Memory diseases

The most common subtype of dementia is AD, representing 60–70% of all dementia cases (21). Hence, this thesis focuses on Alzheimer’s disease and only shortly mentions the features of other dementia subtypes.

The second common subtype after Alzheimer’s disease is vascular dementia accounting for 15–20% of all dementia cases (21). The other common neurodegenerative dementias are Lewy body dementias (22) and frontotemporal dementias (23), but the prevalence and incidence data of these dementias is incomplete and may underestimate the true prevalence (22,23). It is also notable that mixed dementias are common, i.e., having brain changes that are associated with more than single cause of

dementia, and the likelihood of mixed pathologies increases with age (6).

AD is a continuum of five stages (Figure 1). The progress of the disease is usually slow: It may take roughly 15–25 years until asymptomatic AD develops to dementia via a stage of mild cognitive impairment (MCI) (24).

The noticeable symptoms of AD are caused by damage or destruction of the nerve cells (6). First, brain parts that are responsible for learning and memory are affected. Next, other parts of the brain are damaged, leading to problems in basic bodily functions. Eventually, AD is fatal, as current pharmacological treatments can only treat the symptoms, not the root causes (6). The progressive nature through several stages is also seen in other memory diseases (25).

The life expectancy of persons with memory diseases in general is hard to predict (26). For example, in Lewy body dementias, the prognosis may vary from 2 to over 20 years. The prognosis of memory diseases depends on, e.g., the time of the diagnosis, the age of the patient, and the

combination of risk factors. Nevertheless, the average life expectancy usually is between 5 and 15 years after the diagnosis (26).

Figure 1. The five stages of Alzheimer’s disease continuum; modified from 2021 Alzheimer's disease facts and figures (6). The length of each stage varies individually. Similar stages can also be seen in other memory diseases (25).

There is no single cause of AD, and the mechanisms are not yet fully understood (24). However, research around AD is vigorous, and in the past few years considerable progress has been made (24).

Briefly and simplified, the most prominent brain alterations in AD are beta-amyloid plaques, i.e., clumps of a kind of protein fragment, that form outside nerve cells, and tau tangles, i.e., abnormally twisted strands of tau proteins, that form inside nerve cells (6). Plaques may contribute to

neurodegeneration, and tangles interfere with normal transport of nutrients and other molecules that are crucial for nerve cells. In addition, chronic inflammation occurs due to brain’s attempts to clear beta-amyloid and tau proteins, and the death of nerve cells leads to brain atrophy. The brain also gradually loses its ability to metabolize glucose (6).

The characteristics of AD, vascular dementia, Lewy body dementias, and frontotemporal dementia are presented in Table 1.

Preclinical Alzheimer's disease

Mild cognitive impairment

Mild

Alzheimer's disease

Moderate Alzheimer's disease

Severe Alzheimer's disease

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Table 1. The characteristics of the most common dementia subtypes; summarized from Fratiglioni et al. (21), Bang et al. (23), O’Brien and Thomas(27), Walker et al. (22), 2021 Alzheimer's disease facts and figures (6), and Scheltens et al. (24). Alzheimer’s diseaseVascular dementia Lewy body dementiasFrontotemporal dementias Prevalence1 60–70%15–20%10–15%3–26% Subtype examplesAtypical (e.g., posterior cortical atrophy variant), mixed (e.g., with vascular or Lewy body dementia) Small vessel and multi-infarct dementia, AD with cerebrovascular disease Dementia with Lewy bodies, Parkinson’s disease dementia

Frontotemporal dementia, primary progressive aphasia Main clinical featuresSlow and progressive impairment of memory and other cognitive functions causing first MCI and eventually leading to severe dementia

Diverse depending on the location of vascular pathology. Deficits in attention, information processing, and executive function Progressive dementia and cognitive deficits; fluctuating cognition, hallucinations, spontaneous parkinsonism, and unusual sleep behavior

