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Clinical features and diagnosis of Alzheimer disease

Clinical features and diagnosis of Alzheimer disease
Authors:
David A Wolk, MD
Bradford C Dickerson, MD
Section Editor:
Steven T DeKosky, MD, FAAN, FACP, FANA
Deputy Editor:
Janet L Wilterdink, MD
Literature review current through: Jan 2024.
This topic last updated: Oct 08, 2021.

INTRODUCTION — Alzheimer disease (AD) is a neurodegenerative disorder of uncertain cause and pathogenesis that primarily affects older adults and is the most common cause of dementia [1]. The most essential and often earliest clinical manifestation of AD is selective memory impairment, although there are exceptions. While treatments are available that can ameliorate some symptoms of the illness, there is no cure and the disease inevitably progresses in all patients. The first approval by the US Food and Drug Administration (FDA) of a therapy that is potentially disease-modifying provides a mandate for a specific diagnosis of AD in patients with cognitive impairment and dementia.

This topic reviews the clinical manifestations and diagnosis of AD. Other topics review the risk factors and treatment of AD:

●(See "Epidemiology, pathology, and pathogenesis of Alzheimer disease".)

●(See "Treatment of Alzheimer disease".)

Other topics review the approach to patients with cognitive impairment and dementia and the clinical features of other dementia syndromes:

●(See "Evaluation of cognitive impairment and dementia".)

●(See "Mild cognitive impairment: Epidemiology, pathology, and clinical assessment".)

●(See "Etiology, clinical manifestations, and diagnosis of vascular dementia".)

●(See "Clinical features and diagnosis of dementia with Lewy bodies".)

●(See "Frontotemporal dementia: Clinical features and diagnosis".)

CLINICAL FEATURES

Age of onset

●Typical AD – AD is characteristically a disease of older age [2]. It is unusual for AD to occur before age 60. The incidence and prevalence of AD increase exponentially with age, essentially doubling in prevalence every 5 years after the age of 65 years. (See "Epidemiology, pathology, and pathogenesis of Alzheimer disease", section on 'Incidence and prevalence'.)

●Early-onset AD – Onset of symptoms before 65 years of age is uncommon, occurring in approximately five percent of patients with AD. Such patients often present for evaluation due to concerns about job performance. Many of these patients have no clear familial pattern and thus would be considered sporadic. Some exhibit familial clustering, but usually with affected family members being older at symptom onset.

People with early-onset AD often present with symptoms somewhat atypical for this disease, such as language, visual, or mood-behavioral changes rather than predominant memory loss.

●Inherited forms of AD – These rare forms of AD routinely present before 65 years of age, and frequently in the fifth decade or earlier. These account for less than 1 percent of all cases of AD. They typically exhibit an autosomal-dominant inheritance pattern related to mutations in genes that alter beta-amyloid (Aβ) protein production or metabolism, including amyloid precursor protein (APP), presenilin-1 (PSEN1), and presenilin-2 (PSEN2).

In a meta-analysis on 1307 patients with autosomal-dominant AD, the mean age of symptom onset was 46 years and was highly correlated with parental age of onset and mutation type [3]. Patients with PSEN1 mutations had the earliest median age of onset (43 years) (figure 1). The range of symptom onset across all mutation types is nonetheless fairly broad, with some presentations in the fourth decade and some mutations not manifesting symptoms until the seventh decade (see "Early-onset dementia in adults", section on 'Neurodegenerative dementias'). If this is suspected, it is important to collect detailed information about family history to document a potential autosomal-dominant familial pattern.

●AD associated with Down syndrome – Individuals with Down syndrome have an additional gene dose of APP due to trisomy of chromosome 21 and inevitably develop AD pathology. Symptoms emerge at an earlier age, 10 to 20 years younger than the general population with AD [4]. (See "Genetics of Alzheimer disease", section on 'Trisomy 21'.)

Cardinal symptoms

Memory impairment — Memory impairment is the most common initial symptom of AD dementia. Even when not the primary complaint, memory deficits can be elicited in most patients with AD at the time of presentation. Deficits in other cognitive domains may appear with or after the development of memory impairment.

The pattern of memory impairment in AD is distinctive [5]. Declarative episodic memory (memory of events occurring at a particular time and place) is usually profoundly affected in AD. This type of memory depends heavily on the hippocampus and other medial temporal lobe structures. By contrast, subcortical systems supporting procedural memory and motor learning are relatively spared until quite late in the disease. Memory for facts such as vocabulary and concepts (semantic memory) often becomes impaired somewhat later. Semantic memory is supported by neocortical temporal regions, particularly in the anterior temporal lobe. Subtler impairments of semantic memory may be a relatively early feature given early temporal lobe pathology [6].

Within episodic memory, there is a distinction between immediate recall (eg, mental rehearsal of a phone number), memory for recent events (which comes into play once material that has departed from consciousness must be recalled), and memory of more distant events (remote memory). Memory for recent events, served by the hippocampus, entorhinal cortex, and related structures in the medial temporal lobe, is prominently impaired in early AD [7-9]. By contrast, immediate memory (encoded in the sensory association and prefrontal cortices) is spared early on, as are memories that are consolidated for long periods of time (years), which can be recalled without hippocampal function.

The early memory deficit in AD is most precisely described as anterograde long-term episodic amnesia. Long-term memory can encompass time frames from less than a minute to years, but because the absolute time interval over which long-term memory can fail may actually be short (eg, inability to recall a few words after a couple minutes of distraction), patients and caregivers typically describe "short-term memory" problems. For this reason, we try to avoid the confusion afforded by the technical terms of long-term and short-term memory and use the term "recent memory impairment" to refer to the characteristic impairment.

Memory deficits develop insidiously and progress slowly over time, evolving to include deficits of semantic memory and immediate recall. Impairments of procedural memory appear only in late stages of AD.

Memory is usually tested by asking patients to learn and recall a series of words or objects immediately and then at a delay of 5 to 10 minutes. Impaired ability to recall objects with selective cues (hints) or recognize items as previously studied on a recognition memory test represents a more severe deficit and one that may be particularly specific for AD in its early presentation, as it reflects specific involvement of medial temporal lobe function [10]. Questions about orientation and recent current events are also useful memory tests. (See "The mental status examination in adults", section on 'Memory'.)

