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Blood levels of neurofilament light chain (NfL) increase with age in healthy humans and have been shown to predict all-cause human mortality. To determine whether this relationship is conserved across species, we analyzed NfL in the blood of various animals. We observed age-related increases in NfL levels comparable to those seen in humans in mice, cats, dogs and horses. Longitudinal analysis of NfL trajectories in aged mice demonstrated that a faster rate of NfL increase predicts mortality. When comparing baseline NfL levels across 13 species, we found that those with lower baseline NfL levels tended to have longer lifespans; however, the collinearity between body size and life span complicates the interpretation of this finding. NfL was also robustly detected in blood of 39 additional mammalian species, as well as a few reptiles and birds, consistent with a conserved amino acid sequence of the NfL fragment in blood. Given the growing interest in NfL as a biomarker for neurological health and mortality in humans, our findings suggest that NfL may serve as a cross-species blood biomarker for assessing aging interventions and predicting mortality.

Brain Aβ deposition is a key early event in the pathogenesis of Alzheimer´s disease (AD), but the long presymptomatic phase and poor correlation between Aβ deposition and clinical symptoms remain puzzling. To elucidate the dependency of downstream pathologies on Aβ, we analyzed the trajectories of cerebral Aβ accumulation, Aβ seeding activity, and neurofilament light chain (NfL) in the CSF (a biomarker of neurodegeneration) in Aβ-precursor protein transgenic mice. We find that Aβ deposition increases linearly until it reaches an apparent plateau at a late age, while Aβ seeding activity increases more rapidly and reaches a plateau earlier, coinciding with the onset of a robust increase of CSF NfL. Short-term inhibition of Aβ generation in amyloid-laden mice reduced Aβ deposition and associated glial changes, but failed to reduce Aβ seeding activity, and CSF NfL continued to increase although at a slower pace. When short-term or long-term inhibition of Aβ generation was started at pre-amyloid stages, CSF NfL did not increase despite some Aβ deposition, microglial activation, and robust brain Aβ seeding activity. A dissociation of Aβ load and CSF NfL trajectories was also found in familial AD, consistent with the view that Aβ aggregation is not kinetically coupled to neurotoxicity. Rather, neurodegeneration starts when Aβ seeding activity is saturated and before Aβ deposition reaches critical (half-maximal) levels, a phenomenon reminiscent of the two pathogenic phases in prion disease. The poor correlation between brain Aβ deposition and clinical symptoms in Alzheimer´s disease remains puzzling. Here, the authors show a temporal dissociation of Aβ deposition and neurodegeneration.

Personality traits such as Neuroticism and Conscientiousness are associated with Alzheimer disease (AD) pathophysiology in cognitively normal (CN) and impaired individuals, and may represent potential risk or resilience factors, respectively. This study examined the cross-sectional relationship between personality traits and regional tau deposition using positron emission tomography (PET) in cognitively normal older adults. A cohort of CN (Clinical Dementia Rating (CDR) 0, n = 128) older adults completed the NEO Five-Factor Inventory to assess traits of Neuroticism, Extroversion, Openness, Agreeableness, and Conscientiousness and underwent tau-PET and β-amyloid (Aβ)-PET imaging. We utilized linear regression models, adjusting for age, sex, geriatric depression score, and Aβ to evaluate the association between each of the personality traits and regional tau-PET accumulation. Elevated Neuroticism scores were associated with higher tau-PET accumulation in the amygdala (p = .002), entorhinal cortex (p = .012), and inferior temporal cortex (p = .016), as well as with a composite tau-PET measure (p = .002). In contrast, Extroversion, Openness, Agreeableness, and Conscientiousness were not associated with tau deposition in any of these regions (p’s > 0.160). Our results indicate that increased Neuroticism is associated with higher tau pathophysiology in regions known to be vulnerable to AD pathophysiology in CN participants. High Neuroticism scores may therefore serve as a potential risk factor for tau accumulation. Alternatively, personality can change with the onset of AD, thus increased tau levels may affect Neuroticism scores. While future longitudinal studies are needed to determine directionality, our findings suggest early associations between Neuroticism and tau accumulation in CN adults.

