Early-onset dementia in adults

INTRODUCTION — Diagnosis and treatment of progressive cognitive impairment in the younger adult requires a different approach than that of the older adult. In particular, the differential diagnosis is much broader and often requires a more extensive evaluation that includes consideration of both common and rare disorders. Nevertheless, the most common causes of early-onset dementia are the same in younger and older adults: Alzheimer disease (AD), vascular dementia, and frontotemporal dementia (FTD).

Early and rapid evaluation in this population is critical. The financial impact on the person and family can be devastating, as these are adults in their prime working years. Establishment of a clear diagnosis can help with distribution of government-based resources. The impact on spouses or partners, children, and other family members is significant.

The epidemiology, etiology, evaluation, and diagnosis of early-onset dementia will be reviewed here. A more general approach to adults with cognitive impairment or dementia and disease-specific diagnosis and management are presented elsewhere.

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

●(See "Management of the patient with dementia".)

DEFINITIONS

Dementia — Several definitions for dementia exist, but a commonly used framework is one provided by the Diagnostic and Statistical Manual of Mental Disorders (DSM). According to the DSM-5, dementia is defined as significant acquired cognitive impairment in one or more cognitive domains (eg, learning and memory, language, executive function, complex attention, perceptual-motor function, social cognition) that represents a significant decline from previous baseline and interferes with independence in daily activities (table 1) [1]. (See "Evaluation of cognitive impairment and dementia", section on 'Criteria for dementia'.)

While this definition recognizes multiple different cognitive domains, a decline in memory is one of the earliest and most prominent features of Alzheimer disease (AD) dementia and most other forms of dementia. A prominent exception is frontotemporal dementia (FTD), in which memory may be relatively preserved in relation to other cognitive domains such as language function or social cognition, at least initially. For most forms of dementia, however, memory and language dysfunction are generally always present.

Early-onset dementia — Although terminology varies, we consider early-onset dementia to refer to cases of dementia occurring in adults ranging from 18 to 65 years of age. Some authors further subdivide early-onset dementia, using young-onset dementia to refer to cases with an age of onset between 18 and 45 years. This distinction is somewhat arbitrary, however, and most of the causative diseases do not follow such strict age cutoffs. A common approach to differential diagnosis, including consideration of rare diseases, should be followed regardless of the age of the younger adult with new cognitive change.

EPIDEMIOLOGY — The prevalence of early-onset dementia is estimated at 40 to 119 per 100,000 individuals globally, although no broad-based studies have been performed [2-7]. Published studies have used different methodology, inclusion criteria, and age groups. Patients with traumatic brain injury, Down syndrome, and certain types of vascular disease are major patient groups that may or may not be included in these studies.

Several population-based studies illustrate the frequency and range of diagnoses most often responsible for early-onset dementia:

●An epidemiologic study in four London boroughs identified 185 patients with an onset of dementia between 30 to 64 years of age [2]. Approximately 55 percent were felt to have a single progressive neurodegenerative etiology, predominantly Alzheimer disease (AD), frontotemporal dementia (FTD), dementia with Lewy bodies (DLB), dementia related to Parkinson disease (PD), and corticobasal degeneration (including corticobasal syndrome and many other phenotypes) [2]. The remaining 45 percent of patients had the following etiologies: vascular-related cognitive change, alcohol-related cognitive change, Huntington disease (HD), cognitive impairment resulting from multiple sclerosis (MS), prion diseases, dementia related to Down syndrome (predominantly AD), and unknown/unclassified.

The four most common etiologies in the cohort were AD (34 percent), vascular dementia (18 percent), FTD (12 percent), and alcohol-related dementia (10 percent). Notably, the prevalence of dementia doubled every five years after age 35.

●Neurodegenerative disease accounted for approximately one-third of cases in a retrospective review of all 17- to 45-year-old patients given a diagnosis of dementia at a tertiary referral center over an 11-year period [3]. This was followed by autoimmune/inflammatory disease (21 percent), unknown causes (18 percent), and metabolic disease, including mitochondrial and storage diseases (11 percent).

Among the neurodegenerative diseases, FTD accounted for the largest proportion (42 percent) and represented 13 percent of the entire cohort. AD accounted for only 5 percent of those with neurodegenerative disease and 2 percent of the total cohort. This analysis specifically excluded patients with static encephalopathy from traumatic brain injury, acute cerebrovascular events, and patients with Down syndrome.

●Other studies in Japan, Sweden, and elsewhere have also found that AD, FTD, and vascular dementia are the most common dementia etiologies in this age range [4-6,8].

