Caregiver Well-Being and Resources

There are over 11 million people in the United States who provide unpaid care for a loved one with dementia, including Alzheimer’s Disease (AD). Caring for those with dementia often falls to a child, partner, or close friend, and often with little or no disease-specific knowledge or resources. It is a challenging but rewarding role. In 2022, dementia caregivers in Oregon alone contributed over $7 billion in unpaid care and often reported high stress and mental health challenges, with their well-being put on the back burner. Although caregivers report knowing that preserving their own health and social relationships is vital, many find themselves unable to follow through.

An AD or dementia diagnosis affects not only the patient but also their entire support network. Self-care helps to avoid burnout and enables caregivers to provide the best care they can for their loved ones. Like those with dementia, it is also essential for caregivers to remain engaged with their hobbies and social networks. There are a multitude of resources available for caregivers but are only effective if caregivers are informed of them. 

Education in disease progression is essential and can come in two forms: information about the disease itself and information about the resources available to them. There is a sea of information available online, but it can initially seem overwhelming or confusing.

The Alzheimer’s Association is an organization dedicated to Alzheimer’s care and research. Their website provides endless information including educational resources, support groups, and caregiver forums with local chapters across the country. The local Oregon and SW Washington chapter hosts weekly support groups and a variety of other events for people with dementia to attend and groups just for caregivers. The chapter also hosts educational sessions. More information, including events and meeting times, can be found on the Alzheimer’s Association website. You can also subscribe to their monthly newsletter to keep up to date with events and information. They also host AlzConnected, an online discussion forum for both people with dementia and their caregivers to ask questions, share experiences, and provide knowledge.

HOPE Dementia Support hosts support groups in Vancouver and nearby areas in addition to virtual groups. They also offer educational seminars for people looking for more information about dementia or caregiver resources. Attending events can be helpful for a person with AD to stay engaged and allows caregivers to talk with people in a similar situation.

Alzheimer’s Foundation of America (AFA) was founded by an AD caregiver to provide educational resources. AFA offers a helpline, support groups, and information about clinical trials for AD. Their helpline can be contacted at (866) 232-8484.

Counseling services are another option for caregivers and those with dementia. Dr. Meghan Marty founded Rose City Geropsychology and specializes in treating older adults and their families as they deal with life adjustments, cognitive impairment, and related issues. Lori Eckel is a licensed clinical social worker who focuses on supporting families as they navigate dementia and plan future care. The OPAL Institute provides neuropsychological evaluation, therapy, and other services for aging adults and their families.

In many cases, a family is unable to manage dementia care alone. Additional assistance can come in many forms and will vary based on what is most appropriate for each person. For people still able to live at home, home healthcare workers may provide some assistance to reduce the pressure on an unpaid caregiver. Visiting Angels and Home Instead offer in-home assistance. Day centers allow older adults social interaction and care while giving caregivers some time off. Some local options include Thelma’s Place and A Place at the Center. Gentog offers a unique approach with intergenerational daycare by combining care for seniors with daycare for children. When living at home is no longer safe for a person with dementia, many options are available with a range of independence and care including retirement homes, assisted living, and memory care. A resource that may help in finding the most appropriate option is 1st Choice Advisory Services located in Oregon and Washington. They are a free advisory service to help caregivers learn about housing.

Becoming a dementia caregiver comes with many life changes that no one should have to go through without guidance. Luckily, there is a wealth of resources available, and knowing where to look is the vital first step. This helps caregivers to provide the best possible support while also making sure they take care of themselves.

Engaging in clinical trials can be beneficial to a person with dementia and their caregivers too. Clinical trials are voluntary and conducted to see if an investigational product is safe and effective. Some of the reasons to partake include taking an active role in one’s treatment, receiving cognitive and lab testing to monitor the progression of the disease, furthering the body of knowledge for dementia and its treatment, and the ability to regularly meet with a physician specialized in that type of care for free. These benefits can drive a feeling of purpose for the caregiver and the person with dementia. If you are interested in learning more about clinical trials, fill out our online submission form, to begin with a free memory screen.


Alzheimer’s Association. (2023) Alzheimer’s Disease Facts and Figures.

Alzheimer’s Association. (n.d.). Support Groups.

Bressan, V., Visintini, C., & Palese, A. (2020). What do family caregivers of people with dementia need? A mixed‐method systematic review. Health & social care in the community, 28(6), 1942-1960.

Oregon Department of Human Services. (2020) Family Caregiver Handbook.

Normal Aging vs. Early Alzheimer’s Disease

    Differentiating between early Alzheimer’s disease (AD), and normal, age-related cognitive decline is difficult. To determine a diagnosis, biomarker assessments of amyloid plaques and neurofibrillary tangles (NFT) can be used.

       AD is thought to be caused by elevated amyloid-beta protein (Aβ) that instigates NFT formation measured by pTau levels in the blood. As Aβ increases it forms Aβ plaques in the brain that precede memory problems by decades. Amyloid PET scans can assess Aβ levels while blood tests of pTau mirror Amyloid PET scans and have recently become accessible in clinical practice.