Clinicians should compare an informant's report with the patient's report of symptoms of memory loss in daily life, recognizing that many older individuals are unreliable reporters of their own memory impairment and can both overestimate and underestimate their deficits [11]. In addition, lack of insight may cause patients to deny or under-report their symptoms. It is critical to obtain the perspective of someone who knows the patient well.

Executive function and judgment/problem solving — In early stages of AD, impairment in executive function may range from subtle to prominent [12-14]. In many cases, the patient underreports these symptoms, and an informant interview is critical. Family members and coworkers may find the patient less organized or less motivated; multitasking is often particularly compromised. As the disease progresses, an inability to complete tasks typically emerges.

Reduced insight into deficits (anosognosia) is a common but variable feature of AD [15,16]. It is common for patients to underestimate their deficits and offer alibis or explanations for them when they are pointed out. Interviewing an informant who has known the patient over time (usually a family member) is necessary; often it is the family member, not the patient, who brings the complaint of cognitive impairment to medical attention.

Loss of insight increases over time along with overall disease severity [17]. Such loss of insight may be associated with behavioral disturbances. Those with relatively preserved insight are more likely to be depressed; those with more impaired insight are likely to be agitated, be disinhibited, and exhibit psychotic features [18,19]. Lack of insight also may impact safety, as patients may attempt to take on tasks that they no longer have the capacity to perform effectively (eg, driving). (See "Management of the patient with dementia", section on 'Driving'.)

Impairments in other cognitive domains — Other cognitive domains become affected in patients with AD. Visuospatial impairments are often present relatively early, while deficits in language often manifest later in the disease course. These deficits develop and progress insidiously. Less commonly, language deficits, visuospatial abnormalities, or even executive functions may be impaired as the most prominent initial symptom [12,13]. (See 'Atypical presentations' below.)

Behavioral and psychologic symptoms — Neuropsychiatric symptoms are common in AD, particularly in the middle and late course of disease. These can begin with relatively subtle symptoms including apathy, social disengagement, and irritability. Apathy can be difficult to distinguish from depression, which can be difficult to diagnose in the setting of dementia, and the differences should be sought diligently because of treatment implications. In some cases empiric treatment of presumed depression is a reasonable management decision. (See "Management of neuropsychiatric symptoms of dementia", section on 'Depression'.)

More problematic in patient management is the emergence of behavioral disturbances, including agitation, aggression, wandering, and psychosis (hallucinations, delusions, misidentification syndromes). A concomitant medical illness, medication toxicity, and other causes of delirium should be considered whenever new behavioral disturbances arise, especially if acute or subacute. The behavioral disturbances associated with AD are discussed in detail separately. (See "Management of neuropsychiatric symptoms of dementia".)

Other signs and symptoms

Apraxia — Dyspraxia, or difficulty performing learned motor tasks, usually occurs later in the disease after deficits in memory and language are apparent [20]. Before it is clinically manifest, dyspraxia can be elicited by asking the patient to perform ideomotor tasks, ie, pantomime the use of tools (eg, "show me how you would use a comb") [21,22]. Clinical dyspraxia leads to progressive difficulty first with complex, multistep motor activities, then with dressing, using utensils to eat, and other self-care tasks, and is a significant contributor to dependency in mid- to late stages of AD [23].

Olfactory dysfunction — Changes in olfactory function are common in patients with AD and have been explored as a diagnostic tool. However, the predictive value of simple odor detection testing is limited [24,25], and the challenges of standardized assessment have limited widespread use of olfactory assessment [26,27]. Furthermore, olfactory dysfunction is not a clinical symptom that is often noted by patients or their families. That said, it may enhance classification of patients beyond cognitive measures alone [28].

Sleep disturbances — Sleep disturbances are common in patients with AD [29]. Patients with AD spend more time in bed awake and have more fragmented sleep compared with older adults without AD. Such changes may occur very early in the disease process, including in patients who are cognitively normal but have biomarker evidence of Aβ deposition [30-32]. (See "Sleep-wake disturbances and sleep disorders in patients with dementia", section on 'Sleep changes in aging and dementia'.)

Seizures — Seizures occur in 10 to 20 percent of patients with AD, usually in the later stages of disease [33-37]. Younger patients, including those with autosomal-dominant forms of AD, may be at higher risk for seizures, which may occur early in the course of disease [38,39].

The predominant seizure type is focal nonmotor with impaired awareness, with symptoms often suggestive of medial temporal lobe onset (eg, amnestic spells, unexplained emotions, metallic taste, rising epigastric sensation) [39]. (See "Seizures and epilepsy in older adults: Etiology, clinical presentation, and diagnosis", section on 'Epilepsy (unprovoked seizures)'.)

Motor signs — In the early stages, patients with AD generally have a normal neurologic examination except for the cognitive examination. While pyramidal and extrapyramidal motor signs, myoclonus, and seizures do occur in patients with AD, these are typically late-stage findings [40]. If these are clinically apparent in early to middle stages, alternative diagnoses should be considered [41].

Myoclonus may emerge in some patients with AD, typically those with more rapid than usual decline. Similarly, primitive reflexes (grasp, snout reflexes, gegenhalten) and incontinence are late, rather than early, features of AD.

Atypical presentations — A minority of patients with AD do not present in the classic fashion with progressive amnestic dementia [42,43]. Distinguishing these cases from other causes of dementia can be challenging. Neuropathologic studies in such patients have found Alzheimer pathology with an atypical neuroanatomic distribution (particularly neurofibrillary tangles) that corresponds with the anatomy of the most prominent clinical deficits; neuroimaging studies often have corresponding findings [43-48]. Some case series suggest that these atypical forms are more common in early-onset presentations (before 65 years of age) in patients who do not carry one of the autosomal-dominant familial mutations [49,50].

