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•We applied single dipole source localization and meta-analysis in age-related alpha rhythm research.•The elderly group showed slower alpha rhythms and reduced power compared to younger individuals.•Age effects on alpha rhythms manifested differently across brain regions.•The largest age effect on PAF was observed in occipital regions.•The largest age effect on power at PAF was observed in sensorimotor regions. With increasing age, peak alpha frequency (PAF) is slowed, and alpha power is reduced during resting-states with eyes closed. These age-related changes are evident across the whole scalp but remained unclear at the source level. The purpose of this study was to determine whether age impacts the power and frequency of the dominant alpha rhythm equally across source generators or whether the impact of age varies across sources. A total of 28 young adults and 26 elderly adults were recruited. High-density EEG was recorded for 10 mins with eyes closed. Single dipoles for each independent component were localized and clustered based on their anatomical label, resulting in 36 clusters. Meta-analyses were then conducted to assess effect sizes for PAF and power at PAF for all 36 clusters. Subgroup analyses were then implemented for frontal, sensorimotor, parietal, temporal, and occipital regions. The results of the meta-analyses showed that the elderly group exhibited slower PAF and less power at PAF compared to the young group. Subgroup analyses revealed age effects on PAF in parietal (g = 0.38), temporal (g = 0.65), and occipital regions (g = 1.04), with the largest effects observed in occipital regions. For power at PAF, age effects were observed in sensorimotor (g = 0.84) and parietal regions (g = 0.80), with the sensorimotor region showing the largest effect. Our findings show that age-related slowing and attenuation of the alpha rhythm manifests differentially across cortical regions, with sensorimotor and occipital regions most susceptible to age effects.

INTRODUCTION Magnetic resonance imaging (MRI) biomarkers are needed for indexing early biological stages of Alzheimer's disease (AD), such as plasma amyloid‐β (Aβ42/40) positivity in Aβ positron emission tomography (PET) negative individuals. METHODS Diffusion free‐water (FW) MRI was acquired in individuals with normal cognition (NC) and mild cognitive impairment (MCI) with Aβ plasma‐/PET‐ (NC = 22, MCI = 60), plasma+/PET‐ (NC = 5, MCI = 20), and plasma+/PET+ (AD dementia = 21) biomarker status. Gray and white matter FW and fractional anisotropy (FAt) were compared cross‐sectionally and the relationships between imaging, plasma and PET biomarkers were assessed. RESULTS Plasma+/PET‐ demonstrated increased FW (24 regions) and decreased FAt (66 regions) compared to plasma‐/PET‐. FW (16 regions) and FAt (51 regions) were increased in plasma+/PET+ compared to plasma+/PET‐. Composite brain FW correlated with plasma Aβ42/40 and p‐tau181. DISCUSSION FW imaging changes distinguish plasma Aβ42/40 positive and negative groups, independent of group differences in cognitive status, Aβ PET status, and other plasma biomarkers (i.e., t‐tau, p‐tau181, glial fibrillary acidic protein, neurofilament light). Highlights Plasma Aβ42/40 positivity is associated with brain microstructure decline. Plasma+/PET‐ demonstrated increased FW in 24 total GM and WM regions. Plasma+/PET‐ demonstrated decreased FAt in 66 total GM and WM regions. Whole‐brain FW correlated with plasma Aβ42/40 and p‐tau181 measures. Plasma+/PET‐ demonstrated decreased cortical volume and thickness.

