Clinical spectrum of Alzheimer’s disease

The clinical symptoms of AD develop over time. Years or even decades may lie between the first AD brain changes and the onset of clinical symptoms (Nelson et al., 2012). This intermediate stage is called preclinical AD, and can only be detected through biomarkers. The first clinical symptoms denote prodromal or mild cognitive impairment stages, whereas progression of cognitive and functional symptoms is used to stage the severity of AD dementia.

2.1.3.1 Preclinical states, mild cognitive impairment and prodromal Alzheimer’s disease

The preclinical states of AD comprise an asymptomatic at-risk state for AD, where evidence of abnormal amyloid accumulation can be detected either in positron emission tomography (PET) imaging or cerebrospinal fluid (CSF), and presymptomatic AD, where the person has a rare monogenic mutation that causes AD later (Dubois et al., 2010). Persons in these states do not have symptoms, and they differ in the likelihood of progression to the clinical syndrome of AD. For example, a positive amyloid PET scan alone in an asymptomatic person might not be a good predictor of future clinical AD (Iaccarino, Sala, Perani, & for the Alzheimer’s Disease Neuroimaging Initiative,

2019), whereas rare causal mutations inevitably lead to AD pathology and symptoms.

Early cognitive changes without functional impairment can be characterized by mild cognitive impairment (MCI) or by prodromal AD. Of these, MCI is a broader term including non-AD etiologies as well (Dubois & Albert, 2004), and refers to cognitive functioning below age and education expectations. In MCI, the cognitive symptoms are mild enough to not significantly compromise ADLs (Petersen, 2004; Winblad et al., 2004). The concept allows for highly heterogenous etiologies, and can be considered to refer to a clinical syndrome rather than a disease process (Dubois et al., 2010). The concept of mild neurocognitive disorder in the Diagnostic and Statistical Manual for Mental Disorders – Fifth Edition (DSM-5) captures similar clinical features (American Psychiatric Association [APA], 2013). MCI is a risk for future dementia (Petersen et al., 2009), although the reversal rate from MCI to normal cognition can be up to 30 % (Malek-Ahmadi, 2016), depending on the patient group and used criteria for MCI (Thomas et al., 2019). MCI can be further divided into subtypes based on the primarily affected cognitive domain(s): single domain amnestic MCI, multiple domain amnestic MCI, single domain non-amnestic MCI and multiple domain non-amnestic MCI (Petersen et al., 2001; Winblad et al., 2004). These subtypes correspond to an increased risk for specific neurodegenerative diseases (Figure 1).

The brevity of the all-cause MCI concept is problematic when more specific prodromal disease states are investigated. To that end, many researchers and clinicians prefer to use the concept prodromal AD to capture the combination of early amnestic cognitive impairment with biomarker and neuroimaging evidence that support AD pathology (Dubois & Albert, 2004; Dubois et al., 2014). Within the amnestic MCI subdomain, the evidence of AD pathology can increase the accuracy of progression to AD by reflecting a disease rather than merely a clinical syndrome (Dubois et al., 2010).

Figure 1. Flowchart for MCI diagnostic procedures, adapted from Winblad et al. (2004) and Petersen (2009). AD = Alzheimer’s disease, D = depression, DLB = dementia with Lewy bodies, FTD = frontotemporal dementia, MCI = mild cognitive impairment, VaD = vascular dementia.

2.1.3.2 Mild behavioral impairment

In recent years, early NPS have become a major focus of interest (Ismail et al., 2016). Spearheaded by research in non-AD neurocognitive disorders, such as behavioral variant frontotemporal dementia (bvFTD; Neary et al., 1998; Rascovsky et al., 2011), criteria for early neuropsychiatric syndromes have emerged (Taragano et al., 2009). The syndrome of mild behavioral impairment (MBI) was proposed to systematically define early NPS preceding dementia with the following criteria: a major change in patient behavior, symptom onset after age 60 and persistence for at least 6 months, absence of cognitive impairment, normal functioning in social and occupational settings with preserved activities of daily living (Taragano et al., 2009).

The Alzheimer’s Association International Society to Advance Alzheimer’s Research And Treatment – Neuropsychiatric Symptoms Professional Interest Area revised the Taragano criteria in 2016, where the most important change was the removal of MCI as an exclusion criterion for MBI (Ismail et al., 2016).

The revised criteria also outline five behavioral and personality changes, of which at least one must be present: decreased motivation, affective dysregulation, impulse dyscontrol, social inappropriateness, and abnormal perception or thought content. In a population-based study of individuals over 50 years of age, the prevalence of MBI was 10 % based on a previously established cut-off on a rating scale (Creese, Brooker, et al., 2019). Earlier studies have shown that 27 % of older individuals with normal cognition have at least one NPS, commonly in the affective domain (Geda et al., 2008).

While some patients may present with predominantly behavioral changes, cognitive and behavioral symptoms often coexist. Persons with MCI or subjective cognitive decline are at an increased risk of future cognitive decline if NPS are also present (Creese et al., 2019; Pink et al., 2015). If persons with comorbid cognitive symptoms and NPS in these early stages progress to dementia, the diagnoses are mainly AD or frontotemporal dementia (FTD), with a ratio of approximately 1:2 (Taragano et al., 2009).

2.1.3.3 Dementia due to Alzheimer’s disease

Based on the severity of cognitive and functional decline, dementia due to Alzheimer’s disease can be separated to mild, moderate and severe stages (Table 2; Hughes, Berg, Danziger, Coben, & Martin, 1982; Memory Disorders:

Current Care Guidelines, 2017). Ultimately, the patient will require assistance in carrying out their activities of daily living. The most complex ADLs are impaired first and the most basic functions of self-care are preserved longest (Lindbergh, Dishman, & Miller, 2016; Perneczky et al., 2006; Nygård, 2003;

Njegovan, Man-Son-Hing, Mitchell, & Molnar, 2001). NPS may be present even before AD diagnosis (Taragano et al., 2009; Pink et al., 2015), but they become increasingly disturbing as the disease progresses (Piccininni, Di Carlo, Baldereschi, Zaccara, & Inzitari, 2005; Hashimoto et al., 2015).

Table 2. Characteristic symptoms in different stages of AD dementia (adapt-ed from National Current Care Guidelines for Memory Disorders, 2017)

Mild stage (MMSE

18–26, CDR 0.5–1) Moderate stage (MMSE 10–22, CDR ability to work and drive, increased use of memory aids

Impaired IADLs, difficulties in prepar-ing a meal, dressprepar-ing inappropriately,

symptoms Weight loss Weight loss Gait apraxia, primary reflexes, extrapy-ramidal symptoms, secondary frailty BADLs = basic activities of daily living, CDR = Clinical Dementia Rating,

IADLs = instrumental activities of daily living, MMSE = Mini-Mental State Examination.