Memory Decline In Alzheimer's Disease Research Articles

Regional Tau Deposition Reflects Different Pathways of Subsequent Neurodegeneration and Memory Decline in Cognitively Normal Older Adults.

Tau pathology is recognized as a primary contributor to neurodegeneration and clinical symptoms in Alzheimer's disease (AD). This study aims to localize the early tau pathology in cognitively normal older people that is predictive of subsequent neurodegeneration and memory decline, and delineate factors underlying tau-related memory decline in individuals with and without β-amyloid (Aβ). A total of 138 cognitively normal older individuals from the Berkeley Aging Cohort Study underwent 11 C-Pittsburgh Compound-B (PiB) positron emission tomography (PET) to determine Aβ positivity and 18 F-Flortaucipir (FTP) PET to measure tau deposition, with prospective cognitive assessments and structural magnetic resonance imaging. Voxel-wise FTP analyses examined associations between baseline tau deposition and longitudinal memory decline, longitudinal hippocampal atrophy, and longitudinal cortical thinning in AD signature regions. We also examined whether hippocampal atrophy and cortical thinning mediate tau effects on future memory decline. We found Aβ-dependent tau associations with memory decline in the entorhinal and temporoparietal regions, Aβ-independent tau associations with hippocampal atrophy within the medial temporal lobe (MTL), and that widespread tau was associated with mean cortical thinning in AD signature regions. Tau-related memory decline was mediated by hippocampal atrophy in Aβ- individuals and by mean cortical thinning in Aβ+ individuals. Our results suggest that tau may affect memory through different mechanisms in normal aging and AD. Early tau deposition independent of Aβ predicts subsequent hippocampal atrophy that may lead to memory deficits in normal older individuals, whereas elevated cortical tau deposition is associated with cortical thinning that may lead to more severe memory decline in AD. ANN NEUROL 2024;95:249-259.

Adult Hippocampal Neurogenesis in Alzheimer's Disease: An Overview of Human and Animal Studies with Implications for Therapeutic Perspectives Aimed at Memory Recovery.

The mammalian hippocampal dentate gyrus is a niche for adult neurogenesis from neural stem cells. Newborn neurons integrate into existing neuronal networks, where they play a key role in hippocampal functions, including learning and memory. In the ageing brain, neurogenic capability progressively declines while in parallel increases the risk for developing Alzheimer's disease (AD), the main neurodegenerative disorder associated with memory loss. Numerous studies have investigated whether impaired adult neurogenesis contributes to memory decline in AD. Here, we review the literature on adult hippocampal neurogenesis (AHN) and AD by focusing on both human and mouse model studies. First, we describe key steps of AHN, report recent evidence of this phenomenon in humans, and describe the specific contribution of newborn neurons to memory, as evinced by animal studies. Next, we review articles investigating AHN in AD patients and critically examine the discrepancies among different studies over the last two decades. Also, we summarize researches investigating AHN in AD mouse models, and from these studies, we extrapolate the contribution of molecular factors linking AD-related changes to impaired neurogenesis. Lastly, we examine animal studies that link impaired neurogenesis to specific memory dysfunctions in AD and review treatments that have the potential to rescue memory capacities in AD by stimulating AHN.

Gastric acid suppressants and cognitive decline in people with or without cognitive impairment.

IntroductionStudies suggest associations between proton pump inhibitors (PPIs) and dementia risk; however, many neither considered histamine‐2 receptor antagonists (H2RAs) nor baseline cognitive status.MethodsParticipants (National Alzheimer's Coordinating Center Database; 2005–2021) using a PPI or H2RA were compared. Covariate‐adjusted Cox regression was used to estimate hazard ratios (HR) for progression from normal cognition to mild cognitive impairment (MCI), and from MCI to dementia over 5 years. In a propensity‐score–matched subsample of mild–moderate Alzheimer's disease (AD), mixed‐effects negative binomial regression was used to estimate decline in delayed recall memory.ResultsCompared to PPI, H2RA use was associated with earlier progression from MCI to dementia (HR = 1.40 [1.09–1.81]; n = 1701), and with faster memory decline in AD over time (rate ratio = 0.76 [0.64–0.92]; n = 628), but not with progression from normal cognition to MCI (HR = 0.94 [0.71–1.24]; n = 2784).DiscussionCompared to PPIs, H2RAs were associated with cognitive decline, specifically among people with pre‐existing cognitive impairment.

Intestinal dysbiosis promotes immune dysregulation in an animal model of Alzheimer's disease.