INTRODUCTION Alzheimer's disease studies often lack ethnic diversity. METHODS We evaluated associations between plasma biomarkers commonly studied in Alzheimer's (p‐tau181, GFAP, and NfL), clinical diagnosis (clinically normal, amnestic MCI, amnestic dementia, or non‐amnestic MCI/dementia), and Aβ‐PET in Hispanic and non‐Hispanic older adults. Hispanics were predominantly of Cuban or South American ancestry. RESULTS Three‐hundred seventy nine participants underwent blood draw (71.9 ± 7.8 years old, 60.2% female, 57% Hispanic of which 88% were Cuban or South American) and 240 completed Aβ‐PET. P‐tau181 was higher in amnestic MCI (p = 0.004, d = 0.53) and dementia (p < 0.001, d = 0.97) than in clinically normal participants and discriminated Aβ‐PET[+] and Aβ‐PET[‐] (AUC = 0.86). P‐tau181 outperformed GFAP and NfL. There were no significant interactions with ethnicity. Among amnestic MCI, Hispanics had lower odds of elevated p‐tau181 than non‐Hispanic (OR = 0.41, p = 0.006). DISCUSSION Plasma p‐tau181 informs etiological diagnosis of cognitively impaired Hispanic and non‐Hispanic older adults. Hispanic ethnicity may relate to greater likelihood of non‐Alzheimer's contributions to memory loss. Highlights Alzheimer's biomarkers were measured in Hispanic and non‐Hispanic older adults. Plasma p‐tau181 related to amnestic cognitive decline and brain amyloid burden. AD biomarker associations did not differ between Hispanic and non‐Hispanic ethnicity. Hispanic individuals may be more likely to have non‐Alzheimer causes of memory loss.

Advanced aging is associated with robust changes in neural activity. In addition to the well-established age-related slowing of the peak alpha frequency, there is a growing body of evidence showing that older age is also associated with changes in alpha power and beta power. Despite the important progress that has been made, the interacting effects of age and frequency band have not been directly tested in sensor and source space while controlling for aperiodic components. In the current study we address these limitations. We recruited 54 healthy younger and older adults and measured neural oscillations using a high-density electroencephalogram (EEG) system during resting-state with eyes closed. After preprocessing the EEG data and controlling for aperiodic components, we computed alpha and beta power in both sensor and source space. Permutation two-way ANOVAs between frequency band and age group were performed across all electrodes and across all dipoles. Our findings revealed significant interactions in sensorimotor, parietal, and occipital regions. The pattern driving the interaction varied across regions, with older age associated with a progressive decrease in alpha power and a progressive increase in beta power from parietal to sensorimotor regions. Our findings demonstrate that age-related changes in neural oscillations vary as a function of brain region and frequency band. We interpret our findings in the context of clinical and preclinical evidence of age effects on the cholinergic circuit and the Cortico-Basal Ganglia-Thalamo-Cortical (CBGTC) circuit.

INTRODUCTION Amyloid positron emission tomography (PET) is increasingly available for diagnosis of Alzheimer`s disease (AD); however, its practical implications in heterogenous cohorts are debated. METHODS Amyloid PET from 890 National Alzheimer`s Coordinating Center participants with up to 10 years post‐PET follow up was analyzed. Cox proportional hazards and linear mixed models were used to investigate amyloid burden prediction of etiology and prospective functional status and cognitive decline. RESULTS Amyloid positivity was associated with progression from unimpaired to mild cognitive impairment and dementia. Amyloid burden in the unimpaired group was associated with lower initial memory levels and faster decline in memory, language, and global cognition. In the Impaired group, amyloid was associated with lower initial levels and faster decline for memory, language, executive function, and global cognition. DISCUSSION Amyloid burden is an important prognostic marker in a clinically heterogeneous cohort. Future work is needed to establish the proportion of decline driven by AD versus non‐AD processes in the context of mixed pathology. Highlights Our findings highlight the importance of amyloid positron emission tomography (PET) in heterogenous cohorts, including diverse demographics, clinical syndromes, and underlying etiologies. The results also provide evidence that higher amyloid levels were linked to functional progression from unimpaired cognition to mild cognitive impairment (MCI) and from MCI to dementia. In cognitively unimpaired individuals, higher amyloid burden was associated with poorer memory at baseline and subsequent declines in memory, language, and global cognition. Among individuals with cognitive impairment, amyloid burden was associated with worse initial memory, language, executive function, and global cognition, and faster declines over time.

