Introduction

Dementia is a neurodegenerative disease and the leading cause of disability and dependency among older adults worldwide. It was the seventh leading cause of death in adults globally in 2019 [1]. Dementia is a growing public health problem with a major impact on the quality of life of patients and their families, with global medical, social, and informal care costs estimated at $1.3 trillion annually and expected to exceed $2.8 trillion by 2030 [1]. As the condition remains underdiagnosed in low-income countries, these figures could rise substantially. With the significant increase in dementia cases, the number of Emergency Department (ED) visits, hospitalizations, and institutionalizations will rise, as will the associated costs.

Another unmet need is community/patient and caregiver education and literacy about dementia [2–4]. The lack of time in medical consultations, which prevents the physician from discussing with the caregiver how to manage some behavioral disturbances or progressive loss of autonomy in the loved one often results in feelings of sadness and disability, as well as anxiety and depression for the caregiver. On the other hand, the increasing demand for “memory consultations” in some countries has led to long waiting lists, lack of standardization, and inequity in dementia care.

What can we expect by 2030? New treatments with monoclonal antibodies promise better outcomes, but their cost and specificity for certain patient populations may be barriers to their widespread use. Digital health with remote monitoring technologies can enable early intervention and promote patient-centered care. However, definition of the patient pathway, well-defined strategies across the continuum of care, and robust approaches to overcome issues of Internet access and low levels of technological literacy are urgently needed. 

In Portugal, epidemiological and economic data on dementia are scarce and new methodological strategies are needed to improve access to accurate and early diagnosis for specific subgroups and knowledge of their specific characteristics.  Due to the aging of the population and the interactive effects of modifiable risk factors, the health system and society will have to cope with an increasing number of people with dementia. The aim of this study was to use the 360º health analysis framework to provide an overview of good clinical practices, barriers, and gaps for integrated dementia care.

Materials and methods

Using the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) approach, an electronic search was conducted on PubMed database including the last 5 years (from April 2018 to April 2023). Studies on any form of dementia were included using one of the following queries: dementia [MeSH Major Topic] or Alzheimer [MeSH Major Topic] or Lewy body disease [MeSH Major Topic] or frontotemporal dementia [MeSH Major Topic] or Parkinsonism [MeSH Major Topic]). Independent searches were conducted on the different topics to provide a comprehensive review using the following queries: prevalence [MeSh terms]; incidence [MeSh terms]; risk factors [MeSh terms]; diagnosis [MeSH major topic]; treatment [MeSH major topic]; clinical trials [MeSH Terms]; organization and administration [MeSH terms]. Search results were narrowed by selecting human studies, written in Portuguese or English, open access, and including the following article types: case reports, clinical studies, consensus conferences, guidelines, reviews, and systematic reviews. Relevant articles within the scope of the study were selected. Two independent reviewers assessed the articles selected for eligibility by reviewing the title, abstract, or both. Articles related to basic research, diseases other than dementia, and other topics outside the scope of dementia management were excluded (Table 1). A final assessment was performed after fulltext reading for evaluation of the quality of studies and number of participants and for the authors’ scientific assessment.

Inclusion criteria

Articles about epidemiology, risk factors, diagnosis, treatment, and dementia management

Exclusion criteria

Articles about basic research

Articles about diseases other than dementia

Articles on topics outside the scope of dementia care

Articles on topics too specific for the purpose of this study (e.g., disease genetics, pathophysiology, etc.)

Table 1: Criteria for inclusion and exclusion of articles in the review.

Results

A total of 2940 articles were initially retrieved from the PubMed search, of which 195 were included in the review after study criteria assessment (Figure 1). Eight additional articles were included due to their relevance to the scope of this review.

Figure 1: Flowchart of studies included in the review.

Dementia in numbers: Epidemiology & Economics

According to the World Health Organization (WHO), more than 55 million people worldwide are currently estimated to be living with dementia [5], and this number is expected to increase to approximately 153 million by 2050, particularly in low- and middle-income countries (LMIC), where more than 60% of people with dementia live [1,6,7]. The prevalence of the disease varies among ethnic groups within countries [1,6,7]. A recent systematic review and meta-analysis reported a higher incidence of dementia in black compared with white ethnic groups, and similar incidence in Asian and Latino compared with white ethnic groups [8]. The same study reported a higher prevalence of dementia in Malay and Indian compared with Chinese ethnic groups [8]. Despite these numbers, reliable data on the prevalence of the disease among different ethnic and racial groups, as well as among sexual minorities and in different parts of the world, particularly LMIC, are still lacking [1]. Data on young-onset dementia are also very limited [1].