       Preclinical AD is diagnosed when biomarkers are positive, but cognition is normal. Accumulation of Aβ first occurs in the frontal lobes causing multi-tasking difficulty in early AD. Memory issues follow when encoding circuit dysfunction occurs. As changes in the brain progress, neuronal death due to NFTs correlate to cognitive decline, but cognition should also be tested.

       Cognitive tests assess memory, language, visuospatial skills, attention, and executive functioning. The pattern of these deficits in these areas differentiate AD from cognitive problems in normal aging. Mild cognitive impairment (MCI) or prodromal AD is diagnosed before the family says the patient is unsafe to live alone. That is when dementia is present, and the patient is said to have full blown AD. 

     Cognitive assessments are useful in assessing patients at all stages of decline. These tests are widely available. Immediate recall and delayed recall are assessed by examining the ratio between immediate and delayed recall to diagnose early AD compared to using total recall or only delayed recall. Cognitive measures also examine semantic memory. This is the memory of acquired knowledge such as words and facts, which can be one of the first areas affected before MCI is diagnosed. Verbal fluency tasks such as naming items within a category or beginning with a specific letter can be predictive of MCI.

       Episodic memory is encoded through the Papez circuit. When there is a failure in this circuit, there is difficulty learning new information because a person is unable to encode the information, meaning that providing the information multiple times will not improve their performance. Learning is always intact in normal aging; normal ‘forgetfulness’ is due to a retrieval deficit where a person is unable to retrieve information they have previously learned. Neuropsychology tests can identify a retrieval deficit versus an encoding deficit.

       Determining a diagnosis of AD is a result of a variety of tools. Biomarkers examined through imaging and blood tests can aid in diagnosis before MCI is first noticed. Cognitive testing gives insight into memory and other cognitive dysfunction and is helpful in monitoring the progression of MCI and AD. Early diagnosis is advantageous as we continue to research treatments. Biomarker tests are becoming more widely available for people to understand their risks of developing AD during the preclinical stage. There is still much more progress to be made, but these tools offer an initial step in preventing decline in AD.



Bruno, D., Jauregi Zinkunegi, A., Pomara, N., Zetterberg, H., Blennow, K., Koscik, R. L., … & Mueller, K. D. (2023). Cross-sectional associations of CSF tau levels with Rey’s AVLT: A recency ratio study. Neuropsychology37(6), 628.

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DeTure, M.A., & Dickson, D.W. (2019) The neuropathological diagnosis of Alzheimer’s disease. Molecular Neurodegeneration, 14(32).

Hill, Carrie (2022, November 11). Neuropsychological Testing to Evaluate Alzheimer’s Disease. Verywell Health.

National Institute on Aging. (2023, November 22). Memory Problems, Forgetfulness, and Aging. National Institue of Health.

Rasmussen, J., & Langerman, H. (2019). Alzheimer’s disease–why we need early diagnosis. Degenerative neurological and neuromuscular disease, 123-130.

Wright, L. M., De Marco, M., & Venneri, A. (2022). Verbal fluency discrepancies as a marker of the prehippocampal stages of Alzheimer’s disease. Neuropsychology, 37(7), 790-800.

Hope on the Horizon: Breakthrough Investigational Treatments for Neurodegenerative Diseases

Clinical neurodegenerative research is at an exciting crossroads. Scientists and pharmaceutical companies are focusing on a variety of innovative approaches to better understand and treat theses complex diseases, including Alzheimer’s disease (AD), Lewy body dementia (LBD), and Parkinson’s disease (PD). Emerging trials are exploring novel therapies targeting not only symptom management but also disease origination.

At the heart of AriBio’s AR1001 investigational drug’s potential lies its groundbreaking mechanism of action. The oral drug seeks to target the underlying factors responsible for AD, in hopes of slowing down or even halting disease progression. Although first established for erectile dysfunction, AR1001 appears to reduce amyloid b (Ab) protein and increase blood flow in the brain. It’s accomplished via a selective phosphodiesterase 5 inhibitor preventing degradation of secondary messengers (cAMP and cGMP) regulating cellular functioning. By reducing neuroinflammation, promoting neural regeneration, and mitigating the toxic Ab plaque build-up in the brain, AR1001 represents a potential leap forward in AD treatment.

Cognito Therapeutics’ CA-0011 trial showcases a novel route to combat AD. It combines elements of neuroinflammation reduction, neural regeneration promotion, and the mitigation of Ab plaques in the brain. Their innovative investigational device utilizes non-invasive neuromodulation techniques to target specific brain regions associated with cognitive function, achieved by delivering 40Hz gamma stimulation through a self-administered glasses headset. By providing precisely tuned electrical currents, the device aims to modulate neural activity, enhance synaptic plasticity, and promote neural connectivity in a region-specific manner. This neuromodulation approach is designed to optimize brain function and potentially ameliorate cognitive deficits. The device’s non-invasive mechanism of action represents a promising avenue in the quest for effective treatments and cognitive improvements for patients suffering from AD.

