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We characterized the world’s second case with ascertained extreme resilience to autosomal dominant Alzheimer’s disease (ADAD). Side-by-side comparisons of this male case and the previously reported female case with ADAD homozygote for the APOE3 Christchurch ( APOECh ) variant allowed us to discern common features. The male remained cognitively intact until 67 years of age despite carrying a PSEN1 -E280A mutation. Like the APOECh carrier, he had extremely elevated amyloid plaque burden and limited entorhinal Tau tangle burden. He did not carry the APOECh variant but was heterozygous for a rare variant in RELN (H3447R, termed COLBOS after the Colombia–Boston biomarker research study), a ligand that like apolipoprotein E binds to the VLDLr and APOEr2 receptors. RELN-COLBOS is a gain-of-function variant showing stronger ability to activate its canonical protein target Dab1 and reduce human Tau phosphorylation in a knockin mouse. A genetic variant in a case protected from ADAD suggests a role for RELN signaling in resilience to dementia. Case report of an individual heterozygous for a rare RELN-COLBOS variant that confers resilience, via a gain-of-function mechanism, to Alzheimer’s disease.

Action-concept outcomes are useful targets to identify Parkinson’s disease (PD) patients and differentiate between those with and without mild cognitive impairment (PD-MCI, PD-nMCI). Yet, most approaches employ burdensome examiner-dependent tasks, limiting their utility. We introduce a framework capturing action-concept markers automatically in natural speech. Patients from both subgroups and controls retold an action-laden and a non-action-laden text (AT, nAT). In each retelling, we weighed action and non-action concepts through our automated Proximity-to-Reference-Semantic-Field (P-RSF) metric, for analysis via ANCOVAs (controlling for cognitive dysfunction) and support vector machines. Patients were differentiated from controls based on AT (but not nAT) P-RSF scores. The same occurred in PD-nMCI patients. Conversely, PD-MCI patients exhibited reduced P-RSF scores for both texts. Direct discrimination between patient subgroups was not systematic, but it yielded best outcomes via AT scores. Our approach outperformed classifiers based on corpus-derived embeddings. This framework opens scalable avenues to support PD diagnosis and phenotyping.

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 PSEN1Glu280Ala 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 PSEN1Glu280Ala 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.

Background Neuroimaging studies of autosomal dominant Alzheimer’s disease (ADAD) enable characterization of the trajectories of cerebral amyloid-β (Aβ) and tau accumulation in the decades prior to clinical symptom onset. Longitudinal rates of regional tau accumulation measured with positron emission tomography (PET) and their relationship with other biomarker and cognitive changes remain to be fully characterized in ADAD. Methods Fourteen ADAD mutation carriers ( Presenilin-1 E280A) and 15 age-matched non-carriers from the Colombian kindred underwent 2–3 sessions of Aβ (11C-Pittsburgh compound B) and tau (18F-flortaucipir) PET, structural magnetic resonance imaging, and neuropsychological evaluation over a 2–4-year follow-up period. Annualized rates of change for imaging and cognitive variables were compared between carriers and non-carriers, and relationships among baseline measurements and rates of change were assessed within carriers. Results Longitudinal measurements were consistent with a sequence of ADAD-related changes beginning with Aβ accumulation (16 years prior to expected symptom onset, EYO), followed by entorhinal cortex (EC) tau (9 EYO), neocortical tau (6 EYO), hippocampal atrophy (6 EYO), and cognitive decline (4 EYO). Rates of tau accumulation among carriers were most rapid in parietal neocortex (~ 9%/year). EC tau PET signal at baseline was a significant predictor of subsequent neocortical tau accumulation and cognitive decline within carriers. Conclusions Our results are consistent with the sequence of biological changes in ADAD implied by cross-sectional studies and highlight the importance of EC tau as an early biomarker and a potential link between Aβ burden and neocortical tau accumulation in ADAD.

Parkinson’s disease (PD), the second most frequent neurodegenerative disease, affects significantly life quality by a combination of motor and cognitive disturbances. Although it is traditionally associated with basal ganglia dysfunction, cortical alterations are also involved in disease symptoms. Our objective is to evaluate the alterations in brain dynamics in de novo and recently treated PD subjects using a nonlinear method known as Active Information Storage. In the current research, Active Information Storage (AIS) was used to study the complex dynamics in motor cortex spontaneous activity captured using resting state functional Magnetic Resonance Imaging (rs-fMRI) at early-stage in non-medicated and recently medicated PD subjects. Supplementary to AIS, the fractional Amplitude of Low Frequency Fluctuation (fALFF), which is a better-established technique of analysis of rs-fMRI signals, was also evaluated. Compared to healthy subjects, the AIS values were significantly reduced in PD patients over the analyzed motor cortex regions; differences were also found at less extent using the fALFF measure. Correlations between AIS and fALFF values showed that the measures seem to capture similar neuronal phenomena in rs-fMRI data. The highest sensitivity when detecting group differences revealed by AIS, and not captured by traditional linear approaches, suggests that this measure is a promising tool for the analysis of rs-fMRI neural data in PD.

