Each study has a usefulness score out of 100 (rubric version 4.0). Tap a score to see what makes it up.
Highest usefulness score first. Studies without a score come last.
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However, the previous view of significant cholinergic cell loss during aging has been challenged.
Why it matters
This review notes that the previous view of significant cholinergic cell loss during aging has been challenged, while significant degeneration of basal forebrain cholinergic cells occurs in several conditions with cognitive deficits. It reports no treatment, cure or prevention.
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TAR DNA-binding protein (TDP-43) is an evolutionarily conserved heterogeneous nuclear ribonucleoprotein (hnRNP) involved in RNA processing, whose abnormal cellular distribution and post-translational modification are key markers of certain neurodegenerative diseases, such as amyotrophic lateral sclerosis and frontotemporal lobar degeneration.
Why it matters
In human cell lines, TDP-43, a protein whose abnormal location and modification mark ALS and frontotemporal lobar degeneration, limits its own production by binding the 3′ UTR of its own mRNA and making that RNA unstable rather than changing how it is spliced. The authors propose that disease-associated TDP-43 clumps "likely" disrupt this self-regulation. This is cell-based work that does not test a treatment, and the record does not discuss Alzheimer's disease.
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This comprehensive population genetic study in control subjects fills the void for a PARK2 reference dataset.
Why it matters
This large study found that having one copy-number variation in the PARK2 gene was not associated with increased Parkinson disease risk. It provides no evidence that testing or targeting PARK2 helps treat or prevent Alzheimer disease.
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Neurodegenerative tauopathies, of which progressive supranuclear palsy (PSP) is one of the most common, are clinically heterogeneous, reflecting differences in distribution and biochemical composition of tau pathology.
Why it matters
This review describes clinical and pathologic variants of progressive supranuclear palsy, a 4R tauopathy, showing that variants reflect varying anatomical distribution of tau pathology. It concerns progressive supranuclear palsy and does not test any treatment, cure, or prevention for Alzheimer's disease.
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To date, molecular genetic analyses have identified over 500 distinct DNA variants in five disease genes associated with familial Parkinson disease; alpha-synuclein (SNCA), parkin (PARK2), PTEN-induced putative kinase 1 (PINK1), DJ-1 (PARK7), and Leucine-rich repeat kinase 2 (LRRK2).
Why it matters
This review catalogs over 500 DNA variants in five genes linked to familial Parkinson's disease and notes these genes also contribute to other Lewy body diseases. It emphasizes the need for comprehensive genetic screening and functional study of variants, but reports no treatment or cure.
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51/100
CSF Abeta1-14, Abeta1-15, and Abeta1-16 increase during gamma-secretase inhibitor treatment in AD, even at doses that do not affect Abeta1-42 or Abeta1-40, probably because of increased substrate availability of the C99 APP stub (APP beta-CTF) induced by gamma-secretase inhibition.
Why it matters
In this phase II trial of 35 patients with mild to moderate Alzheimer's disease, the gamma-secretase inhibitor LY450139 (semagacestat) caused dose-dependent increases in shorter cerebrospinal fluid amyloid-beta isoforms (1-14, 1-15, and 1-16) but did not affect amyloid-beta 1-40 or 1-42. These shorter isoforms may serve as biomarkers of drug effect, but the study does not show any clinical benefit for treating Alzheimer's disease.
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Microglia, the resident macrophages of the CNS, are exquisitely sensitive to brain injury and disease, altering their morphology and phenotype to adopt a so-called activated state in response to pathophysiological brain insults.
Why it matters
This review describes how microglia change their morphology and phenotype into activated states in response to brain injury and disease, and suggests they could serve as diagnostic markers or influence disease outcomes. It discusses microglial biology and does not report a treatment, cure or prevention for Alzheimer's disease.
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The past 20 years have seen a gain in knowledge on microglia biology and microglia functions in disease that exceeds the expectations formulated when the microglia "immune network" was introduced.
Why it matters
This review summarizes two decades of microglia research and notes ongoing controversy over whether microglia are active or reactive players in neurodegenerative disease, or victims themselves. It reports no treatment, cure or prevention for Alzheimer's disease.
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Mutations in valosin-containing protein (VCP) cause inclusion body myopathy (IBM), Paget's disease of the bone, and frontotemporal dementia (IBMPFD).
Why it matters
This study found that loss of VCP activity causes autophagosomes to accumulate and fail to mature into autolysosomes, and that IBMPFD mutant VCP leads to nondegradative autophagosomes and TDP-43 accumulation. It suggests impaired autophagy explains the pathology in IBMPFD muscle, but it reports no treatment or cure.
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Basophilic Inclusion Body Disease (BIBD) is a tau-negative form of frontotemporal lobar degeneration (FTLD), characterized by neuronal cytoplasmic inclusions (NCI) that are visible on hematoxylin and eosin stain (HE), contain RNA, and are inconsistently ubiquitin-immunoreactive (ir).