Eli Lilly continues to produce evermore promising monoclonal antibodies targeting AD, with one of the newest being Remternetug. These antibodies bind to Ab plaques in the brain, initiating immune cells, or microglia, to clear them. Following in the footsteps of Donanemab, this investigational drug also targets the pyroglutamated structure of Ab in plaque form, but it’s given as a simple injection rather than an IV-infusion. When Remternetug was given to AD patients for 6 months, around 75% resulted in Ab plaque clearance. That took Donanemab 18 months to do, suggesting Remternetug may be a more sufficient therapeutic.

Neflamapimod, developed by EIP Pharma, is a small molecule investigational drug showing promise for a multitude of neurodegenerative diseases. It’s designed to inhibit the enzyme p38 MAP kinase targeting the cholinergic system, believed to be involved in the inflammation and cell dysfunction and death associated with PD, LBD, and AD. By targeting these pathways Neflamapimod’s goal is to reduce neuroinflammation, alleviate some motor symptoms, and potentially slow down cognitive decline. It appears to work best in those with low baseline ptau181 levels and less extensive cortical neurodegeneration. When tested in AD patients, those with ptau181 levels below 2.2 ng/mL resulted in substantial benefits to attention, dementia severity, motor functional mobility, and memory compared to those with higher levels of the biomarker. A similar pattern is seen with DLB patients with normal ptau181 levels improving compared to those with abnormally elevated levels. Based on these findings, a criterion limiting those with higher ptau181 levels could uncover a greater efficacy for those on Neflamipimod to treat DLB. A phase IIb clinical trial, RewinD-LB, is ongoing to evaluate its safety and efficacy, offering optimism for a new therapeutic approach for DLB.

These promising developments bring new hope for improved care and potentially disease-modifying treatments. While there is still much to learn and discover, the field of neurodegenerative disease research is advancing, inching closer to a future with effective interventions and even potential cures. If you, or anyone you know, may be interested in taking part in a clinical trial involving any of the above discussed investigational therapeutics, please reach out to us at 503-548-0908.



Alam, John, et al. “Association of Plasma Phosphorylated Tau with the Response to Neflamapimod Treatment in Patients with Dementia with Lewy Bodies.” Neurology, 1 Sept. 2023, pp. 10.1212/WNL.0000000000207755–10.1212/WNL.0000000000207755, Accessed 31 Oct. 2023.

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Beaney, Abigail. “First Patient Dosed in Phase IIb RewinD-LB Trial for DLB.” Clinical Trials Arena, 14 Aug. 2023, Accessed 31 Oct. 2023.

Benussi, Alberto, et al. “Exposure to Gamma TACS in Alzheimer’s Disease: A Randomized, Double-Blind, Sham-Controlled, Crossover, Pilot Study.” Brain Stimulation, vol. 14, no. 3, May 2021, pp. 531–540,

“Cognito Therapeutics Announces Proprietary Gamma Sensory Stimulation for 6-Months Reduces White Matter Atrophy in Alzheimer’s Disease Patients.”, 1 Aug. 2022,

Senior, Emily Craig. “Another Alzheimer’s Drug Could Be Better than Donanemab.” Mail Online, 19 July 2023, Accessed 31 Oct. 2023.

“Treatment Effect of Neflamapimod Enriched When Excluding High P-Tau181 Level Patients.” Neurology Live, 11 Sept. 2023, Accessed 31 Oct. 2023.

Psychedelics May Help Treat Neurodegenerative Disorders

Alzheimer’s disease (AD) is a devastating neurodegenerative disorder that affects millions of people worldwide. The hallmark features of AD include neuroinflammation, dendritic atrophy, and loss of synapse density in cortical regions controlling cognition, memory, and mood. Recent research has pointed to a potentially groundbreaking therapy using psilocybin, a naturally occurring compound found in certain mushrooms known for its hallucinogenic properties. While some current treatments carry significant risk for adverse side effects, psilocybin and other psychedelics are relatively low risk. This blog discusses the emerging evidence suggesting that psilocybin may hold promise as a treatment for AD due to its ability to promote neuronal growth and modulate neuroinflammation.

Recent studies have demonstrated that psychedelics like psilocybin can stimulate 5-HT2A receptors, promoting cortical neuron growth, activation of neuronal survival mechanisms, and modulation of the immune system. Activation of these receptors induces the expression of immediate early genes (IEGs), which are known to be involved in neuroplasticity. Moreover, psychedelics have been shown to activate signaling pathways that promote neurotrophic factor release, particularly brain-derived neurotrophic factor (BDNF), which plays a crucial role in neuronal growth and survival. BDNF is often reduced in AD, contributing to the progressive loss of spines and synapses associated with dementia. In both human and animal studies, psychedelics like psilocybin increased BDNF expression in the cortex, increasing neuronal growth. These structural changes are accompanied by functional changes, such as an increase in spontaneous excitatory postsynaptic currents (sEPSCs), which indicate improved synaptic activity.