Background To determine whether performance on the Latin American Spanish version of the Face-Name Associative Memory Exam (LAS-FNAME) can differentiate between cognitively intact carriers of an autosomal dominant Alzheimer’s disease mutation (E280A) in Presenilin-1, who are genetically determined to develop early-onset dementia, from matched non-carriers. We also sought to examine whether LAS-FNAME performance is associated with amyloid-β and regional tau burden in mutation carriers. Methods A total of 35 cognitively intact mutation carriers (age range 26–41), 19 symptomatic carriers, and 48 matched non-carriers (age range 27–44) completed a neuropsychological assessment including the LAS-FNAME. A subset of participants (31 carriers [12 symptomatic] and 35 non-carriers) traveled from Colombia to Boston to undergo positron emission tomography (PET) using Pittsburgh compound B to measure mean cortical amyloid-β and flortaucipir for regional tau. ANOVA analyses and Spearman correlations were used to examine group differences and relationships among LAS-FNAME performance and amyloid-β and tau accumulation. Results Compared to non-carriers, cognitively intact mutation carriers had lower scores on the LAS-FNAME Total Scores ( p  = .040). Across all carriers (including symptomatic carriers), higher levels of amyloid-β ( r  = − .436, p  = .018) and regional tau in the entorhinal ( r  = − .394, p  = .031) and inferior temporal cortex ( r  = − .563, p  = .001) were associated with lower LAS-FNAME Total Scores. Conclusions Performance on the LAS-FNAME differentiated between cognitively intact mutation carriers from non-carriers and was associated with greater amyloid and tau burden when examining all carriers. Findings suggest that the LAS-FNAME is sensitive to early clinical and pathological changes and can potentially help track disease progression in Spanish-speaking individuals.

Objective:High levels of stress may increase risk for Alzheimer’s disease (AD) dementia. Religious coping practices to deal with stress (i.e., prayer, having faith, attending religious services) may reduce risk of dementia. Studying religious stress coping in cognitively unimpaired individuals with autosomal-dominant AD (ADAD), who will develop dementia later in life, may inform us about the role of religious coping in modifying the clinical trajectory from preclinical to clinical stages of the disease. We examined religious stress coping in cognitively unimpaired mutation carriers from the world’s largest ADAD kindred and its relation to markers of brain pathology and memory.Participants and Methods:16 cognitively unimpaired Presenilin-1 E280A mutation carriers and 19 age and education-matched noncarrier family members from the Colombia-Boston (COLBOS) Biomarker Study were included. A subsample (n=26; 13 cognitively unimpaired carriers) underwent amyloid and tau PET imaging. Participants completed the Coping Strategies Questionnaire (CAE) that includes a subscale used to assess religious stress coping, where a higher score indicates more coping, and underwent memory testing using the Free and Cued Selective Reminding Test (FCSRT). The Geriatric Depression Scale (GDS) was used to assess depression. Mann-Whitney U tests were used to examine group differences in religious stress coping, brain pathology (i.e., cortical amyloid-beta, entorhinal and precuneus tau), memory, and depression. Nonparametric correlations were used to examine associations among religious stress coping, age, education, depression, memory, and pathology.Results:Carriers had poorer FCSRT immediate free recall than noncarriers (U=84.5, p=.024). There was no difference between groups in CAE religious stress coping, other FCSRT memory scores, nor GDS score (all p>.05). Compared to non-carriers, carriers had more cortical amyloid (U=152.0, p<.001) and more precuneus tau (U=123.0, p=.05). In carriers, religious stress coping was positively associated with education (r=.57, p=.022), FCSRT immediate free recall (a=.75, p<.001), FCSRT cued recall (a=.50, p=.047), and FCSRT delayed recall (r=.52, p=.038). After controlling for education, religious stress coping remained positively associated with FCSRT immediate free recall (r=.65, p=.009), but not other FCSRT memory scores (all p>.05). Religious stress coping was not associated with age or GDS score regardless of controlling for education (all p>.05). In carriers, religious stress coping was negatively associated with entorhinal tau (r=-.73, p=.005) and precuneus tau burden (r=-.58, p=.037). The association between religious stress coping and entorhinal tau remained significant after controlling for education (r=-.67, p=.016), but not precuneus tau (p>.05). Religious stress coping was not associated with cortical amyloid regardless of controlling for education in carriers (all p>.05). None of the associations with brain pathology or memory were significant in the non-carrier group.Conclusions:Religious stress coping was associated with better memory performance and a low AD pathology burden in individuals at genetic risk for developing AD dementia. Future studies with independent and larger samples should further examine religious stress coping strategies and their associations with other AD-related biomarkers, as well as with other risk and protective factors to better understand their role at the preclinical and prodromal stages of Alzheimer’s disease.

