Leukocyte surface biomarkers implicate deficits of innate immunity in sporadic Alzheimer's disease.

INTRODUCTION: Blood-based diagnostics and prognostics in sporadic Alzheimer's disease (AD) are important for identifying at-risk individuals for therapeutic interventions. METHODS: In three stages, a total of 34 leukocyte antigens were examined by flow cytometry immunophenotyping. Data were analyzed by logistic regression and receiver operating characteristic (ROC) analyses. RESULTS: We identified leukocyte markers differentially expressed in the patients with AD. Pathway analysis revealed a complex network involving upregulation of complement inhibition and downregulation of cargo receptor activity and Aß clearance. A proposed panel including four leukocyte markers - CD11c, CD59, CD91, and CD163 - predicts patients' PET Aß status with an area under the curve (AUC) of 0.93 (0.88 to 0.97). CD163 was the top performer in preclinical models. These findings have been validated in two independent cohorts. CONCLUSION: Our finding of changes on peripheral leukocyte surface antigens in AD implicates the deficit in innate immunity. Leukocyte-based biomarkers prove to be both sensitive and practical for AD screening and diagnosis.

Association of Self-Reported Psychological Stress with Cognitive Decline: A Systematic Review.

Psychological stress is a potential modifiable risk factor for cognitive decline. However, the extent to which self-reported psychological stress is differentially associated with decline in specific cognitive domains remains unclear. Differences may be due to heterogeneity in the aspects of psychological stress investigated, for example, neuroticism (which is linked to vulnerability to stress), perceived stress, or exposure to stressful life events. This review aims to establish the associations between these aspects of self-reported psychological stress and cognitive decline. PsychINFO, Embase and MEDLINE were searched from database inception to September 2021. Studies were included if they were observational, prospective, and if they investigated the association between self-reported psychological stress and cognitive decline in adults with a minimum mean age of 40 years at baseline. Thirty studies satisfied the inclusion criteria, with most examining neuroticism (n = 17) as a predictor of cognitive decline. Fewer examined perceived stress (n = 7) or stressful life events (n = 6). There was evidence of an association between neuroticism and cognitive decline, particularly in the domain of memory. Similarly, across studies, perceived stress was also associated with memory decline. Research investigating the relationship between stressful life events and cognitive decline had fewer outcomes to interpret. Overall, the findings highlight that memory may be particularly susceptible to high levels of neuroticism and perceived stress. We identified a lack of research into some cognitive domains, such as executive function, which should be addressed by future studies.

The BDNFVal66Met SNP modulates the association between beta-amyloid and hippocampal disconnection in Alzheimer's disease.

In Alzheimer's disease (AD), a single-nucleotide polymorphism in the gene encoding brain-derived neurotrophic factor (BDNFVal66Met) is associated with worse impact of primary AD pathology (beta-amyloid, Aß) on neurodegeneration and cognitive decline, rendering BDNFVal66Met an important modulating factor of cognitive impairment in AD. However, the effect of BDNFVal66Met on functional networks that may underlie cognitive impairment in AD is poorly understood. Using a cross-validation approach, we first explored in subjects with autosomal dominant AD (ADAD) from the Dominantly Inherited Alzheimer Network (DIAN) the effect of BDNFVal66Met on resting-state fMRI assessed functional networks. In seed-based connectivity analysis of six major large-scale networks, we found a stronger decrease of hippocampus (seed) to medial-frontal connectivity in the BDNFVal66Met carriers compared to BDNFVal homozogytes. BDNFVal66Met was not associated with connectivity in any other networks. Next, we tested whether the finding of more pronounced decrease in hippocampal-medial-frontal connectivity in BDNFVal66Met could be also found in elderly subjects with sporadically occurring Aß, including a group with subjective cognitive decline (N = 149, FACEHBI study) and a group ranging from preclinical to AD dementia (N = 114, DELCODE study). In both of these independently recruited groups, BDNFVal66Met was associated with a stronger effect of more abnormal Aß-levels (assessed by biofluid-assay or amyloid-PET) on hippocampal-medial-frontal connectivity decreases, controlled for hippocampus volume and other confounds. Lower hippocampal-medial-frontal connectivity was associated with lower global cognitive performance in the DIAN and DELCODE studies. Together these results suggest that BDNFVal66Met is selectively associated with a higher vulnerability of hippocampus-frontal connectivity to primary AD pathology, resulting in greater AD-related cognitive impairment.

