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Neurofilament light chain (NfL) is a promising biomarker of active axonal injury and neuronal degeneration. We aimed to characterise cross-sectional and longitudinal plasma NfL measurements and determine the age at which NfL concentrations begin to differentiate between carriers of the presenilin 1 (PSEN1) E280A (Glu280Ala) mutation and age-matched non-carriers from the Colombian autosomal dominant Alzheimer's disease kindred. In this cross-sectional and longitudinal cohort study, members of the familial Alzheimer's disease Colombian kindred aged 8–75 years with no other neurological or health conditions were recruited from the Alzheimer's Prevention Initiative Registry at the University of Antioquia (Medellín, Colombia) between Aug 1, 1995, and Dec 15, 2018. We used a single molecule array immunoassay and log-transformed data to examine the relationship between plasma NfL concentrations and age, and establish the earliest age at which NfL concentrations begin to diverge between mutation carriers and non-carriers. We enrolled a cohort of 1070 PSEN1 E280A mutation carriers and 1074 non-carriers with baseline assessments; of these participants, longitudinal measures (with a mean follow-up of 6 years) were available for 242 mutation carriers and 262 non-carriers. Plasma NfL measurements increased with age in both groups (p<0·0001), and began to differentiate carriers from non-carriers when aged 22 years (22 years before the estimated median age at mild cognitive impairment onset of 44 years), although the ability of plasma NfL to discriminate between carriers and non-carriers only reached high sensitivity close to the age of clinical onset. Our findings further support the promise of plasma NfL as a biomarker of active neurodegeneration in the detection and tracking of Alzheimer's disease and the evaluation of disease-modifying therapies. National Institute on Aging, National Institute of Neurological Disorders and Stroke, Banner Alzheimer's Foundation, COLCIENCIAS, the Torsten Söderberg Foundation, the Swedish Research Council, the Swedish Alzheimer Foundation, the Swedish Brain Foundation, and the Swedish state under the ALF-agreement.

We have previously characterised functional brain abnormalities in young adults at genetic risk for late-onset Alzheimer's disease. To gain further knowledge on the preclinical phase of Alzheimer's disease, we sought to characterise structural and functional MRI, CSF, and plasma biomarkers in a cohort of young adults carrying a high-penetrance autosomal dominant mutation that causes early-onset Alzheimer's disease. Between January and August, 2010, 18–26-year-old presenilin 1 (PSEN1) E280A mutation carriers and non-carriers from the Colombian Alzheimer's Prevention Initiative Registry in Medellín Antioquia, Colombia, had structural MRI, functional MRI during associative memory encoding and novel viewing and control tasks, and cognitive assessments. Consenting participants also had lumbar punctures and venepunctures. Outcome measures were task-dependent hippocampal or parahippocampal activations and precuneus or posterior cingulate deactivations, regional grey matter reductions, CSF Aβ1–42, total tau and phospho-tau181 concentrations, and plasma Aβ1–42 concentrations and Aβ1–42:Aβ1–40 ratios. Structural and functional MRI data were compared using automated brain mapping algorithms and search regions related to Alzheimer's disease. Cognitive and fluid biomarkers were compared using Mann-Whitney tests. 44 participants were included: 20 PSEN1 E280A mutation carriers and 24 non-carriers. The carrier and non-carrier groups did not differ significantly in their dementia ratings, neuropsychological test scores, or proportion of apolipoprotein E (APOE) ɛ4 carriers. Compared with non-carriers, carriers had greater right hippocampal and parahippocampal activation (p=0·001 and p<0·014, respectively, after correction for multiple comparisons), less precuneus and posterior cingulate deactivation (all p<0·010 after correction), and less grey matter in several parietal regions (all p<0·002 uncorrected and corrected p=0·009 in the right parietal search region). In the 20 participants (ten PSEN1 E280A mutation carriers and ten non-carriers) who had lumbar punctures and venepunctures, mutation carriers had higher CSF Aβ1–42 concentrations (p=0·008) and plasma Aβ1–42 concentrations (p=0·01) than non-carriers. Young adults at genetic risk for autosomal dominant Alzheimer's disease have functional and structural MRI findings and CSF and plasma biomarker findings consistent with Aβ1–42 overproduction. Although the extent to which the underlying brain changes are either neurodegenerative or developmental remain to be determined, this study shows the earliest known biomarker changes in cognitively normal people at genetic risk for autosomal dominant Alzheimer's disease. Banner Alzheimer's Foundation, Nomis Foundation, Anonymous Foundation, Forget Me Not Initiative, Boston University Department of Psychology, Colciencias, National Institute on Aging, National Institute of Neurological Disorders and Stroke, and the State of Arizona.

