowledged.

Abstract Background Insulin resistance (IR) and type 2 diabetes have been found to increase the risk for Alzheimer’s clinical syndrome in epidemiologic studies but have not been associated with tau tangles in neuropathological research and have been inconsistently associated with cerebrospinal fluid P-tau181. IR and type 2 diabetes are well-recognized vascular risk factors. Some studies suggest that cardiovascular risk may act synergistically with cortical amyloid to increase tau measured using tau PET. Utilizing data from largely nondemented middle-aged and older adult cohorts enriched for AD risk, we investigated the association of IR and diabetes to tau PET and whether amyloid moderated those relationships. Methods Participants were enrolled in either the Wisconsin Registry for Alzheimer’s Prevention (WRAP) or Wisconsin Alzheimer’s Disease Research Center (WI-ADRC) Clinical Core. Two partially overlapping samples were studied: a sample characterized using HOMA-IR (n=280 WRAP participants) and a sample characterized on diabetic status (n=285 WRAP and n=109 WI-ADRC). IR was measured using the homeostasis model assessment of insulin resistance (HOMA-IR). Tau PET employing the radioligand 18F-MK-6240 was used to detect AD-specific aggregated tau. Linear regression tested the relationship of IR and diabetic status to tau PET standardized uptake value ratio (SUVR) within the entorhinal cortex and whether relationships were moderated by amyloid assessed by amyloid PET distribution volume ratio (DVR) and amyloid PET positivity status. Results Neither HOMA-IR nor diabetic status was significantly associated with tau PET SUVR. The relationship between IR and tau PET SUVR was not moderated by amyloid PET DVR or positivity status. The association between diabetic status and tau PET SUVR was not significantly moderated by amyloid PET DVR but was significantly moderated by amyloid PET positivity status. Among the amyloid PET-positive participants, the estimated marginal tau PET SUVR mean was higher in the diabetic (n=6) relative to the nondiabetic group (n=88). Conclusion Findings indicate that IR may not be related to tau in generally healthy middle-aged and older adults who are in the early stages of the AD clinicopathologic continuum but suggest the need for additional research to investigate whether a synergistic relationship between type 2 diabetes and amyloid is associated with increased tau levels.

BackgroundStory recall (SR) tests have shown variable sensitivity to rate of cognitive decline in individuals with Alzheimer’s disease (AD) biomarkers. Although SR tasks are typically scored by obtaining a sum of items recalled, item-level analyses may provide additional sensitivity to change and AD processes. Here, we examined the difficulty and discrimination indices of each item from the Logical Memory (LM) SR task, and determined if these metrics differed by recall conditions, story version (A vs. B), lexical categories, serial position, and amyloid status.Methodsn = 1,141 participants from the Wisconsin Registry for Alzheimer’s Prevention longitudinal study who had item-level data were included in these analyses, as well as a subset of n = 338 who also had amyloid positron emission tomography (PET) imaging. LM data were categorized into four lexical categories (proper names, verbs, numbers, and “other”), and by serial position (primacy, middle, and recency). We calculated difficulty and discriminability/memorability by item, category, and serial position and ran separate repeated measures ANOVAs for each recall condition, lexical category, and serial position. For the subset with amyloid imaging, we used a two-sample t-test to examine whether amyloid positive (Aβ+) and amyloid negative (Aβ−) groups differed in difficulty or discrimination for the same summary metrics.ResultsIn the larger sample, items were more difficult (less memorable) in the delayed recall condition across both story A and story B. Item discrimination was higher at delayed than immediate recall, and proper names had better discrimination than any of the other lexical categories or serial position groups. In the subsample with amyloid PET imaging, proper names were more difficult for Aβ+ than Aβ−; items in the verb and “other” lexical categories and all serial positions from delayed recall were more discriminate for the Aβ+ group compared to the Aβ− group.ConclusionThis study provides empirical evidence that both LM stories are effective at discriminating ability levels and amyloid status, and that individual items vary in difficulty and discrimination by amyloid status, while total scores do not. These results can be informative for the future development of sensitive tasks or composite scores for early detection of cognitive decline.

The present study investigated: 1) sex differences in polypharmacy, comorbidities, self-rated current health (SRH), and cognitive performance, 2) associations between comorbidities, polypharmacy, SRH, and objective measures of health, and 3) associations of these factors with longitudinal cognitive performance. Analyses included 1039 eligible Wisconsin Registry for Alzheimer’s Prevention (WRAP) participants who were cognitively unimpaired at baseline and had ≥2 visits with cognitive composites, self-reported health history, and concurrent medication records. Repeated measures correlation (rmcorr) examined the associations between medications, co-morbidities, SRH, and objective measures of health (including LIfestyle for BRAin Health Index (LIBRA), and depression). Linear mixed-effect models examined associations between medications, co-morbidities, and cognitive change over time using a preclinical Alzheimer’s cognitive composite (PACC3) and cognitive domain z-scores (executive function, working memory, immediate learning, and delayed recall). In secondary analyses, we also examined whether the number of medications interacted with co-morbidities and whether they modified age-related cognitive trajectories. The number of prescribed medications was associated with worse SRH and a higher number of self-reported co-morbidities. More prescribed medications were associated with a faster decline in executive function, and more comorbidities were associated with faster PACC3 decline. Those with a non-elevated number of co-morbidities and medications performed an average of 0.26 SD higher (better) in executive function and an average of 0.18 SD higher on PACC3 than those elevated on both. Associations between medications, co-morbidities, and executive function, and PACC3 suggest that persons with more co-morbidities and medications may be at increased risk of reaching clinical levels of impairment earlier than healthier, less medicated peers.

While clinically significant cognitive impairment is the key feature of the symptomatic stages of the Alzheimer’s disease (AD) continuum, subtle cognitive decline is now known to occur years before a clinical diagnosis of mild cognitive impairment (MCI) or dementia due to AD is made. The primary aim of this study was to examine criterion validity evidence for an operational definition of “cognitively unimpaired-declining” (CU-D) in the Wisconsin Registry for Alzheimer’s Prevention (WRAP), a longitudinal cohort study following cognition and risk factors from mid-life and on. Cognitive status was determined for each visit using a consensus review process that incorporated internal norms and published norms; a multi-disciplinary panel reviewed cases first to determine whether MCI or dementia was present, and subsequently whether CU-D was present, The CU-D group differed from CU-stable (CU-S) and MCI on concurrent measures of cognition, demonstrating concurrent validity. Participants who changed from CU-S to CU-D at the next study visit demonstrated greater declines than those who stayed CU-S. In addition, those who were CU-D were more likely to progress to MCI or dementia than those who were CU-S (predictive validity). In a subsample with positron emission tomography (PET) imaging, the CU-D group also differed from the CU-S and MCI/Dementia groups on measures of amyloid and tau burden, indicating that biomarker evidence of AD was elevated in those showing sub-clinical (CU-D) decline. Together, the results corroborate other studies showing that cognitive decline begins long before a dementia diagnosis and indicate that operational criteria can detect subclinical decline that may signal AD or other dementia risk.