Month: January 2025

The term dementia refers to a wide range of disorders that can affect a person’s speech, memory, and information processing.

Early symptoms of dementia are very subtle and ambiguous, and they might not be immediately apparent. They also differ from individual to individual and depend on the kind of dementia.

While the symptoms of dementia might vary depending on the underlying cause, some key indicators are common in the early stages of the disorder.

This article will examine the most common early signs of dementia in detail and what to do if you observe them. 

Early Signs of Dementia

Memory issues do not necessarily indicate dementia [1]. For a doctor to diagnose dementia, the symptoms must substantially disrupt your daily life. Treatment options for dementia may help slow cognitive loss if a doctor diagnoses it early, depending on the cause.

Dementia can lead to impairments in:

• memory
• reasoning and problem-solving abilities
• language skills
• communication
• focus

Following are some of the early warning signs of dementia.

Subtle Short-Term Memory Changes

Memory loss may be a precursor to dementia. The alterations are typically minor and affect short-term memory. An individual with dementia may remember events from past years but not what they ate in the morning.

Other short-term memory changes in a person with dementia could include:

• Not remembering where they put things
• Forgetting why they went into a particular room
• Forgetting what they had to do on any particular day
• Trouble completing a task they started

Trouble Finding the Right Words

The inability to communicate one’s thoughts is another early sign of dementia. A person with dementia might have trouble expressing themselves or explaining things. Additionally, they might pause in the middle of a sentence, unsure how to proceed.

Conversations with people who have dementia can be difficult, and it may take them longer than usual to articulate their thoughts or emotions.

Mood Changes

Another common symptom of dementia is a change in mood. Identifying this change in another person with dementia may be easier than recognizing it in yourself if you have the disorder. For example, in the early stages of dementia, depression is common.

Additionally, a person with dementia may appear more anxious or scared than they were previously. They could become easily agitated if their regular daily schedule is changed or they find themselves in unfamiliar or unusual circumstances.

You may also observe a change in personality in addition to mood changes.

Difficulty Finishing Tasks

Another possible early warning sign of dementia is a slight decline in the ability to complete routine tasks. It typically begins with trouble doing more complicated tasks, such as managing finances and bills, following a recipe, or playing a game with several rules.

Besides the inability to complete daily tasks, a person with dementia may have difficulty learning new things or adhering to new routines.

Confusion

Early-stage dementia patients frequently experience confusion. They might have problems recognizing faces, determining the time of day or month, or figuring out where they were.

A variety of factors and circumstances can lead to confusion. For instance, they can lose their car keys or struggle to remember someone they recently met.

Apathy

Apathy, or listlessness, is a common early-stage dementia symptom. A person who has dementia may become disinterested in past interests or hobbies. They could no longer wish to have fun or go out.

They could additionally lose interest in socializing with friends and family and appear emotionally drained.

Having Trouble Following Storylines

Trouble following storylines is another common early indication of dementia. Dementia patients frequently struggle to follow conversations or television shows, or they forget the meaning of words they hear.

Deteriorating Sense of Direction

The onset of dementia can cause a person’s spatial orientation and sense of direction to deteriorate. They can have trouble identifying familiar spots and lose track of how to travel to once-known locations.

Additionally, following a set of directions or step-by-step instructions can get more challenging for them.

Poor Judgement

The loss of sound decision-making skills is another effect of cognitive decline. For example, someone who has dementia might not be able to identify potentially harmful scenarios. 

Another characteristic of dementia-related impaired judgment is the incapacity to use sound financial judgment. Previously prudent individuals may begin giving their money to causes or individuals they don’t know much about.

Inability to Adjust to Change

It might be frightening for someone who is in the early stages of dementia. Suddenly, they are unable to follow what other people are saying or recall familiar faces. They can get lost on the way home because they fail to remember why they went there.

As a result, individuals may have a strong desire for regularity and be reluctant to attempt new things. Having trouble adjusting to changes is another common sign of early dementia.

Repetition

The person may excessively collect goods or repeat routine tasks like shaving or showering. During a conversation, they may ask the same questions repeatedly or repeat the same story.