Progressive deficits in behavior, executive function, or language. The disease may exacerbate many psychiatric disorders. Degeneration of the frontal and temporal cortices Pathological mechanisms Beta-amyloid plaques and tau tangles leading to chronic inflammation and neurodegeneration

No agreed pathological scheme. Cortical and subcortical infarcts, ischemic lesions, and cerebral microbleeds are typical Lewy bodies, i.e., abnormal protein clumps inside nerve cells and neuronal loss

Neuronal loss, gliosis, and microvacuolar changes leading to frontotemporal lobar degeneration. Abnormal protein depositions in some subtypes 1 Prevalence of all dementia cases; AD, Alzheimer’s disease; MCI, mild cognitive impairment

The clinical characteristics of typical AD refer to progressive impairment of episodic memory (28). Memory is the only cognitive domain affected in early AD and the most severely affected domain during disease

progression. These core features are accompanied by either presence of medial temporal lobe atrophy, abnormal cerebrospinal fluid biomarker (e.g., beta-amyloid or tau), specific pattern on positron emission

tomography, or proven autosomal dominant mutation of AD within immediate family (28).

As research evidence has accumulated and diagnostic methods have improved , the definitions of typical and atypical subtypes of AD and their diagnostic criteria have evolved in detail (16,29-32). Nevertheless,

diagnosing AD with absolute certainty requires either a brain biopsy or autopsy after death or both clinical and genetic evidence (28). The

diagnostic features for AD, vascular dementia, Lewy body dementias, and frontotemporal dementias are presented in Table 2.

No widely accepted medication to slow or stop the neurodegeneration yet exists for any of the progressive memory diseases (6,22,23,27). In AD, acetylcholinesterase inhibitors and memantine improve cognitive functions either by increasing the amount of neurotransmitters in the brain or by inhibiting certain receptors that can damage nerve cells (6). Yet their role is mainly symptomatic.

Disease-modifying treatments for AD have been intensively studied.

Amyloid beta pathology has been one of the targets. Recently, the US Food and Drug Administration has approved two anti-amyloid antibodies for the treatment of early or mild AD, aducanumab in 2021 (33) and lecanemab in 2023 (34,35). Their clinical benefit, efficacy and safety needs to be clarified further. In some cases of vascular dementia, drugs for AD may be used (27). For Lewy body dementias some moderately effective drugs for symptoms are available (22). For frontotemporal dementias medications are used to try to manage behavioral symptoms (23).

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Table 2. Summary of the clinical diagnostic features of the most common dementia subtypes. Summarized from Román et al. (36), McKeith et al. (37), Dubois et al. (28), and Bang et al. (23). Alzheimer’s diseaseVascular dementia Lewy body dementiasFrontotemporal dementias Core criteriaEarly and significant memory impairment Dementia (impairment of memory and of two or more cognitive domains) that interferes with activities of daily living, cerebrovascular disease (defined by neurologic examination and brain imaging), and a relationship between the above disorders Central feature: dementia and deficits of attention, executive function, and visuospatial ability; core features (at least 2 out of 3): fluctuating cognition, recurrent visual hallucinations, spontaneous features of parkinsonism

The diagnostic criteria vary between the subtypes, but common features are insidious onset and gradual progression Supportive featuresMedial temporal lobe atrophy/abnormal cerebrospinal fluid biomarkers/specific pattern on PET/proven AD autosomal dominant mutation within the immediate family

Early presence of a gait disturbance, history of unsteadiness and falls, urinary symptoms without urologic disease, pseudobulbar palsy, personality and mood changes, subcortical deficits (e.g., abnormal executive function) REM sleep behavior disorder, severe neuroleptic sensitivity, low dopamine transporter uptake in brain imaging plus various commonly present, but diagnostically unspecific features

Depends on the subtype; mainly behavioral changes or language impairments AD, Alzheimer’s disease; PET, positron emission tomography; REM, rapid eye movement