Autosomal dominant Alzheimer’s disease (ADAD) is genetically determined, but variability in age of symptom onset suggests additional factors may influence cognitive trajectories. Although apolipoprotein E ( APOE ) genotype and educational attainment both influence dementia onset in sporadic AD, evidence for these effects in ADAD is limited. To investigate the effects of APOE and educational attainment on age-related cognitive trajectories in ADAD, we analyzed data from 675 Presenilin-1 E280A mutation carriers and 594 non-carriers. Here we show that age-related cognitive decline is accelerated in ADAD mutation carriers who also have an APOE e4 allele compared to those who do not and delayed in mutation carriers who also have an APOE e2 allele compared to those who do not. Educational attainment is protective and moderates the effect of APOE on cognition. Despite ADAD mutation carriers being genetically determined to develop dementia, age-related cognitive decline may be influenced by other genetic and environmental factors. PSEN1 E280A carriers develop dementia by midlife, but there is variability in disease trajectory. Cognitive decline is accelerated in E280A carriers who also have an APOE e4 allele. Educational attainment moderates the effect of APOE on cognition.

Background Apolipoprotein E ( APOE ) genotypes have been suggested to influence cognitive impairment and clinical onset in presenilin-1 ( PSEN1 ) E280A carriers for autosomal dominant Alzheimer’s disease (ADAD). Less is known about their impact on the trajectory of biomarker changes. Neurofilament light chain (NfL), a marker of neurodegeneration, begins to accumulate in plasma about 20 years prior to the clinical onset of ADAD. In this study we investigated the impact of APOE ε4 and ε2 variants on age-related plasma NfL increases and cognition in PSEN1 E280A mutation carriers. Methods We analyzed cross-sectional data from PSEN1 E280A mutation carriers and non-carriers recruited from the Alzheimer’s Prevention Initiative Registry of ADAD. All participants over 18 years with available APOE genotype, plasma NfL, and neuropsychological evaluation were included in this study. APOE genotypes and plasma NfL concentrations were characterized for each participant. Cubic spline models using a Hamiltonian Markov chain Monte Carlo method were used to characterize the respective impact of at least one APOE ε4 or ε2 allele on age-related log-transformed plasma NfL increases. Linear regression models were estimated to explore the impact of APOE ε4 and ε2 variants and plasma NfL on a composite cognitive test score in the ADAD mutation carrier and non-carrier groups. Results Analyses included 788 PSEN1 E280A mutation carriers (169 APOE ε4 + , 114 ε2 +) and 650 mutation non-carriers (165 APOE ε4 + , 80 ε2 +), aged 18–75 years. APOE ε4 allele carriers were distinguished from ε4 non-carriers by greater age-related NfL elevations in the ADAD mutation carrier group, beginning about three years after the mutation carriers’ estimated median age at mild cognitive impairment onset. APOE ε2 allele carriers had lower plasma NfL concentrations than ε2 non-carriers in both the ADAD mutation carrier and non-carrier groups, unrelated to age, and an attenuated relationship between higher NfL levels on cognitive decline in the ADAD mutation carrier group. Conclusions APOE ε4 accelerates age-related plasma NfL increases and APOE ε2 attenuates the relationship between higher plasma NfL levels and cognitive decline in ADAD. NfL may be a useful biomarker to assess clinical efficacy of APOE -modifying drugs with the potential to help in the treatment and prevention of ADAD.