When to Consult a Doctor

Memory issues and forgetfulness might not always indicate dementia. Memory loss is a normal aspect of aging, but other issues, including exhaustion, poor attention, multitasking, or some nutritional inadequacies, can also cause it. 

However, you should consult a doctor if you or someone you know is experiencing worsening or non-improvement of dementia symptoms.

A doctor or other healthcare provider will most likely recommend the patient to a neurologist. A neurologist can assess the mental and physical health of you or a loved one and figure out whether the symptoms are related to dementia or another condition. A neurologist may prescribe blood testing, brain imaging tests, a neurological checkup, and memory and mental health assessments.

Although dementia is more prevalent in those over 65, it can occasionally strike those in their 30s, 40s, or 50s as well.

You might be able to delay the progression of dementia and preserve mental function for an extended period with treatment and early detection. Treatment options may include medication, cognitive training, and therapy. 

Alzheimer’s Research Association is a non-profit organization dedicated to helping caregivers of Alzheimer’s disease and dementia. We provide the latest information and news about the illness and helpful tips to help caregivers cope with their daily caregiving challenges. We realize the most important thing that a caregiver needs is financial assistance. Therefore, we provide grants to caregivers to ease their financial burden. Caregivers can apply for grants here: Alzheimer’s Grant Application. 

You can also help caregivers in their endeavor by donating as much as possible: Donation To Alzheimer’s Research Associations.

References

1. Emmady, P.D., Schoo, C. and Tadi, P., 2020. Major neurocognitive disorder (dementia).
2. Higuera, V. 11 Early Symptoms of Dementia. Healthline. https://www.healthline.com/health/dementia/early-warning-signs. Published Online: 27th March, 2024. Accessed: 21st January, 2025.
3. Dementia – Early Signs. Better Health Channel. https://www.betterhealth.vic.gov.au/health/conditionsandtreatments/dementia-early-signs. Accessed: 21st January, 2025.

Several studies have implied a link between schizophrenia and dementia. The discovery of similar cholinergic pathway dysfunction in schizophrenia and Alzheimer’s has led to the creation of a novel FDA-approved treatment. Patients with schizophrenia are more likely to develop dementia over their lifespan, which supports research into cholinergic therapy for both disorders.

The FDA has approved xanomeline-trospium, a new schizophrenia medication that targets muscarinic receptors. Ongoing phase 3 trials are looking into its possible benefits for Alzheimer’s treatment.

Alzheimer’s is the most prevalent type of dementia and typically appears in people 65 years of age or older. The disease gradually impairs memory and other cognitive abilities like spatial orientation, reasoning, language, and abstract thought by destroying brain cells.

In addition to experiencing several physical and psychological challenges, people with Alzheimer’s frequently exhibit signs of anxiety, agitation, aggression, and occasionally psychosis.

There is no known treatment for the pathologic process that results in Alzheimer’s. However, drugs are available to treat psychological issues and slow the disease progression, but only for months rather than years.

Schizophrenia is a mental condition that typically develops in people in their late teens and early 30s. Among the symptoms are delusions and hallucinations, which are also present in people with Alzheimer’s, trouble organizing thoughts, and a diminished capacity for expressing or displaying emotion. People diagnosed with schizophrenia also exhibit attention issues and difficulty applying newly learned information.

The inability to retrieve recent memories is only a minor aspect of the illness, whereas memory issues are the hallmark of Alzheimer’s Furthermore, there are drugs to treat schizophrenia and considerably reduce its symptoms, unlike Alzheimer’s.

Link Between Alzheimer’s and Schizophrenia

Despite the stark differences between schizophrenia and Alzheimer’s, their epidemiological relationship suggests that they share certain neuropathologic traits.

According to a meta-analysis, schizophrenia patients have more than double the lifetime dementia risk [1].

Schizophrenia and Alzheimer’s have similar abnormalities in the cholinergic pathways, which supports investigation into muscarinic agonists in both disorders.

In the fall of 2024, the U.S. Food and Drug Administration (FDA) approved trospium and xanomeline, launching the first new method of managing schizophrenia in over 50 years [2]. This has prompted researchers to reevaluate the muscarinic agonist xanomeline in Alzheimer’s disease [3]. For instance, the ADEPT phase 3 clinical study program is currently assessing xanomeline-trospium [4].