●Posterior cortical atrophy – This syndrome manifests with progressive cortical visual impairment [42,46,51-56]. Patients are often first evaluated by optometrists or ophthalmologists for visual complaints, such as difficulty reading and driving [43,54]. A proposed consensus classification framework requires three or more of the following early or presenting features [57]:

•Space perception deficit

•Simultanagnosia (ie, the inability to integrate a visual scene despite adequate visual acuity to resolve individual elements)

•Object perception deficit

•Constructional dyspraxia

•Environmental agnosia

•Oculomotor apraxia (the inability to direct gaze accurately to a new target)

•Dressing apraxia

•Optic ataxia (the inability to reach accurately under visual guidance)

•Alexia

•Left/right disorientation

•Acalculia

•Limb apraxia

•Apperceptive prosopagnosia

•Agraphia

•Homonymous visual field defect

•Finger agnosia

In addition, there should be relative sparing of anterograde memory function, speech and nonvisual language functions, executive functions, and behavior and personality. Neuroimaging usually shows predominant occipitoparietal or occipitotemporal atrophy, hypometabolism, or hypoperfusion [45,57-60].

Some patients with a biparietal variant present with dyspraxia and have difficulty completing simple bimanual tasks, such as dressing [42,61]. Other early clinical features can include visuospatial disorientation, dysgraphia, and language impairment with semantic memory deficits (see 'Memory impairment' above). Neuropathologic examination and neuroimaging studies demonstrate prominent involvement of the parietal lobes bilaterally.

In most patients, neuropathologic examination reveals Alzheimer pathology with a greater predominance of pathology involving visual association areas and even primary visual cortex compared with more typical presentations [43,55,59,62]. A minority of patients with this syndrome have alternative pathologies, such as dementia with Lewy bodies (DLB), corticobasal degeneration (CBD), prion disease, or frontotemporal lobar degeneration (FTLD) [55,59,63,64]. In such patients, other core features of the respective diseases are usually present (eg, fluctuating cognition, recurrent visual hallucinations, and parkinsonism in DLB; limb rigidity, akinesia, dystonia, or myoclonus in CBD) [57]. (See "Clinical features and diagnosis of dementia with Lewy bodies" and "Corticobasal degeneration", section on 'Clinical features' and "Diseases of the central nervous system caused by prions" and "Frontotemporal dementia: Epidemiology, pathology, and pathogenesis".)

●Primary progressive aphasia – Primary progressive aphasia (PPA) refers to a clinically and pathologically heterogeneous group of neurodegenerative disorders characterized by progressive language difficulty with relative sparing of memory and other cognitive functions, at least early in the disease course. Based on the type of language impairment, PPA is further subclassified into three variants: nonfluent, semantic, or logopenic. PPA is usually associated with FTLD rather than Alzheimer pathology. However, a significant percentage (up to one-third) are found at autopsy to have AD instead [42,43,45,65-67]. The clinical variant of PPA most likely to be due to AD is the logopenic variant, characterized by frequent word-finding pauses and paraphasic speech errors without major grammar or comprehension deficits [45,67-71]. AD pathology is also sometimes found in patients with nonfluent or semantic variants of PPA, but this is less common [42,43]. (See "Frontotemporal dementia: Clinical features and diagnosis".)

In patients with logopenic variant PPA, structural imaging often shows predominant left posterior perisylvian or parietal atrophy [72]. 18-F fluorodeoxyglucose positron emission tomography (FDG-PET) and single-photon emission computed tomography (SPECT) may highlight hypometabolism or hypoperfusion in the same areas. Elevated signal with amyloid PET imaging suggests a role for AD pathology and is seen in approximately 85 percent of logopenic variant cases and in approximately 20 percent of semantic and nonfluent variants in one series [73], but some cases have mixed pathologies [74], so amyloid PET should not be viewed as diagnostic of AD.

●Dysexecutive or "frontal" variant – A subset of patients with AD present with prominent deficits in executive function relative to amnesia. In one case series of 88 such patients, magnetic resonance imaging (MRI) revealed more thinning in the frontoparietal cortical regions, the clinical course appeared to involve more rapid progression, and the prevalence of the apolipoprotein E (APOE) ε4 allele was lower compared with the more typical AD patients with prominent memory deficits [75,76].

Mixed dementias — It is common for Alzheimer pathology to coexist with other processes, including vascular lesions, cortical Lewy bodies, TAR DNA binding protein 43 (TDP-43) deposits, argyrophilic grain disease, and Parkinson disease. The combination of two pathologies can influence the clinical presentation and course of the disease and present diagnostic challenges [77]. In general, these additional pathologies result in greater likelihood of dementia and faster than usual rate of decline [78-80].

As expected, the most common combination is that of AD and vascular dementia. This is discussed in detail separately. (See "Etiology, clinical manifestations, and diagnosis of vascular dementia".)

Another combination that is described is that of diffuse Lewy body and AD dementia [81-83]. In affected patients, prominent memory loss can coexist with one or more features of DLB, including visual hallucinations, fluctuations in sensorium, parkinsonism, and falls. (See "Clinical features and diagnosis of dementia with Lewy bodies".)

CLINICAL COURSE — AD progresses inexorably. The progress of the disease can be measured with mental status scales such as the Mini-Mental State Examination (MMSE), the Montreal Cognitive Assessment (MoCA), the clinical dementia rating (CDR) scale, and/or an instrument measuring independent daily function such as the Functional Activities Questionnaire (table 1). While the clinical course as measured by such scales is not necessarily linear, a number of studies have found that patients decline 3 to 3.5 points on average on the MMSE each year [84-87], with a minority (<10 percent) having a more rapidly progressive decline of 5 to 6 points on annual MMSE [88]. (See "Mental status scales to evaluate cognition", section on 'Longitudinal assessment'.)

An older age of onset of AD (>80 years) may be associated with a slower rate of decline compared with younger patients [89]. Conversely, early neuropsychiatric symptoms including psychosis, agitation, and aggression have been associated with more rapid decline [90].

The average life expectancy after a diagnosis of AD has been reported to be between 8 and 10 years but may range from 3 to 20 years, and it depends heavily on how impaired the person is at the time of diagnosis [91-94]. Survival also relates to age at onset of symptoms. Patients generally succumb to terminal-stage complications that relate to advanced debilitation, such as dehydration, malnutrition, and infection. (See "Care of patients with advanced dementia".)