Our current understanding of response inhibition comes from go/no-go studies that draw conclusions based on the overt movement of single limbs (i.e., a single finger pushing a button). In general, go/no-go paradigms have found that an individual’s ability to correctly inhibit the motor system is indicative of a healthy central nervous system. However, measuring inhibition by an overt behavioral response may lack the sensitivity to conclude whether the motor system is completely inhibited. Therefore, our goal was to use behavioral and neurophysiological measures to investigate inhibition of the motor system during a full-body reaching task. When directly comparing neurophysiological and behavioral measures, we found that neurophysiological measures were associated with a greater number of errors during no-go trials and faster onset times during go trials. Further analyses revealed a negative correlation between errors and onset times, such that the muscles that activated the earliest during go trials also had the greatest number of errors during no-go trials. Together, our observations show that the absence of an overt behavioral response does not always translate to total inhibition of the motor system.

INTRODUCTION Early‐onset Alzheimer's disease (EOAD) may have distinct biomarker and clinical features from late‐onset AD (LOAD). EOAD is understudied in ethnically heterogeneous populations. METHODS We studied EOAD (N = 44, age 64.7 ± 5.5, 55% female, 52% Hispanic/Latino), LOAD (N = 113), early‐onset non‐AD (EOnonAD, N = 114), and clinically normal (CN, N = 93) individuals from the 1Florida Alzheimer's Disease Research Center. Group differences and demographic interactions were evaluated in plasma (phosphorylated tau217, glial fibrillary acidic protein, neurofilament light chain), neuroimaging (amyloid positron emission tomography, brain magnetic resonance imaging), and global function (Mini‐Mental State Examination, Clinical Dementia Rating Sum of Boxes). RESULTS AD‐related biomarkers and global function were consistently worse in EOAD than EOnonAD and CN, and similar or worse than LOAD. Among EOAD, younger age related to greater amyloid burden among non‐Hispanic/Latino individuals only. AD‐related biomarker changes were more severe in females than males among non‐Hispanic/Latino EOAD, but more severe among males in Hispanic/Latino EOAD. DISCUSSION The biological and clinical features of EOAD may differ by sex and ethnicity. Highlights Alzheimer's disease (AD) biomarkers and global functional measures were measured in Hispanic and non‐Hispanic individuals with early‐onset AD (EOAD). Overall, AD‐related biomarkers and global function were consistently worse in EOAD than non‐AD cognitive decline and controls, and similar or worse than late‐onset AD. Younger age related to greater amyloid burden among non‐Hispanic EOAD, but not Hispanic EOAD. Hispanic EOAD males had more severe changes than females, contrasting findings in non‐Hispanic EOAD (females more severe than males).

INTRODUCTION Glial fibrillary acidic protein (GFAP) may contribute to Alzheimer's pathology at early disease stages. GFAP moderation of Alzheimer's disease (AD)‐related neurodegeneration and cognition is unclear. METHODS We examined plasma GFAP moderation of AD biomarkers (amyloid beta [Aβ]‐positron emission tomography [PET][A]; plasma phosphorylated tau‐181 [p‐tau181][T1]), neurodegeneration (plasma NfL[Nplasma]; structural magnetic resonance imaging [MRI][NMRI]), and cognition (Cogmemory; Cogexecutive) in two cohorts: University of California San Francisco (UCSF) (N = 212, 91.0% non‐Hispanic/Latino White [NHLW], age = 74.7 [7.6] years, 75.9% cognitively unimpaired [CU]) and 1Florida Alzheimer's Disease Research Centers (1FLADRC; N = 582, 32.8% NHLW, age = 70.7 [8.5] years, 28.9% CU). RESULTS Plasma GFAP consistently moderated A–T1 (UCSF: β = 0.46, p = 0.012; 1FLADRC: β = 0.12, p = 0.029). The association between elevated Aβ‐PET and increased (p‐tau) was strengthened at higher GFAP concentrations. In 1FLADRC, GFAP moderated T1–Nplasma/MRI. In UCSF, GFAP moderated T1–Cogmemory/executive and NMRI–Cogmemory/executive. Higher GFAP consistently related to worse neurodegeneration and cognition (main effects). DISCUSSION Across demographically and clinically heterogeneous cohorts, plasma GFAP is a key moderator of AD and may help identify individuals at greatest risk of AD‐related neurodegeneration and cognitive decline. Highlights AD biomarkers were measured in two demographically and clinically distinct cohorts. Plasma GFAP moderated Aβ‐PET to p‐tau associations in both UCSF and 1FLADRC. Cohort‐dependent, GFAP moderated p‐tau to neurodegeneration and cognition associations. All moderations revealed strengthened disease associations with higher plasma GFAP. Plasma GFAP may help identify individuals at greatest risk of AD‐related decline.

