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Tauopathy

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tauopathy
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Tauopathy
Normal tau function
Tau protein phosphorylation and hyperphosphorylation
Tauopathy diseases
Tauopathy symptoms
Tauopathy treatment
Alzheimer’s disease

Tauopathy

Tauopathy belongs to a diverse group of neurodegenerative diseases featuring progressive dying-back neurodegeneration of specific neuronal populations in association with accumulation of abnormal forms of the microtubule-associated tau (τ) protein often leading to dementia and clinically diagnosed as atypical Parkinson syndromes 1. Tau is normally a microtubule-associated protein that appears to play an important role in ensuring proper axonal transport, but in tauopathies tau becomes hyperphosphorylated and disengages from microtubules, with consequent misfolding and deposition into inclusions that mainly affect neurons, but also glia 2. A body of experimental evidence suggests that the development of tau inclusions leads to the neurodegeneration observed in tauopathies, and there is a growing interest in developing tau-directed therapeutic agents.

Some examples of tauopathy are:

  • Alzheimer’s disease
  • Progressive supranuclear palsy (PSP) also referred to as Steele-Richardson-Olszewski syndrome
  • Corticobasal degeneration
  • Frontotemporal lobar degeneration, also known as Pick’s disease

It is well-established that the clinical symptoms characteristic of tauopathies correlate with deficits in synaptic function and neuritic connectivity early in the course of disease, but mechanisms underlying these critical pathogenic events are not fully understood. Biochemical in vitro evidence fueled the widespread notion that microtubule stabilization represents tau’s primary biological role and that the marked atrophy of neurites observed in tauopathies results from loss of microtubule stability. However, this notion contrasts with the mild phenotype associated with tau deletion. Instead, an analysis of cellular hallmarks common to different tauopathies, including aberrant patterns of protein phosphorylation and early degeneration of axons, suggests that alterations in kinase-based signaling pathways and deficits in axonal transport (AT) associated with such alterations contribute to the loss of neuronal connectivity triggered by pathogenic forms of tau. Here, we review a body of literature providing evidence that axonal pathology represents an early and common pathogenic event among human tauopathies. Observations of axonal degeneration in animal models of specific tauopathies are discussed and similarities to human disease highlighted. Finally, we discuss potential mechanistic pathways other than microtubule destabilization by which disease-related forms of tau may promote axonopathy.

Tau protein was initially identified by Weingarten et al. 3 as a heat stable protein factor that would convert 6S dimers of tubulin into 36S rings necessary for microtubule polymerization. They named this factor tau (τ) for its ability to induce tubule formation. Phosphorylation of tau was found to promote a conformational change favoring depolymerization of the tubulin assembly 4. Brion et al. 5 first reported immunohistochemical evidence of tau in paired helical filaments in 1985. Later the same year, Grundke-Iqbal et al. 6 reported that bovine tau preparations reacted with antibodies to Alzheimer paired helical filaments and that affinity purified antibodies labeled neurofibrillary tangles (NFT) and dystrophic neurites, but not amyloid-β (Aβ) plaques. Neve et al. 7 subsequently used cDNA clones for tau and mapped the tau gene to 17q21.

Normal tau function

The primary function of tau within the brain appears to be the binding of tubulin to promote polymerization and stabilization of microtubules (see list below) 3. Tau stabilizes and stiffens microtubules such that it supports the lengthy axon. Interactions with tubulin are dynamic processes with equal binding properties to both polymerized and non-polymerized tubulin, which regulates neurite polarity, axonal sprouting, and neuroplasticity, i.e., morphogenesis, and regulates axonal transport through interactions with motor proteins 8. Microtubule binding confers a conformational change 4, influences other diverse cellular processes 9, and interacts with other natively unfolded protein such as TDP-43, FUS, and alpha-synuclein 10. A number of studies suggest alternative functions, including cell cycle regulation via tyrosine kinase, plasma membrane interaction, and synaptic function 11.