The risk of having a diagnosis of clinical dementia increases with age, doubling approximately  every 5 years up to age 85 [9]. Women are more likely to have the disease than men after the age of 80, while men are more likely to have the disease before the age of 70 [9].

In several high-income countries of North America and Europe, a decreasing trend in the incidence of all-cause dementia has been observed over the past 40 years, probably due to educational, socioeconomic, health care, and lifestyle changes [6,10,11]. In contrast, the prevalence of age-specific dementia is increasing in Japan, South Korea, Hong Kong, Taiwan, and LMIC. The absolute number of people with dementia worldwide is expected to increase substantially in the coming years [6].   

Alzheimer’s disease (AD) is the most common subtype of dementia (60–80%), followed by vascular dementia (VaD; 13%), Lewy body dementia (LBD; 5%), Parkinson’s disease dementia (3.6%), and frontotemporal dementia (FTD) (3%) [1]. Although FTD is not common in all age groups, it is one of the most common subtypes below the age of 65, accounting for approximately 10% of all cases in this age group [12].

Despite remarkable advances in diagnostic biomarkers, most epidemiologic studies are based on old sets of clinical diagnostic criteria or algorithms based on brief cognitive screening tests, which may not be sensitive or specific for early stages of the disease and do not distinguish between different etiologies of dementia, thus underestimating its true prevalence and incidence [10].

The World Health Organization (WHO) estimated a global societal cost of dementia in 2019 of US$1.3 trillion, depending on the severity of the disease and income region. Worldwide, the estimated annual cost per person with dementia is approximately US$16,000 for mild dementia, US$27,000 for moderate dementia, and US$36,000 for severe dementia [13]. AD is associated with an estimated $236 billion in direct and long-term costs in the United States [1]. Unpaid caregiving costs are currently estimated at approximately $220 billion annually [1].

Dementia in Portugal

Epidemiologic studies on cognitive impairment in Portugal are scarce, as are data on the prevalence of different forms of dementia. Garcia et al. estimated the number of Portuguese people with dementia to be 92,470 and those with AD to be 48,706 in 1991, based on European prevalence rates [14]. Nunes et al. conducted the first Portuguese epidemiologic study of neurocognitive disorders in people aged 55-79 years living in a northern region of the country (9,015 inhabitants) and estimated a prevalence of dementia of 2.7% (1,146 participants) and similar proportions of AD and VaD subtypes. However, the sample was not nationally representative [15]. Santana et al. estimated the prevalence of dementia in 2013 to be 5.9% of people aged 60 years or older (160,287 people) by extrapolating the prevalence of dementia in Western Europe [16]. Gonçalves-Pereira and colleagues applied a 10/66 Dementia Research Group (DRG) population based research program in two geographical areas in southern Portugal (one urban and one rural site), excluding nursing home residents [14]. The prevalence of dementia was 9.23% using the 10/66 DRG algorithm and 3.65% using DSM-IV criteria, with AD being the most common dementia (41.9%). Apart from the fact that these results cannot be generalized to the whole country, the figures suggest that previous studies may have underestimated the true prevalence of dementia in Portugal. According to the most recent data, the number of people living with dementia in Portugal in 2019 was 200,994 [7].

The cost of dementia therapies in Portugal was estimated at around 37 million euros per year in 2013, with rivastigmine, donepezil, and memantine being the most prescribed therapies. However, more studies are needed on the direct and indirect costs of the disease [16].

Risk factors for dementia

Dementia is a multifactorial disease with non-modifiable risk factors, such as age and genetics, and several potentially modifiable risk factors that can potentially be targeted to reduce the prevalence of the disease (Table 2).

