APOE3 Christchurch Heterozygosity and Autosomal Dominant Alzheimer's Disease.

BACKGROUND: Variants in APOE and PSEN1 (encoding apolipoprotein E and presenilin 1, respectively) alter the risk of Alzheimer's disease. We previously reported a delay of cognitive impairment in a person with autosomal dominant Alzheimer's disease caused by the PSEN1 E280A variant who also had two copies of the apolipoprotein E3 Christchurch variant (APOE3 Ch). Heterozygosity for the APOE3 Ch variant may influence the age at which the onset of cognitive impairment occurs. We assessed this hypothesis in a population in which the PSEN1 E280A variant is prevalent. METHODS: We analyzed data from 27 participants with one copy of the APOE3 Ch variant among 1077 carriers of the PSEN1 E280A variant in a kindred from Antioquia, Colombia, to estimate the age at the onset of cognitive impairment and dementia in this group as compared with persons without the APOE3 Ch variant. Two participants underwent brain imaging, and autopsy was performed in four participants. RESULTS: Among carriers of PSEN1 E280A who were heterozygous for the APOE3 Ch variant, the median age at the onset of cognitive impairment was 52 years (95% confidence interval [CI], 51 to 58), in contrast to a matched group of PSEN1 E280A carriers without the APOE3 Ch variant, among whom the median age at the onset was 47 years (95% CI, 47 to 49). In two participants with the APOE3 Ch and PSEN1 E280A variants who underwent brain imaging, 18F-fluorodeoxyglucose positron-emission tomographic (PET) imaging showed relatively preserved metabolic activity in areas typically involved in Alzheimer's disease. In one of these participants, who underwent 18F-flortaucipir PET imaging, tau findings were limited as compared with persons with PSEN1 E280A in whom cognitive impairment occurred at the typical age in this kindred. Four studies of autopsy material obtained from persons with the APOE3 Ch and PSEN1 E280A variants showed fewer vascular amyloid pathologic features than were seen in material obtained from persons who had the PSEN1 E280A variant but not the APOE3 Ch variant. CONCLUSIONS: Clinical data supported a delayed onset of cognitive impairment in persons who were heterozygous for the APOE3 Ch variant in a kindred with a high prevalence of autosomal dominant Alzheimer's disease. (Funded by Good Ventures and others.).

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

INTRODUCTION: 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. METHODS: 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. RESULTS: 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. DISCUSSION: 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. HIGHLIGHTS: 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.

Plasma p-tau217 predicts in vivo brain pathology and cognition in autosomal dominant Alzheimer's disease.

INTRODUCTION: Plasma-measured tau phosphorylated at threonine 217 (p-tau217) is a potential non-invasive biomarker of Alzheimer's disease (AD). We investigated whether plasma p-tau217 predicts subsequent cognition and positron emission tomography (PET) markers of pathology in autosomal dominant AD. METHODS: We analyzed baseline levels of plasma p-tau217 and its associations with amyloid PET, tau PET, and word list delayed recall measured 7.61 years later in non-demented age- and education-matched presenilin-1 E280A carriers (n = 24) and non-carrier (n = 20) family members. RESULTS: Carriers had higher plasma p-tau217 levels than non-carriers. Baseline plasma p-tau217 was associated with subsequent amyloid and tau PET pathology levels and cognitive function. DISCUSSION: Our findings suggest that plasma p-tau217 predicts subsequent brain pathological burden and memory performance in presenilin-1 E280A carriers. These results provide support for plasma p-tau217 as a minimally invasive diagnostic and prognostic biomarker for AD, with potential utility in clinical practice and trials. HIGHLIGHTS: Non-demented presenilin-1 E280A carriers have higher plasma tau phosphorylated at threonine 217 (p-tau217) than do age-matched non-carriers. Higher baseline p-tau217 is associated with greater future amyloid positron emission tomography (PET) pathology burden. Higher baseline p-tau217 is associated with greater future tau PET pathology burden. Higher baseline p-tau217 is associated with worse future memory performance.

Sex differences in blood biomarkers and cognitive performance in individuals with autosomal dominant Alzheimer's disease.

INTRODUCTION: Plasma tau phosphorylated at threonine 217 (P-tau217) and neurofilament light (NfL) have emerged as markers of Alzheimer's disease (AD) pathology. Few studies have examined the role of sex in plasma biomarkers in sporadic AD, yielding mixed findings, and none in autosomal dominant AD. METHODS: We examined the effects of sex and age on plasma P-tau217 and NfL, and their association with cognitive performance in a cross-sectional study of 621 Presenilin-1 E280A mutation carriers (PSEN1) and non-carriers. RESULTS: As plasma P-tau217 levels increase, cognitively unimpaired female carriers showed better cognitive performance than cognitively unimpaired male carriers. Yet, as disease progresses, female carriers had a greater plasma NfL increase than male carriers. There were no sex differences in the association between age and plasma biomarkers among non-carriers. DISCUSSION: Our findings suggest that, among PSEN1 mutation carriers, females had a greater rate of neurodegeneration than males, yet it did not predict cognitive performance. HIGHLIGHTS: We examined sex differences in plasma P-tau217 and NfL in Presenilin-1 E280A (PSEN1) mutation carriers and non-carriers. Female carriers had a greater plasma NfL increase, but not P-tau217, than male carriers. As plasma P-tau217 levels increase, cognitively unimpaired female carriers showed better cognitive performance than cognitively unimpaired male carriers. The interaction effect of sex by plasma NfL levels did not predict cognition among carriers.