Some physiologic functions of tau 3:

  • Stabilization of microtubules
  • Actin binding and cytoskeletal integrity
  • Regulating neurite polarity
  • Axonal sprouting
  • Neuroplasticity
  • Axonal transport
  • Cell cycle regulation
  • Plasma membrane interaction
    Synaptic transmission (“synaptic brake”)

Physiologic tau phosphorylation is therefore integral to life across species as a productive response to a variety of stressors including insulin dysfunction, glucose deprivation, starvation, hypothermia, hibernation, anesthesia, and glucocorticoids, among other conditions (see list below) 12. Physiologic tau phosphorylation may also regulate subcellular localization of tau, which in turn may influence signaling cascades or synaptic function 13. A number of post-translational modifications apart from phosphorylation also occur which may have functional implications 14. Among these are O-glycosylation, advanced glycation and the Maillard reaction, ubiquitination, nitration, SUMOylation, prolyl-isomerization, acetylation, and truncation 15.

Some stimuli for tau phosphorylation 12:

  • Insulin dysfunction
  • Glucose deprivation
  • Starvation
  • Hibernation
  • Hypothermia
  • Anesthesia
  • Glucocorticoids
  • Opiates
  • Alcohol

Studies increasingly suggest a role for physiologic tau phosphorylation in synaptic function 13. Tau is normally present at both pre- and post-synaptic sites [68], and accumulates as hyperphosphorylated tau at these sites in Alzheimer’s disease 16. Whether tau diffuses across the synapse under normal conditions is an open question. Synaptic stimulation nevertheless induces site-specific, subsynaptic tau phosphorylation 17. Tau mRNA has also been identified in axons and at subsynaptic sites, suggesting a role for local translation of tau in maintaining axonal integrity and synaptic function 18. Tau may also modulate signaling of synaptic neurotransmitter receptors, with post-synaptic tau phosphorylation acting as a “synaptic brake” via a complex and incompletely resolved mechanism. Glycogen synthase kinase 3 beta (GSK3β)-mediated tau phosphorylation, for example, may regulate neurotransmitter receptor endocytosis and negatively influence long term depression 13.

The biology of hibernation is interesting in that tau protein transitions to a PHF-like phosphorylated state, involving epitopes typically related to tau phosphorylation in Alzheimer’s disease. Yet the phosphorylation state is completely reversible upon arousal from torpor and return to euthermic conditions 19. This tends to suggest that tau phosphorylation in Alzheimer’s disease is a reactive phenomenon rather than a primary toxic process, and raises the issue of whether controlled hyperphosphorylation of tau confers cellular protection.

Tau has been shown to bind filamentous actin of dendritic spines as further evidence of its role in cytoskeletal integrity 20. Other studies have localized tau to the nucleus and the centrosome, in addition to the mitotic spindle microtubules of dividing cells 21, suggesting that tau phosphorylation might be involved in nucleus-cytoplasm translocation and cell cycle transition. Tau can also bind DNA, whereas tau phosphorylation may prevent DNA binding 22. Nucleolar organization and protection of genomic DNA is still another potential function 23. Tau is found in association with RNA as part of a ribonucleoproteome, complexing with RNA and a variety of proteins 24. Finally, tau is also expressed in astrocytes and oligodendrocytes, the latter with all six isoforms, although with a lesser degree of microtubule binding 25. Oligodendrocyte tau appears to be involved in microtubule stability during morphogenesis and myelination 26.

Tau protein phosphorylation and hyperphosphorylation

Normal tau is a highly soluble natively unfolded protein 27, which contrasts with hyperphosphorylated p-tau in NFT which is highly insoluble 28. The latter should be distinguished from physiologic tau phosphorylation, which is an ongoing dynamic process in the brain, and a necessary, tightly regulated process 19. Phosphorylation regulates interactions involved in subcellular distribution and axonal transport 29, organelle delivery to the somatodendritic compartment 30, neurotransmitter receptors 31, apolipoprotein E 32, Src kinases 33, and Pin1 34. Because of its high number of serine and threonine residues, tau protein is an excellent substrate for protein kinases, especially proline-directed kinases such as GSK3β 19. Tau phosphorylation by cyclin dependent kinases and mitogen activated protein kinases 35, emphasize the role of tau metabolism in cellular division and proliferation. Non-proline directed kinases are also involved 36. GSK3β and cdk5 may play a relatively more prominent role in tau phosphorylation in the human brain 35. Interconnection of the kinase network, promiscuity of protein kinases, and the tendency of phosphorylation sites to cluster present technical challenges to the study of tau phosphorylation in vivo. The phosphorylation yield at any given site is low and can be difficult to assess. Site directed mutagenesis results in complex alterations in ionic properties, which limits the significance of experimental findings 35.