APP – amyloid precursor protein; PSEN1, PSEN2 – presently 1/2, MAPT – gene encoding the tau protein involved in auxopathies, DALY –disability-adjusted life years, PM2.5 – fine particulate matter, NO2 – nitrogen dioxide

Table 2: Potentially modifiable risk factors for dementia.

Non-modifiable risk factors

Age

Aging is a complex and irreversible process involving multiple organs and cell systems and is considered the strongest non-modifiable risk factor for the development of dementia [17–19]. The risk of dementia increases with age, with an estimated 19% of people aged 75-84 years and up to 50% of people over 85 years developing the disease [17].

Genetics

Although most cases of AD and related dementias are sporadic, genes play a role in risk for these diseases. About 70% of the risk of developing AD can be attributed to genetics, although only a few cases are hereditary [20,21]. The main genes associated with AD are amyloid precursor protein (APP) and presently 1/2 (PSEN1/2), which are responsible for familial and early-onset AD (<5% of cases). Apo lipoprotein E (APOE) variant ɛ4 is the major driver of sporadic AD, leading to late-onset AD (LOAD) in the general population [17,20,21]. Other risk factors for LOAD include single nucleotide polymorphisms in CLU, PICALM, CR1, BIN1, ABCA7, CD2AP, CD33, EPHA1, and MS4A cluster [20].

Less is known about the genes involved in non-AD dementias. A family history of FTD is one of the most important risk factors for the disease. Approximately 40% of cases have a family history of dementia, but less than 10% have a clear autosomal dominant inheritance pattern [12]. More than 10 genes have been associated with FTD, with the gene encoding the tau protein involved in  taupathies (MAPT) and the gene encoding progranulin (PGRN) and intronic expansion of a hexanucleotide repeat in C9orf72 accounting for about 60% of familial FTD [22].

APOE, glucocerebrosidase, and alpha-synuclein have been associated with LBD [21]. Mutations in the NOTCH3 gene are associated with the development of autosomal dominant cerebral arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL), which can cause VaD.

Although genetic risk strongly influences the development of dementia, it is the combination of an individual’s genetic makeup and exposure to environmental factors that determines the onset of the disease [10].

Gender

Studies have shown gender differences in the development of dementia. Women are disproportionately affected, with a higher prevalence of the disease at all ages, more disability-adjusted life years, and a higher proportion of related deaths [1]. Some studies show that women are at higher risk for AD, while men are at higher risk for VaD [18].

Several factors may explain these differences, including selective survival of men with healthier cardiovascular (CV) risk profiles, educational attainment, and biological mechanisms such as hormone exposure [9,19,23]. The literature suggests that estrogens have a clear role in modulating the risk of dementia, with evidence that hormone replacement therapy may have both beneficial and harmful effects. However, further studies are needed to confirm these findings [19,23].

Modifiable risk factors

The Lancet Commission on Dementia Prevention, Intervention and Care 2020 update identified 12 modifiable risk factors for dementia that account for approximately 40% of all dementia cases worldwide: low education, hypertension, hearing impairment, smoking, midlife obesity, depression, physical inactivity, diabetes, social isolation, excessive alcohol consumption, head injury, and air pollution [6].

Education

Low educational attainment, especially lack of secondary education, is one of the most prevalent modifiable factors for dementia. Higher levels of childhood and lifelong education reduce the risk of dementia [24–26], particularly in those with a high genetic predisposition [27]. However, there is no evidence that it is a protective factor against FTD [12].  Several population studies have shown that cognitive stimulation (in the form of leisure-time cognitive activities) in mid- and late-life is also associated with a lower risk of dementia [28–30].

Hypertension

The association between blood pressure and dementia is complex. Midlife hypertension (40-65 years) is associated with an increased risk of dementia in later life in several studies [20,31–33]. On the other hand, lowering blood pressure in later life appears to be associated with an increased risk of dementia. U-shaped associations have been observed in people aged 75 years and older, with a systolic blood pressure (SBP) of 160-170 mmHg being associated with the lowest risk of dementia [32,33]. However, further studies are needed to confirm these findings in LMIC and in racially, ethnically and socioeconomically diverse populations, as well as in older age groups [32].

