Dominant Alzheimer Research Articles

CSF proteomics identifies early changes in autosomal dominant Alzheimer’s disease

In this high-throughput proteomic study of autosomal dominant Alzheimer's disease (ADAD), we sought to identify early biomarkers in cerebrospinal fluid (CSF) for disease monitoring and treatment strategies. We examined CSF proteins in 286 mutation carriers (MCs) and 177 non-carriers (NCs). The developed multi-layer regression model distinguished proteins with different pseudo-trajectories between these groups. We validated our findings with independent ADAD as well as sporadic AD datasets and employed machine learning to develop and validate predictive models. Our study identified 137 proteins with distinct trajectories between MCs and NCs, including eight that changed before traditional AD biomarkers. These proteins are grouped into three stages: early stage (stress response, glutamate metabolism, neuron mitochondrial damage), middle stage (neuronal death, apoptosis), and late presymptomatic stage (microglial changes, cell communication). The predictive model revealed a six-protein subset that more effectively differentiated MCs from NCs, compared with conventional biomarkers.

Connectome-based predictive modeling of brain pathology and cognition in Autosomal Dominant Alzheimer's Disease.

Autosomal Dominant Alzheimer's Disease (ADAD) through genetic mutations can result in near complete expression of the disease. Tracking AD pathology development in an ADAD cohort of Presenilin-1 (PSEN1) E280A carriers' mutation has allowed us to observe incipient tau tangles accumulation as early as 6 years prior to symptom onset. Resting-state functional Magnetic Resonance Imaging (fMRI) and Positron-Emission Tomography (PET) scans were acquired in a group of PSEN1 carriers (n=32) and non-carrier family members (n=35). We applied Connectome-based Predictive Modeling (CPM) to examine the relationship between the participant's functional connectome and their respective tau/amyloid-β levels and cognitive scores (word list recall). CPM models strongly predicted tau concentrations and cognitive scores within the carrier group. The connectivity patterns between the temporal cortex, default mode network, and other memory networks were the most informative of tau burden. These results indicate that resting-state fMRI methods can complement PET methods in early detection and monitoring of disease progression in ADAD.

γ-Secretase activity, clinical features, and biomarkers of autosomal dominant Alzheimer's disease: cross-sectional and longitudinal analysis of the Dominantly Inherited Alzheimer Network observational study (DIAN-OBS)