Why it matters
This study investigated whether the distribution of the FUS protein is altered in basophilic inclusion body disease, a tau-negative form of frontotemporal lobar degeneration. It concerns a different disease and does not address treating, curing or preventing Alzheimer's disease.
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Transactive response DNA-binding protein 43 (TDP-43) forms abnormal ubiquitinated and phosphorylated inclusions in brain tissues from patients with amyotrophic lateral sclerosis (ALS) and frontotemporal lobar degeneration.
Why it matters
In laboratory work, TDP-43 assembled into stress granules under oxidative stress, and specific parts of the protein were needed for this, though stress granule markers were not found inside TDP-43 inclusions in ALS spinal cord. This is early cell and tissue work on a possible early disease mechanism, not a treatment.
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Neural stem cell (NSC) transplantation represents an unexplored approach for treating neurodegenerative disorders associated with cognitive decline such as Alzheimer disease (AD).
Why it matters
In aged triple transgenic mice with Alzheimer's-like pathology, hippocampal neural stem cell transplantation rescued spatial learning and memory deficits. This was an animal study, so it is not yet known whether neural stem cell transplantation would be effective or safe in people with Alzheimer's disease.
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Our data suggest that vascular abnormalities, independently of blood pressure levels, may play a role in the setting of subjective memory complaints as well as of WMH in elderly hypertensive patients.
Why it matters
Among 198 older people with high blood pressure and memory complaints, stiffer arteries (measured by pulse wave velocity) went with poorer memory in men, even after allowing for the usual heart-risk factors. More white matter changes on MRI went with thicker, stiffer neck arteries, older age, and higher von Willebrand Factor, a blood marker of blood-vessel lining problems. The authors suggest artery health may matter for memory beyond blood pressure numbers alone. But everyone was measured once, so this shows a link, not a cause, and no treatment was tested.
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The disease protein in frontotemporal lobar degeneration with ubiquitin-positive inclusions (FTLD-U) and amyotrophic lateral sclerosis (ALS) was identified recently as the TDP-43 (TAR DNA-binding protein 43), thereby providing a molecular link between these two disorders.
Why it matters
In cultured cells, expressing TDP-43 C-terminal fragments produced cytoplasmic aggregates that were ubiquitinated and abnormally phosphorylated, along with splicing abnormalities. This is cell-culture work supporting a hypothesis about disease steps, not a treatment or prevention study.
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Phosphorylated and proteolytically cleaved TDP-43 is a major component of the ubiquitin-positive inclusions in the most common pathological subtype of frontotemporal lobar degeneration (FTLD-U).
Why it matters
This study looked at whether TDP-43 protein builds up in the brains of some people with Alzheimer's disease and dementia with Lewy bodies, but it says the pathological significance of this buildup in these disorders is unknown. It does not show any treatment, cure, or prevention for Alzheimer's disease.
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Mitochondrial dysfunction is a prominent feature of Alzheimer disease but the underlying mechanism is unclear.
Why it matters
In lab-grown M17 cells made to produce extra amyloid precursor protein (APP), about 40% of cells with normal APP and more than 80% with the APPswe mutant showed fragmented mitochondria bunched around the nucleus. Blocking the enzyme that cuts APP to make amyloid-beta (with "beta-site APP-cleaving enzyme inhibitor IV") abolished these changes, which suggests the mitochondrial damage in these cells depended on amyloid-beta production. These were cell experiments only, so they do not show that the same happens in people or that blocking this enzyme would help patients.
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TDP-43 (also known as TARDBP) regulates different processes of gene expression, including transcription and splicing, through RNA and DNA binding.
Why it matters
In lab experiments, the authors report "the first experimental evidence that TDP-43 continuously shuttles between nucleus and cytoplasm in a transcription-dependent manner", and found that removing the protein's C-terminus produced "large nuclear and cytoplasmic aggregates", while disrupting its RNA-binding domain reduced its presence in the nucleoplasm. The abnormal placement and clumping of TDP-43 that this work set out to explain is linked in the study to frontotemporal lobar degeneration (FTLD) and ALS. The study does not mention Alzheimer's, includes no patients, and tests no treatment.
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Alzheimer's disease (AD) is characterized by extracellular deposits of amyloid-beta protein which attract dense clusters of microglial cells.
Why it matters
In aged APP23 transgenic mice, an animal model of Alzheimer's disease, 538 genes were differentially expressed in tissue around amyloid plaques compared with plaque-free tissue, and one of these was the microglia-associated gene TREM2. This is mouse work and does not establish a treatment, cure or prevention for Alzheimer's disease in people.
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55 of the 152 (36.2 %) aMCI subjects progressed to AD.