Introduction Subjective cognitive decline (SCD) has been associated with elevated amyloid levels and increased risk of future cognitive decline, as well as modifiable variables, including depression, anxiety, and physical inactivity. Participants generally endorse greater and earlier concerns than their close family and friends (study partners [SPs]), which may reflect subtle changes at the earliest stages of disease among participants with underlying neurodegenerative processes. However, many individuals with subjective concerns are not at risk of Alzheimer's disease (AD) pathology, suggesting that additional factors, such as lifestyle habits, may be contributory. Methods We examined the relation between SCD, amyloid status, lifestyle habits (exercise, sleep), mood/anxiety, and demographic variables among 4481 cognitively unimpaired older adults who are being screened for a multi‐site secondary prevention trial (A4 screen data; mean ±SD: age = 71.3 ±4.7, education = 16.6 ±2.8, 59% women, 96% non‐Hispanic or Latino, 92% White]. Results On the Cognitive Function Index (CFI) participants endorsed higher concerns compared to SPs. Participant concerns were associated with older age, positive amyloid status, worse mood/anxiety, lower education, and lower exercise, whereas SP concerns were associated with older participant age, male gender of participant, positive amyloid status of participant, and worse participant‐reported mood/anxiety. Discussion Findings suggest that modifiable/lifestyle factors (e.g., exercise, education) may be associated with participant concerns among cognitively unimpaired individuals and highlight the importance of further examining how modifiable factors impact participant‐ and SP‐reported concerns, which may inform trial recruitment and clinical interventions.

Alzheimer's disease (AD) is characterized by the presence of amyloid β (Aβ) plaques, neurofibrillary tangles, and neurodegeneration, evidence of which may be detected in vivo via cerebrospinal fluid (CSF) sampling. Physical activity (PA) has emerged as a possible modifier of these AD-related pathological changes. Consequently, the aim of this study was to cross-sectionally examine the relationship between objectively measured PA and CSF levels of Aβ42 and tau in asymptomatic late-middle-aged adults at risk for AD. Eighty-five cognitively healthy late-middle-aged adults (age = 64.31 years, 61.2% female) from the Wisconsin Registry for Alzheimer's Prevention participated in this study. They wore an accelerometer (ActiGraph GT3X+) for one week to record free-living PA, yielding measures of sedentariness and various intensities of PA (i.e., light, moderate, and vigorous). They also underwent lumbar puncture to collect CSF, from which Aβ42, total tau, and phosphorylated tau were immunoassayed. Regression analyses were used to examine the association between accelerometer measures and CSF biomarkers, adjusting for age, sex, and other relevant covariates. Engagement in moderate PA was associated with higher Aβ42 (P = .008), lower total tau/Aβ42 (P = .006), and lower phosphorylated tau/Aβ42 (P = .030). In contrast, neither light nor vigorous PA was associated with any of the biomarkers. Increased sedentariness was associated with reduced Aβ42 (P = .014). In this cohort, moderate PA, but not light or vigorous, was associated with a favorable AD biomarker profile, while sedentariness was associated with greater Aβ burden. These findings suggest that a physically active lifestyle may play a protective role against the development of AD.

Neurofilament light chain (NfL) is a neuronal cytoskeletal protein that has been identified as a marker of neurodegeneration in diseases of the central nervous system. In this study, we investigated whether NfL in the aqueous humor (AH) can serve as a marker of neurodegeneration in glaucoma in a racially diverse North American population. Single-center, case-control study. We enrolled patients with various types and stages of glaucoma undergoing planned ophthalmic surgery as part of their routine care and compared them with patients without glaucoma undergoing phacoemulsification for age-related cataract. We collected AH from 39 glaucoma patients and 10 patients without glaucoma. AH NfL was quantified using the Single-Molecule Array (Simoa) NF-light assay (Quanterix). Demographic information, such as age, body mass index, sex, and self-reported race, as well as clinical information, such as pre-operative intraocular pressure (IOP), maximum IOP, and number of pre-operative glaucoma medications, was obtained by reviewing the medical record. Levels of AH NfL. In a model controlling for age and body mass index (BMI), NfL was significantly elevated in AH from glaucoma patients (mean: 429 pg/mL; standard deviation [SD]: 1136 pg/mL) compared to AH from patients without glaucoma (mean: 3.1 pg/mL; SD: 1.9 pg/mg): P = 0.002. Higher AH NfL was associated with higher maximum IOP (R = 0.44, P = 0.005), higher pre-operative IOP (R = 0.46, P = 0.003), and more pre-operative glaucoma medications (R = 0.61, P < 0.001). There was no association between AH NfL and Humphrey visual field mean deviation (R = -0.20, P = 0.220), retinal nerve fiber layer thickness as measured with optical coherence tomography (R = 0.07, P = 0.694), or glaucoma stage (R = 0.015, P = 0.935). Our findings suggest that AH NfL may have clinical utility as a marker of glaucomatous neurodegeneration.