EVALUATION

Clinical assessment — AD should be suspected in any older adult with insidious onset, progressive decline in memory, and at least one other cognitive domain leading to impaired functioning. Thus, a detailed cognitive and general neurologic examination is paramount. Clinicians should also consider potential contributors to the dementia syndrome such as adverse effects of medication, depression, and metabolic disorders and deficiencies. (See "Evaluation of cognitive impairment and dementia", section on 'Evaluation'.)

Many clinicians make use of standardized mental status scales to document the presence and progression of dementia. The Montreal Cognitive Assessment (MoCA) [95,96] is our preferred brief assessment tool because it has better sensitivity for executive and language dysfunction compared with other brief tests such as the Mini-Mental State Examination (MMSE). The typical cutoff score for normal performance on the MoCA is 26 (ie, 25 and below is considered abnormal). Cutoffs should be adjusted based on appropriate norms, including education adjustment [97]. The MoCA is available online and in several languages at www.mocatest.org. (See "Mental status scales to evaluate cognition", section on 'Montreal Cognitive Assessment (MoCA)'.)

The diagnosis of dementia cannot be made simply on the basis of a low score on one of these tests; the most important part of the diagnostic evaluation is a detailed history including the perspective of an informant (eg, spouse or adult child), interviewed separately from the patient if possible. The use of validated questionnaires to document the preservation or loss of independent function, as well as the presence or types of neuropsychiatric symptoms, is also an important part of the evaluation. Validated questionnaires to measure cognitive symptoms also can be helpful [98]. Additional detail on these instruments is presented separately. (See "Mental status scales to evaluate cognition".)

Role of neuropsychologic testing — Formal neuropsychologic assessment can be helpful in the evaluation of individuals with cognitive impairment and dementia. Cognitive testing under standardized conditions using demographically appropriate norms is more sensitive to the presence of impairments, especially impairments of executive function. Neuropsychologic assessment can be useful in a variety of settings:

●To establish a baseline in order to follow the patient over time. (See "Evaluation of cognitive impairment and dementia", section on 'Neuropsychological testing'.)

●To help differentiate among different forms of neurodegenerative dementias or between a neurodegenerative dementia and other etiologies of cognitive impairment, such as cerebrovascular disease or depression. (See "Evaluation of cognitive impairment and dementia", section on 'Neuropsychological testing'.)

●To assess competencies and guide recommendations pertaining to driving, financial decisions, and need for increasing supervision. (See "Management of the patient with dementia".)

●To identify opportunities for compensatory or rehabilitative treatment strategies. (See "Management of the patient with dementia", section on 'Rehabilitation'.)

Neuroimaging — Brain imaging, preferably with magnetic resonance imaging (MRI), is indicated in the evaluation of patients with suspected AD [99]. Brain MRI can document potential alternative or additional diagnoses including cerebrovascular disease, other structural diseases (chronic subdural hematoma, cerebral neoplasm, normal pressure hydrocephalus), and regional brain atrophy suggesting frontotemporal dementia (FTD) or other types of neurodegenerative disease. (See "Evaluation of cognitive impairment and dementia", section on 'Neuroimaging'.)

●MRI – Structural MRI findings in AD include both generalized and focal atrophy, as well as white matter lesions. In general, these findings are nonspecific.

The most characteristic focal finding in AD is reduced hippocampal volume or medial temporal lobe atrophy [47,100-103]. Because hippocampal volumes decline in normal aging, however, age-specific criteria are needed [100,101,104]. The finding of hippocampal atrophy provides incremental support for a diagnosis of AD in a patient with a typical clinical presentation, but it is not sufficiently specific to contribute significantly to the accuracy of the diagnosis over the clinical assessment alone [105]. Some studies have suggested that MRI features may predict rate of decline of AD and in the future may guide treatment decisions [85,106]. Hippocampal volumetry using age-corrected norms available from the Alzheimer Disease Neuroimaging Initiative can predict rates of progression of mild cognitive impairment (MCI) to dementia [107]. However, the tools to generate these measurements are not in wide use, nor have these findings been validated in a clinical practice setting.

●FDG-PET and SPECT – Functional brain imaging with 18-F fluorodeoxyglucose positron emission tomography (FDG-PET) or single-photon emission computed tomography (SPECT) reveals distinct regions of hypometabolism (PET) and hypoperfusion (SPECT) in AD. These areas include the hippocampus, the precuneus (mesial parietal lobes), and the lateral parietal and posterior temporal cortex [9,108-113]. In practice, FDG-PET may be most useful in distinguishing AD from FTD in patients with atypical presentations [114-117], as well as discriminating from non-neurodegenerative conditions, such as depression. FDG-PET and SPECT are the only functional neuroimaging methods that are currently reasonably widely available for clinical use.

●Amyloid PET imaging – Amyloid PET tracers (florbetapir F-18, flutemetamol F-18, florbetaben F-18) measure amyloid lesion burden in the brain; these aid in the diagnosis of AD, differentiating AD from other causes of dementia [117-140]. A large study of the use of amyloid PET imaging in clinical decision-making was completed in December 2017 (NCT02420756) and revealed that an amyloid PET result significantly impacted clinical management and etiologic diagnosis [141]. At present, these scans are generally not covered by most health insurances plans in the United States.

These tracers have been approved by regulatory agencies in the United States and elsewhere as qualitative assessments of beta-amyloid (Aβ) plaque density [142,143]. Since there are issues with how much ligand binding to plaques constitutes a "positive" scan, the US Food and Drug Administration (FDA) approval specifies that an amyloid PET scan that is negative decreases the likelihood that a patient with dementia has AD. In a symptomatic dementia patient, a positive scan indicates that the person has amyloid plaque pathology, but such a finding does not rule out a coexisting pathology. Based on the FDA approval label, scans are determined positive or negative based on a radiologist's clinical read, although there are more quantitative approaches that are used in research and may complement such clinical assessments.

A consensus opinion of the Amyloid Imaging Task Force, the Society of Nuclear Medicine, and the Alzheimer's Association concluded that amyloid imaging is not appropriate in patients who meet the core clinical criteria for probable AD and have a typical age of onset, and such a scan should not be used to determine dementia severity [144]. These guidelines may be adjusted with the approval of aducanumab, for which a positive amyloid scan is generally believed to be a prerequisite [145]. (See "Treatment of Alzheimer disease", section on 'Aducanumab'.)

