Loewenstein, David

Emerging evidence suggests that systemic physiological factors may influence plasma biomarker concentrations of Alzheimer’s disease (AD) and related neurodegenerative processes, potentially affecting their specificity for central nervous system pathology. This study examined the relationship of demographic factors and medical comorbidities with plasma biomarkers of AD and neurodegeneration in a community-dwelling cohort of Black/African American (B/AA) older adults (N = 141). Participants underwent plasma assessment of phosphorylated tau at threonine 217 (p-Tau217), glial fibrillary acidic protein (GFAP), and neurofilament light chain (NfL). Results showed associations between plasma p-Tau217 and amyloid PET positivity, and significant intercorrelations among p-Tau217, GFAP, and NfL. Stepwise regression models incorporated demographics, amyloid PET status, and laboratory measures of renal, metabolic, and lipid function as predictors for each biomarker. p-Tau217 was primarily predicted by amyloid PET and renal function; GFAP by age and sex; and NfL by renal function, age, and sex. Findings indicate plasma biomarker concentrations in B/AA older adults reflect both central AD-related pathology and systemic physiological factors, particularly renal function, and demographic influences. Results underscore the importance of accounting for comorbid medical conditions and demographic characteristics when interpreting blood-based biomarkers and highlight the need for comprehensive medical phenotyping to improve diagnostic specificity and clinical utility.

Background: Plasma NfL (pNfL) levels are elevated in many neurological disorders. However, the utility of pNfL in a clinical setting has not been established. Objective: In a cohort of diverse older participants, we examined: 1) the association of pNfL to age, sex, Hispanic ethnicity, diagnosis, and structural and amyloid imaging biomarkers; and 2) its association to baseline and longitudinal cognitive and functional performance. Methods: 309 subjects were classified at baseline as cognitively normal (CN) or with cognitive impairment. Most subjects had structural MRI and amyloid PET scans. The most frequent etiological diagnosis was Alzheimer’s disease (AD), but other neurological and neuropsychiatric disorders were also represented. We assessed the relationship of pNfL to cognitive and functional status, primary etiology, imaging biomarkers, and to cognitive and functional decline. Results: pNfL increased with age, degree of hippocampal atrophy, and amyloid load, and was higher in females among CN subjects, but was not associated with Hispanic ethnicity. Compared to CN subjects, pNfL was elevated among those with AD or FTLD, but not those with neuropsychiatric or other disorders. Hippocampal atrophy, amyloid positivity and higher pNfL levels each added unique variance in predicting greater functional impairment on the CDR-SB at baseline. Higher baseline pNfL levels also predicted greater cognitive and functional decline after accounting for hippocampal atrophy and memory scores at baseline. Conclusion: pNfL may have a complementary and supportive role to brain imaging and cognitive testing in a memory disorder evaluation, although its diagnostic sensitivity and specificity as a stand-alone measure is modest. In the absence of expensive neuroimaging tests, pNfL could be used for differentiating neurodegenerative disease from neuropsychiatric disorders.

Better tools for assessing cognitive impairment in the early stages of Alzheimer's disease (AD) are required to enable diagnosis of the disease before substantial neurodegeneration has taken place and to allow for detection of subtle changes in the early stages of progression of the disease. The National Institute on Aging and the Alzheimer's Association convened a meeting to discuss state‐of‐the art methods for cognitive assessment, including computerized batteries, as well as new approaches in the pipeline. Speakers described research using novel tests of object recognition, spatial navigation, attentional control, semantic memory, semantic interference, prospective memory, false memory, and executive function as among the tools that could provide earlier identification of individuals with AD. In addition to early detection, there is a need for assessments that reflect real‐world situations so as to better assess functional disability. It is especially important to develop assessment tools that are useful in ethnically, culturally, and linguistically diverse populations as well as in individuals with neurodegenerative disease other than AD.