Numerous phosphatases dephosphorylate tau in vitro, especially PP2A which is thought to also play a role in vivo 37. Activity of tau protein phosphatases is further regulated by endogenous inhibitors, which themselves are subject to regulatory phosphorylation 35, emphasizing the complexity of tau phosphorylation.

The broad property of “hyperphosphorylation” is a hallmark of tau aggregates in Alzheimer’s disease, numerous other tauopathies, and aging 38. Many phosphorylation sites occupied in PHF tau may be occupied in the normal brain 35. In advanced disease, most of the approximately 39 potential Alzheimer’s disease phosphorylation sites 39 are phosphorylated, with total phosphate content in p-tau pathological aggregates three times that of physiologic tau 40. One study in transgenic mice reports that pathological hyperphosphorylation is characterized by an increase in the proportion of phosphorylation at given residues, rather than an increase in the total number of phosphorylated residues 14, suggesting that tau “hyperphosphorylation” reflects an exaggerated physiologic phosphorylation, rather than disorganized phosphorylation at random sites receptive to phosphate groups. Still other studies suggest a role for molecular isomerism catalyzed by proline isomerase, with cis isomers of the Thr231 proline motif of p-tau variously labeling lesional brain tissue in Alzheimer’s disease and former professional athletes, as well as acutely traumatized murine neurons and axons in acute or recent trauma in humans 41. Trans isomers of p-tau are said to be “physiological” 42, although their specific role in the diversity of cellular tau functions is unclear.

It is noteworthy that antibodies used in p-tau analyses in vitro and in vivo react to highly selective epitopes, each with functional and pathological implications. The widely used monoclonal antibody AT8, for example, is used to identify tau phosphorylation at Ser 202, Thr 205, and Ser 208, which in turn identifies a wide spectrum of tau aggregates including the “pre-tangle” in autopsy brain 43. Pretangle aggregates are not otherwise apparent using histologic dyes such as hematoxylin and eosin, or silver impregnation techniques such as Bielschowsky silver. For this reason, p-tau as identified by AT8 immunohistochemistry may lack any associated pathological alteration (such as a morphologically identifiable NFT). Pathology with a hypothesized link to repetitive traumatic brain injury (TBI) for example is often entirely immunohistochemical, with no tissue reaction that would otherwise suggest that an injury has taken place. This tends to raise questions about p-tau immunoreactivity as an indicator of cell death with repetitive traumatic brain injury exposure. This may also explain the lack of eloquence regarding p-tau and clinical signs 44. Phosphorylation at Thr 212 and Ser 214, identified in tissues by monoclonal antibody AT100, may be a better indicator of more advanced pathology 45, less sensitive than AT8 but more specific for pathological aggregates.

Decomposition and associated artifacts are synonymous with postmortem human brain analyses, and may be underappreciated. It is known, for example, that postmortem changes in the phosphorylation state is a dynamic process, with dephosphorylation of p-tau occurring rapidly postmortem, in a site-specific manner 46. P-tau autopsy tissues may preferentially label buried epitopes, i.e., resistant to degradation. The patterns of immunoreactivity in the human brain may therefore be skewed toward postmortem artifact and away from solubility or in vivo biological relevance.

Hyperphosphorylation of tau may result from an imbalance in the activity of tau protein kinases and tau phosphatases, which in turn may be necessary for the formation of pathological fibrils. The conversion of physiologic tau to filamentous tau is believed to be a multi-step processes, with microtubule detachment as the initial step 47. A number of biological mechanisms have been suggested 48. Higher concentrations of tau may also influence conformational changes necessary for fibril formation 49. Interestingly, 3R tau is said to facilitate twisted paired helical filaments such as those seen in classical Alzheimer’s disease NFT, while 4R tau has a tendency to assemble into straight filaments such as described in progressive supranuclear palsy 50. Whether fibrillar or PHF tau signifies cytotoxicity, versus a productive response to the aging process or cellular stress, remains an open question 51. Direct experiments verifying a feed-forward pathological cascade are sparse, with some studies showing no correlation between NFT accumulation and length of microtubules 52. Still other studies demonstrating adduct formation (e.g., advanced glycation, advanced lipid peroxidation), and sequestration of redox active transition metals, may indicate that p-tau aggregation, up to and including PHF tau, is a productive response to cellular stress 53.