Neurofilament light chain (NfL) is a promising fluid biomarker of disease progression for various cerebral proteopathies. Here we leverage the unique characteristics of the Dominantly Inherited Alzheimer Network and ultrasensitive immunoassay technology to demonstrate that NfL levels in the cerebrospinal fluid ( n  = 187) and serum ( n  = 405) are correlated with one another and are elevated at the presymptomatic stages of familial Alzheimer’s disease. Longitudinal, within-person analysis of serum NfL dynamics ( n  = 196) confirmed this elevation and further revealed that the rate of change of serum NfL could discriminate mutation carriers from non-mutation carriers almost a decade earlier than cross-sectional absolute NfL levels (that is, 16.2 versus 6.8 years before the estimated symptom onset). Serum NfL rate of change peaked in participants converting from the presymptomatic to the symptomatic stage and was associated with cortical thinning assessed by magnetic resonance imaging, but less so with amyloid-β deposition or glucose metabolism (assessed by positron emission tomography). Serum NfL was predictive for both the rate of cortical thinning and cognitive changes assessed by the Mini–Mental State Examination and Logical Memory test. Thus, NfL dynamics in serum predict disease progression and brain neurodegeneration at the early presymptomatic stages of familial Alzheimer’s disease, which supports its potential utility as a clinically useful biomarker. In a longitudinal cohort of familial Alzheimer’s disease patients, the rate of change of blood biomarker levels identifies disease carriers much earlier than absolute levels and predicts both neurodegeneration and cognitive decline.

Background Rare cases of autosomal dominant Alzheimer's disease (ADAD) can provide unique insights into Alzheimer's disease (AD) pathobiology. Pathogenic variants in PSEN1 or PSEN2 are the most common causes of ADAD. PSEN1 or PSEN2 can form the catalytic core of the γ‐secretase complex, which, in turn, directly mediates the production of longer, aggregation‐prone Aβ peptides relative to shorter, non‐aggregating peptides. Given the great deal of heterogeneity seen in ADAD ‐ with ages of symptom onset (AAO) ranging from the 20s to 70s – we examined whether variant‐level variations in γ‐secretase function and Aβ production can explain variant‐level differences in ADAD progression. Method Expression of mutant or wild‐type PSEN1/2 in cell culture and measurement of Aβ production, coupled with literature‐derived AAO and in vivo clinical, cognitive, and biomarker data from the Dominantly Inherited Alzheimer's Network Observational Study (DIAN). Result Aβ peptide production from 161 known pathogenic mutations in PSEN1 and 70 variants in PSEN2 were assessed in vitro. Aβ production (particularly the Aβ42/40 and Aβ37/42 ratios) by individual PSEN1 variants was strongly correlated with AAO, with more abnormal γ‐secretase function associated with earlier AAO. Aβ production among PSEN2 variants with known homologs in PSEN1 showed strong associations with AAO, whereas Aβ production in PSEN2 variants without known PSEN1 homologs was similar to wild‐type for many (but not all) variants. In a subset of 55 PSEN1 variants with available data from DIAN, variant‐level Aβ production profiles correlated with all clinical (CDR), cognitive (Logical Memory; MMSE), and biomarker (Amyloid PET, structural MRI, CSF ptau) measures examined, as well as with observed longitudinal rates of biomarker and clinical progression of ADAD. Further, accounting for variant‐level Aβ production measured in vitro improved prediction of in vivo clinical, cognitive, and biomarker trajectories beyond history derived estimates of AAO. Conclusion These data and the associated literature strongly suggest that the course of ADAD is fundamentally shaped by variant‐level effects on γ‐secretase function and Aβ production. In addition to providing a unique line of support for the “amyloid hypothesis” of AD, these results provide compelling support for γ‐secretase modulation (GSM) as a promising approach to treat AD.