Predicting sporadic Alzheimer's disease progression via inherited Alzheimer's disease-informed machine-learning.

INTRODUCTION: Developing cross-validated multi-biomarker models for the prediction of the rate of cognitive decline in Alzheimer's disease (AD) is a critical yet unmet clinical challenge. METHODS: We applied support vector regression to AD biomarkers derived from cerebrospinal fluid, structural magnetic resonance imaging (MRI), amyloid-PET and fluorodeoxyglucose positron-emission tomography (FDG-PET) to predict rates of cognitive decline. Prediction models were trained in autosomal-dominant Alzheimer's disease (ADAD, n = 121) and subsequently cross-validated in sporadic prodromal AD (n = 216). The sample size needed to detect treatment effects when using model-based risk enrichment was estimated. RESULTS: A model combining all biomarker modalities and established in ADAD predicted the 4-year rate of decline in global cognition (R2 = 24%) and memory (R2 = 25%) in sporadic AD. Model-based risk-enrichment reduced the sample size required for detecting simulated intervention effects by 50%-75%. DISCUSSION: Our independently validated machine-learning model predicted cognitive decline in sporadic prodromal AD and may substantially reduce sample size needed in clinical trials in AD.

Awareness of genetic risk in the Dominantly Inherited Alzheimer Network (DIAN).

INTRODUCTION: Although some members of families with autosomal dominant Alzheimer's disease mutations learn their mutation status, most do not. How knowledge of mutation status affects clinical disease progression is unknown. This study quantifies the influence of mutation awareness on clinical symptoms, cognition, and biomarkers. METHODS: Mutation carriers and non-carriers from the Dominantly Inherited Alzheimer Network (DIAN) were stratified based on knowledge of mutation status. Rates of change on standard clinical, cognitive, and neuroimaging outcomes were examined. RESULTS: Mutation knowledge had no associations with cognitive decline, clinical progression, amyloid deposition, hippocampal volume, or depression in either carriers or non-carriers. Carriers who learned their status mid-study had slightly higher levels of depression and lower cognitive scores. DISCUSSION: Knowledge of mutation status does not affect rates of change on any measured outcome. Learning of status mid-study may confer short-term changes in cognitive functioning, or changes in cognition may influence the determination of mutation status.

Effect of BDNFVal66Met on disease markers in dominantly inherited Alzheimer's disease.

OBJECTIVE: Previous studies suggest that the brain-derived neurotrophic factor (BDNF) Val66Met (rs6265) polymorphism may influence symptom onset in Alzheimer's disease (AD). Our recent cross-sectional findings suggest that Met66 may influence clinical expression in dominantly inherited AD (DIAD) through its effects on tau. However, it remains unclear whether carriage of Met66 in DIAD results in faster increases in cerebrospinal fluid (CSF) tau and ptau181 , and whether these increases are associated with accelerated brain volume loss and memory decline. METHODS: A total of 211 subjects (101 mutation noncarriers, 110 mutation carriers), who were cognitively normal, as defined by a Clinical Dementia Rating global score of 0, completed assessments of cognitive function, neuroimaging, and CSF sampling over 3.5 years as part of the Dominantly Inherited Alzheimer's Network. RESULTS: In mutation carriers, Met66 carriers showed faster memory decline (4×), hippocampal volume loss (16×), and CSF tau and ptau181 increases (6×) than Val66 homozygotes. BDNF did not influence rates of cortical ß-amyloid accumulation or change in CSF Aß42 levels in mutation carriers. In mutation noncarriers, BDNF genotype had no effect on change in cognition, brain volume, cortical ß-amyloid accumulation, or change in any CSF measures of tau, ptau181 , and CSF Aß42 . INTERPRETATION: As in sporadic AD, the deleterious effects of ß-amyloid on cognitive function, brain volume loss, and CSF tau in DIAD mutation carriers are less in Val66 homozygotes. The BDNF Val66Met polymorphism should be considered as a potential moderator of clinical trial outcomes in current treatment and prevention trials in DIAD and sporadic AD. Ann Neurol 2018;84:424-435.

Combined neuropathological pathways account for age-related risk of dementia.