Carriers of the PSEN1-E280A variant, the largest known autosomal dominant Alzheimer's disease (ADAD) cohort, typically experience mild cognitive impairment by age 44 and dementia by 49. Emerging evidence suggests gait speed (GS) may be an early marker of cognitive decline. While past research focused on older adults, recent studies explore muscle decline in younger individuals. This study examines the relationship between GS and cognition within the Colombian PSEN1-E280A cohort. The study included 134 individuals from families affected by early-onset ADAD with the PSEN1 gene variant. Among them, 66 were carriers (including 5 with mild cognitive impairment and 5 with dementia), while 68 were non-carriers. The participants had a mean age of 32 years (SD = 8.72), with 49.3% being male. Cognitively-unimpaired status was defined by Functional Assessment Staging (FAST) scores <2. Muscle function was assessed through single-task GS, and its association with cognitive function and functional stages was analyzed. Univariate and multivariate analyses were conducted to explore these relationships. The carrier group had a mean GS of 1.56 m/s, compared to 1.64 m/s for the non-carrier group (p = 0.307). On the MMSE, all carriers scored an average of 26.55 (SD = 4.56), while non-carriers scored 28.81 (SD = 1.24), a statistically significant difference (p < 0.001). GS was significantly slower in the cognitively-impaired group compared to cognitively-unimpaired group (1.37 m/s vs. 1.63 m/s; p = 0.042). Pearson correlation analysis revealed a weak positive correlation between GS and MMSE (r = 0.18; p = 0.041), with this effect being more pronounced in the impaired group. Our findings show that single-task GS does not differentiate young individuals with ADAD due to PSEN1-E280A but is significantly associated with global cognitive function, particularly in cognitively-impaired individuals. This suggests that gait impairments emerge as cognitive decline progresses, consistent with findings in sporadic Alzheimer's disease, where motor dysfunction often appears in early symptomatic stages. These results reinforce the link between motor decline and cognitive impairment. Further research is needed to explore the interplay between cognitive and physical performance in this population.

Background Carriers of the PSEN1‐E280A variant, the largest known autosomal dominant Alzheimer's disease (ADAD) cohort, typically experience mild cognitive impairment by age 44 and dementia by 49. Emerging evidence suggests gait speed (GS) may be an early marker of cognitive decline. While past research focused on older adults, recent studies explore muscle decline in younger individuals. This study examines the relationship between GS and cognition within the Colombian PSEN1‐E280A cohort. Method The study included 134 individuals from families affected by early‐onset ADAD with the PSEN1 gene variant. Among them, 66 were carriers (including 5 with mild cognitive impairment and 5 with dementia), while 68 were non‐carriers. The participants had a mean age of 32 years (SD = 8.72), with 49.3% being male. Cognitively‐unimpaired status was defined by Functional Assessment Staging (FAST) scores <2. Muscle function was assessed through single‐task GS, and its association with cognitive function and functional stages was analyzed. Univariate and multivariate analyses were conducted to explore these relationships. Result The carrier group had a mean GS of 1.56 m/s, compared to 1.64 m/s for the non‐carrier group (p = 0.307). On the MMSE, all carriers scored an average of 26.55 (SD = 4.56), while non‐carriers scored 28.81 (SD = 1.24), a statistically significant difference (p < 0.001). GS was significantly slower in the cognitively‐impaired group compared to cognitively‐unimpaired group (1.37 m/s vs. 1.63 m/s; p = 0.042). Pearson correlation analysis revealed a weak positive correlation between GS and MMSE (r = 0.18; p = 0.041), with this effect being more pronounced in the impaired group. Conclusion Our findings show that single‐task GS does not differentiate young individuals with ADAD due to PSEN1‐E280A but is significantly associated with global cognitive function, particularly in cognitively‐impaired individuals. This suggests that gait impairments emerge as cognitive decline progresses, consistent with findings in sporadic Alzheimer's disease, where motor dysfunction often appears in early symptomatic stages. These results reinforce the link between motor decline and cognitive impairment. Further research is needed to explore the interplay between cognitive and physical performance in this population.

We conducted an in-depth longitudinal study on an individual carrying the presenilin 2 p.Asn141Ile mutation, traditionally associated with dominantly inherited Alzheimer’s disease (AD), who has remarkably remained asymptomatic past the expected age of clinical onset. This study combines genetic, neuroimaging and biomarker analyses to explore the underpinnings of this resilience. Unlike typical progression in dominantly inherited AD, tau pathology in this case was confined to the occipital region without evidence of spread, potentially explaining the preservation of cognitive functions. Genetic analysis revealed several variants that, although not previously associated with protection against AD, suggest new avenues for understanding disease resistance. Notably, environmental factors such as significant heat exposure and a unique proteomic profile rich in heat shock proteins might indicate adaptive mechanisms contributing to the observed phenotype. This case underscores the complexity of Alzheimer’s pathology and suggests that blocking tau deposition could be a promising target for therapeutic intervention. The study highlights the need for further research to identify and validate the mechanisms that could inhibit or localize tau pathology as a strategy to mitigate or delay the onset of Alzheimer’s dementia. A rare case of asymptomatic dominantly inherited Alzheimer’s reveals confined tau pathology and unique proteomic features, highlighting potential resilience mechanisms decades beyond expected onset.