Background Perceived social support is an individual's sense of available emotional support from family and social networks. In neurodegenerative diseases, it has been explored as a potential protective factor against cognitive decline. Identifying modifiable factors is especially crucial for high‐risk populations. Individuals with autosomal dominant Alzheimer's disease (ADAD) typically develop early‐onset dementia, with research suggesting that certain factors may influence the timing of clinical onset. This study investigated the effects of perceived social support on cognitive performance in members of the Colombian kindred with the PSEN1 E280A mutation. Method This study included 144 cognitively‐unimpaired individuals from the PSEN1 E280A cohort (64 carriers, 80 non‐carriers) from the Rita/NGF biomarker study. The mean age was 30.33(SD5.74) years for carriers and 34.38(SD9.23) for non‐carriers. Cognitive function was assessed using the MMSE and CERAD Word List Delayed Recall, while depression was measured with the Geriatric Depression Scale (GDS). Perceived social support was evaluated using the Multidimensional Scale of Perceived Social Support (MSPSS), which captures support from three sources: family, friends, and significant others. Group comparisons and associations were analyzed using the Mann‐Whitney‐Wilcoxon test and Spearman correlations. Results Carriers had lower MMSE scores than non‐carriers (carriers: 26.3, SD 1.4; non‐carriers: 28.8, SD 1.3; p =  0.033) and reported more depressive symptoms (carriers: 2.8, SD 3.4; non‐carriers: 1.6, SD 2.2; p =  0.039). Additionally, carriers perceived lower overall social support (5.1 SD 1.3) compared to non‐carriers (5.6 SD 1.2; p =  0.014), with the difference largely driven by reduced support from family and significant others. These differences remained statistically significant even after controlling for depressive symptoms. However, perceived social support was not linked to cognition, age, or education. Conclusion This study found significant differences in overall perceived social support between carriers and non‐carriers in individuals with autosomal dominant AD. Longitudinal follow‐up of this population is essential to further explore the relationship between perceived social support and other cognitive functions, such as executive function. Evaluating perceived support may help identify modifiable risk factors for dementia and inform interventions aimed at enhancing mental and brain health in individuals at high risk for AD.

Perceived social support is an individual's sense of available emotional support from family and social networks. In neurodegenerative diseases, it has been explored as a potential protective factor against cognitive decline. Identifying modifiable factors is especially crucial for high-risk populations. Individuals with autosomal dominant Alzheimer's disease (ADAD) typically develop early-onset dementia, with research suggesting that certain factors may influence the timing of clinical onset. This study investigated the effects of perceived social support on cognitive performance in members of the Colombian kindred with the PSEN1 E280A mutation. This study included 144 cognitively-unimpaired individuals from the PSEN1 E280A cohort (64 carriers, 80 non-carriers) from the Rita/NGF biomarker study. The mean age was 30.33(SD5.74) years for carriers and 34.38(SD9.23) for non-carriers. Cognitive function was assessed using the MMSE and CERAD Word List Delayed Recall, while depression was measured with the Geriatric Depression Scale (GDS). Perceived social support was evaluated using the Multidimensional Scale of Perceived Social Support (MSPSS), which captures support from three sources: family, friends, and significant others. Group comparisons and associations were analyzed using the Mann-Whitney-Wilcoxon test and Spearman correlations. Carriers had lower MMSE scores than non-carriers (carriers: 26.3, SD 1.4; non-carriers: 28.8, SD 1.3; p =  0.033) and reported more depressive symptoms (carriers: 2.8, SD 3.4; non-carriers: 1.6, SD 2.2; p =  0.039). Additionally, carriers perceived lower overall social support (5.1 SD 1.3) compared to non-carriers (5.6 SD 1.2; p =  0.014), with the difference largely driven by reduced support from family and significant others. These differences remained statistically significant even after controlling for depressive symptoms. However, perceived social support was not linked to cognition, age, or education. This study found significant differences in overall perceived social support between carriers and non-carriers in individuals with autosomal dominant AD. Longitudinal follow-up of this population is essential to further explore the relationship between perceived social support and other cognitive functions, such as executive function. Evaluating perceived support may help identify modifiable risk factors for dementia and inform interventions aimed at enhancing mental and brain health in individuals at high risk for AD.