Genetic variants that cause autosomal dominant Alzheimer's disease are highly penetrant but vary substantially regarding age at symptom onset (AAO), rates of cognitive decline, and biomarker changes. Most pathogenic variants that cause autosomal dominant Alzheimer's disease are in presenilin 1 (PSEN1), which encodes the catalytic core of γ-secretase, an enzyme complex that is crucial in production of amyloid β. We aimed to investigate whether the heterogeneity in AAO and biomarker trajectories in carriers of PSEN1 pathogenic variants could be predicted on the basis of the effects of individual PSEN1 variants on γ-secretase activity and amyloid β production. For this cross-sectional and longitudinal analysis, we used data from participants enrolled in the Dominantly Inherited Alzheimer Network observational study (DIAN-OBS) via the DIAN-OBS data freeze version 15 (data collected between Feb 29, 2008, and June 30, 2020). The data freeze included data from 20 study sites in research institutions, universities, hospitals, and clinics across Europe, North and South America, Asia, and Oceania. We included individuals with PSEN1 pathogenic variants for whom relevant genetic, clinical, imaging, and CSF data were available. PSEN1 pathogenic variants were characterised via genetically modified PSEN1 and PSEN2 double-knockout human embryonic kidney 293T cells and immunoassays for Aβ37, Aβ38, Aβ40, Aβ42, and Aβ43. A summary measure of γ-secretase activity (γ-secretase composite [GSC]) was calculated for each variant and compared with clinical history-derived AAO using correlation analyses. We used linear mixed-effect models to assess associations between GSC scores and multimodal-biomarker and clinical data from DIAN-OBS. We used separate models to assess associations with Clinical Dementia Rating Sum of Boxes (CDR-SB), Mini-Mental State Examination (MMSE), and Wechsler Memory Scale-Revised (WMS-R) Logical Memory Delayed Recall, [11C]Pittsburgh compound B (PiB)-PET and brain glucose metabolism using [18F] fluorodeoxyglucose (FDG)-PET, CSF Aβ42-to-Aβ40 ratio (Aβ42/40), CSF log10 (phosphorylated tau 181), CSF log10 (phosphorylated tau 217), and MRI-based hippocampal volume. Data were included from 190 people carrying PSEN1 pathogenic variants, among whom median age was 39·0 years (IQR 32·0 to 48·0) and AAO was 44·5 years (40·6 to 51·4). 109 (57%) of 190 carriers were female and 81 (43%) were male. Lower GSC values (ie, lower γ-secretase activity than wild-type PSEN1) were associated with earlier AAO (r=0·58; p<0·0001). GSC was associated with MMSE (β=0·08, SE 0·03; p=0·0043), CDR-SB (-0·05, 0·02; p=0·0027), and WMS-R Logical Memory Delayed Recall scores (0·09, 0·02; p=0·0006). Lower GSC values were associated with faster increase in PiB-PET signal (p=0·0054), more rapid decreases in hippocampal volume (4·19, 0·77; p<0·0001), MMSE (0·02, 0·01; p=0·0020), and WMS-R Logical Memory Delayed Recall (0·004, 0·001; p=0·0003). Our findings suggest that clinical heterogeneity in people with autosomal dominant Alzheimer's disease can be at least partly explained by different effects of PSEN1 variants on γ-secretase activity and amyloid β production. They support targeting γ-secretase as a therapeutic approach and suggest that cell-based models could be used to improve prediction of symptom onset. US National Institute on Aging, Alzheimer's Association, German Center for Neurodegenerative Diseases, Raul Carrea Institute for Neurological Research, Japan Agency for Medical Research and Development, Korea Health Industry Development Institute, South Korean Ministry of Health and Welfare, South Korean Ministry of Science and ICT, and Spanish Institute of Health Carlos III.

The pathogenicity of PSEN2 variants is tied to Aβ production and homology to PSEN1.

Though recognized as a potential cause of Autosomal Dominant Alzheimer's Disease, the pathogenicity of many PSEN2 variants remains uncertain. We compared Aβ production across all missense PSEN2 variants in the Alzforum database and, when possible, to corresponding PSEN1 variants. We expressed 74 PSEN2 variants, 21 of which had homologous PSEN1 variants with the same amino acid substitution, in HEK293 cells lacking PSN1/2. Aβ production was compared to age at symptom onset (AAO) and between homologous PSEN1/2 variants. Aβ42/40 and Aβ37/42 ratios were associated with AAO across PSEN2 variants, strongly driven by PSEN2 variants with PSEN1 homologs. PSEN2 AAO was 18.3 years later compared to PSEN1 homologs. Aβ ratios from PSEN1 / 2 homologs were highly correlated, suggesting a similar mechanism of γ-secretase dysfunction. 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.

APOE Christchurch enhances a disease-associated microglial response to plaque but suppresses response to tau pathology.

Apolipoprotein E ε4 (APOE4) is the strongest genetic risk factor for late-onset Alzheimer's disease (LOAD). A recent case report identified a rare variant in APOE, APOE3-R136S (Christchurch), proposed to confer resistance to autosomal dominant Alzheimer's Disease (AD). However, it remains unclear whether and how this variant exerts its protective effects. We introduced the R136S variant into mouse Apoe (ApoeCh) and investigated its effect on the development of AD-related pathology using the 5xFAD model of amyloidosis and the PS19 model of tauopathy. We used immunohistochemical and biochemical analysis along with single-cell spatial transcriptomics and proteomics to explore the impact of the ApoeCh variant on AD pathological development and the brain's response to plaques and tau. In 5xFAD mice, ApoeCh enhances a Disease-Associated Microglia (DAM) phenotype in microglia surrounding plaques, and reduces plaque load, dystrophic neurites, and plasma neurofilament light chain. By contrast, in PS19 mice, ApoeCh suppresses the microglial and astrocytic responses to tau-laden neurons and does not reduce tau accumulation or phosphorylation, but partially rescues tau-induced synaptic and myelin loss. We compared how microglia responses differ between the two mouse models to elucidate the distinct DAM signatures induced by ApoeCh. We identified upregulation of antigen presentation-related genes in the DAM response in a PS19 compared to a 5xFAD background, suggesting a differential response to amyloid versus tau pathology that is modulated by the presence of ApoeCh. These findings highlight the ability of the ApoeCh variant to modulate microglial responses based on the type of pathology, enhancing DAM reactivity in amyloid models and dampening neuroinflammation to promote protection in tau models. This suggests that the Christchurch variant's protective effects likely involve multiple mechanisms, including changes in receptor binding and microglial programming.