Current evidence suggests that systemic inflammation promotes Alzheimer's Disease (AD) and recent reports demonstrated that circulating neutrophils migrate into the AD brain inducing neuroinflammation and cognitive deficits in animal models of AD. However, how peripheral immune dysregulation occurs and promotes neuroinflammation and memory decline in AD is still unknown. Even though descriptive reports suggest the involvement of the microbiome in AD, the mechanisms behind AD pathology are not explored. In this context, we aim to better understand the dysregulation of leukocyte subpopulations in AD by addressing the gut-blood-brain axis. By taking advantage of the 3xTg-AD mouse model we addressed peripheral inflammation during early disease stages. To this aim, we performed: 1) an intestinal microbiota analysis; 2) characterization of circulating inflammatory mediators; and 3) immunophenotypization of peripheral blood. In our study we show a clear intestinal dysbiosis in the 3xTg-AD mice, characterized by higher abundance of taxa known to cause proinflammatory conditions. In agreement, we also found increased intestinal permeability and accumulation of immature precursors and aged neutrophils in circulating blood, suggesting a strong peripheral dysregulation in the early phases of the disease. Altogether, our data suggest microbiota as a modulator of leukocyte activation and migration into the brain. Therefore, targeting the gut-blood-brain axis in AD could lead to new immunomodulatory strategies for AD treatment.

Local Sleep and Alzheimer's Disease Pathophysiology.

Even prior to the onset of the prodromal stages of Alzheimer’s disease (AD), a constellation of sleep disturbances are apparent. A series of epidemiological studies indicate that multiple forms of these sleep disturbances are associated with increased risk for developing mild cognitive impairment (MCI) and AD, even triggering disease onset at an earlier age. Through the combination of causal manipulation studies in humans and rodents, as well as targeted examination of sleep disturbance with respect to AD biomarkers, mechanisms linking sleep disturbance to AD are beginning to emerge. In this review, we explore recent evidence linking local deficits in brain oscillatory function during sleep with local AD pathological burden and circuit-level dysfunction and degeneration. In short, three deficits in the local expression of sleep oscillations have been identified in relation to AD pathophysiology: (1) frequency-specific frontal deficits in slow wave expression during non-rapid eye movement (NREM) sleep, (2) deficits in parietal sleep spindle expression, and (3) deficits in the quality of electroencephalographic (EEG) desynchrony characteristic of REM sleep. These deficits are noteworthy since they differ from that seen in normal aging, indicating the potential presence of an abnormal aging process. How each of these are associated with β-amyloid (Aβ) and tau pathology, as well as neurodegeneration of circuits sensitive to AD pathophysiology, are examined in the present review, with a focus on the role of dysfunction within fronto-hippocampal and subcortical sleep-wake circuits. It is hypothesized that each of these local sleep deficits arise from distinct network-specific dysfunctions driven by regionally-specific accumulation of AD pathologies, as well as their associated neurodegeneration. Overall, the evolution of these local sleep deficits offer unique windows into the circuit-specific progression of distinct AD pathophysiological processes prior to AD onset, as well as their impact on brain function. This includes the potential erosion of sleep-dependent memory mechanisms, which may contribute to memory decline in AD. This review closes with a discussion of the remaining critical knowledge gaps and implications of this work for future mechanistic studies and studies implementing sleep-based treatment interventions.

The role of innate immunity in Alzheimer's disease.

The amyloid hypothesis has dominated Alzheimer's disease (AD) research for almost 30years. This hypothesis hinges on the predominant clinical role of the amyloid beta (Aβ) peptide in propagating neurofibrillary tangles (NFTs) and eventual cognitive impairment in AD. Recent research in the AD field has identified the brain-resident macrophages, known as microglia, and their receptors as integral regulators of both the initiation and propagation of inflammation, Aβ accumulation, neuronal loss, and memory decline in AD. Emerging studies have also begun to reveal critical roles for distinct innate immune pathways in AD pathogenesis, which has led to great interest in harnessing the innate immune response as a therapeutic strategy to treat AD. In this review, we will highlight recent advancements in our understanding of innate immunity and inflammation in AD onset and progression. Additionally, there has been mounting evidence suggesting pivotal contributions of environmental factors and lifestyle choices in AD pathogenesis. Therefore, we will also discuss recent findings, suggesting that many of these AD risk factors influence AD progression via modulation of microglia and immune responses.

Context Memory in Alzheimer's Disease: The "Who, Where, and When".

Context memory, a component of episodic system, refers to the ability to retrieve conditions under which an event has occurred, such as who was present during that event and where and when it occurred. Context memory has been found to be compromised in older adults, an issue that we investigated in Alzheimer's disease (AD). Thirty-one participants with AD and 35 older adults were asked to generate three autobiographical events. Afterward, they were asked to remember the names of all people who were evoked during the events, and the names for any location that was mentioned during the events. Participants were also asked to remember the year, season, month and day of the week when the events occurred. Compared to older adults, participants with AD showed lower memory for "who" (p < .001), "where" (p < .05), and "when" (p < .01). Compared to "who" and "where", both participants with AD and older adults showed pronounced difficulties in remembering the "when". these findings highlight difficulties in remembering temporal information as an indication of context memory decline in AD. The difficulties in retrieving temporal information are discussed in terms of timing failures and hippocampal degenerations in AD.

Autobiographical Memory Performance in Alzheimer's Disease Depends on Retrieval Frequency.