OBJECTIVE: Our objectives were to characterize the inter-relation of known dementia-related neuropathologies in one comprehensive model and quantify the extent to which accumulation of neuropathologies accounts for the association between age and dementia. METHODS: We used data from 1,362 autopsied participants of three community-based clinicopathological cohorts: the Religious Orders Study, the Rush Memory and Aging Project, and the Minority Aging Research Study. We estimated a series of structural equation models summarizing a priori hypothesized neuropathological pathways between age and dementia risk individually and collectively. RESULTS: At time of death (mean age, 89 years), 44% of our sample had a clinical dementia diagnosis. When considered individually, our vascular, amyloid/tau, neocortical Lewy body, and TAR DNA-binding protein 43 (TDP-43)/hippocampal sclerosis pathology pathways each accounted for a substantial proportion of the association between age and dementia. When considered collectively, the four pathways fully accounted for all variance in dementia risk previously attributable to age. Pathways involving amyloid/tau, neocortical Lewy bodies, and TDP-43/hippocampal sclerosis were interdependent, attributable to the importance of amyloid beta plaques in all three. The importance of the pathways varied, with the vascular pathway accounting for 32% of the association between age and dementia, wheraes the remaining three inter-related degenerative pathways together accounted for 68% (amyloid/tau, 24%; the Lewy body, 1%; and TDP-43/hippocampal sclerosis, 43%). INTERPRETATION: Age-related increases in dementia risk can be attributed to accumulation of multiple pathologies, each of which contributes to dementia risk. Multipronged approaches may be necessary if we are to develop effective therapies. Ann Neurol 2018;84:10-22.

Cerebral quantitative susceptibility mapping predicts amyloid-ß-related cognitive decline.

See Derry and Kent (doi:10.1093/awx167) for a scientific commentary on this article.The large variance in cognitive deterioration in subjects who test positive for amyloid-ß by positron emission tomography indicates that convergent pathologies, such as iron accumulation, might combine with amyloid-ß to accelerate Alzheimer's disease progression. Here, we applied quantitative susceptibility mapping, a relatively new magnetic resonance imaging method sensitive to tissue iron, to assess the relationship between iron, amyloid-ß load, and cognitive decline in 117 subjects who underwent baseline magnetic resonance imaging and amyloid-ß positron emission tomography from the Australian Imaging, Biomarkers and Lifestyle study (AIBL). Cognitive function data were collected every 18 months for up to 6 years from 100 volunteers who were either cognitively normal (n = 64) or diagnosed with mild cognitive impairment (n = 17) or Alzheimer's disease (n = 19). Among participants with amyloid pathology (n = 45), higher hippocampal quantitative susceptibility mapping levels predicted accelerated deterioration in composite cognition tests for episodic memory [ß(standard error) = -0.169 (0.034), P = 9.2 × 10-7], executive function [ß(standard error) = -0.139 (0.048), P = 0.004), and attention [ß(standard error) = -0.074 (0.029), P = 0.012]. Deteriorating performance in a composite of language tests was predicted by higher quantitative susceptibility mapping levels in temporal lobe [ß(standard error) = -0.104 (0.05), P = 0.036] and frontal lobe [ß(standard error) = -0.154 (0.055), P = 0.006]. These findings indicate that brain iron might combine with amyloid-ß to accelerate clinical progression and that quantitative susceptibility mapping could be used in combination with amyloid-ß positron emission tomography to stratify individuals at risk of decline.

Trajectories of depressive and anxiety symptoms in older adults: a 6-year prospective cohort study.