Basal forebrain volume and metabolism in carriers of the Colombian mutation for autosomal dominant Alzheimer's disease.

We aimed to study atrophy and glucose metabolism of the cholinergic basal forebrain in non-demented mutation carriers for autosomal dominant Alzheimer's disease (ADAD). We determined thelevel of evidence for or against atrophy and impaired metabolism of the basal forebrain in 167 non-demented carriers of the Colombian PSEN1 E280A mutation and 75 age- and sex-matched non-mutation carriers of the same kindred using a Bayesian analysis framework. We analyzed baseline MRI, amyloid PET, and FDG-PET scans of the Alzheimer's Prevention Initiative ADAD Colombia Trial. We found moderate evidence against an association of carrier status with basal forebrain volume (Bayes factor (BF10) = 0.182). We found moderate evidence against a difference of basal forebrain metabolism (BF10 = 0.167). There was only inconclusive evidence for an association between basal forebrain volume and delayed memory and attention (BF10 = 0.884 and 0.184, respectively), and between basal forebrain volume and global amyloid load (BF10 = 2.1). Our results distinguish PSEN1 E280A mutation carriers from sporadic AD cases in which cholinergic involvement of the basal forebrain is already detectable in the preclinical and prodromal stages. This indicates an important difference between ADAD and sporadic AD in terms of pathogenesis and potential treatment targets.

α-Synuclein seed amplification assay detects Lewy body co-pathology in autosomal dominant Alzheimer's disease late in the disease course and dependent on Lewy pathology burden.

Amyloid beta and tau pathology are the hallmarks of sporadic Alzheimer's disease (AD) and autosomal dominant AD (ADAD). However, Lewy body pathology (LBP) is found in ≈ 50% of AD and ADAD brains. Using an α-synuclein seed amplification assay (SAA) in cerebrospinal fluid (CSF) from asymptomatic (n=26) and symptomatic (n=27) ADAD mutation carriers, including 12 with known neuropathology, we investigated the timing of occurrence and prevalence of SAA positive reactivity in ADAD in vivo. No asymptomatic participant and only 11% (3/27) of the symptomatic patients tested SAA positive. Neuropathology revealed LBP in 10/12 cases, primarily affecting the amygdala or the olfactory areas. In the latter group, only the individual with diffuse LBP reaching the neocortex showed α-synuclein seeding activity in CSF in vivo. Results suggest that in ADAD LBP occurs later than AD pathology and often as amygdala- or olfactory-predominant LBP, for which CSF α-synuclein SAA has low sensitivity. Cerebrospinal fluid (CSF) real-time quaking-induced conversion (RT-QuIC) detects misfolded α-synuclein in ≈ 10% of symptomatic autosomal dominant Alzheimer's disease (ADAD) patients. CSF RT-QuIC does not detect α-synuclein seeding activity in asymptomatic mutation carriers. Lewy body pathology (LBP) in ADAD mainly occurs as olfactory only or amygdala-predominant variants. LBP develops late in the disease course in ADAD. CSF α-synuclein RT-QuIC has low sensitivity for focal, low-burden LBP.