Studies in recent years have increasingly implicated soluble, low-n tau assembly intermediates as the toxic or biologically active species 54. The same concept is invoked for Aβ in Alzheimer’s disease 55. This again suggests that the most readily identifiable postmortem lesions detected by immunohistochemistry may be the least biologically relevant. In one inducible transgenic model, progression of insoluble tau pathology was noted after suppression of mutated tau gene expression, during the process of functional recovery 56.

Tauopathy diseases

The broad term “tauopathy” was first suggested in 1997 for a familial degenerative tauopathy 57 and is often used to connote diverse neurodegenerative diseases characterized by p-tau accumulations with various morphologies and clinical correlates. To the extent that tauopathy implies the accumulation of p-tau as a rate-limiting factor for disease pathogenesis, the terminology may be unfortunate. A convincing case could be made that p-tau is a disease response, perhaps even a productive disease response 51. The term “tauopathy” may be subclassified into “primary” tauopathy, in which p-tau accumulation is the major pathological finding, or “secondary” tauopathy, in which some other protein deposit occurs (e.g., Aβ, prion protein) 35. P-tau in sporadic primary tauopathies may not correlate with neuronal loss in some diseases 58. Rigorously defined, true primary tauopathies may be limited to frontotemporal lobar degenerations associated with pathogenic mutations of the tau gene (MAPT) on chromosome 17 (FTDP-17) 59. Like familial Alzheimer’s disease with APP mutations, the role of tau mutation in the molecular pathology is unclear. Some studies suggest that MAPT mutation causes chromosomal instability and aneuploidy 60, rather than the elaboration of a toxic tau species per se.

Sporadic tauopathies are currently classified as frontotemporal lobar degeneration-tau (FTLD-tau), which encompasses Pick disease, progressive supranuclear palsy, and corticobasal degeneration 58. Interestingly, MAPT remains the most substantial association by genome wide association analysis 61, and patients with MAPT tau mutation have clinical and pathological features that overlap with progressive supranuclear palsy and corticobasal degeneration 62. Corticobasal degeneration and progressive supranuclear palsy clinical phenotypes tend to contain lesions composed mainly of 4R tau, which supports dysfunctional microtubule binding as a factor in neurodegeneration. Pick disease phenotype (the least common of the sporadic FTLD-tau phenotypes), on the other hand, contains lesions comprised of 3R tau. Given the tendencies toward tau isoform specificity in FTLD-tau, it is tempting to suggest specific isoforms as therapeutic targets 63. Such a construct would require p-tau as inherently toxic, however, which is not established.

Diseases with tau neuropathology 64

  • Frontotemporal dementia and parkinsonism linked to chromosome 17 (FTDP-17)
  • Alzheimer’s disease
  • Aging
  • Primary age-related tauopathy
  • Aging-related tau astrogliopathy
  • Progressive supranuclear palsy
  • Pick’s disease
  • Argyrophilic grain disease
  • Corticobasal degeneration
  • Progressive subcortical gliosis
  • Amyotrophic lateral sclerosis/parkinsonism-dementia complex
  • Diffuse neurofibrillary tangles with calcification
  • Dementia pugilistica
  • Tangle-only dementia
  • Down syndrome
  • Gerstmann-Straussler-Scheinker disease
  • Hallervorden-Spatz disease
  • Creutzfeldt-Jakob disease
  • Globular glial tauopathy
  • Niemann-Pick disease type C
  • Prion protein cerebral amyloid angiopathy
  • Subacute sclerosing panencephalitis
  • Myotonic dystrophy
  • Non-guanamian motor neuron disease with neurofibrillary tangles
  • Postencephalitic parkinsonism
  • Meningioangiomatosis
  • Tuberous Sclerosis

Tauopathy symptoms

Memory loss is the key symptom of Alzheimer’s disease. An early sign of the disease is usually difficulty remembering recent events or conversations. As the disease progresses, memory impairments worsen and other symptoms develop.

At first, a person with Alzheimer’s disease may be aware of having difficulty with remembering things and organizing thoughts. A family member or friend may be more likely to notice how the symptoms worsen.

Brain changes associated with Alzheimer’s disease lead to growing trouble with:

Memory

Everyone has occasional memory lapses. It’s normal to lose track of where you put your keys or forget the name of an acquaintance. But the memory loss associated with Alzheimer’s disease persists and worsens, affecting the ability to function at work or at home.