●Tau PET imaging – A number of tau PET imaging tracers have been in development and hold potential as markers of the tauopathy of AD. A number of studies have demonstrated that these tracers better track disease progression and more highly associate with patterns of atrophy and clinical features than amyloid PET does [146,147].

One such tracer, flortaucipir F-18, was approved by the FDA for determining the burden of neurofibrillary tangles in individuals being evaluated for AD; this tracer is not useful for measuring non-AD tauopathies such as frontotemporal lobar degeneration (FTLD) [148,149]. As with amyloid PET, there is limited insurance coverage of this agent.

Role of biomarkers — There are several widely investigated biomarkers for the molecular and degenerative process of AD that can be supportive of a diagnosis of AD but are not yet recommended for routine diagnostic purposes (table 2) [12]. Such testing can add incremental confidence to a clinical diagnosis of AD, however, and can be useful in certain circumstances, including early-onset dementia and atypical presentations of AD in which the differential diagnosis includes other non-amyloid neurodegenerative diseases such as FTD. Evidence of the presence of amyloid is also likely to guide initiation of aducanumab, which specifically targets this protein. (See "Treatment of Alzheimer disease", section on 'Aducanumab'.)

Molecular biomarkers of Aβ protein deposition include:

●Low cerebrospinal fluid (CSF) Aβ42 (or Aβ42:Aβ40 ratio)

●Positive amyloid PET imaging using one of the amyloid PET tracers

Appropriate use guidance states that one of these tests should be positive in patients who are treated with aducanumab. (See "Treatment of Alzheimer disease", section on 'Aducanumab'.)

Biomarkers of tau deposition (a key component of neurofibrillary tangles) include:

●Increased CSF total tau and phospho-tau

●Tau PET imaging using flortaucipir F-18

In addition to these molecular biomarkers, there are several topographic or neurodegenerative biomarkers used to assess the downstream brain changes that correlate with the regional distribution of neuronal dysfunction and eventual neuronal death associated with AD [150]. These include medial temporal lobe atrophy on MRI and reduced glucose metabolism in the temporoparietal regions on FDG-PET. (See 'Neuroimaging' above.)

In general, the topographic biomarkers are less specific than the molecular biomarkers but correlate better with the emergence of clinical symptoms. None of these tests is valid as a standalone diagnostic test and their combination may best predict outcomes [151]. Research criteria have begun to incorporate these biomarkers in the definition of AD with the goal of providing a biologically based diagnosis rather than a purely clinical diagnosis [152]. These criteria define AD based on the presence of Aβ and tau biomarkers and are irrespective of the patient's clinical impairments. Markers of neurodegeneration also provide information about disease staging, and, taken together, this has been referred to as the amyloid, tau, and neurodegeneration (ATN) framework.

Plasma biomarkers show promise but do not currently have an established role in clinical practice; more studies are needed [153-156]. Decreased APOE and APOE ε4 plasma levels as well as a variety of other plasma/serum and CSF proteins have been assessed for predictive value for AD in persons without dementia and in patients with MCI [157-160]. Ongoing research is investigating the role of such biomarkers that may help distinguish AD from other forms of dementia [161,162]. In particular, measures of plasma phospho-tau181 and phospho-tau217 have demonstrated strong correlation with CSF phospho-tau measures and association with amyloid and tau PET imaging [161-163]. Similarly, a plasma measure of β42/β40 using an immunoprecipitation and liquid chromatography-mass spectrometry assay has shown promise in detection of amyloid [164] and can be commercially ordered, although it is not currently covered by insurance payers in the United States.

Studies of these and other emerging plasma/serum and CSF biomarkers for AD in the assessment of prognosis are discussed in more detail separately. (See "Mild cognitive impairment: Prognosis and treatment", section on 'CSF biomarkers' and "Mild cognitive impairment: Prognosis and treatment", section on 'Plasma biomarkers'.)

Other laboratory testing — Routine laboratory tests are not useful in the positive diagnosis of AD; however, some laboratory tests are indicated to exclude contributing secondary causes or conditions that may exacerbate cognitive impairment. (See "Evaluation of cognitive impairment and dementia", section on 'Laboratory testing'.)

Genetic testing — Genetic testing is not recommended in the routine evaluation of patients with AD. APOE genotyping adds marginally to the predictive value of clinical criteria for AD and may stratify risk of progression of amnesic MCI to AD, but both false positives and negatives occur [165,166].

Genetic testing for APP, PSEN1, and PSEN2 mutations is commercially available but should be reserved for cases in which young-onset dementia occurs in the setting of a family history positive for an autosomal-dominant distribution of early-onset cases. This should not be performed in asymptomatic family members or patients without appropriate professional genetic counseling, since there would be implications for family members as well as the patient. (See "Genetics of Alzheimer disease", section on 'Genetic testing'.)

DIAGNOSIS — A detailed clinical assessment provides reasonable diagnostic accuracy for AD in the majority of patients, although sensitivity and specificity in particular are limited [12]. That said, misdiagnosis is almost always another neurodegenerative or nonreversible cause. The clinical criteria for AD include a history of insidious onset and progressive course of cognitive decline, exclusion of other etiologies, and documentation of cognitive impairments in one or more domains.

Definitive diagnosis of AD requires histopathologic examination, which is rarely done in life [167-169]. The diagnosis of AD in practice depends on the clinical criteria outlined below.

Alzheimer disease dementia — Criteria for the diagnosis of probable AD dementia have been established by the National Institute on Aging and the Alzheimer's Association (NIA-AA) and most recently updated in 2011 [12,41].