Cholinergic Pathway Dysfunction in Alzheimer’s and Schizophrenia

The cholinergic system is a neurotransmitter system that controls various aspects of brain function and immune response. It regulates cognitive processes in the brain, including learning, memory, attention, and processing speed. Additionally, it controls arousal, sleep-wake cycles, and sensory processing. It also contributes to immune response regulation and homeostasis maintenance [5].

The cholinergic system includes acetylcholine (a neurotransmitter), cholinergic receptors (that modulate neural activity), and choline acetyltransferase and acetylcholinesterase enzymes [6].

The cholinergic system affects many bodily functions, particularly memory and cognition. However, cholinergic inputs also drive gastrointestinal and genitourinary processes, temperature regulation, and muscle movement.

Additionally, while acetylcholine works as the common neurotransmitter activating cholinergic receptors, receptor subtypes encompass muscarinic receptors (subtypes M1–M5) and nicotinic receptors (subtypes N1 and N2).

Multiple effects of cholinergic inputs throughout the body raise the possibility of systemic adverse outcomes. Anticholinergic medications, for instance, may cause constipation, urine retention, decreased sweating, elevated heart rate, vision changes, and impaired cognitive function.

Conversely, cholinergic medications may result in vision changes, decreased heart rate, bowel urgency, and diaphoresis.

Despite this, cholinergic medications can also improve cognitive function. For instance, donepezil, a non-selective cholinesterase inhibitor, is prescribed to treat Alzheimer’s disease. However, donepezil may also cause several side effects that can change pulmonary, neurological, genitourinary, cardiovascular, and gastrointestinal processes.

While cholinergic medications can aid Alzheimer’s patients, studies have revealed abnormalities in cholinergic neurotransmission and cholinergic neuron loss in the disease’s pathophysiology [7].

In schizophrenia, cholinergic inputs are essential for controlling dopamine release from certain brain regions. While striatal M4 receptors encourage dopaminergic neurotransmission, striatal M3 receptors suppress dopaminergic outputs. Therefore, receptor subtypes and the particular cholinergic receptor targeted by medication must be considered when analyzing the effects of cholinergic pharmaceuticals.

Schizophrenia: Targeting Muscarinic Receptors

In 1957, scientists began developing muscarinic receptor agonists to treat schizophrenia. First, they thoroughly examined arecoline, a hallucinogenic alkaloid found in betel nut. A tiny, open-label trial found preliminary evidence that the naturally generated muscarinic cholinergic agonist arecoline could help control schizophrenia symptoms, with arecoline exposure resulting in brief periods of clarity [8].

Further initial analyses verified a correlation between higher conception and lower ratings on symptom scales assessing symptoms in individuals with schizophrenia [9]. These resulted in the creation of xanomeline, a synthetic arecoline derivative with M1 and M4 selectivity.

In a phase 2 experiment, xanomeline showed early promise in treating cognitive symptoms in Alzheimer’s patients. Unexpectedly, psychotic symptoms decreased in direct proportion to the dosage of xanomeline [10]. In addition to an anticipated procognitive pharmacologic impact, researchers argued that this revealed a previously unidentified antipsychotic action.

Researchers replicated these results in a small study of individuals with schizophrenia who were not responding to treatment. Unfortunately, while xanomeline treatment side effects did not overlap with those seen with antipsychotics, enhanced peripheral cholinergic effects hampered successful therapy [11].

Targeting Muscarinic Receptors with Xanomeline and Trospium

Researchers used xanomeline with the peripheral muscarinic antagonist trospium to reduce peripheral cholinergic adverse effects [12]. Trospium is a quaternary amine that does not penetrate the blood-brain barrier in pharmacologically significant quantities, in contrast to xanomeline. This enables the specific targeting of M1 and M4 receptors in the brain with fewer side effects. Peripherally, trospium counteracts possible side effects without interfering with xanomeline’s advantages by specifically inhibiting the same receptors that xanomeline stimulates.