To have maximal benefit, Alzheimer's disease-modifying treatments might need to be started before the onset of clinical symptoms. Mutations of the PSEN1 gene are inherited as fully penetrant, autosomal-dominant traits, which almost always result in the clinical onset of Alzheimer's disease before the age of 65 years. We aimed to evaluate the efficacy, including possible delayed emergence of cognitive impairment, and safety of crenezumab, an anti-amyloid monoclonal antibody, in cognitively unimpaired carriers of the PSEN1 mutation at high imminent risk of developing symptoms due to Alzheimer's disease. This 5-8-year common-close, double-blind, placebo-controlled, single-centre trial screened kindred members aged 30-60 years from the main health-care site in Medellín, Colombia. Participants who were cognitively unimpaired and carried the PSEN1 autosomal-dominant mutation were randomly assigned 1:1 to receive placebo or subcutaneous crenezumab (investigators and participants were masked to treatment allocation), with an initial 300 mg dose every 2 weeks that increased to 720 mg every 2 weeks, and a later optional increase to 60 mg/kg intravenously every 4 weeks. Randomisation was stratified by age, education, APOE ɛ4 carrier status, and baseline Clinical Dementia Rating. Mutation non-carriers received placebo and were included in a 1:2 ratio of non-carriers to carriers to maintain genotype masking and include a genetic kindred control. Dual primary outcomes were the annualised rates of change in the Alzheimer's Prevention Initiative (API) preclinical autosomal-dominant Alzheimer's disease (ADAD) composite test total score and Free and Cued Selective Reminding Test-Cueing Index (FCSRT-CI) assessed in randomised participants who received at least one dose of the study drug, according to treatment assignment. Primary endpoints were assessed with a random coefficient regression model with a missing-at-random assumption adjusting for randomisation factors. Safety endpoints for mutation carriers were assessed in randomised participants who received at least one dose of the study drug. This trial is registered with ClinicalTrials.gov (NCT01998841) and is completed. 619 Colombian API registrants were prescreened, 315 were assessed for eligibility, and 252 were enrolled (crenezumab-carrier, n=85; placebo-carrier, n=84; placebo-non-carrier, n=83; 160 [63%] women and 92 [37%] men) between Dec 20, 2013, and Feb 27, 2017. 237 (94%) completed the trial, with final data collection on March 22, 2022. The annualised rate of change in the API ADAD composite was -1·10 (SE 0·29) in the crenezumab group and -1·43 (0·29) in the placebo group (between-group difference 0·33 [95% CI -0·48 to 1·13]; p=0·43). The annualised rate of change in FCSRT-CI was -0·03 (0·00) in the crenezumab group and -0·04 (0·00) in the placebo group (between-group difference 0·01 [0·00 to 0·02]; p=0·16). All participants had at least one adverse event; serious adverse events occurred in 23 (27%) of 84 in the crenezumab group and 21 (25%) of 84 in the placebo group. No fatalities occurred. Crenezumab therapy administered for 5-8 years did not result in significant benefits on our primary clinical outcomes in cognitively unimpaired participants predisposed to developing ADAD dementia; secondary and exploratory outcomes also showed no significant effect on removal of amyloid plaques or other clinical or biomarker outcomes. Together with the results of other anti-amyloid β trials, robust fibrillar amyloid removal appears necessary for clinical efficacy in people with elevated brain amyloid. This study will further inform the biomarker, cognitive, and clinical trajectory of preclinical ADAD, the risk of clinical progression in amyloid-positive and amyloid-negative mutation carriers, and the size and design of future secondary and primary prevention trials. US National Institute on Aging (NIA), Banner Alzheimer's Institute, Genentech, F Hoffmann-La Roche.