A recent meta-analysis reported that the use of either calcium channel blockers or angiotensin II receptor blockers was significantly associated with a lower risk of dementia compared with angiotensin-converting enzyme inhibitors and beta-blockers, but the same was not true for diuretics [34].

Obesity

Several studies have shown that midlife obesity (35-64 years) is associated with an increased risk of developing dementia in later life, independent of other vascular or socioeconomic risk factors [35]. There are no clinical trials with data on the effect of weight loss before the age of 65 on the prevention of dementia [36,37]. Body mass index (BMI) decreases in the years prior to a diagnosis of dementia [36–38]. Recent studies have shown an inverse correlation between late-life BMI and dementia risk [39], and this difference appears to be most pronounced in those with a genetic predisposition to higher BMI [40].

Diabetes

Both type 1 and type 2 diabetes are associated with a high risk of dementia, which increases with duration and severity of diabetes [41–43] and, independently, with glycated hemoglobin (HbA1c) variability over the years [44]. A Cochrane review showed no effect of intensive versus standard diabetes control on cognitive decline or dementia [45], and a Korean cohort study showed that a history of hypoglycemia in people with diabetes was associated with a higher risk of dementia [46]. The effect of antidiabetic therapy in providing increased protection against dementia is inconsistent in the literature [47]. 

Smoking

Compelling evidence indicates that tobacco smoking is associated with an increased risk of dementia [7,48–51]. There is limited and weak observational evidence linking passive smoking to an increased risk of cognitive impairment or dementia [52]. Some studies have suggested that smoking cessation reduces the risk of dementia even later in life [48,50,53,54] and that early cessation has benefits, highlighting the importance of smoking cessation in midlife [54].

Cardiovascular risk factors

Extensive clinical and epidemiological evidence has demonstrated a strong association between dementia and heart failure [55], atherosclerosis [56], and stroke [57–59] independently. Up to 64% of people aged 65 years or older with a history of stroke have cognitive impairment, and up to one-third develop dementia [59]. A recent systematic review and meta-analysis and a retrospective cohort study showed that atrial fibrillation (AF) is a risk factor for dementia in both young (<65 years) and old age, but the underlying mechanisms remain unclear [60,61]. Atrial cardiopathy (an abnormality in the structure or function of the left atrium) was also significantly associated with an increased risk of dementia, with only a small percentage of the effect mediated by AF or stroke [62]. There is also strong evidence that chronic kidney disease and albuminuria are risk factors for dementia [63–65].

The relationship between hypercholesterolemia and dementia risk remains unclear due to conflicting evidence. A 2016 Cochrane review reported that statins given to older people at risk of vascular disease did not prevent cognitive decline or dementia [6]. On the other hand, a 2018 meta-analysis of 25 cohort studies suggested that statin use may reduce the incidence of all types of dementia but not VaD [66]. Further studies are needed to clarify these issues. A recent cohort study showed that low levels of highdensity lipoprotein cholesterol were significantly associated with incident AD up to several decades later, both in early adulthood (35‐50 years) and in middle adulthood (51‐60 years), as were high triglyceride levels in early adulthood (35‐50 years) [67].

A UK study of 7,899 people aged 50 years who were followed for 25 years calculated a CV health score based on several CV risk factors (smoking, obesity, fasting glucose, blood cholesterol, blood pressure) and concluded that better scores were associated with a lower risk of dementia in people without CV disease [6]. These findings emphasize the importance of controlling CV risk factors in midlife.

Physical inactivity

Approximately one-third of the adult population in the United States, Europe, and the United Kingdom is physically inactive [68]. Physical inactivity is associated with an increased risk of dementia [6,50,69]. Exercise can reduce weight and diabetes risk, improve CV function, decrease glutamine, and increase hippocampal neurogenesis [6,50]. Epidemiologic studies show that physical activity is an independent protective factor against dementia [50,70–72].

Hearing impairment

Hearing impairment is very common in older adults, affecting up to two-thirds of people over the age of 70 [73], but is severely undertreated, with less than 20% of adults receiving any treatment for the condition (e.g., hearing aids) [73]. A growing body of evidence shows that hearing loss is an independent risk factor for dementia [74–76] and precedes the onset of dementia by 5 to 10 years [75]. A direct effect on brain volume and an indirect effect on social engagement, mental health, and physical activity may explain the increased risk of dementia [6,50,75,77], but more research is needed to investigate the potential causal mechanisms underlying this association.