INTRODUCTION Commercially available plasma p‐tau217 biomarker tests are not well studied in ethnically diverse samples. METHODS We evaluated associations between ALZPath plasma p‐tau217 and amyloid‐beta positron emission tomography (Aβ‐PET) in Hispanic/Latino (88% of Cuban or South American ancestry) and non‐Hispanic/Latino older adults. One‐ and two‐cutoff ranges were derived and evaluated to assess agreement with Aβ‐PET. RESULTS A total of 239 participants underwent blood draw and Aβ‐PET (age 70.8 ± 7.8, 55.2% female, education 15.6 ± 3.4 years, 48.9% Hispanic/Latino, 94.9% white). Plasma p‐tau217 showed excellent discrimination of Aβ‐PET positive and negative participants (visual read: AUC = 0.91 [0.87–0.95], p < 0.001; Centiloids quantification: AUC = 0.90 [0.86–0.94]). There was a greater percent agreement between low p‐tau217 and negative Aβ‐PET (95.8%) than high p‐tau217 and positive Aβ‐PET (86.3%). Analyses within ethnicity‐specific subgroups suggested similar p‐tau217 performance. DISCUSSION Plasma p‐tau217 (ALZPath) relates to brain Aβ in Hispanic/Latino and non‐Hispanic/Latino older adults. Independent validation and replication are necessary to establish reference ranges and inform appropriate contexts of use across ethno‐racially diverse populations. HIGHLIGHTS Plasma p‐tau217 (ALZPath) and Aβ‐PET were measured in Hispanic/Latino and non‐Hispanic/Latino older adults. Plasma p‐tau217 accurately discriminated Aβ‐PET positive and negative participants. Applying a two‐cutoff “intermediate” plasma p‐tau217 approach could reduce need for more invasive and costly testing. Plasma p‐tau217 associations with Aβ‐PET were strong within both Hispanic/Latino and non‐Hispanic/Latino groups.

INTRODUCTION Factors underlying discordant visual and quantitative amyloid beta–positron emission tomography (Aβ‐PET) results and their clinical implications are not well understood. METHODS Participants from the 1Florida Alzheimer's Disease Research Center (1FLADRC) underwent Aβ‐PET, blood draw, brain magnetic resonance imaging (MRI), and neuropsychological testing. We evaluated differences in demographics, apolipoprotein E (APOE) status, biomarkers, and cognition among older adults with concordant and discordant visual‐quantitative Aβ‐PET. Discordance was defined as positive visual read (V) of Aβ‐PET with below‐threshold Centiloid quantification (Q; CL <25; V+/Q–) or negative visual read with CL ≥25 (V–/Q+). RESULTS We studied 386 participants (mean age ± SD: 70.7 ± 7.8, 55.2% female, 44.6% Hispanic White). Compared to V+/Q–, V–/Q+ had a higher frequency of APOE ε4 carriers (40%). Black/African American participants were overrepresented in V–/Q+ (40.9%). Both discordant groups had higher plasma phosphorylated tau 217 (p‐tau217) and glial fibrillary acidic protein (GFAP) than V–/Q– but lower than V+/Q+. Discordant groups had greater gray matter volume and better cognitive performance than V+/Q+. DISCUSSION Discordant Aβ‐PET findings likely hold clinical significance and may reflect early stages of neuropathological progression. Highlights Groups with concordant/discordant visual‐quantitative amyloid beta–positron emission tomography (Aβ‐PET) results were compared. Visual–/quant+ were more likely than visual+/quant– to be apolipoprotein E (APOE) ε4 carriers and Black/African American. Discordant groups had higher plasma phosphorylated tau 217 (p‐tau217) and glial fibrillary acidic protein (GFAP) than concordant negative. Discordant groups had less atrophy and better cognition than concordant positive. Centiloid quantification should supplement visual reads in clinical settings.