Risk factors for early-onset dementia may vary according to the underlying etiology of the dementia. Although genetic etiologies are more common in early-onset dementia compared with late-onset dementia, the majority of cases of both early-onset and late-onset dementia (excluding autosomal dominant AD, FTD, and HD) do not have an identifiable monogenetic cause.

There is a higher rate of vascular disease in patients with early-onset dementia of any type. Many of the risk factors for early-onset dementia identified in population-based studies relate to increased vascular risk, including stroke, transient ischemic attack, chronic kidney disease, cardiovascular disease, hypertension, chronic alcohol use, and drug intoxication [6,9,10].

CAUSES OF EARLY-ONSET DEMENTIA

Neurodegenerative dementias — Neurodegenerative etiologies are the most common cause of cognitive decline and dementia in adults age 35 and older [3]. Of the neurodegenerative diseases, Alzheimer disease (AD) is most common, particularly nearing the age of 65 years. Frontotemporal dementia (FTD) and vascular dementia are equal to or more prevalent than AD at the younger end of the spectrum [3,11].

●Alzheimer disease – AD in younger adults is most often sporadic; genetic mutations account for approximately 1 to 6 percent of all cases [12]. Family history of early-onset dementia increases the risk of finding a dominantly inherited genetic mutation (table 2) [13]. These include the following:

•Presenilin 1 (PSEN1) – Causative mutations in PSEN1 are the most common genetically confirmed cause of early-onset familial AD, accounting for over 50 percent of such cases. Mutations are fully penetrant, with a median age of onset of 43 years [14]. Inheritance of mutations in this gene may be associated with a higher prevalence of other neurologic signs that precede the development of cognitive deficits, particularly in patients with disease onset earlier than age 40 years [15]. Notable initial features in some but not all families include myoclonus, seizures, spasticity, and cerebellar ataxia [16,17]. (See "Genetics of Alzheimer disease", section on 'Presenilin 1'.)

•Presenilin 2 (PSEN2) – Mutations in the PSEN2 gene found on chromosome 1q are a much rarer cause of familial early-onset AD. Mutations are estimated to be 95 percent penetrant, and the median age of onset is later and more variable than with other mutations (figure 1). PSEN2 has greater than 60 percent homology with PSEN1. (See "Genetics of Alzheimer disease", section on 'Presenilin 2'.)

•Amyloid precursor protein (APP) – APP mutations account for up to 15 percent of genetically confirmed cases of early-onset familial AD. Causative mutations in APP are fully penetrant. AD in people with Down syndrome, which frequently emerges in the fifth decade, is due to replication of the APP gene on chromosome 21 and thus a 1.5 gene dose. (See "Genetics of Alzheimer disease", section on 'Amyloid precursor protein' and "Genetics of Alzheimer disease", section on 'Trisomy 21'.)

The cognitive features of AD in patients with autosomal dominant forms of the disease are largely similar to those of sporadic AD [15,17,18]. Amnestic symptoms are present in nearly all patients at presentation; the most common nonamnestic manifestations include behavioral changes, aphasia, and visual agnosia. (See "Clinical features and diagnosis of Alzheimer disease", section on 'Cardinal symptoms'.)

Sporadic early-onset AD has several clinical features that are distinct from late-onset AD. Early-onset AD tends to have a more aggressive course than late-onset AD [19]. Imaging often shows global cortical atrophy and less frequent hippocampal atrophy (unlike the hippocampal atrophy characteristic of late-onset AD). Nonamnestic presentations (eg, posterior cortical atrophy syndrome, logopenic primary progressive aphasia, behavioral/dysexecutive variant) are more common in younger patients. (See "Clinical features and diagnosis of Alzheimer disease", section on 'Atypical presentations'.)

Certain genetic polymorphisms have been associated with increased risk of developing AD, most notably and powerfully the apolipoprotein E epsilon 4 (APOE ε4) allele. Particularly when inheritance is homozygous, APOE ε4 both increases the risk of AD and lowers the age of onset for disease compared with those without the ε4 allele [20]. Homozygous inheritance of this gene is often associated with onset of cognitive changes prior to age 65 years [21]. Other known mutations associated with other forms of neurodegenerative dementia have also been identified in patients diagnosed with early-onset dementia including mutations in tau and others associated with Parkinson disease (PD) [22]. (See "Genetics of Alzheimer disease", section on 'Apolipoprotein E'.)