OBJECTIVE: Depressive and anxiety symptoms are common in older adults, significantly affect quality of life, and are risk factors for Alzheimer's disease. We sought to identify the determinants of predominant trajectories of depressive and anxiety symptoms in cognitively normal older adults. METHOD: Four hundred twenty-three older adults recruited from the general community underwent Aß positron emission tomography imaging, apolipoprotein and brain-derived neurotrophic factor genotyping, and cognitive testing at baseline and had follow-up assessments. All participants were cognitively normal and free of clinical depression at baseline. Latent growth mixture modeling was used to identify predominant trajectories of subthreshold depressive and anxiety symptoms over 6 years. Binary logistic regression analysis was used to identify baseline predictors of symptomatic depressive and anxiety trajectories. RESULTS: Latent growth mixture modeling revealed two predominant trajectories of depressive and anxiety symptoms: a chronically elevated trajectory and a low, stable symptom trajectory, with almost one in five participants falling into the elevated trajectory groups. Male sex (relative risk ratio (RRR) = 3.23), lower attentional function (RRR = 1.90), and carriage of the brain-derived neurotrophic factor Val66Met allele in women (RRR = 2.70) were associated with increased risk for chronically elevated depressive symptom trajectory. Carriage of the apolipoprotein epsilon 4 allele (RRR = 1.92) and lower executive function in women (RRR = 1.74) were associated with chronically elevated anxiety symptom trajectory. CONCLUSION: Our results indicate distinct and sex-specific risk factors linked to depressive and anxiety trajectories, which may help inform risk stratification and management of these symptoms in older adults at risk for Alzheimer's disease. Copyright © 2017 John Wiley & Sons, Ltd.

Sex, amyloid, and APOE ε4 and risk of cognitive decline in preclinical Alzheimer's disease: Findings from three well-characterized cohorts.

INTRODUCTION: Our objective was to investigate the effect of sex on cognitive decline within the context of amyloid ß (Aß) burden and apolipoprotein E genotype. METHODS: We analyzed sex-specific effects on Aß-positron emission tomography, apolipoprotein, and rates of change on the Preclinical Alzheimer Cognitive Composite-5 across three cohorts, such as the Alzheimer's Disease Neuroimaging Initiative, Australian Imaging, Biomarker and Lifestyle, and Harvard Aging Brain Study (n = 755; clinical dementia rating = 0; age (standard deviation) = 73.6 (6.5); female = 55%). Mixed-effects models of cognitive change by sex, Aß-positron emission tomography, and apolipoprotein ε4 were examined with quadratic time effects over a median of 4 years of follow-up. RESULTS: Apolipoprotein ε4 prevalence and Aß burden did not differ by sex. Sex did not directly influence cognitive decline. Females with higher Aß exhibited faster decline than males. Post hoc contrasts suggested that females who were Aß and apolipoprotein ε4 positive declined faster than their male counterparts. DISCUSSION: Although Aß did not differ by sex, cognitive decline was greater in females with higher Aß. Our findings suggest that sex may play a modifying role on risk of Alzheimer's disease-related cognitive decline.

BDNF Val66Met moderates memory impairment, hippocampal function and tau in preclinical autosomal dominant Alzheimer's disease.

SEE ROGAEVA AND SCHMITT-ULMS DOI101093/AWW201 FOR A SCIENTIFIC COMMENTARY ON THIS ARTICLE: The brain-derived neurotrophic factor (BDNF) Val66Met polymorphism is implicated in synaptic excitation and neuronal integrity, and has previously been shown to moderate amyloid-ß-related memory decline and hippocampal atrophy in preclinical sporadic Alzheimer's disease. However, the effect of BDNF in autosomal dominant Alzheimer's disease is unknown. We aimed to determine the effect of BDNF Val66Met on cognitive function, hippocampal function, tau and amyloid-ß in preclinical autosomal dominant Alzheimer's disease. We explored effects of apolipoprotein E (APOE) ε4 on these relationships. The Dominantly Inherited Alzheimer Network conducted clinical, neuropsychological, genetic, biomarker and neuroimaging measures at baseline in 131 mutation non-carriers and 143 preclinical autosomal dominant Alzheimer's disease mutation carriers on average 12 years before clinical symptom onset. BDNF genotype data were obtained for mutation carriers (95 Val66 homozygotes, 48 Met66 carriers). Among preclinical mutation carriers, Met66 carriers had worse memory performance, lower hippocampal glucose metabolism and increased levels of cerebrospinal fluid tau and phosphorylated tau (p-tau) than Val66 homozygotes. Cortical amyloid-ß and cerebrospinal fluid amyloid-ß42 levels were significantly different from non-carriers but did not differ between preclinical mutation carrier Val66 homozygotes and Met66 carriers. There was an effect of APOE on amyloid-ß levels, but not cognitive function, glucose metabolism or tau. As in sporadic Alzheimer's disease, the deleterious effects of amyloid-ß on memory, hippocampal function, and tau in preclinical autosomal dominant Alzheimer's disease mutation carriers are greater in Met66 carriers. To date, this is the only genetic factor found to moderate downstream effects of amyloid-ß in autosomal dominant Alzheimer's disease.