In the five-week randomized, double-blind EMERGENT-1 phase 2 trial, researchers assessed the combination of xanomeline and trospium and noticed most side effects during the first two weeks. Additionally, they weren’t severe enough to end therapy. Crucially, the incidence of sedation or drowsiness side events was comparable in the treatment and placebo groups.

Furthermore, researchers did not see any clinically significant alterations in body weight or metabolic markers commonly linked to antipsychotics [12].

Additional phase 3 assessment in the five-week, randomized, double-blind, placebo-controlled EMERGENT-2 and -3 trials verified effectiveness on a primary endpoint: complete decrease in positive and negative symptoms of schizophrenia (PANSS). The trials further showed safety, with comparable treatment termination rates in both the treatment and placebo groups.

Secondary results in both trials were PANSS subscale decreases when compared to placebo. This suggests a distinct effectiveness profile that tackles both positive and negative schizophrenia symptoms.

Alzheimer’s: Targeting Muscarinic Receptors

Although xanomeline’s potential for treating Alzheimer’s disease was initially assessed by researchers in the late 1990s, the study came to a standstill.

In 1997, a multicenter, double-blind, placebo-controlled study with 343 patients was published [13]. This six-month study of xanomeline at 75 mg, 150 mg, and 225 mg daily demonstrated improvements in cognitive subscale measures of the Alzheimer’s Disease Assessment Scale as well as dose-dependent improvements in psychotic symptoms, such as agitation, hallucinations, delusions, vocal outbursts, and suspiciousness.

About 52% of individuals discontinued xanomeline medication at the maximum dose, with gastrointestinal side effects being the most frequently reported adverse event. Researchers added trospium, a peripheral cholinergic blocker, to prevent peripheral adverse effects, just like in schizophrenia.

As a consequence, investigators are now back to treating Alzheimer’s patients using xanomeline in combination with trospium, with the ADEPT phase 3 clinical trial program currently underway [4].

Future Prospects

The combination of trospium and xanomeline provides a significant new strategy after more than 50 years of treatments that only addressed dopaminergic pathways. The development of xanomeline and trospium for Alzheimer’s disease shows promise because of the known procognitive effects of cholinergic therapies and indications of similar pathophysiology in cholinergic pathways affecting symptoms in both schizophrenia and Alzheimer’s.

As this combination continues to be developed in a series of phase 3 trials for the management of Alzheimer’s disease, additional therapeutic effects may enhance results for two very distinct illnesses.

Alzheimer’s Research Association is a non-profit organization dedicated to helping caregivers of Alzheimer’s disease and dementia. We provide the latest information and news about the illness and helpful tips to help caregivers cope with their daily caregiving challenges. We realize the most important thing that a caregiver needs is financial assistance. Therefore, we provide grants to caregivers to ease their financial burden. Caregivers can apply for grants here: Alzheimer’s Grant Application. 

You can also help caregivers in their endeavor by donating as much as possible: Donation To Alzheimer’s Research Associations.