Accrual of functional redundancy along the lifespan and its effects on cognition.

Despite the necessity to understand how the brain endures the initial stages of age-associated cognitive decline, no brain mechanism has been quantitatively specified to date. The brain may withstand the effects of cognitive aging through redundancy, a design feature in engineered and biological systems, which entails the presence of substitute elements to protect it against failure. Here, we investigated the relationship between functional network redundancy and age over the human lifespan and their interaction with cognition, analyzing resting-state functional MRI images and cognitive measures from 579 subjects. Network-wide redundancy was significantly associated with age, showing a stronger link with age than other major topological measures, presenting a pattern of accumulation followed by old-age decline. Critically, redundancy significantly mediated the association between age and executive function, with lower anti-correlation between age and cognition in subjects with high redundancy. The results suggest that functional redundancy accrues throughout the lifespan, mitigating the effects of age on cognition.

Impact of APOE ε4 and ε2 on plasma neurofilament light chain and cognition in autosomal dominant Alzheimer's disease.

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.

Effect of apolipoprotein genotype and educational attainment on cognitive function in autosomal dominant Alzheimer's disease.

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.

Episodic memory impairment in children and adolescents at risk for schizophrenia: A role for context processing.

People with schizophrenia experience episodic memory impairments that have been theorized to reflect deficits in processing context (e.g., spatio-temporal features tied to a specific event). Although past research has reported episodic memory impairments in young people at-risk for schizophrenia, the extent to which these impairments reflect context processing deficits remains unknown. We addressed this gap in the literature by examining whether children and adolescents at risk for schizophrenia exhibit context processing deficits during free recall, a memory task with high contextual demands. Our sample included three groups (N = 58, 9-16 years old) varying in risk for schizophrenia:16 high-risk, unaffected first-degree relatives of patients with schizophrenia, bipolar disorder, and/or schizoaffective disorder, 22 clinical control participants with a comorbid disorder (ADHD and/or an anxiety disorder), and 20 healthy control participants. Participants first completed a free recall task and then completed a recognition memory task. Based on established theories of episodic memory, we assumed that context processing played a more pivotal role in free recall than recognition memory. Consequently, if schizophrenia risk is associated with context processing deficits, then memory impairment should be present in free recall measures that are most sensitive to context processing (i.e., recall accuracy and temporal contiguity). Consistent with this prediction, free recall accuracy and temporal contiguity were lower for the high-risk group than the healthy controls, whereas recognition memory was comparable across groups. These findings suggest that episodic memory impairments associated with schizophrenia in unaffected, first-degree relatives may reflect context processing deficits.

The association between hippocampal volume and memory in pathological aging is mediated by functional redundancy.

Hippocampal neurodegeneration, a primary component of Alzheimer's disease pathology, relates to poor cognition; however, the mechanisms underlying this relationship are not well understood. Using a sample of cognitively normal older adults and individuals with mild cognitive impairment, this study aims to determine the topological properties of functional networks accompanying hippocampal atrophy in aging, along with their association to cognition and clinical progression. We considered two conceptually differing topological properties: redundancy (the existence of alternative channels of functional commutation) and local efficiency (the efficiency of local information exchange). Hippocampal redundancy, but not local efficiency, mediated the association between low hippocampal volume and low memory in both the whole sample and in ß-amyloid positive participants. Additionally, participants with high hippocampal volume, redundancy, and memory clustered separately from those with low values on all three measures, with the latter group showing higher conversion rates to dementia within three years. Together, these results demonstrate that reduced hippocampal redundancy is one mechanism through which hippocampal atrophy associates with memory impairment in healthy and pathological aging.

Frontoparietal network resilience is associated with protection against cognitive decline in Parkinson's disease.

Though Parkinson's disease is primarily defined as a movement disorder, it is also characterized by a range of non-motor symptoms, including cognitive decline. The onset and progression of cognitive decline in individuals with Parkinson's disease is variable, and the neurobiological mechanisms that contribute to, or protect against, cognitive decline in Parkinson's disease are poorly understood. Using resting-state functional magnetic resonance imaging data collected from individuals with Parkinson's disease with and without cognitive decline, we examined the relationship between topological brain-network resilience and cognition in Parkinson's disease. By leveraging network attack analyses, we demonstrate that relative to individuals with Parkinson's disease experiencing cognitive decline, the frontoparietal network in cognitively stable individuals with Parkinson's disease is significantly more resilient to network perturbation. Our findings suggest that the topological robustness of the frontoparietal network is associated with the absence of cognitive decline in individuals with Parkinson's disease.