Observational studies suggest that treatment of hearing loss (e.g., hearing aids) may reduce the burden of dementia by up to 8% [6]. However, evidence from several small clinical trials has been inconsistent. Some studies suggest that treatment of hearing loss may improve memory, but this has not been seen in people without dementia or in studies of people with AD [78].

Depression

Depression is associated with the incidence of dementia but is also part of the prodrome and early stages of dementia [6]. Several studies support that depression is associated with an increased risk of dementia, especially in the later stages of life [6,50,68,79]. However, few studies have distinguished between treated and untreated depression as a risk factor for dementia. Evidence on the role of antidepressants in reducing the risk of dementia is lacking. Animal models have shown that selective serotonin reuptake inhibitors may reduce amyloid plaque burden and cognitive impairment [80], but robust evidence in humans is lacking and needed. 

Social isolation

Social contact is thought to be a protective factor against dementia, with a number of studies suggesting that social isolation increases the risk of dementia. This association is complex and interrelated with other risk factors [6,50,81]. Several studies have shown that it is the quality and diversity of the social network, rather than its size, that predicts protection against cognitive decline and dementia [81]. Targeted interventions aimed at reducing social isolation and providing a social network for older people may act as a protective factor against dementia and other geriatric syndromes [6,50].

Alcohol consumption

Alcohol is strongly linked to cultural patterns. The relationship between alcohol consumption and cognitive function depends on the frequency and amount of alcohol consumed. Heavy drinking is associated with brain changes, cognitive impairment, and dementia [82]. However, there are not enough data to predict what amount of alcohol increases the risk of dementia. 

An overview of systematic reviews on the epidemiology of alcohol consumption and risk of dementia or cognitive decline showed that the risk of dementia may decrease with light to moderate drinking (less than 21 units per week) [83]. The UK Whitehall study showed a higher risk of dementia among those who drank more than 14 units of alcohol per week and among long-term abstainers, with the risk increasing linearly with higher levels of consumption [84].

Head injury

Traumatic brain injury (TBI) is considered a risk factor for AD and other dementias, increasing proportionally with the severity and frequency of TBI [85–87]. Approximately 5% of all cases of dementia worldwide are thought to be due to TBI [88]. A systematic review and meta-analysis conducted in 2021 found a moderate association between TBI and the risk of dementia, but no association between TBI and the risk of AD [89]. It also reported a higher risk of dementia in Asian people, males, and people with a mean age below 65 years [89]. A cohort study conducted in 2021 supported TBI as a risk factor for dementia, but did not find an association between TBI and specific types of dementia [85]. Blood-brain barrier dysfunction, mitochondrial function, β-amyloid pathology, chronic neuroinflammation, tau deposition, vascular damage [90], and white matter degeneration may play a role in the development of dementia [89].

Air pollution

High levels of nitrogen dioxide (NO2) and fine particulate matter (PM2.5) from traffic and residential wood burning are associated with dementia. In a systematic review of exposure to air pollutants and incident dementia, exposure to PM2.5, NO2, and carbon monoxide were all associated with an increased risk of dementia [6].

Sleep disorders

Growing evidence suggests that sleep disturbances such as insomnia, sleep-disordered breathing (such as obstructive sleep apnea), disrupted circadian rhythms, sleep-related movement disorders, and excessive daytime sleepiness are associated with a 50-80% increased risk of dementia [77,91]. A U-shaped association has been reported between sleep duration and risk of mild cognitive impairment or dementia, with an increased risk of dementia observed with less than 5 hours and more than 10 hours of sleep [6].

Diet

Several foods (green vegetables, berries, fish, and olive oil), nutrients (B vitamins, vitamin E, and omega-3 fatty acids), and phytochemicals (flavonoids) have been associated with a reduced risk of dementia [92]. No study has reported a beneficial effect of supplementation for the prevention of dementia [6]. More recently, studies have focused on the effect of whole diets rather than individual nutrients, concluding that diets such as the Mediterranean diet (high intake of vegetables, fruits, nuts, cereals, and olive oil and low intake of saturated fat and meat) may reduce the risk of dementia [77,93–95].