References

1. Ahmad, K., Hassan Baig, M., Mushtaq, G., Amjad Kamal, M., H. Greig, N. and Choi, I., 2017. Commonalities in biological pathways, genetics, and cellular mechanism between Alzheimer disease and other neurodegenerative diseases: an in silico-updated overview. Current Alzheimer Research, 14(11), pp.1190-1197.
2. U.S. Food and Drug Administration Approves Bristol Myers Squibb’s COBENFY™ (xanomeline and trospium chloride), a First-In-Class Muscarinic Agonist for the Treatment of Schizophrenia in Adults. Bristol Myers Squibb. Press Release. https://news.bms.com/news/corporate-financial/2024/U.S.-Food-and-Drug-Administration-Approves-Bristol-Myers-Squibbs-COBENFY-xanomeline-and-trospium-chloride-a-First-In-Class-Muscarinic-Agonist-for-the-Treatment-of-Schizophrenia-in-Adults/default.aspx. Published Online: 26th September, 2024. Accessed: 9th January, 2025.
3. Kang, M., Watson, C., Cummings, J.L., Grossberg, G.T., Marcus, R. and Yeung, P., 2023, July. Design of ADEPT‐2, a phase 3, parallel group study to evaluate KarXT [xanomeline‐trospium] as a treatment for psychosis associated with Alzheimer’s disease. In Alzheimer’s Association International Conference. ALZ.
4. Open-Label Extension Study to Assess the Long-Term Safety and Tolerability of KarXT in Subjects With Psychosis Associated With Alzheimer’s Disease (ADEPT-3). ClinicalTrials.gov. https://clinicaltrials.gov/study/NCT05980949. Last Updated: 6th January, 2025. Accessed: 9th January, 2025.
5. Li, X., Yu, B., Sun, Q., Zhang, Y., Ren, M., Zhang, X., Li, A., Yuan, J., Madisen, L., Luo, Q. and Zeng, H., 2018. Generation of a whole-brain atlas for the cholinergic system and mesoscopic projectome analysis of basal forebrain cholinergic neurons. Proceedings of the National Academy of Sciences, 115(2), pp.415-420.
6. Halder, N. and Lal, G., 2021. Cholinergic system and its therapeutic importance in inflammation and autoimmunity. Frontiers in immunology, 12, p.660342.
7. Lyness, S.A., Zarow, C. and Chui, H.C., 2003. Neuron loss in key cholinergic and aminergic nuclei in Alzheimer disease: a meta-analysis. Neurobiology of aging, 24(1), pp.1-23.
8. Pfeiffer, C.C. and Jenney, E.H., 1957. The inhibition of the conditioned response and the counteraction of schizophrenia by muscarinic stimulation of the brain. Annals of the New York Academy of Sciences, 66(3), pp.753-764.
9. Sullivan, R.J., Allen, J.S., Otto, C., Tiobech, J. and Nero, K., 2000. Effects of chewing betel nut (Areca catechu) on the symptoms of people with schizophrenia in Palau, Micronesia. The British Journal of Psychiatry, 177(2), pp.174-178.
10. Bodick, N.C., Offen, W.W., Levey, A.I., Cutler, N.R., Gauthier, S.G., Satlin, A., Shannon, H.E., Tollefson, G.D., Rasmussen, K., Bymaster, F.P. and Hurley, D.J., 1997. Effects of xanomeline, a selective muscarinic receptor agonist, on cognitive function and behavioral symptoms in Alzheimer disease. Archives of neurology, 54(4), pp.465-473.
11. Shekhar, A., Potter, W.Z., Lightfoot, J., Lienemann D Pharm, J., Dubé, S., Mallinckrodt, C., Bymaster, F.P., McKinzie, D.L. and Felder, C.C., 2008. Selective muscarinic receptor agonist xanomeline as a novel treatment approach for schizophrenia. American Journal of Psychiatry, 165(8), pp.1033-1039.
12. Correll, C.U., Angelov, A.S., Miller, A.C., Weiden, P.J. and Brannan, S.K., 2022. Safety and tolerability of KarXT (xanomeline–trospium) in a phase 2, randomized, double-blind, placebo-controlled study in patients with schizophrenia. Schizophrenia, 8(1), p.109.
13. Bodick, N.C., Offen, W.W., Levey, A.I., Cutler, N.R., Gauthier, S.G., Satlin, A., Shannon, H.E., Tollefson, G.D., Rasmussen, K., Bymaster, F.P. and Hurley, D.J., 1997. Effects of xanomeline, a selective muscarinic receptor agonist, on cognitive function and behavioral symptoms in Alzheimer disease. Archives of neurology, 54(4), pp.465-473.
14. Understand the difference between schizophrenia and Alzheimer’s. The Advocate. https://www.theadvocate.com/baton_rouge/entertainment_life/louisiana_health/understand-the-difference-between-schizophrenia-and-alzheimer-s/article_f0d50d72-f5d4-5f96-b7cd-8a5a114a87ff.html. Published Online: 13th September, 2015. Accessed: 10th January 2025.
15. Exploring the Link Between Schizophrenia and Alzheimer’s. Psychiatrist.com. https://www.psychiatrist.com/news/exploring-the-link-between-schizophrenia-and-alzheimers/. Published Online: 1st November, 2024. Accessed: 9th January, 2025.