Amyloid burden and incident depressive symptoms in cognitively normal older adults.

OBJECTIVE: Several studies have reported that non-demented older adults with clinical depression show changes in amyloid-ß (Aß) levels in blood, cerebrospinal fluid and on neuroimaging that are consistent with those observed in patients with Alzheimer's disease. These findings suggest that Aß may be one of the mechanisms underlying the relation between the two conditions. We sought to determine the relation between elevated cerebral Aß and the presence of depression across a 54-month prospective observation period. METHODS: Cognitively normal older adults from the Australian Imaging Biomarkers and Lifestyle study who were not depressed and had undergone a positron emission tomography scan to classify them as either high Aß (n = 81) or low Aß (n = 278) participated. Depressive symptoms were assessed using the Geriatric Depression Scale - Short Form at 18-month intervals over 54 months. RESULTS: Whilst there was no difference in probable depression between groups at baseline, incidence was 4.5 (95% confidence interval [CI] 1.3-16.4) times greater within the high Aß group (9%) than the low Aß group (2%) by the 54-month assessment. CONCLUSIONS: Results of this study suggest that elevated Aß levels are associated with a 4.5-fold increased likelihood of developing clinically significant depressive symptoms on follow-up in preclinical Alzheimer's disease. This underscores the importance of assessing, monitoring and treating depressive symptoms in older adults with elevated Aß. Copyright © 2016 John Wiley & Sons, Ltd.

BDNF Val66Met in preclinical Alzheimer's disease is associated with short-term changes in episodic memory and hippocampal volume but not serum mBDNF.

BACKGROUND: The brain-derived neurotrophic factor (BDNF) Val66Met polymorphism Met allele exacerbates amyloid (Aß) related decline in episodic memory (EM) and hippocampal volume (HV) over 36-54 months in preclinical Alzheimer's disease (AD). However, the extent to which Aß+ and BDNF Val66Met is related to circulating markers of BDNF (e.g. serum) is unknown. We aimed to determine the effect of Aß and the BDNF Val66Met polymorphism on levels of serum mBDNF, EM, and HV at baseline and over 18-months. METHODS: Non-demented older adults (n = 446) underwent Aß neuroimaging and BDNF Val66Met genotyping. EM and HV were assessed at baseline and 18 months later. Fasted blood samples were obtained from each participant at baseline and at 18-month follow-up. Aß PET neuroimaging was used to classify participants as Aß- or Aß+. RESULTS: At baseline, Aß+ adults showed worse EM impairment and lower serum mBDNF levels relative to Aß- adults. BDNF Val66Met polymorphism did not affect serum mBDNF, EM, or HV at baseline. When considered over 18-months, compared to Aß- Val homozygotes, Aß+ Val homozygotes showed significant decline in EM and HV but not serum mBDNF. Similarly, compared to Aß+ Val homozygotes, Aß+ Met carriers showed significant decline in EM and HV over 18-months but showed no change in serum mBDNF. CONCLUSION: While allelic variation in BDNF Val66Met may influence Aß+ related neurodegeneration and memory loss over the short term, this is not related to serum mBDNF. Longer follow-up intervals may be required to further determine any relationships between serum mBDNF, EM, and HV in preclinical AD.

ß-Amyloid, APOE and BDNF Genotype, and Depressive and Anxiety Symptoms in Cognitively Normal Older Women and Men.

OBJECTIVE: To examine how ß-amyloid (Aß), APOE and BDNF genotypes, and cortisol relate to depressive and anxiety symptoms in cognitively normal older women and men. METHODS: Cross-sectional data were analyzed from 423 older adults from the Australian Imaging Biomarkers and Lifestyle study. Analyses of covariance evaluated associations between Aß, APOE and BDNF genotype, and cortisol in relation to severity of depressive and anxiety symptoms. RESULTS: Among Aß+ older adults, APOE ε4 carriage was associated with greater severity of anxiety symptoms (d = 0.55); and in the full sample, APOE ε4 carriage was linked to greater severity of depressive (d = 0.26) and anxiety (d = 0.21) symptoms. Among Aß+ women, ε4 carriers reported greater anxiety symptoms than non-ε4 carriers (d = 0.83), and female BDNF rs6265 Val66 Met allele carriers reported greater depressive symptoms (d = 0.29). CONCLUSION: Sex moderated the relationship between Aß, APOE genotype, and BDNF genotype in predicting severity of anxiety and depressive symptoms in cognitively normal older adults.