Alzheimer's disease (AD) is characterized by memory disturbances primarily caused by pathogenic mechanisms affecting medial temporal lobe structures. As proposed by current theories of memory formation, this decrease is mediated by the age of the acquired knowledge. However, they cannot fully explain specific patterns of retrograde amnesia in AD. In the current study we examined an alternative approach and investigated whether the extent and severity of retrograde amnesia in AD is mediated by the frequency of memory retrieval or whether it depends on the mere age of knowledge. We compared recall of autobiographical incidents from three life periods in patients with amnestic mild cognitive impairment (aMCI), patients with early dementia of Alzheimer type (eDAT), and healthy control (HC) individuals using the Autobiographical Memory Interview. Retrieval frequency was operationalized by a paired comparison analysis. In contrast to HC individuals, recall of autobiographical incidents was impaired in patients with aMCI and eDAT following Ribot's gradient, with a reduced memory loss for remote compared to more recent life events. However, there was a strong effect of retrieval frequency on memory performance with frequently retrieved incidents memorized in more detail than less frequently retrieved episodes. Remote memories were recalled more often than recent ones. These findings suggest that more frequently retrieved autobiographical memories generally become more independent of the hippocampal complex and might thus be better protected against early hippocampal damage related to AD. Hence, the extent of retrograde amnesia in AD appears mainly mediated by the frequency of memory retrieval, which could plausibly explain why cognitive activity can effectively delay the onset of memory decline in AD.

Generation of the Cdk5 activator p25 is a memory mechanism that is affected in early Alzheimer's disease.

About 15 years ago it was proposed that generation of the truncated protein p25 contributes to toxicity in Alzheimer’s disease (AD). p25 is a calcium-dependent degradation product of p35, the principal activator of cyclin-dependent kinase 5 (Cdk5). The biochemical properties of p25 suggested that its generation would cause Cdk5 overactivation and tau hyperphosphorylation, a prerequisite for neurofibrillary tangle (NFT) formation. Whilst this model was appealing as it explained NFT formation, many laboratories could not confirm the finding of increased p25 generation in brain from AD patients. On the contrary, it emerged that p25 levels are reduced in AD. This reduction occurs primarily in the early stages of the disease. Further, p25 generation in the mouse hippocampus is associated with normal memory formation and p25 overexpression enhances synaptogenesis. Therefore, it transpires that p25 generation is a molecular memory mechanism that is impaired in early AD. I discuss the prospect that investigation of p25-regulated proteins will shed light into mechanisms underlying synaptic degeneration associated with memory decline in AD.

New therapeutic strategy for Alzheimer's disease using antidiabetes agents.

New therapeutic strategy for Alzheimer's disease using antidiabetes agents.

Increased Hippocampal Default Mode Synchronization during Rest in Middle-Aged and Elderly APOE ε4 Carriers: Relationships with Memory Performance

The apolipoprotein (APOE) ε4 allele is a strong genetic risk factor for Alzheimer's disease (AD). Intrinsic fluctuations of brain activity measured by fMRI during rest may be sensitive to AD-related neuropathology. In particular, functional connectivity of the default-mode network (DMN) has gained recent attention as a possible biomarker of disease processes and associated memory decline in AD. Here, we tested the hypothesis of APOE-related alterations in DMN functional connectivity in 95 healthy individuals between 50 and 80 years of age, including 33 carriers of the ε4 allele. Based on previous studies, we hypothesized increased hippocampal DMN synchronization in APOE ε4 carriers. This was supported using independent component analysis in combination with a dual-regression approach for analysis of resting state data. Whole-brain analysis suggested effects also in other areas, including the posterior cingulate cortex, parietal cortex, and parahippocampal regions. DMN synchronization showed a negative correlation with performance on a test of memory functioning, suggesting a neurocognitive significance of the brain activity patterns during rest. Our findings indicate that increased genetic vulnerability for AD is reflected in increased hippocampal DMN synchronization during rest several years before clinical manifestation. We propose that the results reflect ε4-related failure in hippocampal decoupling, which might elevate the total hippocampal metabolic burden and increase the risk of cognitive decline and AD. The results provide an important confirmation of specific genotype effects on intrinsic fluctuations and support the use of functional connectivity indices as imaging-derived endophenotypes in the emerging field of imaging genetics.

Accelerated Memory Decline in Alzheimer's Disease With Apolipoprotein 4 Allele

To investigate a possible effect of the apolipoprotein (APOE) ϵ4 allele on memory decline in Alzheimer's disease (AD), we examined 64 AD patients with the APOE ϵ3/3, ϵ3/4, or ϵ4/4 allele using the Alzheimer Disease Assessment Scale-Cognitive subscale (ADAS-Cog) and its subtests at the initial examination and at the 1-year follow-up visit. One-year changes in the scores of the Word Recall subtest, Word Recognition subtest, and total ADAS-Cog were significantly correlated with the number of APOE ϵ4 alleles after controlling for the effects of age, sex, education, test interval, and baseline scores. Findings revealed that APOE ϵ4 allele is related to an accelerated memory decline in AD.