Why it matters
In 152 people with amnestic mild cognitive impairment from a three-year donepezil/vitamin E trial, 55 (36.2%) progressed to Alzheimer's disease. Of the white matter regions scored on their entry MRI, only periventricular hyperintensities were linked to a higher risk of progression (hazard ratio 1.59, 95% CI 1.24–2.05), after adjusting for age, education and treatment arm. The authors suggest this vascular-type damage contributes to Alzheimer's onset independently of Alzheimer pathology, but this is an association in a trial subset, not proof of cause.
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Loss-of-function mutations in progranulin (GRN) cause ubiquitin- and TAR DNA-binding protein 43 (TDP-43)-positive frontotemporal dementia (FTLD-U), a progressive neurodegenerative disease affecting approximately 10% of early-onset dementia patients.
Why it matters
This study found that people homozygous for the T-allele of rs5848 in the GRN gene had a 3.2-fold increased risk of TDP43-positive frontotemporal dementia, and that miR-659 can regulate GRN expression. It identifies a genetic risk factor for a type of frontotemporal dementia, not a treatment, cure, or prevention for Alzheimer's disease.
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51/100
These results demonstrate that temporoparietal regions show differential rates of atrophy on MRI during prodromal Alzheimer disease (AD).
Why it matters
In people with mild cognitive impairment who progressed to Alzheimer's disease, several temporoparietal regions showed faster atrophy than in those who did not progress. These atrophy rates correlated with changes in clinical status, but the study does not test any treatment or prevention.
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Pathologic TAR-DNA-binding protein 43 (TDP-43) is a disease protein in frontotemporal lobar degeneration with ubiquitin-positive inclusions (FTLD-U) and amyotrophic lateral sclerosis.
Why it matters
This study found that TDP-43 pathology was present in about 26% of Alzheimer's disease cases and was linked to longer disease duration, but not to how the disease presented clinically. It does not test any treatment or prevention, so it has no direct implications for treating, curing, or preventing Alzheimer's disease.
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Recently, mutations in the progranulin (PGRN) gene were found to cause familial and apparently sporadic frontotemporal lobe dementia (FTLD).
Why it matters
This laboratory work found that progranulin levels are reduced in cerebrospinal fluid from frontotemporal dementia patients with a PGRN mutation and that progranulin promotes neuronal survival and neurite outgrowth in cultured neurons. It is cell and patient-sample research, so it does not yet show any treatment, cure or prevention for Alzheimer's disease.
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51/100
APOE genotype is a major genetic risk factor for late-onset Alzheimer disease (AD).
Why it matters
In mice bred to develop Alzheimer-like amyloid plaques, adding extra ABCA1, a protein that loads fat onto apoE (the protein made by the APOE risk gene), led to "significantly less" amyloid buildup and "an almost complete absence" of dense plaques. The same mice had more fat-loaded apoE in their spinal fluid. That supports the authors' view that this apoE step affects amyloid, and that boosting ABCA1 "may have a therapeutic effect". This was genetic engineering in mice only: no drug was given, memory was not reported, and nothing was tested in people.
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Of 214 participants, 48 showed no decline on any test, 126 showed decline on only 1 test in 1 or more domains, and 40 showed decline on 2 or more tests in 1 or more domains.
Why it matters
In this prospective study, APOE epsilon4 homozygotes aged 60 and older at entry showed cognitive domain decline more often than heterozygotes and noncarriers before any diagnosis of mild cognitive impairment or Alzheimer's disease. This indicates that cognitive decline can be detected earlier in people with two copies of the risk allele, but it does not provide a treatment or prevention.
From across this topic
10 of the 4,748 studies in this topic, picked by a fixed rule (a hash of each study's address), not by score or date; each page of this list shows a different 10. The same 10 appear here every time.
- Panax ginseng and Panax quinquefolius: From pharmacology to toxicology
- Tangle-bearing neurons survive despite disruption of membrane integrity in a mouse model of tauopathy
- Neuroprotection Against Oxidative Stress: Phytochemicals Targeting TrkB Signaling and the Nrf2-ARE Antioxidant System
- Naturally secreted oligomers of amyloid β protein potently inhibit hippocampal long-term potentiation in vivo
- Analytical validation of plasma p ‐tau217 on the SP‐X platform
- Developmental immunohistochemistry of growth inhibitory factor in normal brains and brains of patients with Down syndrome
- Selective induction of calcineurin activity and signaling by oligomeric amyloid beta
- Rare genetic variation in fibronectin 1 (FN1) protects against APOEε4 in Alzheimer's disease
- Sulforaphene Ameliorates Neuroinflammation and Hyperphosphorylated Tau Protein via Regulating the PI3K/Akt/GSK-3β Pathway in Experimental Models of Alzheimer's Disease
- Cross-sectional associations of plasma vitamin D with plasma phosphorylated tau-181 and plasma neurofilament light chain in older adults with memory complaints