Rare cases of autosomal dominant Alzheimer's disease (ADAD) can provide unique insights into Alzheimer's disease (AD) pathobiology. Pathogenic variants in PSEN1 or PSEN2 are the most common causes of ADAD. PSEN1 or PSEN2 can form the catalytic core of the γ-secretase complex, which, in turn, directly mediates the production of longer, aggregation-prone Aβ peptides relative to shorter, non-aggregating peptides. Given the great deal of heterogeneity seen in ADAD - with ages of symptom onset (AAO) ranging from the 20s to 70s - we examined whether variant-level variations in γ-secretase function and Aβ production can explain variant-level differences in ADAD progression. Expression of mutant or wild-type PSEN1/2 in cell culture and measurement of Aβ production, coupled with literature-derived AAO and in vivo clinical, cognitive, and biomarker data from the Dominantly Inherited Alzheimer's Network Observational Study (DIAN). Aβ peptide production from 161 known pathogenic mutations in PSEN1 and 70 variants in PSEN2 were assessed in vitro. Aβ production (particularly the Aβ42/40 and Aβ37/42 ratios) by individual PSEN1 variants was strongly correlated with AAO, with more abnormal γ-secretase function associated with earlier AAO. Aβ production among PSEN2 variants with known homologs in PSEN1 showed strong associations with AAO, whereas Aβ production in PSEN2 variants without known PSEN1 homologs was similar to wild-type for many (but not all) variants. In a subset of 55 PSEN1 variants with available data from DIAN, variant-level Aβ production profiles correlated with all clinical (CDR), cognitive (Logical Memory; MMSE), and biomarker (Amyloid PET, structural MRI, CSF ptau) measures examined, as well as with observed longitudinal rates of biomarker and clinical progression of ADAD. Further, accounting for variant-level Aβ production measured in vitro improved prediction of in vivo clinical, cognitive, and biomarker trajectories beyond history derived estimates of AAO. These data and the associated literature strongly suggest that the course of ADAD is fundamentally shaped by variant-level effects on γ-secretase function and Aβ production. In addition to providing a unique line of support for the \"amyloid hypothesis\" of AD, these results provide compelling support for γ-secretase modulation (GSM) as a promising approach to treat AD.

INTRODUCTION Though recognized as a potential cause of autosomal dominant Alzheimer's disease, the pathogenicity of many PSEN2 variants remains uncertain. We compared amyloid beta (Aβ) production across all missense PSEN2 variants in the AlzForum database and, when possible, to corresponding PSEN1 variants. METHODS We expressed 74 PSEN2 variants, 21 of which had known, homologous PSEN1 pathogenic variants with the same amino acid substitution, in HEK293 cells lacking presenilin 1/2. Aβ production was compared to age at symptom onset (AAO) and between PSEN1/2 homologs. RESULTS Aβ42/40 and Aβ37/42 ratios correlated with AAO across all PSEN2 variants, strongly driven by the subset of PSEN2 variants with PSEN1 homologs. Aβ production across PSEN1/2 homologs was highly correlated. PSEN2 AAO correlated with AAO in PSEN1 homologs but was an average of 18.3 years later. DISCUSSION The existence of a PSEN1 homolog and patterns of Aβ production are important considerations in assessing the pathogenicity of previously reported and new PSEN2 variants. Highlights There were associations between the patterns of amyloid beta (Aβ) production across presenilin 2 (PSEN2) variants and age at symptom onset (AAO). PSEN2 variants for which there is a known, corresponding variant in presenilin 1 (PSEN1) are more likely to have abnormal Aβ production patterns that strongly correlate with AAO, compared to those that lack a known PSEN1 counterpart (“non‐homologous PSEN2 variants”). Most PSEN2 variants lacking PSEN1 counterparts had Aβ42/40 ratios close to those of wild‐type PSN2, arguing against their pathogenicity. Homologous PSEN1 and PSEN2 variants had correlated Aβ42/40 and Aβ37/42 ratios, indicating that the corresponding amino acid substitution in each presenilin may have largely similar biochemical effects on γ‐secretase processivity.