Symptoms: Frontotemporal Dementia vs Alzheimer's
Cognitive Symptoms of Alzheimer's Disease
The most prominent symptom of Alzheimer's Disease is memory disturbance, which affects daily activities [1]. In the later stages of Alzheimer's disease, patients have increasing trouble with non-memory functions, including problem-solving and planning.
Aphasia, or trouble with speech or writing, is another common symptom, as is visuospatial disturbance, which can lead to disorientation about times or places [1]. Patients with Alzheimer's also experience difficulties in making judgements and struggle to maintain personal hygiene. Mood and personality changes are common, accompanied by withdrawal from friends, family, and community [1].
Non-Cognitive Symptoms of Alzheimer's Disease
Non-cognitive symptoms of Alzheimer's Disease can include gait and balance dysfunction, olfactory dysfunction, and psychiatric symptoms such as suspiciousness, paranoia, delusions, and visual hallucinations [2, 3]. Depression is also common in Alzheimer's Disease, present in about 17% of patients [4].
As the disease progresses, patients may display little interest in self-care, work and household tasks, social and family activities, and the emotional needs of others [5]. In the later stages of the disease, patients often have significant trouble talking, moving, or responding to what's happening around them [1].
Frontotemporal Dementia Symptoms
Frontotemporal Dementia (FTD), on the other hand, is categorized based on the presence of behavioural and language-related symptoms. The disease is progressive and has several stages.
Behavioral Symptoms
Patients with FTD may exhibit actions that are socially inappropriate or out of character. A lack of interest or enthusiasm in activities is a common symptom of FTD. Patients may act impulsively without considering the consequences of their actions. Individuals with FTD may neglect their personal hygiene and self-care. Repetitive or compulsive behaviours are common in FTD [6]. Behavioural FTD is, therefore, more like Alzheimer's Disease.
Language-Related Symptoms
Patients with language related FTD frequently struggle with speech production or comprehension. Recalling words or forming sentences can be challenging. Patients may lose their ability to read and write effectively. Interacting with others can become challenging due to language and behavioural changes [6].
Common Symptoms of Frontotemporal Dementia
In both subtypes of FTD, later stages of the illness are characterized by psychiatric disorders such as disinhibition, impulsive acts, lack of empathy, stereotypies, and changes in eating habits. In some cases, patients may also present with extrapyramidal symptoms, which are movement disorders often associated with Parkinsonian symptoms [7].
It's important to note that the symptoms of FTD can vary significantly from person to person, depending on the specific areas of the brain affected.
Prevalence: Frontotemporal Dementia vs Alzheimer's
When it comes to the prevalence of Alzheimer's Disease and Frontotemporal Dementia (FTD), there are some striking differences and similarities.
Alzheimer's Disease
Alzheimer's Disease shows a strong correlation with age. Multiple studies approximated the prevalence of Alzheimer's Disease in the United States among individuals aged 71 and older was 13.9%, and this increased with age, from 5.0% of those aged 71-79 years to 37.4% of those aged 90 and older [8, 9].
Frontotemporal Dementia
Frontotemporal Dementia (FTD) is a common cause of early-onset dementia, with varying prevalence rates reported in different studies. The estimated point prevalence (total number of cases) of FTD is between 15 and 22 per 100,000 people, and the incidence (new cases per year) is between 2.7 and 4.1 per 100,000 people per year [10].
A recent meta-analysis found that the prevalence of FTD among dementia patients over 65 was 2.7%, whereas 12% in dementia patients under 65 years old, demonstrating the early onset of FTD relative to Alzheimer's Disease and other dementias, like Lewy Body Dementia. The review also identified significant disparities in methodology and diagnostic criteria, where the prevalence in the general population likely ranges from 0.1 to 4.6 cases per 100,000 individuals [11].
Causes: Frontotemporal Dementia vs Alzheimer's
Alzheimer's Disease (AD) and Frontotemporal Dementia (FTD) are both complex conditions with a variety of potential causes. The exact causes of both AD and FTD are still unknown, but several factors have been associated with the development of these diseases.
Genetics
Age is the most significant risk factor for AD, with most people who develop the disease being 65 years of age or older [1]. Genetics also play a crucial role in AD, with specific genes linked to the disease. For instance, mutations of presenilins 1 and 2 and of the APP gene have been identified in families with early-onset AD [12]. The type 4 allele of the apolipoprotein E gene (APOE-epsilon 4) is another recognized risk factor [13].
Genetics play a more critical role in FTD. It has been found that up to 50% of FTD cases are familial, meaning patients with FTD will have a family member who is also affected by FTD [14, 15]. Several genes that penetrate at 100% have been identified, meaning possessing this gene is almost certain to cause FTD. This is why genetic testing is ethically tricky, as it may reveal your predisposition for future FTD. For instance, mutations in the tau gene have been linked to FTD [16]. Other genes, such as MAPT, GRN, and C9orf72, have been found in 60% of familial FTD cases, which is very high [14].