Drugs

Recent studies suggest that anticholinergics (including antihistamines, sleep agents, and treatments for overactive bladder) may be associated with a risk of developing dementia, particularly AD. These drugs are commonly used in the geriatric population and should be prescribed with special caution [50].

Visual impairment

Visual impairment is a major global health problem. A recent systematic review concluded that visual impairment is associated with cognitive decline and dementia, but the underlying mechanism is unclear [96]. Another recent study showed that cataract extraction significantly reduced the risk of developing dementia [97].

Others

The possible involvement of infectious agents in AD and other dementias has long been suggested [98,99]. The neurocognitive consequences of untreated human immunodeficiency virus (HIV) infection are well documented, and antiretroviral therapy has dramatically reduced the incidence of HIV-associated dementia. However, a U.S. cohort study concluded that despite antiretroviral therapy, people with HIV are at increased risk of dementia as they age and are diagnosed with dementia on average 10 years earlier than demographically similar people without HIV. Further research on risk factors for dementia in people treated for HIV is an unmet need [100]. 

Several observational studies have shown an increased risk of AD after COVID-19 infection. Inflammation and immune response are likely to play a relevant role in this association [98,99]. A recent systematic review and meta-analysis of 292,157 individuals found an association between influenza vaccination and a significantly lower risk of dementia [101], and a claimsbased cohort study of 935,887 influenza vaccinated-unvaccinated matched pairs corroborated these findings, estimating an approximately 40% reduction in the development of AD in patients who received the influenza vaccine compared with those who did not [102]. A large UK cohort has provided some insight into the beneficial role of treatment and prevention of vitamin D deficiency on brain health and dementia risk, but randomized controlled trials are needed to confirm these findings [103].  Several studies have shown an increased risk of dementia in people with Down syndrome, especially at younger ages, which may be explained by the overexpression of genes involved in amyloid precursor protein processing and Alzheimer’s neuropathic changes caused by trisomy 21 [58].

Emerging perspectives suggest an involvement of the gut microbiota in neurocognitive decline via a microbiota-gut-brain axis [104]. The specific mechanisms involved in this association remain largely unknown. Inflammatory bowel diseases such as ulcerative colitis (UC) and Crohn’s disease (CD) have been potentially linked to changes in the composition of the microbiota and may be associated with an increased risk of dementia, but the evidence is conflicting [104].  A Danish and a German study recently reported a small increase in the risk of all‐cause dementia in both UC and CD, with the Danish study also suggesting an association with FTD in CD patients [104,105]. 

Approaches for risk reduction

Dementia is a multifactorial disease with several potentially modifiable risk factors. Public health and individually tailored interventions targeting these risk factors have the potential to reduce the prevalence of the disease (Figure 2) [6,7,50,106]. Recent evidence suggests that high-risk populations may benefit most from these interventions compared with low-risk populations [6,50,106].

Most interventions are lifestyle-related. According to the American Heart Association’s Cardiovascular Health (CVH) guidelines, maintaining ideal levels of physical activity, fasting plasma glucose, and total cholesterol and stop smoking substantially reduce the risk of dementia in later life [106]. However, more research is required to explore the relationship between a favorable CVH score and cognitive outcomes in cognitively asymptomatic older populations.  Other interventions include maintaining a healthy diet and sleep pattern, reducing alcohol consumption, using hearing protection, preventing brain injury, and remaining cognitively and socially active. Public health measures to reduce air pollution and promote children’s education may also be helpful [6].

Despite the growing knowledge of modifiable risk factors for dementia, there is little evidence on the representativeness and methodology of interventions. There is a need to include marginalized populations, to consider exposure across the lifespan rather than only in midlife, and to ensure consensus on outcome measures that could be included in other chronic disease studies [1].