Disclosure of positron emission tomography amyloid imaging results: A preliminary study of safety and tolerability.

INTRODUCTION: Three (18)F-labeled radiopharmaceuticals have been Food and Drug Administration-approved for the identification of cortical amyloidosis in clinical settings. Although there has been strong debate among professionals as to the ethical and social consequences of disclosing such information, increasing numbers of participants are being recruited into secondary prevention trials for which they are likely to, and/or desire to, receive their positron emission tomography (PET) imaging results. METHODS: Healthy older adults (n = 63, mean age = 62 years) enrolled in a preclinical Alzheimer's disease (AD) biomarkers trial, and 11 requested disclosure of PET amyloid imaging results to their treating neurologist, per institutional review board-approved study protocol. These individuals completed a follow-up psychoeducational program and structured interviews to assess impact of disclosure on several key psychological factors. RESULTS: Four of 11 subjects demonstrated increased amyloid aggregation and reported that they were not surprised, particularly given their family histories and subjective memory concerns. All indicated that they had shared this information with pertinent significant others; they were satisfied with their level of social support, and the imaging results had motivated them to change their lifestyle by exercising more, changing their diet, and planning ahead. Amyloid-positive participants showed little change in levels of depressive, anxiety, and stress symptoms, subjective sense of memory impairment, or on measures of intrusion, avoidance, and hyperarousal, and reported risk of self-harm. DISCUSSION: Disclosure of PET amyloid status did not significantly impact mood, subjective sense of memory impairment, or perceived risk of developing AD; nor was this associated with significant emotional impact, irrespective of actual amyloid burden status. Those subjects with increased amyloid burden were more likely than those without significant amyloidosis to make positive changes to their lifestyle (e.g., engaging in more exercise and changing their diet).

Effect of amyloid on memory and non-memory decline from preclinical to clinical Alzheimer's disease.

High amyloid has been associated with substantial episodic memory decline over 18 and 36 months in healthy older adults and individuals with mild cognitive impairment. However, the nature and magnitude of amyloid-related memory and non-memory change from the preclinical to the clinical stages of Alzheimer's disease has not been evaluated over the same time interval. Healthy older adults (n = 320), individuals with mild cognitive impairment (n = 57) and individuals with Alzheimer's disease (n = 36) enrolled in the Australian Imaging, Biomarkers and Lifestyle study underwent at least one positron emission tomography neuroimaging scan for amyloid. Cognitive assessments were conducted at baseline, and 18- and 36-month follow-up assessments. Compared with amyloid-negative healthy older adults, amyloid-positive healthy older adults, and amyloid-positive individuals with mild cognitive impairment and Alzheimer's disease showed moderate and equivalent decline in verbal and visual episodic memory over 36 months (d's = 0.47-0.51). Relative to amyloid-negative healthy older adults, amyloid-positive healthy older adults showed no decline in non-memory functions, but amyloid-positive individuals with mild cognitive impairment showed additional moderate decline in language, attention and visuospatial function (d's = 0.47-1.12), and amyloid-positive individuals with Alzheimer's disease showed large decline in all aspects of memory and non-memory function (d's = 0.73-2.28). Amyloid negative individuals with mild cognitive impairment did not show any cognitive decline over 36 months. When non-demented individuals (i.e. healthy older adults and adults with mild cognitive impairment) were further dichotomized, high amyloid-positive non-demented individuals showed a greater rate of decline in episodic memory and language when compared with low amyloid positive non-demented individuals. Memory decline does not plateau with increasing disease severity, and decline in non-memory functions increases in amyloid-positive individuals with mild cognitive impairment and Alzheimer's disease. The combined detection of amyloid positivity and objectively-defined decline in memory are reliable indicators of early Alzheimer's disease, and the detection of decline in non-memory functions in amyloid-positive individuals with mild cognitive impairment may assist in determining the level of disease severity in these individuals. Further, these results suggest that grouping amyloid data into at least two categories of abnormality may be useful in determining the disease risk level in non-demented individuals.