Protein Abnormalities
Amyloid and tau protein abnormalities have long been considered the leading causes of AD. The amyloid hypothesis, the predominant framework for AD research for over two decades, suggests that beta-amyloid (Aβ) accumulation in the brain is a primary factor initiating neurodegeneration in AD [17, 18]. Neurofibrillary tangles are another characteristic feature of AD, consisting of abnormal Tau protein clusters [19]. Both of these protein clusters primarily form in the midbrain and temporal lobe.
In the case of FTD, one of the primary causes is the loss of nerve cells in the frontal and temporal lobes of the brain. This is often accompanied by an accumulation of atypical forms of two proteins, tau and TDP-43. When these proteins don't function normally, they can damage nerve cells [20].
Environmental Factors and Lifestyle
Environmental factors such as bacterial and viral infections, heavy metal ions, diet, sleep, stress, and gut microbiota or oral health are also risk factors for Alzheimer's Disease [19]. Lifestyle factors, including a history of depression, smoking, cardiovascular disease, and previous traumatic brain injury, can also increase the risk of developing AD, although they are not direct causes [1].
Other Factors
Certain conditions, such as diabetes and hypertension, as well as environmental stresses or injury to the head, are proposed to contribute to the onset of AD [21].
Other factors contributing to FTD include diseases like Pick disease and frontotemporal degeneration with ubiquitin-positive inclusions [16].
It's important to note that while these factors have been associated with AD and FTD, they do not guarantee the development of the diseases. More research is needed to fully understand the causes of AD and FTD.
Pathology: Frontotemporal Dementia vs Alzheimer's
The pathology of neurodegenerative diseases is highly multifaceted, with each disease presenting through a unique set of pathological features. In this section, we will delve into the pathology of AD and FTD.
Alzheimer's Disease
The pathology of Alzheimer's Disease (AD) is intricate, involving several key features that contribute to the progression of the disease. The most recognized hallmarks of AD are the accumulation of extracellular β-amyloid (amyloid plaques) and intraneuronal tau aggregates (neurofibrillary tangles) [22]. These abnormal protein deposits lead to synaptic loss and amyloid deposits in the blood supply, which are essential for the pathological diagnosis of AD [22].
In addition to these typical markers, AD is often associated with other age-related co-pathologies, such as cerebrovascular lesions, Lewy and TDP-43 pathologies, hippocampal sclerosis, or argyrophilic grain disease [22]. These co-occurring pathologies can speed up disease progression [22].
Another important aspect of AD pathology is the dysfunction of brain capillaries. Structural alterations of the brain capillaries, partially due to amyloid deposits, may contribute to AD pathology by increasing the permeability of peripheral toxins and infections into the brain [23].
Microglia, the primary immune cells in the brain, also play an important role in AD pathology. They may promote pro-inflammatory states and toxicity, contributing to neurodegeneration and generally failing their homeostatic role [24].
Lastly, neuronal and synaptic loss is a critical aspect of AD pathology. These "negative" lesions, combined with the "positive" lesions of amyloid plaques and neurofibrillary tangles, contribute to the cognitive decline and memory loss characteristic of AD [25].
Importantly, non-symptomatic pathology of AD precedes symptom onset by 5-10 years; thus, the pathology is already quite advanced by the time symptoms are noticed.
Frontotemporal Dementia
The pathology of FTD, also known as frontotemporal lobar degeneration (FTLD), is characterized by distinct molecular classes of aggregated proteins, the most common being TAR DNA-binding protein-43 (TDP-43), tau, and fused in sarcoma (FUS) [26]. The disease can be divided into three subtypes based on these proteins: TDP-43 or FUS proteinopathy (protein abnormality) and tauopathy [26].
On a macro scale, FTD is marked by severe atrophy of the frontal and temporal brain lobes, and the initial symptoms increase in severity over time as the disease progresses. The clinical deterioration is paralleled by the exacerbation of pathological findings and the spreading of pathology to broader brain regions [26].
The neuropathology of early disease is marked by severe astrogliosis (scarring) of both the frontal and temporal cortices and neuronal loss, which is more evident in the upper cortical layers of the frontal lobe. In late Disease, neuronal loss also occurs in deeper layers of the neocortex and the CA1 sector of the hippocampal memory centre [27].
To summarize, AD and FTD are both common forms of dementia, where FTD is known to have an early age of onset and be caused by genetic factors passed down in families. AD is characterized by β-amyloid plaques and neurofibrillary tangles, starting in the midbrain, and progressing to the neocortex. In contrast to AD, FTD begins in the frontal and temporal lobes and progresses to the hindbrain. There is a great need to further study the factors contributing to FTD and AD to increase treatments and management strategies.