Neuroinflammation is increasingly recognized as a critical component of AD pathophysiology. Psychedelics have shown potential in modulating the immune system and reducing inflammation. By promoting cortical neuron growth and modulating neuroinflammation, psilocybin may have the potential to simultaneously address two significant components of AD pathophysiology.

One of the most promising aspects of psychedelic medicine is the long-lasting therapeutic effects observed after a single administration. Clinical trials and preclinical studies have demonstrated that psychedelic-assisted therapy can elicit therapeutic responses lasting for months. In some cases, this effect has been associated with increased neuroplasticity. In addition to promoting neuronal growth and modulating neuroinflammation, using psilocybin to activate 5-HT2A receptors has been shown to improve mitochondrial function. Mitochondrial dysfunction and oxidative stress are common features of neurodegenerative diseases like AD. By enhancing mitochondrial function, psilocybin may further contribute to its therapeutic potential for AD.

 While the evidence supporting the use of psilocybin for treating neurodegenerative disorders like AD is still limited, the emerging research is promising. The unique ability of psychedelics to promote both structural and functional neuroplasticity through the activation of 5-HT2A receptors makes them an intriguing candidate for further exploration as a potential treatment for AD. As we continue to investigate the therapeutic potential of psychedelics, it is crucial to conduct further research to better understand their mechanisms of action and assess their safety and efficacy for treating neurodegenerative diseases. Collaborative efforts between researchers, medical professionals, and therapeutic facilitators will be essential to unlock the full potential of psychedelic medicine and offer hope to those affected by devastating neurological disorders like AD.

Reference: Saeger, H. N., & Olson, D. E. (2022). Psychedelic-inspired approaches for treating neurodegenerative disorders. Journal of Neurochemistry, 162, 109–127. 

Rationale for Amyloid-Beta Targeting Therapies for Early AD Treatment

Recent translational studies have led to a model of Alzheimer’s disease (AD) pathophysiology that focuses on the accumulation of amyloid-beta (Aβ) plaques between 20-30 years prior to the spread of tau, neuronal loss, and appearance of clinical symptoms. These findings have enabled the current research landscape to evolve to include preclinical stages of AD, when treatment success is predicted to be higher. There are a number of contributing factors that lead to a person developing AD. However, the multifactorial nature of AD largely plays into the reasoning researchers are focusing on Aβ accumulation for potential therapeutic interventions for early AD.

As discussed in previous blogs, Aβ is an enzymatic product of the amyloid precursor protein (APP) gene. An imbalance of Aβ production in the brain and extra-cellular clearance precedes Aβ protein misfolding and aggregation into brain plaques in AD. Mutations in APP can make enzymes involved in processing it bind more tightly to it, causing more of these misfolded Aβ protein fragments to be produced. Additionally, the APP gene can be processed by 3 main proteases: β-secretase and gamma-secretase promote toxic Aβ production, whereas A-secretase produces healthy, soluble Aβ. Dysregulation in these secretases can result in Aβ over production. Although an excess of Aβ proves detrimental, Aβ protein is necessary for normal neurotransmission and synaptic plasticity, so knocking out the APP gene altogether is not a viable solution. Large-scale genome-wide association studies have identified over 50 additional genetic risk factors for AD, and while they do not denote the exact cause of the disease, most are involved in maintaining Aβ homeostasis. For instance, those with early-onset AD often have mutations in at least one of three genes: APP, presenilin 1 (PSEN1), and presenilin 2 (PSEN 2), and have increased Aβ due to genetic driven-dysregulation. This is compared to those with late-onset AD, with Aβ plaques largely attributed to reduced cellular quality control.
Another well-known genetic association with Aβ metabolism and homeostasis is an individual’s apolipoprotein (APOE) genotype. In-vitro and mouse models have shown that APOE moderates the activity of specific enzymes and downstream Aβ production. Those with an APOE E4 genotype were found to have significantly higher Aβ secretion, and those with two copies resulted in a 5-13-fold increase in AD incidence. Although our genes can be important in determining health status, sometimes it’s the downstream events, after protein production, that can initiate dysfunction. These post-translational, or epigenetic, changes further modify gene expression and protein production and degradation, continuing to alter Aβ levels.
In an attempt to protect the brain from Aβ plaques, microglia activate to prevent Aβ plaque spread, help with Aβ clearance, and attempt to limit Aβ accumulation. A dysregulation in these microglia, or a normal regulation under Aβ conditions, can further induce Aβ aggregation in the brain. Transforming growth factor-beta1 (TGFβ-1) is a neuroprotective, anti-inflammatory growth factor that stimulates Aβ clearance. In those with early AD, this growth factor is selectively impaired. The presence of Aβ can induce detrimental microglia activity, causing the release of pro-inflammatory cytokines and interfering with anti-inflammatory cytokine synthesis. For example, the cytokine tumor necrosis factor-alpha (TNF-α) results in increased synthesis of Aβ peptides, and its presence perpetuates more TNF- α in a vicious cycle. Studies have found that TNF-α levels are elevated in both mild cognitive impairment (MCI) and AD. Therefore, Aβ is again a common factor in the culmination of events that can lead to disease progression. Since microglia have both beneficial and detrimental effects on the brain when associated with Aβ, an undiscovered temporal factor may be at play, indicating that only at certain stages can microglia constructively intervene. More research is needed to elucidate this further.