People with Alzheimer’s disease may:

  • Repeat statements and questions over and over
  • Forget conversations, appointments or events, and not remember them later
  • Routinely misplace possessions, often putting them in illogical locations
  • Get lost in familiar places
  • Eventually forget the names of family members and everyday objects
  • Have trouble finding the right words to identify objects, express thoughts or take part in conversations

Thinking and reasoning

Alzheimer’s disease causes difficulty concentrating and thinking, especially about abstract concepts such as numbers.

Multitasking is especially difficult, and it may be challenging to manage finances, balance checkbooks and pay bills on time. These difficulties may progress to an inability to recognize and deal with numbers.

Making judgments and decisions

The ability to make reasonable decisions and judgments in everyday situations will decline. For example, a person may make poor or uncharacteristic choices in social interactions or wear clothes that are inappropriate for the weather. It may be more difficult to respond effectively to everyday problems, such as food burning on the stove or unexpected driving situations.

Planning and performing familiar tasks

Once-routine activities that require sequential steps, such as planning and cooking a meal or playing a favorite game, become a struggle as the disease progresses. Eventually, people with advanced Alzheimer’s may forget how to perform basic tasks such as dressing and bathing.

Changes in personality and behavior

Brain changes that occur in Alzheimer’s disease can affect moods and behaviors. Problems may include the following:

  • Depression
  • Apathy
  • Social withdrawal
  • Mood swings
  • Distrust in others
  • Irritability and aggressiveness
  • Changes in sleeping habits
  • Wandering
  • Loss of inhibitions
  • Delusions, such as believing something has been stolen

Preserved skills

Many important skills are preserved for longer periods even while symptoms worsen. Preserved skills may include reading or listening to books, telling stories and reminiscing, singing, listening to music, dancing, drawing, or doing crafts.

These skills may be preserved longer because they are controlled by parts of the brain affected later in the course of the disease.

Tauopathy treatment

To date, there are no approved and established pharmacologic treatment options for tauopathies 65. Available treatment strategies are based mainly on small clinical trials, miscellaneous case reports, or small case-controlled studies. The results of these studies and conclusions about the efficacy of the medication used are often contradictory. Approved therapeutic agents for Alzheimer´s dementia, such as acetylcholinesterase inhibitors and memantine, have been used off-label to treat cognitive and behavioral symptoms in tauopathies, but the outcome has not been consistent. Therapeutic agents for the symptomatic treatment of Parkinson’s disease (levodopa or dopamine agonists) are used for motor symptoms in tauopathies. For behavioral or psychopathological symptoms, treatment with antidepressants-especially selective serotonin reuptake inhibitors-could be helpful. Antipsychotics are often not well tolerated because of their adverse effects, which are pronounced in tauopathies; these drugs should be given very carefully because of an increased risk of cerebrovascular events. In addition to pharmacologic options, physical, occupational, or speech therapy can be applied to improve functional abilities. Each pharmacologic or nonpharmacologic intervention should be fitted to the specific symptoms of the individual patient, and decisions about the type and duration of treatment should be based on its efficacy for the individual and the patient’s tolerance. Currently, no effective treatment is available that targets the cause of these diseases. Current research focuses on targeting tau protein pathology, including pathologic aggregation or phosphorylation; these approaches seem to be very promising.

The identification and validation of druggable targets that affect tau pathology has proven to be much more difficult than for the Aβ senile plaque pathology of Alzheimer’s disease. In the latter, the identification of the β- and γ-secretase enzymes involved in Aβ cleavage from the amyloid precursor protein led to the rapid initiation of drug discovery programs targeting these proteolytic systems, although there has yet to be clinical success with drugs directed to these enzymes. Thus, while there is evidence of tau proteolysis, it is still debatable as to how much such cleavage contributes to pathology in tauopathies. Furthermore, the large number of candidate proteases has resulted in uncertainty as to which might be the most important enzyme target. A similar uncertainty exists for the tau kinases, as a large number of enzymes have been implicated in the hyperphosphorylation of tau. In contrast, the identity of tau enzyme targets that regulate post-translational O-glycosylation and acetylation are generally well understood, but these modify a large number of proteins, raising questions of whether prolonged modulation of these enzymes will lead to side-effects. A similar concern can be raised regarding the modulation of targets linked to cellular proteostatic systems, such as those involved in proteasomal protein degradation or autophagy, where specificity of action may be difficult. It is likely that many of these concerns have led to pharmaceutical interest in non-enzymatic strategies, including reduction of tau expression and tau immunotherapy. As noted, tau anti-sense oligonucleotide approaches are being considered, and a large number of ongoing tau immunotherapy trials should soon provide initial indications of the merits of this strategy. In addition, there is still interest in the potential of brain-penetrant MT-stabilizing agents in compensating for axonal transport deficiencies that may occur in tauopathies, with TPI-287 presently in Phase 1 clinical testing. Finally, MB has been shown to affect tau pathology in several models and Phase 3 clinical trials are presently ongoing with the related molecule, LMTX.