Dementia prediction models

Several dementia prediction models have been developed, but only a few have been externally validated. These include the Cardiovascular Risk Factors, Aging and Dementia (CAIDE) score (long-term risk of dementia in middle-aged adults), the Australian National University Alzheimer’s Disease Risk Index (ANU-ADRI; individual exposure to risk factors known to be associated with an increased risk of AD in later life), the Brief Dementia Screening Indicator (BDSI; risk of dementia in older adults), and the Dementia Risk Score (risk of dementia in older adults) [107]. Of the 12 modifiable risk factors described above, only air pollution and hearing loss are not included in these models [21,107]. Three other models have recently undergone external validation: Mehta’s RxDx-Dementia Risk Index (risk of dementia in patients with type 2 diabetes mellitus and hypertension), Nori’s Alzheimer’s Disease and Related Dementias (risk of AD and dementias in patients aged 45 years and older), and Walters Dementia Risk Score (5-year risk of first recorded dementia diagnosis in patients aged 60-79 years) [108].

Last year, the first dementia risk score calculated in a middleaged Southern European population followed for 20 years was presented, allowing early identification of individuals who could be targeted for dementia prevention based on intensive risk factor control [109].

Dementia diagnosis

AD is the most common cause of dementia, followed by VaD. Less common causes include LBD, FTD and Parkinson’s disease dementia. The differential diagnosis of dementia can be challenging due to overlapping symptoms [110]. 

The first AD guidelines were published in 1984 by the National Institute of Neurological and Communicative Disorders and Stroke and the Alzheimer’s disease and Related Disorders Association task force [111]. It was not until 2011 that the most recent guidelines were published, with the main difference from the 1984 guidelines being the recognition of different stages of AD and the inclusion of AD biomarkers. In 2016, the Aβ-amyloid tau neurodegeneration (ATN) classification was proposed to categorize multidomain biomarker findings [112]. 

Molecular imaging has provided insight into Alzheimer’s neuropathology [113]. It is now acknowledged that neuropathological changes occurring approximately 30 years before clinical onset consist of deposition of Aβ plaques, neurofibrillary tangles composed of misfolded hyperphosphorylated tau (a naturally unfolded protein that assumes an abnormal configuration in the tauopathy brain), neuronal loss, and neuroinflammation with glial activation.

The clinical diagnosis of dementia begins with an assessment of symptoms and medical history, physical examination, and screening for treatable causes (such as thyroid disease or vitamin deficiencies). Because neuropathological changes can aid in the diagnosis, the analysis of biomarkers (physiologic, chemical, or anatomic parameters that effectively reflect certain pathophysiologic processes) can then be performed. Patients’ clinical assessment is summarized in (Figure 3) [112].

 

AD, Alzheimer’s disease; CSF, cerebrospinal fluid; PET, positron emission tomography

Figure 3: Clinical assessment of patients with suspected dementia

In AD, biomarkers are assessed either by neuroimaging techniques (non-invasive) [110,113] or by mass spectrometry or immunoassay quantification of cerebrospinal fluid (CSF) markers of neuropathologic changes. The CSF markers Aβ42, Aβ42/β40 ratio, and p-tau are typically reserved for patients with earlyonset, progressive, or unexplained mild cognitive decline or with comorbidities that make AD diagnosis unclear [112].

Non-invasive techniques may focus on either the detection of amyloid deposition or neurodegeneration. A Cochrane systematic review from 2020 showed that magnetic resonance imaging (MRI) was not sufficient for early diagnosis of AD [114]. Fluorodeoxyglucose positron emission tomography (FDG-PET) subsequently emerged as a more specific biomarker for early diagnosis of AD, but has the disadvantage that by the time the technique detects hypometabolism, neuronal loss may be too advanced [110,112].

Early biomarkers that theoretically detect the first stages of

the disease, such as tau PET, Aβ PET, or structural MRI (sMRI), sometimes fail to distinguish between atypical phenotypes of AD and other dementias [110].

New processing methods for existing techniques (voxelbased morphometry, deformation-based morphometry [DBM], tensor-based morphometry [TBM], pattern-based morphometry [PBM], data-driven methods) have been developed to improve diagnostic accuracy. Other methods, such as functional MRI (fMRI) and optical coherence tomography (OCT), and other biomarkers, such as synaptic vesicle glycoprotein 2A (SV2A) and receptor for advanced glycation end products (RAGE), are currently being tested [110].