Toxicity within the Aβ pathway is believed to play a crucial role in the progression of AD. Studies have suggested a temporal progression of Aβ pathophysiology from the spread of Aβ aggregation to the formation of plaques in the brain. While the causal effect is not fully established, evidence suggests that Aβ aggregation may facilitate and have a synergistic effect on other pathophysiological pathways, triggering downstream effects such as tau misfolding, tangle formation, and eventual neurodegeneration. Understanding this relationship is crucial for unraveling the pathogenesis of AD.

In summary, the central role of Aβ in AD pathophysiology demonstrates why it is a viable target for early treatment options. Aβ accumulation during preclinical stages presents a critical time period for intervention. Imbalances in Aβ production and clearance contribute to plaque formation, while genetic risk factors can trigger further disruption of Aβ homeostasis. When microglia fail to effectively limit Aβ accumulation, Aβ aggregation is accelerated. The resulting toxicity is thought to start a cascade of events, causing disease progression. Continued research holds potential for the development of effective therapies targeting Aβ in the early stages of AD, potentially improving treatment outcomes for individuals affected by this devastating disease.



The Amyloid-β Pathway in Alzheimer’s Disease

Hampel H; Hardy J; Blennow K; Chen C; Perry G; Kim SH; Villemagne VL; Aisen P; Vendruscolo M; Iwatsubo T; Masters CL; Cho M; Lannfelt L; Cummings JL; Vergallo A

Understanding Why Tangles Spread in Alzheimer’s Disease: Part II

Part I of this 2-part blog series discussed possibilities why neurofibrillary tangles (NFTs) spread in the brains of people with Alzheimer’s disease (AD). Phosphorylated tau protein (p-Tau) 217, a potential mediator between amyloid plaque accumulation and NFTs, and sTREM2, a microglial activation marker showing correlation to rising p-tau and plaque thresholds due to its instigation of phosphorylating the tau protein are two key factors that may affect the proliferation of NFTs. However, we cannot pinpoint these factors as the sole reason for NFT propagation, as the research is inconsistent. Alzheimer’s is a very complex disease and researchers have difficulty determining how it develops with multiple variables at play (e.g., genes, environment, diet, various strands of p-Tau, etc.). Even with these complexities, probabilities and correlations emerge to point us in a direction of focus.

Next, we’ll discuss the patterns that tangles use to spread throughout the brain. Particularly, how location and higher neuronal firing in areas of the brain could propagate the spread of NFTs and how that correlates to the rate of cognitive decline.

A recent study investigated 3 models predicting tangle spread: one being functional, and the other two being structural. The functional model maintained the highest accuracy (r=0.58), inferring that tau is likely to spread based on which brain networks are most active, rather than how the brain is structured. Previous research has also found tau to be increasingly released during neuronal stimulation.

Where tangles begin accumulating in the brain is theorized to indicate the rate of cognitive decline. There is a large variation in how slowly or quickly people decline when diagnosed with AD, possibly due in part to the differing locations that tangles first begin. It is hypothesized that if tau aggregates in a less active or connected region of the brain, tangles are expected to spread slowly, whereas if tau aggregates in a highly active or densely connected region, tangles will spread quicker, and cognition will decline at a faster rate. A recent study replicated this theory. Interestingly, those who were more likely to have tangles in active neocortical, or hub regions, were younger participants, whereas the older participants had tangles located in less active/connected limbic regions. Those with symptomatic AD were found to have tangles in hub regions with an increased rate of tau aggregation over time, especially in younger people. Evidence suggests that tau accumulation beginning in a hub region leads to a higher likeliness of experiencing AD symptoms at an earlier age. At this time, we don’t know what makes tau aggregate in certain brain regions of some versus differing regions for others, but perhaps genes play a role in steering this variability.

Research has depicted risk alleles linked to AD. Carriers of the E4 variant of the APOE gene tend to accumulate more tangles in various brain regions with the temporal lobe as a particular hot spot, when compared to E3 variant carriers. Those carrying the E2 variant have even less tau burden when compared to E3 carriers. Interestingly, amyloid deposition seems to have little effect on tau burden in the case of E4 carriers, as the allele itself appears to drive the spread of NFTs. Future research remains to identify amyloid deposition as the strongest driver in tau accumulation, whereas involvement of the E4 allele may promote further tau accumulation, and E2 (identified as a protective gene against AD) diminishes tau accumulation, even in amyloid positive people.