●NIA-AA criteria for probable AD dementia require the presence of dementia and the following characteristics:

•Interference with ability to function at work or at usual activities

•A decline from a previous level of functioning and performing

•Not explained by delirium or major psychiatric disorder

•Cognitive impairment established by history-taking from the patient and a knowledgeable informant; and objective bedside mental status examination or neuropsychologic testing

•Cognitive impairment involving a minimum of two of the following domains:

-Impaired ability to acquire and remember new information

-Impaired reasoning and handing of complex tasks, poor judgment

-Impaired visuospatial abilities

-Impaired language functions

-Changes in personality, behavior, or comportment

•Other core clinical criteria include:

-Insidious onset

-Clear-cut history of worsening

-Initial and most prominent cognitive deficits are one of the following: amnestic presentation (ie, impairment in learning and recall of recently learned information) or nonamnestic presentations (including either a language presentation, with prominent word-finding deficits; a visuospatial presentation, with visual cognitive deficits; or a dysexecutive presentation, with prominent impairment of reasoning, judgment, and/or problem solving)

•No evidence of substantial concomitant cerebrovascular disease, core features of dementia with Lewy bodies (DLB), prominent features of behavioral variant frontotemporal dementia (FTD) or prominent features of semantic or nonfluent/agrammatic variants of primary progressive aphasia (PPA), or evidence of another concurrent, active neurologic or non-neurologic disease or use of medication that could have a substantial effect on cognition

●NIA-AA criteria for possible AD dementia include either of the following clinical scenarios [12]:

•Atypical course – The core clinical criteria above are met in terms of the nature of the cognitive deficits, but there is either a sudden onset of cognitive impairment or insufficient historical detail or objective documentation of progressive decline.

•Etiologically mixed presentation – All of the core clinical criteria for AD dementia are met, but the individual also has evidence of concomitant cerebrovascular disease, features of DLB other than the dementia itself, or evidence for another neurologic or medical comorbidity or medication that could have a substantial effect on cognition.

●The Diagnostic and Statistical Manual of Mental Disorders (DSM) criteria for AD are also commonly used. Criteria for AD were revised in 2013 (table 3) [170]. The DSM-5 definition of probable AD (now called major neurocognitive disorder due to AD) differs from prior versions in that the cognitive domains have been renamed and expanded to include learning and memory, language, executive function, complex attention, perceptual-motor, and social cognition. Previously, the criteria recognized five domains (memory, aphasia, apraxia, agnosia, and executive function). Like prior versions, the criteria continue to require both memory impairment and evidence of decline in at least one other cognitive domain. New to the criteria is the recognition of genetic testing results, if known, as supportive of a diagnosis of probable AD.

While less substantially validated compared with the NIA-AA criteria, the DSM-IV criteria appeared to have similar accuracy [99,171]. The performance characteristics of the DSM-5 criteria compared with the DSM-IV and NIA-AA criteria are not yet known.

MCI due to Alzheimer disease — Amnestic mild cognitive impairment (MCI) refers to a state of circumscribed anterograde long-term memory impairment with preserved general cognitive and social functioning [172]. Amnestic MCI frequently represents an early stage of AD, with a progression rate to dementia at approximately 10 to 15 percent per year [172,173]. Nonamnestic MCI, in which cognitive domains outside of memory are affected, is less frequently associated with prodromal AD but may be in a significant minority of patients. (See "Mild cognitive impairment: Epidemiology, pathology, and clinical assessment", section on 'Amnestic MCI' and "Mild cognitive impairment: Prognosis and treatment", section on 'Progression to dementia'.)

Formal clinical diagnostic criteria for MCI due to AD have been developed by a panel convened by the NIA-AA [174]. These include:

●A concern regarding cognition reported by the patient or informant or observed by the clinician

●Objective evidence of impairment in one or more cognitive domains that is not explained by age or education

●Preservation of independence in functional abilities

●Impairments do not meet criteria for dementia

MCI may occur as a prodrome to several neurodegenerative dementias, as well as non-neurodegenerative conditions (eg, depression, medicine effects). Therefore, the specific designation of MCI due to AD is used when a biomarker associated with AD (eg, cerebrospinal fluid [CSF] testing of beta-amyloid [Aβ], tau, and phospho-tau; amyloid imaging; or functional scan consistent with AD) is present in the affected subject (table 2). Using the NIA-AA criteria on a cohort of research subjects with MCI, individuals with cognitive impairment and both amyloid and neuronal injury biomarkers had an approximately 60 percent progression rate to AD dementia over three years [175]. By contrast, individuals with amnestic MCI and both negative amyloid and neuronal injury markers have a low progression rate: 12 percent over three years in one study [176].

The International Working Group (IWG) recognizes a similar clinical presentation that, when accompanied by biomarker evidence of AD, is referred to as prodromal AD [150,177]. The designation of prodromal AD has been associated with similar progression rates compared with the NIA-AA criteria [175].

Preclinical Alzheimer disease — Preclinical AD refers to the stage of AD in which the molecular pathology of AD is already present in the brain but is not yet clinically expressed. Individuals are by definition asymptomatic and cognitively normal. Preclinical AD is defined by biomarker measures and is only recommended for use in research, in the context of clinical trials for early intervention strategies and the longitudinal study of people at risk. According to the IWG, preclinical AD encompasses two groups [178]:

●Asymptomatic at risk for AD refers to cognitively normal individuals with evidence of AD molecular pathology by laboratory or imaging biomarkers. It is not currently known whether progression to symptomatic AD is inevitable in such individuals. Autopsy data revealing that people may die with normal cognition and pathologic changes of AD sufficient to make a diagnosis suggest that symptomatic AD will not occur in every subject with amyloid in the brain.

●Presymptomatic AD also refers to cognitively normal and asymptomatic carriers of a dominantly inherited gene mutation that causes AD. Symptoms of AD will almost certainly develop in these individuals over a normal lifespan. (See "Genetics of Alzheimer disease", section on 'Early-onset Alzheimer disease'.)

The NIA-AA framework proposes three stages of preclinical AD, recognizing that some individuals will not progress beyond stage 1 or stage 2, and that individuals in stage 3 are probably most likely to progress to MCI and AD dementia (figure 2) [179]. As described above, a subsequent NIA-AA research framework was published in 2018 that further explicates the continuum of AD, with the disease being defined by amyloid, tau, and neurodegeneration (ATN) biomarkers in the context of the clinical stages from preclinical to MCI to dementia stages [152]. These are research criteria that have not yet been validated through longitudinal studies, and they are not currently recommended for use outside a research setting.

DIFFERENTIAL DIAGNOSIS — The most common disorders considered in the differential diagnosis of AD are vascular dementia and other neurodegenerative dementias. The two most common neurodegenerative dementias after AD are dementia with Lewy bodies (DLB) and frontotemporal dementia (FTD).