Generation and characterization of an iPS cell line (PUMCi006-A) from skin fibroblasts of a patient with an M239T mutation in PSEN2 gene

Presenilin-2 (PSEN2) mutation is one of the pathogenic factors of autosomal dominant early-onset Alzheimer's disease (EOAD). We generated a human induced pluripotent stem cell (iPSC) line from fibroblasts of an EOAD patient carrying PSEN2 mutation (c.716 T > C) utilizing Sendai reprogramming kit. The resulting iPSC line carried patient-specific point mutation, exhibited typical iPSC morphology, retained a normal karyotype, expressed pluripotency markers, and could form embryoid bodies. Established iPSC line serve as valuable resource for EOAD disease pathogenesis modelling and drug screening.

BDNF Val66Met moderates episodic memory decline and tau biomarker increases in early sporadic Alzheimer's disease.

Allelic variation in the brain-derived neurotrophic factor (BDNF) Val66Met polymorphism has been shown to moderate rates of cognitive decline in preclinical sporadic Alzheimer's disease (AD; i.e., Aβ + older adults), and pre-symptomatic autosomal dominant Alzheimer's disease (ADAD). In ADAD, Met66 was also associated with greater increases in CSF levels of total-tau (t-tau) and phosphorylated tau (p-tau181). This study sought to determine the extent to which BDNF Val66Met is associated with changes in episodic memory and CSF t-tau and p-tau181 in Aβ + older adults in early-stage sporadic AD. Aβ + Met66 carriers (n = 94) and Val66 homozygotes (n = 192) enrolled in the Alzheimer's Disease Neuroimaging Initiative who did not meet criteria for AD dementia, and with at least one follow-up neuropsychological and CSF assessment, were included. A series of linear mixed models were conducted to investigate changes in each outcome over an average of 2.8years, covarying for CSF Aβ42, APOE ε4 status, sex, age, baseline diagnosis, and years of education. Aβ + Met66 carriers demonstrated significantly faster memory decline (d = 0.33) and significantly greater increases in CSF t-tau (d = 0.30) and p-tau181 (d = 0.29) compared to Val66 homozygotes, despite showing equivalent changes in CSF Aβ42. These findings suggest that reduced neurotrophic support, which is associated with Met66 carriage, may increase vulnerability to Aβ-related tau hyperphosphorylation, neuronal dysfunction, and cognitive decline even prior to the emergence of dementia. Additionally, these findings highlight the need for neuropsychological and clinicopathological models of AD to account for neurotrophic factors and the genes which moderate their expression.

Surface-Based Probabilistic Fiber Tracking in Superficial White Matter.

The short association fibers or U-fibers travel in the superficial white matter (SWM) beneath the cortical layer. While the U-fibers play a crucial role in various brain disorders, there is a lack of effective tools to reconstruct their highly curved trajectory from diffusion MRI (dMRI). In this work, we propose a novel surface-based framework for the probabilistic tracking of fibers on the triangular mesh representation of the SWM. By deriving a closed-form solution to transform the spherical harmonics (SPHARM) coefficients of 3D fiber orientation distributions (FODs) to local coordinate systems on each triangle, we develop a novel approach to project the FODs onto the tangent space of the SWM. After that, we utilize parallel transport to realize the intrinsic propagation of streamlines on SWM following probabilistically sampled fiber directions. Our intrinsic and surface-based method eliminates the need to perform the necessary but challenging sharp turns in 3D compared with conventional volume-based tractography methods. Using data from the Human Connectome Project (HCP), we performed quantitative comparisons to demonstrate the proposed algorithm can more effectively reconstruct the U-fibers connecting the precentral and postcentral gyrus than previous methods. Quantitative validations were then performed on post-mortem MRIs to show the reconstructed U-fibers from our method more faithfully follow the SWM than volume-based tractography. Finally, we applied our algorithm to study the parietal U-fiber connectivity changes in autosomal dominant Alzheimer's disease (ADAD) patients and successfully detected significant associations between U-fiber connectivity and disease severity.

