Aimee L. Pierce

Nicotinamide is a coenzyme involved in cellular oxidation-reduction reactions that can inhibit Class III histone deacetylases (HDACs) or sirtuins. HDAC inhibition can affect numerous therapeutic pathways, including tau phosphorylation. We tested the hypothesis that nicotinamide treatment could reduce tau phosphorylation in early Alzheimer disease (AD). We performed a randomized, placebo-controlled, phase 2a proof-of-concept trial to evaluate the safety and tolerability of 48 weeks of treatment with 1,500 mg of nicotinamide twice a day. The primary outcome was level of tau phosphorylated at threonine 231 (p-tau₂₃₁) in CSF. Prespecified secondary outcomes were levels of p-tau₁₈₁, total tau, amyloid β40 (Aβ₄₀), and Aβ₄₂ in CSF and the clinical measures Alzheimer's Disease Assessment Scale (ADAS-cog13), Alzheimer's Disease Cooperative Study-Activities of Daily Living Scale-Mild Cognitive Impairment (ADCS-ADL-MCI), and Clinical Dementia Rating Summary of Boxes (CDR-SB). Participants were recruited at 2 academic clinical centers. Enrollment criteria included diagnosis of mild cognitive impairment or mild dementia with CSF biomarker confirmation of AD. The Holm-Bonferroni procedure was used to control type I error within biomarker and clinical domains. Of 47 participants enrolled (mean age = 73.8 years; 43% female), 1 dropped out before treatment initiation and 6 before completion, including 2 in the nicotinamide and 4 in the placebo arm. Adverse events (AEs) were balanced by arm, with few attributed to treatment. Common AEs included infections and nervous system disorders. There was no statistically significant benefit of nicotinamide on the primary outcome of week 48 change from baseline in CSF p-tau₂₃₁ (analysis of covariance; estimated mean difference in change between arms = -2.06, SE = 4.03; p = 0.61), with observed mean decline in CSF p-tau₂₃₁ greater in the nicotinamide arm (-4.7 ± 14.5) than in the placebo arm (-2.3 ± 10.6). No significant effects of treatment were observed on secondary biomarker outcomes (CSF p-tau₁₈₁, Aβ₄₀, Aβ₄₂, and total tau) in similar models (all p values >0.05), with observed mean changes in CSF p-tau₁₈₁ (0.4 ± 29.8 vs 10.4 ± 41.8) and total tau (8.4 ± 228.6 vs 60.5 ± 237.5) favoring nicotinamide compared with placebo. At week 48, nicotinamide-treated participants experienced less decline on CDR-SB (mixed-effect model with repeated measures; estimate = -1.42, SE = 0.65; p = 0.03 unadjusted for multiple comparisons), without significant differences in cognitive (ADAS-cog; estimate = -1.93, SE = 1.93; p = 0.32) or functional (ADCS-ADL-MCI; estimate = -3.10, SE = 1.86; p = 0.10) outcomes. Nicotinamide was safe but did not alter AD biomarkers. This study provides Class I evidence that in patients with MCI or mild dementia with positive CSF AD biomarkers, 48 weeks of nicotinamide, 3,000 mg daily, is no better than placebo in reducing CSF p-tau₂₃₁. ClinicalTrials.gov: NCT03061474.

Objectives The vast majority of studies on aging, cognition, and dementia focus on non-Hispanic white subjects. This paper adds to the extant literature by providing insight into the African American aging experience. Here we describe the study design and baseline characteristics of the African American Dementia and Aging Project (AADAPt) study, which is exploring aging and cognition in African American older adults in Oregon. Methods African American older adults (n=177) participated in AADAPt, a longitudinal study that collected data on cognitive, physical, and social functioning in annual visits since 2000. Results AADAPt participants had risk factors for developing dementia in future, such as hypertension and hyperlipidemia, but also reported protective factors such as high social engagement. Conclusions The AADAPt project offers new insights into aging in older African Americans that includes data on cognition, social engagement, and physical health, which are crucial for understanding the experience of under-represented groups and making future studies more inclusive. Clinical Implications These findings reflect a window of time for a geographically-focused cohort, and the lessons learned from this study likely have broader implications for shaping the health of these older African American adults.

Background: List learning and memory tests are frequently used to evaluate older adults for late life cognitive disorders, such as Alzheimer’s disease. The Word List subtest of the Consortium to Establish a Registry for Alzheimer’s Disease (CERAD) neuropsychological battery has been widely‐used in clinical research, including clinical trials, to identify and track such disorders. It is also freely‐available, as it is in the public domain. However, normative data, especially in robustly intact older adults, is lacking.Method: CERAD Word List data from 897 older adults (age in years: M = 81.1, SD = 8.1, range 55‐100; 67% women; education in years: M = 14.8, SD = 2.8, range = 7‐24) deemed to be cognitively intact at two annual visits in a longitudinal observational study from the Uniform Data Set of the National Alzheimer’s Coordinating Center were used to generate predicted Word List scores based on age, sex, and education. Predicted scores were compared to observed scores to preliminarily validate these normative values.Result: For six primary scores from the Word List subtest (Trial 1, Trial 2, Trial 3, Total Acquisition, Delay Recall, Recognition Total Correct), the three demographic variables significantly predicted test scores, with R²s ranging from 0.03 – 0.18 (p‐values0.40), indicating preliminary support for these prediction scores.Conclusion: Although further validation is needed in independent intact and impaired samples, the current demographically‐based prediction scores provide normative data for the CERAD Word List subtest for older adults being evaluated for cognitive complaints. The inclusion of additional variables needs to be examined to improve the accuracy of these prediction scores. Nonetheless, normative data allows providers and researchers to be confident in using this learning and memory test in clinics and clinical trials.

Purpose of review Alzheimer’s disease (AD) and frontotemporal dementia can often be diagnosed accurately with careful clinical history, cognitive testing, neurological examination, and structural brain MRI. However, there are certain circumstances wherein detection of specific biomarkers of neurodegeneration or underlying AD pathology will impact the clinical diagnosis or treatment plan. We will review the currently available biomarkers for AD and frontotemporal dementia (FTD) and discuss their clinical importance. Recent findings With the advent of ¹⁸F-labeled tracers that bind amyloid plaques, amyloid PET is now clinically available for the detection of amyloid pathology and to aid in a biomarker-supported diagnosis of AD or mild cognitive impairment (MCI) due to AD. It is not yet possible to test for the specific FTD pathologies (tau or TDP-43); however, a diagnosis of FTD may be “imaging supported” based upon specific MRI or FDG-PET findings. Cerebrospinal fluid measures of amyloid-beta, total-tau, and phospho-tau are clinically available and allow detection of both of the cardinal pathologies of AD: amyloid and tau pathology. Summary It is appropriate to pursue biomarker testing in cases of MCI and dementia when there remains diagnostic uncertainty and the result will impact diagnosis or treatment. Practically speaking, due to the rising prevalence of amyloid positivity with advancing age, measurement of biomarkers in cases of MCI and dementia is most helpful in early-onset patients, patients with atypical clinical presentations, or when considering referral for AD clinical trials.

In a Perspective, Aimee Pierce and Claudia Kawas discuss risk factors and pathologies of dementia in the oldest-old.