●Vascular dementia is caused by either ischemic or hemorrhagic strokes or small vessel cerebrovascular disease. Diagnosis is most specific if there is a stroke-like course of illness, neurologic signs of stroke on examination, and imaging evidence of cerebrovascular disease. However, the course of illness may appear smoothly progressive, and there may be no elementary neurologic signs. Cerebrovascular disease commonly co-occurs with AD. With increasing age, it is more common than not to find both AD and cerebrovascular disease in the brain of a patient with dementia. (See "Etiology, clinical manifestations, and diagnosis of vascular dementia".)

●DLB may be the second most common type of degenerative dementia after AD. Clinical features that help distinguish this from AD include prominent early appearance of visual hallucinations, along with parkinsonism, cognitive fluctuations, dysautonomia, rapid eye movement (REM) sleep behavior disorder, and neuroleptic sensitivity. (See "Clinical features and diagnosis of dementia with Lewy bodies".)

●FTD is a neuropathologically and clinically heterogeneous disorder characterized by focal degeneration of the frontal and/or temporal lobes. Early alteration of personality, social and emotional behavior, and executive functioning are prominent clinical characteristics of behavioral variant FTD. Primary progressive aphasia (PPA) is a form of FTD in which gradually progressive language impairment is the core feature early in the course. There are three major subtypes, with the semantic and nonfluent variants being associated usually with frontotemporal lobar degeneration (FTLD) pathologies (usually tau or TDP-43). PPA, particularly the logopenic variant, can also be a presentation of AD. (See "Frontotemporal dementia: Clinical features and diagnosis" and 'Atypical presentations' above.)

SOCIETY GUIDELINE LINKS — Links to society and government-sponsored guidelines from selected countries and regions around the world are provided separately. (See "Society guideline links: Cognitive impairment and dementia".)

INFORMATION FOR PATIENTS — UpToDate offers two types of patient education materials, "The Basics" and "Beyond the Basics." The Basics patient education pieces are written in plain language, at the 5th to 6th grade reading level, and they answer the four or five key questions a patient might have about a given condition. These articles are best for patients who want a general overview and who prefer short, easy-to-read materials. Beyond the Basics patient education pieces are longer, more sophisticated, and more detailed. These articles are written at the 10th to 12th grade reading level and are best for patients who want in-depth information and are comfortable with some medical jargon.

Here are the patient education articles that are relevant to this topic. We encourage you to print or e-mail these topics to your patients. (You can also locate patient education articles on a variety of subjects by searching on "patient info" and the keyword(s) of interest.)

●Basics topics (see "Patient education: Dementia (including Alzheimer disease) (The Basics)" and "Patient education: Caring for someone with Alzheimer disease or dementia (The Basics)" and "Patient education: Evaluating memory and thinking problems (The Basics)")

●Beyond the Basics topics (see "Patient education: Dementia (including Alzheimer disease) (Beyond the Basics)")

SUMMARY AND RECOMMENDATIONS

●Age at onset – Alzheimer disease (AD) is usually a disease of older age. The incidence increases exponentially with age over 65 years.

Early-onset (onset of symptoms in a person younger than 65) AD is unusual, and in some but not all cases is familial. Familial early-onset AD makes up less than 1 percent of cases (several hundred families around the world) and often follows an autosomal-dominant pattern of inheritance. (See 'Age of onset' above.)

●Clinical features

•Cognitive deficits – These appear and progress insidiously. Memory impairment, specifically loss of memory of recent events, is the most frequent feature of AD and is usually its first manifestation. Other cognitive deficits appear with or after the development of memory impairment. Executive dysfunction and impaired visuospatial skills tend to be affected early, while deficits in language function and behavioral symptoms often manifest later. (See 'Clinical features' above.)

•Neuropsychiatric and behavioral symptoms – These are common in middle and late stages of AD but may occur early in the course in some patients. (See 'Behavioral and psychologic symptoms' above and "Management of neuropsychiatric symptoms of dementia".)

•Noncognitive neurologic deficits – Pyramidal and extrapyramidal motor signs, myoclonus, and seizures can occur in late stages of AD but are uncommon in early and middle stages. (See 'Other signs and symptoms' above.)

•Atypical presentations – These include a visual variant (posterior cortical atrophy), a variant with progressive aphasia, and a variant with progressive executive dysfunction as the predominant symptom. Atypical presentations are more common in younger people with AD. (See 'Atypical presentations' above.)

●Clinical course – AD is inexorably progressive, but the rate of progression can vary. The average life expectancy after diagnosis has been reported to be between 8 and 10 years but may range from 3 to 20 years. (See 'Clinical course' above.)

●Diagnosis – AD should be suspected in any older adult with insidious onset, progressive decline in memory, and at least one other cognitive domain leading to impaired functioning. The diagnosis of AD is made in large part by this clinical assessment. (See 'Clinical assessment' above.)

Neuropsychologic testing may provide confirmatory information and aid in patient management. A neuroimaging study should be obtained on every patient suspected of having AD. (See 'Role of neuropsychologic testing' above and 'Neuroimaging' above.)

In selected cases (eg, those with young age of onset or atypical presentations), other imaging or biomarker tests including 18-F fluorodeoxyglucose positron emission tomography (FDG-PET), cerebrospinal fluid (CSF) testing, or amyloid/tau PET may be helpful, although access and reimbursement for these tests may present challenges. If use of aducanumab is being considered, confirmation of amyloid status is necessary with either amyloid PET or CSF testing. (See 'Neuroimaging' above and 'Role of biomarkers' above.)

ACKNOWLEDGMENT — The UpToDate editorial staff acknowledges Thomas Grabowski, Jr, MD, who contributed to an earlier version of this topic review.

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Topic 5071 Version 39.0

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76 : Distribution of pathology in frontal variant Alzheimer's disease.

77 : Clinical-neuropathological correlations in Alzheimer's disease and related dementias.

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79 : Cognitive impairment, decline and fluctuations in older community-dwelling subjects with Lewy bodies.

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92 : Survival after initial diagnosis of Alzheimer disease.