Single-nucleus RNA sequencing demonstrates an autosomal dominant Alzheimer’s disease profile and possible mechanisms of disease protection

Highly penetrant autosomal dominant Alzheimer's disease (ADAD) comprises a distinct disease entity as compared to the far more prevalent form of AD in which common variants collectively contribute to risk. The downstream pathways that distinguish these AD forms in specific cell types have not been deeply explored. We compared single-nucleus transcriptomes among a set of 27 cases divided among PSEN1-E280A ADAD carriers, sporadic AD, and controls. Autophagy genes and chaperones clearly defined the PSEN1-E280A cases compared to sporadic AD. Spatial transcriptomics validated the activation of chaperone-mediated autophagy genes in PSEN1-E280A. The PSEN1-E280A case in which much of the brain was spared neurofibrillary pathology and harbored a homozygous APOE3-Christchurch variant revealed possible explanations for protection from AD pathology including overexpression of LRP1 in astrocytes, increased expression of FKBP1B, and decreased PSEN1 expression in neurons. The unique cellular responses in ADAD and sporadic AD require consideration when designing clinical trials.

Autosomal Dominant Alzheimer's Disease Mutations in Human Microglia Are Not Sufficient to Trigger Amyloid Pathology in WT Mice but Might Affect Pathology in 5XFAD Mice.

Several genetic variants that affect microglia function have been identified as risk factors for Alzheimer's Disease (AD), supporting the importance of this cell type in disease progression. However, the effect of autosomal dominant mutations in the amyloid precursor protein (APP) or the presenilin (PSEN1/2) genes has not been addressed in microglia in vivo. We xenotransplanted human microglia derived from non-carriers and carriers of autosomal dominant AD (ADAD)-causing mutations in the brain of hCSF1 WT or 5XFAD mice. We observed that ADAD mutations in microglia are not sufficient to trigger amyloid pathology in WT mice. In 5XFAD mice, we observed a non-statistically significant increase in amyloid plaque volume and number of dystrophic neurites, coupled with a reduction in plaque-associated microglia in the brain of mice xenotransplanted with ADAD human microglia compared to mice xenotransplanted with non-ADAD microglia. In addition, we observed a non-statistically significant impairment in working and contextual memory in 5XFAD mice xenotransplanted with ADAD microglia compared to those xenotransplanted with non-ADAD-carrier microglia. We conclude that, although not sufficient to initiate amyloid pathology in the healthy brain, mutations in APP and PSEN1 in human microglia might cause mild changes in pathological and cognitive outcomes in 5XFAD mice in a manner consistent with increased AD risk.

APOE3ch alters microglial response and suppresses Aβ-induced tau seeding and spread

A recent case report described an individual who was a homozygous carrier of the APOE3 Christchurch (APOE3ch) mutation and resistant to autosomal dominant Alzheimer's Disease (AD) caused by a PSEN1-E280A mutation. Whether APOE3ch contributed to the protective effect remains unclear. We generated a humanized APOE3ch knock-in mouse and crossed it to an amyloid-β (Aβ) plaque-depositing model. We injected AD-tau brain extract to investigate tau seeding and spreading in the presence or absence of amyloid. Similar to the case report, APOE3ch expression resulted in peripheral dyslipidemia and a marked reduction in plaque-associated tau pathology. Additionally, we observed decreased amyloid response and enhanced microglial response around plaques. We also demonstrate increased myeloid cell phagocytosis and degradation of tau aggregates linked to weaker APOE3ch binding to heparin sulfate proteoglycans. APOE3ch influences the microglial response to Aβ plaques, which suppresses Aβ-induced tau seeding and spreading. The results reveal new possibilities to target Aβ-induced tauopathy.

Clinical Manifestations.