Lower functional hippocampal redundancy in mild cognitive impairment.

With an increasing prevalence of mild cognitive impairment (MCI) and Alzheimer's disease (AD) in response to an aging population, it is critical to identify and understand neuroprotective mechanisms against cognitive decline. One potential mechanism is redundancy: the existence of duplicate elements within a system that provide alternative functionality in case of failure. As the hippocampus is one of the earliest sites affected by AD pathology, we hypothesized that functional hippocampal redundancy is protective against cognitive decline. We compared hippocampal functional redundancy derived from resting-state functional MRI networks in cognitively normal older adults, with individuals with early and late MCI, as well as the relationship between redundancy and cognition. Posterior hippocampal redundancy was reduced between cognitively normal and MCI groups, plateauing across early and late MCI. Higher hippocampal redundancy was related to better memory performance only for cognitively normal individuals. Critically, functional hippocampal redundancy did not come at the expense of network efficiency. Our results provide support that hippocampal redundancy protects against cognitive decline in aging.

Brainwide functional networks associated with anatomically- and functionally-defined hippocampal subfields using ultrahigh-resolution fMRI.

The hippocampus is critical for learning and memory and may be separated into anatomically-defined hippocampal subfields (aHPSFs). Hippocampal functional networks, particularly during resting state, are generally analyzed using aHPSFs as seed regions, with the underlying assumption that the function within a subfield is homogeneous, yet heterogeneous between subfields. However, several prior studies have observed similar resting-state functional connectivity (FC) profiles between aHPSFs. Alternatively, data-driven approaches investigate hippocampal functional organization without a priori assumptions. However, insufficient spatial resolution may result in a number of caveats concerning the reliability of the results. Hence, we developed a functional Magnetic Resonance Imaging (fMRI) sequence on a 7 T MR scanner achieving 0.94 mm isotropic resolution with a TR of 2 s and brain-wide coverage to (1) investigate the functional organization within hippocampus at rest, and (2) compare the brain-wide FC associated with fine-grained aHPSFs and functionally-defined hippocampal subfields (fHPSFs). This study showed that fHPSFs were arranged along the longitudinal axis that were not comparable to the lamellar structures of aHPSFs. For brain-wide FC, the fHPSFs rather than aHPSFs revealed that a number of fHPSFs connected specifically with some of the functional networks. Different functional networks also showed preferential connections with different portions of hippocampal subfields.

Age-related differences in recognition in associative memory.

Aging is often accompanied by associative memory changes, although their precise nature remains unclear. This study examines how recognition of item position in the context of associative memory differs between younger and older adults. Participants studied word pairs (A-B, C-D) and were later tested with intact (A-B), reversed (D-C), recombined (A-D), and recombined and reversed (B-C) pairs. When participants were instructed to respond "Old" to both intact and reversed pairs, and "New" to recombined, and recombined and reversed pairs, older adults showed worse recognition for recombined and reversed pairs relative to younger adults (Experiment 1). This finding also emerged when flexible retrieval demands were increased by asking participants to respond "Old" only to intact pairs (Experiment 2). These results suggest that as conditions for flexible retrieval become more demanding, older adults may show worse recognition in associative memory tasks relative to younger adults.

Effects of environmental enrichment on anxiety-like behavior, sociability, sensory gating, and spatial learning in male and female C57BL/6J mice.

The influence of housing on cognition and emotional regulation in mice presents a problem for the study of genetic and environmental risk factors for neuropsychiatric disorders: standard laboratory housing may result in low levels of cognitive function or altered levels of anxiety that leave little room for assessment of deleterious effects of experimental manipulations. The use of enriched environment (EE) may allow for the measurement of a wider range of performance in cognitive domains. Cognitive and behavioral effects of EE in male mice have not been widely reproduced, perhaps due to variability in the application of enrichment protocols, and the effects of EE in female mice have not been widely studied. We have developed an EE protocol using common laboratory equipment that, without a running wheel for exercise, results in significant cognitive and behavioral effects relative to standard laboratory housing conditions. We compared male and female wild-type C57BL/6J mice reared from weaning age in an EE to those reared in a standard environment (SE), using common measures of anxiety-like behavior, sensory gating, sociability, and spatial learning and memory. Sex was a significant factor in relevant elevated plus maze (EPM) measures, and bordered on significance in a social interaction (SI) assay. Effects of EE on anxiety-like behavior and sociability were indicative of a general increase in exploratory activity. In male and female mice, EE resulted in reduced prepulse inhibition (PPI) of the acoustic startle response, and enhanced spatial learning and use of spatially precise strategies in a Morris water maze task.