Table 1. Summary of tau-directed therapeutic strategies with associated opportunities and challenges.

Target/StrategyOpportunitiesChallenges
Tau KinasesEnzyme targets; Industry
expertise; Clear disease relevance		Which kinase(s)?; Drug selectivity;
On/off-target toxicities
O-GlcNacase (OGA)Enzyme target; Prototype drug
tested in mouse models		Further target validation; Multiple
proteins modified by OGA
Tau
Acetyltransferase(s)		Enzyme target; Increasing
literature reports of relevance		Further target validation; Multiple
proteins modified by acetyltransferase(s)
Tau CleavageEnzyme targets; Compelling
literature		Which protease(s)?; Multiple proteins
cleaved by candidate proteases
Tau FibrillizationClear disease relevance; Multiple
reported inhibitors; LMTX in P3
testing		Difficult to inhibit protein-protein
interactions; Many non-drug-like
example inhibitors
ProteostasisClear disease relevance;
Conceptually appealing		What is best target?; Can proteostatic
systems be safely modulated?
Tau ExpressionAmenable to ASO approaches;
Intriguing in vivo data		Long-term safety of tau reduction; ASO
brain distribution
Microtubule
stabilizer		Reasonably compelling target
validation; TPI-287 in P1 testing		Long-term safety
Tau ImmunotherapyTarget validation; Industry
expertise; Passive immunization
generally safe		Best epitope(s)?; Sufficient antibody
exposure in brain; Exosomal release of
tau?
[Source 2 ]

Alzheimer’s disease

Drugs

Current Alzheimer’s medications can help for a time with memory symptoms and other cognitive changes. Two types of drugs are currently used to treat cognitive symptoms:

  • Cholinesterase inhibitors. These drugs work by boosting levels of cell-to-cell communication by preserving a chemical messenger that is depleted in the brain by Alzheimer’s disease. The improvement is modest. Cholinesterase inhibitors may also improve neuropsychiatric symptoms, such as agitation or depression. Commonly prescribed cholinesterase inhibitors include donepezil (Aricept), galantamine (Razadyne) and rivastigmine (Exelon). The main side effects of these drugs include diarrhea, nausea, loss of appetite and sleep disturbances. In people with cardiac conduction disorders, serious side effects may include cardiac arrhythmia.
  • Memantine (Namenda). This drug works in another brain cell communication network and slows the progression of symptoms with moderate to severe Alzheimer’s disease. It’s sometimes used in combination with a cholinesterase inhibitor. Relatively rare side effects include dizziness and confusion.

Sometimes other medications such as antidepressants may be prescribed to help control the behavioral symptoms associated with Alzheimer’s disease.

Creating a safe and supportive environment

Adapting the living situation to the needs of a person with Alzheimer’s disease is an important part of any treatment plan. For someone with Alzheimer’s, establishing and strengthening routine habits and minimizing memory-demanding tasks can make life much easier.

You can take these steps to support a person’s sense of well-being and continued ability to function:

  • Always keep keys, wallets, mobile phones and other valuables in the same place at home, so they don’t become lost.
  • Keep medications in a secure location. Use a daily checklist to keep track of dosages.
  • Arrange for finances to be on automatic payment and automatic deposit.
  • Carry a mobile phone with location capability so that a caregiver can track its location. Program important phone numbers into the phone.
  • Make sure regular appointments are on the same day at the same time as much as possible.
  • Use a calendar or whiteboard in the home to track daily schedules. Build the habit of checking off completed items.
  • Remove excess furniture, clutter and throw rugs.
  • Install sturdy handrails on stairways and in bathrooms.
  • Ensure that shoes and slippers are comfortable and provide good traction.
  • Reduce the number of mirrors. People with Alzheimer’s may find images in mirrors confusing or frightening.
  • Make sure that the person with Alzheimer’s carries identification or wears a medical alert bracelet.
  • Keep photographs and other meaningful objects around the house.
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