In recent years, there has been an increase in the number of case reports of families with autosomal dominant Alzheimer's disease (ADAD) in Latin America (LA). Nevertheless, little is known about the clinical phenotypes and demographic characteristics of mutations in each country. Past literature has proved that variants in LA have different and unique characteristics than those reported in Asia, North America, and Europe. Clinical heterogeneity in ADAD supports the need to study clinical phenotypes, especially in preclinical stages, to develop cognitive and clinical markers of the disease. We aimed to describe clinical and cognitive characteristics at baseline assessment of an Argentina PSEN1 p.M146L family enrolled at DIAN. Fifteen Dian Participants living in Buenos Aires and its suburbs and in Taco Pozo, a rural and isolated community from the Province of Salta, positive for the PSEN1 p.M146L mutation, were recruited. DNA was obtained from peripheral blood leukocytes according to standard protocols. In addition, exon 5 of the PSEN1 gene was PCR-amplified, and Sanger sequencing was performed. NACC Uniform Data Set clinical assessment, including the 2.0 UDS Neuropsychological Battery, was administered. Two groups were used to compare cognitive data: Patients with CDR:0 (n:10) and patients with CDR>0 (n:5). The mean age at symptom onset reported in this cohort was 42,90 (SD: 4,62). Significant differences were found in several cognitive measures: Logical Memory Immediate, TMT B and Digit Backward (<0,001); MMSE, Category Fluency Animals, TMT A and Digit Symbol(<0,05). In neurological signs, paraplegia was reported in one of the patients. As expected, differences in neuropsychological tests showed a prevalence of memory deficits, however, dysexecutive symptoms were also present for this mutation. Paraplegia in PSEN1 p.M146L has not been reported in the literature so far. Ongoing longitudinal work will be important in tracking changes in this cohort. Other characteristics, proper of underrepresented groups, such as socioeconomic status, education, race, and ethnicity, deserve appropriate follow-up. Future studies are planned, comparing urban and rural populations in this cohort with the same mutation.

22 Semantic Processing and its Relation to Brain Pathology in Individuals with Autosomal Dominant Alzheimer's Disease: Preliminary Findings from the Colombia-Boston Biomarker Study

Objective:Semantic processing dysfunction has been shown to be an early indicator of cognitive decline in Alzheimer's disease (AD) and has been linked to early accumulation of AD-pathology. We examined semantic processing and its relation to AD pathology in non-demented individuals from a Colombian kindred with autosomal dominant AD due to the Presenilin1 E280A mutation (PSEN1).Participants and Methods:A total of 13 cognitively unimpaired PSEN1 mutation carriers (mean age: 36.92± 4.94), 7 carriers with mild cognitive impairment (MCI; mean age: 45±2.65), and 17 family non-carriers (mean age: 36±6.38) from the Colombia-Boston (COLBOS) longitudinal biomarker study were included. We used the Bateria IV Woodcock-Munoz verbal analogies and text comprehension subtests to examine semantic processing, the Mini-Mental State Examination (MMSE) to assess global cognition and the CERAD word list delayed recall task to measure verbal memory. Participants also underwent PiB and flortaucipir-PET to measure mean cortical amyloid and regional tau burden (entorhinal cortex and precuneus), respectively. Mann-Whitney U tests and Spearman's Rho correlations compared group differences in semantic processing, and its associations with age and pathological markers. Post-hoc analyses excluded carriers with MCI and controlled for education.Results:Carriers (including cognitively unimpaired and symptomatic individuals) performed significantly worse on the MMSE (carriers: 14.55, non-carriers: 24.24; U=81.00, p=.006), CERAD word list delayed recall (carriers: 13.63, non-carriers: 25.32; U=48.00, p=.001), and text comprehension (carriers: 16.36, non-carriers: 23.81; l/=107.00, p=.042,) than non-carriers, and showed a trend towards worse performance on verbal analogies (carriers: 17.16, non-carriers: 23.68; U=124.50, p=.077). There were no differences in text comprehension or verbal analogies performance between cognitively-unimpaired carriers and non-carriers.Across the whole sample, age was negatively associated with performance on verbal analogies (r=-.341, p=.039), but not text comprehension (r=-.136, p=.428). Among carriers only, better MMSE and CERAD delayed recall performance was associated with higher verbal analogies (r=.561, p=&lt;.001; r=.662, p=&lt;.001, respectively) and text comprehension scores (r=.468, p=.004; r=.480, p=.003, respectively). Greater amyloid burden was associated with worse verbal analogies performance (r=-.432, p=.007) and text comprehension (r=-.430, p=.008). Greater entorhinal cortex (r=-.384, p=.016) and precuneus tau burden (r=-.318, p=.049) was associated with worse performance on verbal analogies, but not text comprehension. These associations did not survive when excluding carriers with MCI or controlling for education.Conclusions:Preliminary results show that non-demented mutation carriers had worse performance in semantic processing than non-carriers and performance was associated with markers of AD pathology. These findings suggest that changes in semantic processing may be early indicators of disease progression in individuals at increased risk for Alzheimer's disease dementia. Future studies with larger samples need to examine the role of education and the longitudinal trajectory of semantic processing dysfunction in AD.