●Frontotemporal dementia – FTD is a clinically and pathologically heterogeneous disease characterized by focal degeneration of the frontal and/or temporal lobes. The clinical syndromes of FTD include behavioral variant FTD, involving progressive change in personality and behavior, and primary progressive aphasias, which involve progressive deterioration in one or more aspects of language. (See "Frontotemporal dementia: Clinical features and diagnosis".)

Although once felt to predominate in the early-onset dementia populations, FTD is now thought to have a prevalence that increases with age; however, approximately one-third of all cases of FTD are early onset. The prevalence ranges up to 20 per 100,000 individuals in the early-onset population [23].

Causative mutations have been identified in up to 40 percent of all cases. Identified genetic mutations include C9orf72 (the most common cause of familial FTD), microtubule-associated protein tau (MAPT), progranulin (GRN), and others. (See "Frontotemporal dementia: Epidemiology, pathology, and pathogenesis".)

●Neurodegenerative disease associated with tau – Neurodegenerative diseases associated with abnormal accumulation of tau include clinical phenotypes ranging from certain variants of FTD to corticobasal syndrome and progressive supranuclear palsy [24]. Many of these diseases begin with cognitive and behavioral changes, which can frequently occur before the age of 65 years, accompanied by additional motor system signs and symptoms. Many of these entities have significant overlap in both pathology and clinical phenotype. (See "Corticobasal degeneration" and "Progressive supranuclear palsy (PSP): Clinical features and diagnosis".)

●Dementia with Lewy bodies (DLB) – DLB is a less common cause of early-onset dementia. The mean age at onset of DLB is 75 years, although early-onset cases are increasingly recognized. Most cases of DLB are sporadic. In addition to cognitive dysfunction, core clinical features of DLB include cognitive fluctuations, visual hallucinations, and parkinsonism. Rapid eye movement (REM) sleep behavior disorder is another common, often early, sign of DLB. Recognized genetic associations in one or more studies include alpha-synuclein gene duplication or triplication, glucocerebrosidase gene mutations, gamma-synuclein gene mutations, and potentially presenilin mutations. (See "Clinical features and diagnosis of dementia with Lewy bodies" and "Epidemiology, pathology, and pathogenesis of dementia with Lewy bodies".)

●Parkinson disease dementia – PD is a rare cause of early-onset dementia. The risk for dementia with PD is higher with longer duration of the disease, older age, and older age at onset of disease [25]. Certain forms of PD with identified genetic mutations (such as the glucocerebrosidase gene) tend to have an early onset of disease and can present with early cognitive dysfunction [26]. (See "Cognitive impairment and dementia in Parkinson disease".)

Vascular diseases

●Vascular dementia – Rates and definitions of vascular dementia as a cause of early-onset dementia vary widely. In addition, there may be geographical variance based on regional dietary and cultural preferences.

Individuals with poorly controlled vascular risk factors from an early age and strokes at a young age are at high risk for early-onset vascular dementia. Common contributing factors in younger patients include multiple cerebral infarctions, multiple subcortical infarctions (frequently lacunar infarctions), hemorrhagic infarctions, and chronic widespread small vessel ischemic disease. Compared with older adults, younger adults with vascular dementia are more likely to have lacunar infarctions and prominent frontal-executive dysfunction [27]. (See "Etiology, clinical manifestations, and diagnosis of vascular dementia".)

●Cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL) – CADASIL is an autosomal dominant, inherited angiopathy caused by mutations in the NOTCH3 gene on chromosome 19. The major clinical manifestations of CADASIL are transient ischemic attack and ischemic stroke, cognitive deficits with early executive dysfunction, migraine with aura, and neuropsychiatric disturbances. A family history of multiple strokes and dementia is often present. Increasing subcortical infarct burden tends to lead to early-onset dementia beginning around age 50 to 60 years [28]. A similar phenotype has also been described in association with mutations in cathepsin-A (CTSA), termed cathepsin A-related arteriopathy with strokes and leukoencephalopathy (CARASAL) [29]. (See "Cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL)".)

●Cerebral amyloid angiopathy (CAA) – CAA is a rare cause of early-onset dementia. Although infarcts may occur in patients aged 50 to 60 years, cognitive impairment typically occurs later, when there is greater accumulation of vascular hemorrhage and infarcts. APOE ε4 carriers are at high risk for development of CAA, with homozygotes at higher risk for early presentation. (See "Cerebral amyloid angiopathy".)

●Primary angiitis of the central nervous system – Primary angiitis of the central nervous system is a rare entity caused by an immune-mediated attack on small and medium blood vessels in the brain parenchyma, spinal cord, and leptomeninges. Cognitive dysfunction occurs in the majority of patients; other common features include headaches, seizure, stroke, and cerebral hemorrhage. The estimated annual incidence rate is 2.4 cases per 1,000,000 person-years [30]. (See "Primary angiitis of the central nervous system in adults".)