There is still much to be determined in understanding why and how NFTs spread in the brain, how location of its aggregation plays a role in the rate of cognitive decline, and how genes and other environmental factors play a role. Identifying potential influences that lessen or increase the burden of tau and amyloid plaque assist in the knowledge of preventative measures and aid in the target of treatment. Nevertheless, more research is needed to confirm results and find successful therapies in halting the onset or spread of AD.




Alzforum. (2022, September 08). What drives tangles to spread? answers start rolling in. Alzforum: Networking for a cure.

Understanding Why Tangles Spread in Alzheimer’s Disease: Part I

             As discussed in our previous blogs, the study of Alzheimer’s disease (AD) concentrates on its two primary biomarkers: phosphorylated Tau protein (p-tau), that reflects neurofibrillary tangles (NFTs), and amyloid beta (Aβ), that forms amyloid plaques. The give and take between plaques and NFTs complicate the understanding of how AD develops and spreads, as it is hypothesized that Aβ accumulation activates the phosphorylation of tau (i.e., p-tau) therefore instigating NFT formation. Clinically, as NFTs proliferate through the brain, a person’s cognition declines in correspondence with the rate and location where NFTs are spreading. However, it is unclear how this process is controlled and how plaques stimulate it, causing difficulty in finding a successful therapy, or cure, for AD.

             A rise in phosphorylated tau is indicative of plaque formation; p-tau181, p-tau217, and p-tau231 are the most telling isoforms. Research has found that p-tau217 mediates the interplay between plaques and tangles. One study compared regional plaque accumulation and p-tau217 thresholds to understand which has a stronger influence on the spread of tangles. Findings show that p-tau217 was the main predictor for the spread of NFTs. However, the association between p-tau217 and NFTs decreased as the disease progressed. Plaque load and p-tau tend to plateau in those with AD, but tangles continue to spread. With these findings, perhaps p-tau217 is the initial spark that induces tangles, but once the NFTs have made a prominent presence, tangles themselves take over the continuity of spreading. This indicates that p-tau217 could be a therapeutic target for AD, but only in the early stages.

             Taking the focus of AD pathology a step earlier in the process, another study sought out how plaques give rise to p-tau to begin with. Research has labeled sTREM2, a microglial activation marker, as a connection to rising p-tau. Microglia are the immune scavenger cells in the brain. This study compared three groups of people: amyloid-negative controls, early amyloid accumulators, and late amyloid accumulators to dissect the association of plaques and p-tau. Results found that plaques and increased sTREM2 and p-tau181 correlated, but differed between the stages of AD. In early accumulators, plaques were found to instigate microglia in a way to activate the phosphorylation of p-tau181, allowing it to increase. However, in late accumulators, sTREM2 appeared to weaken p-tau181’s effect. Nonetheless, these results have been found reversed in other research, making it difficult to understand the connection of microglia’s role in brain atrophy.

             Phosphorylated tau may have a role in the progression of NFTs as described above, but how can these higher concentrations of p-tau, and its eventual plateau, explain the patterns that tangles spread throughout the brain? Stay tuned for Part II of this blog, where we discuss how location and higher neuronal firing in areas could propagate the spread of NFTs and how this associates with the occurrence and rate of cognitive decline.



Alzforum. (2022, September 08). What drives tangles to spread? answers start rolling in. Alzforum: Networking for a cure.

The Interplay Between Alzheimer’s Disease Biomarkers and Predicting Cognitive Decline

      Alzheimer’s disease (AD) biomarkers allow the identification of those at risk of developing AD and will aid in preventing the disease. The two primary biomarkers of AD are phosphorylated Tau protein, which forms neurofibrillary tangles (NFTs), and amyloid beta (Aβ), which forms amyloid plaques. The Amyloid hypothesis posits Aβ buildup activates the misfolding of Tau via hyper-phosphorylation (p-Tau) leading to NFT formation that kills neurons. Two types of p-Tau can be measured through blood tests or cerebrospinal fluid (CSF) and can indicate an accumulation of Aβ presence in the brain prior to symptom onset.

         Cognitively normal older adults who are positive for both plaques and NFTs decline much faster than those without either biomarker as well as older adults who only have plaques. Those with the presence of both pathologies (i.e., plaques and NFTs) have about a 15-20 times higher risk of developing dementia or mild cognitive impairment. Furthermore, brain regions in which NFTs have spread also indicate worsening decline in cognition. For example, those with both plaques and NFTs in the neocortex perform worse on tests of cognition (specifically global cognition, semantic fluency, and executive function) than those with NFTs that are still contained in the medial temporal lobe (MTL) that subserves memory function. As NFTs spread to the neocortex, multiple domains of cognition begin to deteriorate, which is indicative of a much higher risk of progressing quickly to dementia. The presence of both plaques and especially NFTs predict cognitive decline. Once p-Tau levels spike in CSF NFT presence is clearer and cognitive decline begins.