Analytical medicine also plays an important role in the diagnosis of dementia. Novel biomarkers, such as blood-based tests for Aβ, tau, or neurofilaments, are being used in selected populations. However, biomarker concentrations are lower in blood than in CSF, which poses a challenge to their use in clinical practice [112].

The clinical heterogeneity of FTD is also reflected radiologically, making it necessary to combine clinical manifestations with imaging findings [115].

An optimal biomarker is currently lacking. Therefore, improvements in existing methods and a combination of different diagnostic modalities are possible ways to improve early detection of AD and other dementias [110,116]. The combination of neuroimaging and artificial intelligence, through machine learning and deep learning, is also likely to become relevant in the near future [116].

Dementia treatment

	Nonpharmacologic interventions
Music therapy	Receptive/passive music therapy (listening to music); active music therapy (singing, improvising, playing instruments, clapping, dancing); singing a song associated with a memory to promote well-being, socialization, familiarity, and reduce anxiety. Rhythmic auditory cues to improve gait.
Art therapy	Creative activities (crayon or watercolor, coloring familiar objects, or drawing pictures based on memories or favorite seasons).
Aromatherapy	Administration of scented oils (e.g., lavender, lemon balm, orange, or cedar extracts) via diffusion, patches, or skin cream to induce calm and positive effects.
Animal-assisted therapy	Interaction with animals (most commonly with dogs) or feeding, grooming, and dressing the animals, or a more structured therapeutic program; to promote well-being, socialization, emotional support, and sensory stimulation.
Horticultural therapy	Indoor or outdoor gardening, adapted gardening tools; activities include picking seeds, filling containers, planting roots or seeds, touching, watering, organizing containers, cleaning floors, harvesting, cutting and washing; making potpourri, making a flower basket.
Light treatment	Exposure to certain levels of light (outdoor sunlight, light boxes, light visors worn on the head, ceiling lights, or dawndusk simulation) to improve circadian rhythms and behavior.
Massage	Tactile or therapeutic touch applied to the back, shoulders, neck, hands, or feet by a qualified massage therapist or trained staff or family members to induce a calm and positive effect.
Cognitive rehabilitation	Cognitive training, cognitive stimulation, cognitive rehabilitation, occupational therapy to adapt to cognitive limitations through compensatory strategies; to support activity engagement; reasoning exercises; compensatory mnemonic techniques such as visual imagery, face-name association, calendars, notes; puzzles, word games.
ADL training	Practicing restorative and compensatory techniques for daily self-care and household activities.
Physical exercise	Practicing moderate-intensity physical activity 3-4 times per week for 30-45 minutes; aerobic exercise (e.g., walking, cycling); resistance training (e.g., arm exercises such as biceps curls, forward shoulder raises, lateral raises using handheld dumbbells, and leg exercises such as sit-to-stand weighted exercises); dance; mind-body exercises (tai chi, yoga, qigong, pilates); virtual reality (stationary cycling or walking systems); fitness-based home video game consoles (e.g., Microsoft Kinect TM, Nintendo Wii Sports TM).

Despite extensive and ongoing research in the field, no effective treatment for neurodegenerative diseases has been established. The established approach should always comprise a multidisciplinary assessment, include symptomatic nonpharmacologic and pharmacologic strategies, and focus on improving the patient’s quality of life and reducing the burden on caregivers (Table 3 and Figure 4) [117].

Smarts homes	Labeling drawers and closet doors, visible workstations, providing ADL equipment, eliminating distractions; electronic medication dispensers, electronic orientation clocks, robotic device trackers and motion detectors, door alarms, memory aids, picture button phones, and stove reminder systems.
	Pharmacologic interventions
Anti-dementia agent	Cholinesterase inhibitors (donepezil, galantamine, rivastigmine) N-methyl-D-aspartate receptor antagonists (memantine)
Symptomatic treatment/ Adjuvant drugs	Antidepressants, mood stabilizers, antipsychotics, benzodiazepines (important to avoid polypharmacy)
	Other interventions
	Management of comorbidities (management of risk factors for vascular comorbidities)
	Caregiver and community support
	Nutrition and hygiene management
	Palliative and end-of-life care

Table 3: Nonpharmacologic and pharmacologic strategies for patients with dementia.