93 : A reevaluation of the duration of survival after the onset of dementia.

94 : Factors that influence survival in a probable Alzheimer disease cohort.

95 : The Montreal Cognitive Assessment, MoCA: a brief screening tool for mild cognitive impairment.

96 : Montreal Cognitive Assessment for the diagnosis of Alzheimer's disease and other dementias.

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104 : Age, Alzheimer disease, and brain structure.

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121 : 11C PiB and structural MRI provide complementary information in imaging of Alzheimer's disease and amnestic mild cognitive impairment.

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123 : Current and future uses of neuroimaging for cognitively impaired patients.

124 : Cognitively unimpaired HIV-positive subjects do not have increased 11C-PiB: a case-control study.

125 : Alzheimer disease identification using amyloid imaging and reserve variables: proof of concept.

126 : 18F-flutemetamol amyloid imaging in Alzheimer disease and mild cognitive impairment: a phase 2 trial.

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128 : Use of florbetapir-PET for imaging beta-amyloid pathology.

129 : Cerebral amyloid-βPET with florbetaben (18F) in patients with Alzheimer's disease and healthy controls: a multicentre phase 2 diagnostic study.

130 : Association between in vivo fluorine 18-labeled flutemetamol amyloid positron emission tomography imaging and in vivo cerebral cortical histopathology.

131 : Using positron emission tomography and florbetapir F18 to image cortical amyloid in patients with mild cognitive impairment or dementia due to Alzheimer disease.

132 : Amyloid imaging in Alzheimer's disease: comparison of florbetapir and Pittsburgh compound-B positron emission tomography.

133 : Cerebral PET with florbetapir compared with neuropathology at autopsy for detection of neuritic amyloid-βplaques: a prospective cohort study.

134 : Amyloid-βassessed by florbetapir F 18 PET and 18-month cognitive decline: a multicenter study.

135 : Stronger effect of amyloid load than APOE genotype on cognitive decline in healthy older adults.

136 : Pittsburgh compound B and the postmortem diagnosis of Alzheimer disease.

137 : Post-mortem correlates of in vivo PiB-PET amyloid imaging in a typical case of Alzheimer's disease.

138 : Prevalence of amyloid PET positivity in dementia syndromes: a meta-analysis.

139 : Prevalence of cerebral amyloid pathology in persons without dementia: a meta-analysis.

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143 : Brain amyloid imaging--FDA approval of florbetapir F18 injection.

144 : Appropriate use criteria for amyloid PET: a report of the Amyloid Imaging Task Force, the Society of Nuclear Medicine and Molecular Imaging, and the Alzheimer's Association.

145 : Aducanumab: Appropriate use recommendations.

146 : Association of In Vivo [18F]AV-1451 Tau PET Imaging Results With Cortical Atrophy and Symptoms in Typical and Atypical Alzheimer Disease.

147 : Untangling tau imaging.

148 : Positron Emission Tomography Imaging With [18F]flortaucipir and Postmortem Assessment of Alzheimer Disease Neuropathologic Changes.

149 : Sensitivity-Specificity of Tau and AmyloidβPositron Emission Tomography in Frontotemporal Lobar Degeneration.

150 : Revising the definition of Alzheimer's disease: a new lexicon.

151 : Use of Flutemetamol F 18-Labeled Positron Emission Tomography and Other Biomarkers to Assess Risk of Clinical Progression in Patients With Amnestic Mild Cognitive Impairment.

152 : NIA-AA Research Framework: Toward a biological definition of Alzheimer's disease.

153 : Cerebrospinal fluid biomarkers in Alzheimer disease: a fractional improvement?

154 : Fluctuations of CSF amyloid-beta levels: implications for a diagnostic and therapeutic biomarker.

155 : Longitudinal changes of CSF biomarkers in memory clinic patients.

156 : Biomarkers for cognitive impairment and dementia in elderly people.

157 : Clinical and biomarker changes in dominantly inherited Alzheimer's disease.

158 : Blood-based protein biomarkers for diagnosis of Alzheimer disease.

159 : Plasma levels of apolipoprotein E and risk of dementia in the general population.

160 : CSF and blood biomarkers for the diagnosis of Alzheimer's disease: a systematic review and meta-analysis.

161 : Blood phosphorylated tau 181 as a biomarker for Alzheimer's disease: a diagnostic performance and prediction modelling study using data from four prospective cohorts.

162 : Discriminative Accuracy of Plasma Phospho-tau217 for Alzheimer Disease vs Other Neurodegenerative Disorders.

163 : Longitudinal plasma p-tau217 is increased in early stages of Alzheimer's disease.

164 : High-precision plasmaβ-amyloid 42/40 predicts current and future brain amyloidosis.

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166 : Apolipoprotein E status as a predictor of the development of Alzheimer's disease in memory-impaired individuals.

167 : Neuropathological stageing of Alzheimer-related changes.

168 : Consensus recommendations for the postmortem diagnosis of Alzheimer's disease. The National Institute on Aging, and Reagan Institute Working Group on Diagnostic Criteria for the Neuropathological Assessment of Alzheimer's Disease.

169 : Diagnosis of Alzheimer's disease.

170 : Diagnosis of Alzheimer's disease.

171 : Validity of dementia diagnoses in the Danish hospital registers.

172 : Mild cognitive impairment: clinical characterization and outcome.

173 : Prediction of probable Alzheimer's disease in memory-impaired patients: A prospective longitudinal study.

174 : The diagnosis of mild cognitive impairment due to Alzheimer's disease: recommendations from the National Institute on Aging-Alzheimer's Association workgroups on diagnostic guidelines for Alzheimer's disease.

175 : Prevalence and prognosis of Alzheimer's disease at the mild cognitive impairment stage.

176 : Putting the New Alzheimer Disease Amyloid, Tau, Neurodegeneration (AT[N]) Diagnostic System to the Test.

177 : Advancing research diagnostic criteria for Alzheimer's disease: the IWG-2 criteria.

178 : Harmonized diagnostic criteria for Alzheimer's disease: recommendations.

179 : Toward defining the preclinical stages of Alzheimer's disease: recommendations from the National Institute on Aging-Alzheimer's Association workgroups on diagnostic guidelines for Alzheimer's disease.

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