Depressive symptoms and hippocampal volume in autosomal dominant Alzheimer's disease.

Depressive symptoms are among early behavioral changes in Alzheimer's disease (AD); however, the relationship between neurodegeneration and depressive symptoms remains inconclusive. To better understand this relationship in preclinical AD, we examined hippocampal volume and depressive symptoms in cognitively unimpaired carriers of the presenilin-1 (PSEN1) E280A mutation for autosomal dominant AD. A total of 27 PSEN1 mutation carriers and 26 non-carrier family members were included. Linear regression was used to test the relationship between hippocampal volume and 15-item Geriatric Depression Scale. Carriers and non-carriers did not differ in depressive symptoms or hippocampal volume. Within carriers, lower hippocampal volume was associated with greater depressive symptoms, which remained significant after adjusting for age and cognition. This relationship was not significant in non-carriers. Hippocampal neurodegeneration may underlie depressive symptoms in preclinical autosomal dominant AD. These findings provide support for the utility of targeting depressive symptoms in AD prevention. We compared unimpaired autosomal dominant Alzheimer's disease (AD) mutation carriers and non-carriers. Carriers and non-carriers did not differ in severity of depressive symptoms. In carriers, hippocampal volume was inversely associated with depressive symptoms. Depressive symptoms may be a useful target in AD prevention.

A - 21 Sex Differences in Cortical Thickness and Cognition in Individuals with Autosomal Dominant Alzheimer's Disease.

Cortical thinning is a marker of neurodegeneration. Individuals with autosomal dominant Alzheimer's disease (ADAD) develop early-onset dementia with virtually 100% certainty. Cortical thickness fluctuates across the ADAD lifespan, from early-life increased thickness to atrophy proximal to clinical onset. Females have higher cortical thickness and better cognition than males as they age. We examined sex differences in cortical thickness and cognitive performance in adults with ADAD. We assessed 85 Presenilin-1 E280A mutation carriers (74 cognitively-unimpaired, 11 mildly-impaired) from the Colombia-Boston Biomarker Study of ADAD. Mean age was 35.7 (SD = 10), education 10.2 (SD = 9), and 55 were female. Global cognition was measured using Mini-Mental State Examination (MMSE), and memory using CERAD Word List Delayed Recall. Participants underwent structural brain MRI. T-tests assessed between-group differences. Pearson correlations examined associations between cortical thickness and cognition. There were no sex differences in cortical thickness or cognitive performance (all ps > =0.05). For carriers, greater cortical thickness was associated with higher MMSE (r = 0.40, p < 0.001) and memory recall scores (r = 0.43, p < 0.01). Female carriers drove this effect, where greater cortical thickness was associated with higher MMSE (r = 0.46, p < 0.001) and memory recall scores (r = 0.47, p < 0.001); these associations were non-significant in male carriers alone. In cognitively-unimpaired female carriers, increased cortical thickness was associated with worse MMSE (r = -0.44, p < 0.001). We found sex differences in the relation between cortical thickness and cognition in ADAD carriers, which may be relevant to the differential vulnerability and progression of ad in females and males. Future work should investigate potential underlying mechanisms contributing to this sex difference.

H - 06 Associations between Non-verbal Reasoning Abilities and Brain Pathology in a Colombian Cohort with Autosomal Dominant Alzheimer's Disease.