       Biomarker positivity is required in the new diagnostic criteria of preclinical AD under the National Institute on Aging and Alzheimer’s Association (NIA-AA) without any clinical symptoms. Furthermore, these biomarkers provide us an opportunity for preventative treatments in those at risk for AD before symptom onset. Eli Lily is utilizing this tactic in their assessment of Donanemab to slow the progression of cognitive decline in those at risk for AD based on elevated blood p-Tau levels. The investigational drug is a monoclonal antibody that removes Aβ plaques in the brain. Although previous and current clinical trials with Donanemab show great promise, the drug only targets plaques, not NFTs. Although it’s indicated that NFTs develop during ongoing plaque accumulation, there is evidence that people can still form NFTs without the presence of Aβ plaques. The trial mentioned above requires participants to have a positive p-Tau blood test, meeting a certain threshold of tau that is hypothetically indicative of future cognitive decline. However, p-Tau levels can change much earlier in one’s lifetime in response to amyloid deposition and may prove unable to forecast measurable cognitive decline in the typical period of a clinical trial. This makes it difficult to know when cognitively intact adults will decline and how fast they could decline. Perhaps prevention trials should push to enroll people who are deemed cognitively normal but test positive for the presence of plaques and NFTs. In this case, it may be more telling of how we can measure and determine the timeline of cognitive decline in its response to a preventative investigational drug within the length of a 2–3-year clinical trial. 

         Even with the proven removal of deposited Aβ plaques, research is still struggling to show a clinical benefit. Removing Aβ plaques improves elevated biomarker levels associated with AD, but how early should this be done to improve patient’s lives, or at a minimum, slow further decline.

Destined to Decline: Plaque-Tangle Combo Foretells Impairment. 2022, June 30. Alzforum. Retrieved August, 9, 2022 from 

Eli Lilly and Company. (2022). Clinical Trial Information. Lilly.

Could Non-Optimal Sleeping Patterns Predict Cognitive Decline and Change in Brain Structure?

       Sleep plays a critical role in our cognitive processing, maintenance of psychological health, emotional processing, consolidation of memories, and is when, waste products in the central nervous system are cleared. Previously we discussed correlations between neurodegenerative disorders and sleep problems, specifically about not getting enough sleep and how Alzheimer’s disease (AD) and Parkinson’s disease (PD) share similar sleep abnormalities. Common concerns about sleep in AD and PD include insomnia, excessive daytime sleepiness, or abnormal motor activity while sleeping. Although many factors are involved with sleep difficulties (e.g., medication side effects), AD and PD are diseases that can damage areas of the brain that control sleep, leading to further disruption in one’s well-being. However, a difficult question remains: which problem starts first? Does the pathology of AD or PD lead to an inability to attain sufficient sleep, or does non-optimal sleep aid in the development of cognitive decline, and further, a neurodegenerative disease?

        A recent study showed that sleep problems likely precede cognitive dysfunction and that sleep duration predicts cognitive decline. The study gathered baseline average sleep duration and cognitive test scores from subjects aged 38 to 73 years old. Follow up data (i.e., average sleep duration, cognitive testing, neuroimaging) was collected about 8 years after baseline. An interesting finding emerged from the study, suggesting that not only was less sleep predictive of cognitive decline, but also too much sleep. Those who slept too much or too little than the average sleep duration overall (i.e., 7 hours) scored worse on tests of memory, fluid intelligence, reaction time, and executive function. Similar results emerged at follow-up, while the higher the reported abnormal sleep duration at baseline, the worse the cognitive scores at follow-up. The study indicates a “sweet spot” in consistent sleep duration, being about 7 hours, as test scores and mental well-being remained higher compared to consistent abnormal sleepers overall. Also long-term, consistent, under/oversleeping in middle adulthood is more predictive of worsening cognitive performance and mental health later in life, indicating middle adulthood as a critical period for sleep.

     Another measure of change, MRI results, collected at follow-up showed that those who reported optimal sleep duration at baseline had a significantly higher volume of gray matter compared to non-optimal sleepers. Regions of gray matter loss most pronounced in non-optimal sleepers involved the precentral cortex, lateral orbitofrontal cortex, and the hippocampus.

       Gray matter deterioration is a prominent feature of AD due to neuronal loss, causing progressive cognitive dysfunction. Consistent with previous findings is the reduction of gray matter in the lateral orbitofrontal cortex and hippocampus, both of which are associated with poor or disrupted sleep patterns in older adults. Previous research linked sleep duration and cognitive decline potentially due to the disruption in slow-wave sleep, which is associated with memory consolidation and amyloid deposition, both prominent abnormalities in AD.