Objective:Neurofilament light chain (NfL), a plasma-based biomarker for neurodegeneration, is a promising marker for early Alzheimer disease (AD) detection in individuals at increased risk. We previously reported that Presenilin1 (PSEN1) E280A carriers have increased levels of plasma NfL relative to non-carrier family members twenty years before the onset of clinical symptoms. Abstract reasoning is one of the first cognitive abilities to deteriorate in AD. Here, we examined whether levels of plasma NfL were associated with non-verbal abstract reasoning performance in non-demented PSEN1-E280A carriers and non-carriers.Participants and Methods:A total of 798 members of the Colombian kindred with the PSEN1 E280A mutation (462 cognitively-unimpaired and 336 non-carriers; mean age= 34.02 (10.53), mean education= 8.23(4.60), 57% females and 43% males) were included in the study. Participants completed the Raven’s Progressive Matrices (RPM), Mini Mental State Examination (MMSE), and underwent blood sampling. Plasma NfL concentrations were measured with a single molecule array (Simoa) method. Mann-Whitney U test and education-adjusted Spearman partial correlation were used to examine group differences and associations between abstract reasoning performance and NfL levels.Results:Non-carriers were older (p<.001) and had higher levels of education than carriers (p=.025). Compared to non-carriers, carriers had higher levels of NfL (p=.014), lower performance on the MMSE (p<.001) and on the RPM (p=.001). In the whole sample, performance on the RPM was significantly associated with age (r= -.144, p<.001), and MMSE score (r=.198, p<.001). In carriers only, performance on the RPM was negatively associated with NfL levels (r=-.121, p=.009). This association was not significant in non-carriers.Conclusions:Our findings support the hypothesis that plasma NfL levels may be indicators of disease progression and early cognitive dysfunction in autosomal dominant AD. Future work with NfL, abstract reasoning and memory with larger samples across the preclinical/prodromal spectrum will allow a more comprehensive examination of these associations.

Subjective Cognitive Decline (SCD) may be an early indicator of risk for Alzheimer's disease (AD). Findings regarding sex differences in SCD are inconsistent. Studying sex differences in SCD within cognitively unimpaired individuals with autosomal-dominant AD (ADAD), who will develop dementia, may inform sex-related SCD variations in preclinical AD. We examined sex differences in SCD within cognitively unimpaired mutation carriers from the world's largest ADAD kindred and sex differences in the relationship between SCD and memory performance. We included 310 cognitively unimpaired Presenilin-1 (PSEN-1) E280A mutation carriers (51% females) and 1998 noncarrier family members (56% females) in the study. Subjects and their study partners completed SCD questionnaires and the CERAD word list delayed recall test. ANCOVAs were conducted to examine group differences in SCD, sex, and memory performance. In carriers, partial correlations were used to examine associations between SCD and memory performance covarying for education. Females in both groups had greater self-reported and study partner-reported SCD than males (all < 0.001). In female mutation carriers, greater self-reported ( = 0.02) and study partner-reported SCD ( < 0.001) were associated with worse verbal memory. In male mutation carriers, greater self-reported ( = 0.03), but not study partner-reported SCD ( = 0.11) was associated with worse verbal memory. Study partner-reported SCD may be a stronger indicator of memory decline in females males in individuals at risk for developing dementia. Future studies with independent samples and preclinical trials should consider sex differences when recruiting based on SCD criteria.

Alzheimer's disease (AD) is known to impact semantic access, which is frequently evaluated using the Category Fluency (Animals) test. Recent studies have suggested that in addition to overall category fluency scores (total number of words produced over time), poor clustering could signal AD-related cognitive difficulties. In this study, we examined the association between category fluency clustering performance (i.e., stating words sequentially that are all contained within a subcategory, such as domestic animals) and brain pathology in individuals with autosomal dominant Alzheimer's disease (ADAD). A total of 29 non-demented carriers of the Presenilin1 E280A ADAD mutation and 32 noncarrier family members completed the category fluency test (Animals) and the Mini-Mental State Examination (MMSE). The participants also underwent positron emission tomography (PET) scans to evaluate amyloid-beta in the neocortex and tau in medial temporal lobe regions. Differences between carriers and noncarriers on cognitive tests were assessed with Mann-Whitney tests; associations between cognitive test performance and brain pathology were assessed with Spearman correlations. Animal fluency scores did not differ between carriers and noncarriers. Carriers, however, showed a stronger association between animal fluency clustering and AD brain pathology (neocortical amyloid and entorhinal tau) relative to noncarriers. This study indicates that using category fluency clustering, but not total score, is related to AD pathophysiology in the preclinical and early stages of the disease.