Declines in non-verbal reasoning abilities have been linked to Alzheimer's disease (ad) progression. Individuals with autosomal dominant ad (ADAD) are genetically determined to develop early-onset dementia. We examined the relation between non-verbal reasoning abilities and brain pathology in a Colombian cohort with ADAD due to the Presenilin-1 (PSEN1) E280A mutation. A total of 25 carriers of the PSEN1 E280A mutation (16 cognitively-unimpaired carriers [x- age = 35.25 +/- 4.04]; 9 with mildly impaired (age = 45.56 +/- 2.60), and 27 non-carriers (age = 36.11 +/- 5.59) were included. A summary non-verbal reasoning score was calculated from performance on the Judgment of Line Orientation and the Spanish WAIS-IV Matrix Reasoning and Visual Puzzles subtests. Participants also completed the Mini-mental State Examination (MMSE) and underwent amyloid and tau PET imaging. Mann-Whitney U test and education-adjusted Spearman partial correlations were used to examine group differences and associations between pathology levels and non-verbal reasoning. Compared to carriers, non-carriers had higher MMSE and non-verbal reasoning scores (p = 0.006). In carriers only, lower non-verbal reasoning was associated with greater mean cortical amyloid (r = -0.427, p = 0.037) and greater precuneus tau (r = -0.516, p = 0.010). No significant associations were observed after excluding the impaired carriers from the analyses. Our findings suggest that changes in non-verbal reasoning abilities are evident in early symptomatic ADAD stages and are related to ad brain pathology. Future longitudinal work is needed to characterize the progression of non-verbal reasoning deficits in ADAD. Future research should also examine performance between older adults and people at risk for sporadic ad.

Psychological Status of the Participants in Alzheimer's Prevention Initiative Autosomal Dominant Alzheimer's Disease Colombia.

The SARS-CoV2 global pandemic impacted participants in the Alzheimer's Prevention Initiative (API) Autosomal Dominant Alzheimer's Disease (ADAD) clinical trial, who faced three stressors: 1) fear of developing dementia; 2) concerns about missing treatment; and 3) risk of SARS-CoV2 infection. To describe the frequency of psychological disorders among the participants of the API ADAD Colombia clinical study, treated by a holistic mental health team during the COVID-19 pandemic. The extent of use of mental health team services was explored considering different risk factors, and users and non-users of these services were compared. Participants had free and optional access to psychology and psychiatry services, outside of the study protocol. Descriptive statistics was used to analyze the frequency of the mental health difficulties. A multivariable logistic regression model has been used to assess associations with using this program. 66 participants were treated by the Mental Health Team from March 1, 2020, to December 31, 2020. Before and after the start of the pandemic, the most common psychological problems were anxiety (36.4% before, 63.6% after) and depression (34.8% before, 37.9% after). 70% of users assisted by psychology and 81.6% of those assisted by psychiatry felt that the services were useful for them. Female sex, depression, and anxiety before the pandemic were positively associated with being assisted by either psychology or psychiatry, while the association with hyperlipidemia was negative. A holistic mental health program, carried out in the context of a study, could mitigate psychopathology during pandemics such as COVID-19.

FMRI Complexity Correlates with Tau-PET and Cognitive Decline in Late-Onset and Autosomal Dominant Alzheimer's Disease.

Neurofibrillary tangle pathology detected with tau-PET correlates closely with neuronal injury and cognitive symptoms in Alzheimer's disease (AD). Complexity of rs-fMRI has been demonstrated to decrease with cognitive decline in AD. We hypothesize that the rs-fMRI complexity provides an index for tau-related neuronal injury and cognitive decline in the AD process. Data was obtained from the Alzheimer's Disease Neuroimaging Initiative (ADNI3) and the Estudio de la Enfermedad de Alzheimer en Jalisciences (EEAJ) study. Associations between tau-PET and rs-fMRI complexity were calculated. Potential pathways relating complexity to cognitive function mediated through tau-PET were assessed by path analysis. We found significant negative correlations between rs-fMRI complexity and tau-PET in medial temporal lobe of both cohorts, and associations of rs-fMRI complexity with cognitive scores were mediated through tau-PET. The association of rs-fMRI complexity with tau-PET and cognition, suggests that a reduction in complexity is indicative of tau-related neuropathology and cognitive decline in AD processes.