       Overall, sleep has an important role in cognitive functioning and there are many factors involved with poor sleeping (e.g., genetic factors, medication side effects) or the development of a neurodegenerative disease. It is nearly impossible to identify a definitive cause, however research is continuously expanding to find potential preventative measures at best. In this discussion, although sleep disturbances may occur before the onset of cognitive decline and perhaps the development of a neurodegenerative disease, there may be hidden underlying factors associated with AD or PD pathology that are setting the course well before sleep disturbances appear.

Alzforum. (2022, May 11). Sleep: Too little, or too much, foreshadows brain shrinkage. Alzforum, networking for a cure.
Li, Y., Sahakian, B. J., Kang, J., Langley, C., Zhang, W., Xie, C., … & Feng, J. (2022). The brain structure and genetic mechanisms underlying the nonlinear association between sleep duration, cognition and mental health. Nature Aging, 1-13.
Wu, Z., Peng, Y., Hong, M., & Zhang, Y. (2021). gray matter deterioration pattern during alzheimer’s disease progression: A regions-of-interest based surface morphometry study. Frontiers in Aging Neuroscience, 13, 23.

Parkinson’s Disease and Dementia with Lewy Bodies: Could Molecule ATH-1017 Show Efficacy for Treatment of Each?

Dementia with Lewy bodies (DLB), Parkinson’s disease (PD), and Parkinson’s disease dementia (PDD) are all neurodegenerative diseases embodied under Lewy Body disorders and have significant overlap in their pathologies, symptoms, and prognoses. Although closely related, these diseases have unique enough criteria to differentiate between them. Parkinson’s disease and DLB have identical pathologies, but early cognitive symptoms are associated with DLB over PD. Furthermore, if dementia occurs before, concurrently, or within 1 year of motor parkinsonism, DLB is diagnosed. If dementia occurs more than 1 year after an established PD diagnosis, then PDD is diagnosed. 

Both PDD and DLB typically follow the same Alzheimer’s disease (AD) dementia stages and nearly all PD patients experience some degree of cognitive deficit. Pathologically, PD is characterized by neurodegeneration and the formation of Lewy bodies (i.e., made up of misfolded alpha-synuclein) first in brainstem neurons, and then cortical structures as the disease advances. Cognitive deficits in PD are associated with deficits in various neurotransmitters (NT), with a deficiency of dopamine as the principal abnormality. Cognitive deficits are less common in PD when tremor is observed at onset, or in those with tremor predominant syndrome. Most common forms of neuropsychological deficits observed with PD involve executive dysfunction or mild subcortical dementia exemplified by difficulty in word list generation, organizational skills, and multi-tasking. 

Like PD, DLB is associated with Lewy bodies in the brainstem. However, those with DLB tend to have Lewy bodies in the substantia nigra to a lesser severity than patients with PD. Preferentially, with DLB, Lewy bodies are present in the cortex (e.g., limbic and paralimbic regions), with neocortical participation most severe in the temporal lobe. AD-type pathology is also seen, with senile plaque and neurofibrillary tangle deposition, regional neuronal loss, synapse loss, and NT deficits. Common cognitive deficits in DLB include delusions, hallucinations, fluctuating cognition/attention, REM sleep behavior disorder, depression, memory impairment, and disturbances in executive function. Parkinsonism in DLB consists of rigidity, bradykinesia, and dystonia, with rest tremor less frequent. 

Promising treatments for AD, PDD, and DLB tends to focus on therapeutic strategies that target neurotrophic factors to induce protection of existing neurons, promotion of synaptogenesis, neuronal growth, and regenerative mechanisms, which in turn, anticipates improved cognition, decreased inflammation, and improved cerebral blood flow; slowing the progression of neurodegeneration and negative effects that stem from it. Specifically, a small molecule approach that allows passage through the blood brain barrier and reaches all regions of the brain is a superior strategy in comparison to other non-efficient and invasive deliveries to the brain. Due to the stark overlap in these diseases, a medication used for AD may soon prove efficacious for the Lewy Body disorders as well.

A molecule known as ATH-1017 has potential promise for treatment of AD and may have efficacy for PD and DLB as well. ATH-1017 facilitates progress of hepatic growth factor (HGF) function and enables signal transduction through MET phosphorylation. Both HGF and MET activity in the central nervous system incorporate neuroprotective and neurotrophic effects, as well as modulation of neurogenesis and neuronal maturation. Findings suggest that ATH-1017 therapy has potential for pro-cognitive effects in those with AD, and now research is being conducted on the effects it may have on those with PDD or DLB, as there are many shared pathological characteristics between these disorders. Here at the Center for Cognitive Health, we offer clinical trials for PD/DLB and AD assessing the effects of ATH-1017. If interested, give us a call at 503-207-2066 or visit Our Webpage, where you can find a listing of all of the clinical trials being held at the Center.

Cummings, J., Mega, M. (2003). Neuropsychiatry and behavioral neuroscience. Oxford University Press. 
Athira Pharma. (2022). Are You or Someone You Know Living with Parkinson’s Disease Dementia or Dementia with Lewy Bodies? Consider Participating in the SHAPE Trial. Shape Trial.