●Secondary central nervous system vasculitis – Secondary central nervous system vasculitis may be caused by a variety of vasculitides associated with systemic autoimmune diseases or as a result of infection. The forms of vasculitis most likely to involve the central nervous system are Behçet syndrome, polyarteritis nodosa, vasculitides associated with antineutrophil cytoplasmic antibodies, and cryoglobulinemic vasculitis. (See "Primary angiitis of the central nervous system in adults", section on 'Alternative diagnoses'.)

Varicella zoster virus is an increasingly recognized cause of vasculitis with or without dermatologic manifestations that can affect people at any age [31]. (See "Varicella zoster virus vasculopathy".)

●Reversible cerebral vasoconstriction syndrome – In rare patients, reversible cerebral vasoconstriction syndrome (RCVS) can lead to irreversible edema, strokes, and other events that result in early-onset vascular dementia. (See "Reversible cerebral vasoconstriction syndrome", section on 'Clinical course and prognosis'.)

Infectious diseases

●Prion disease – Prion disease can be acquired, sporadic, or genetic. Creutzfeldt-Jakob disease (CJD) is the most frequent sporadic prion disease, affecting approximately 1 in 1,000,000 people annually. Cognitive dysfunction in sporadic prion disease is prominent and often rapidly progressive. Myoclonus affects more than 90 percent of patients but may not be present in the early stages. The average age of onset of sporadic CJD is 60 years, but the illness often occurs in younger patients [32,33]. (See "Creutzfeldt-Jakob disease".)

Variant CJD, acquired through oral consumption of brain and spinal cord or affected meat products from infected cattle (cross-species transmission), often affects people of younger age, with a median age of onset of 26 years [34]. Variant CJD is associated with a variety of nonspecific psychiatric symptoms (depression, anxiety, delusions), and diagnosis may be delayed.

Familial prion diseases (including familial CJD, Gerstmann-Straussler-Scheinker syndrome, and fatal familial insomnia) are also a cause of early-onset dementia. (See "Variant Creutzfeldt-Jakob disease" and "Diseases of the central nervous system caused by prions".)

●HIV-associated neurocognitive disorder (HAND) – Many patients infected with human immunodeficiency virus (HIV) eventually develop some form of HAND. In a cohort of 1555 HIV-infected individuals with a mean age of 43 years, 52 percent had some degree of neuropsychological impairment, and 2 percent had frank HIV dementia [35]. Antiretroviral treatment can potentially delay the onset of HIV-associated dementia, but milder cognitive impairment continues to develop in HIV-infected individuals despite active treatment.

Risk factors for the development of HIV dementia include older age, significant immunosuppression prior to initiation of combination antiretroviral therapy, comorbid infections (eg, hepatitis B or C), and substance abuse [36]. (See "HIV-associated neurocognitive disorders: Epidemiology, clinical manifestations, and diagnosis".)

●Other infectious causes – Other infectious causes of early-onset dementia include herpes encephalitis, neurosyphilis (particularly with HIV coinfection), Whipple's disease, and progressive multifocal leukoencephalopathy (PML). (See "Herpes simplex virus type 1 encephalitis" and "Neurosyphilis" and "Whipple's disease" and "Progressive multifocal leukoencephalopathy (PML): Epidemiology, clinical manifestations, and diagnosis".)

Inflammatory and autoimmune diseases

●Multiple sclerosis (MS) – Cognitive dysfunction on neuropsychological testing can be detected in 45 to 65 percent of patients with MS [37], although frank dementia is uncommon and usually encountered only in severely affected patients [38]. Cortical lesion burden and brain atrophy, rather than the T2 hyperintense white matter lesion volume, correlate most strongly with degree of cognitive impairment [39]. The most common cognitive domains affected include memory, attention, and speed of information processing. As patients with MS survive to more advanced ages, clinical dementia in the fifth and sixth decades of life is occurring with greater frequency [40]. (See "Manifestations of multiple sclerosis in adults", section on 'Cognitive impairment'.)

●Paraneoplastic and autoimmune limbic encephalitis – Paraneoplastic limbic encephalitis is characterized by acute or subacute mood and behavioral changes, short-term memory problems, complex-partial seizures (including faciobrachial dystonic seizures in patients with anti-leucine-rich glioma inactivated 1 [LGI1] antibodies [41]), and cognitive dysfunction [42,43]. By definition, the condition is associated with an underlying neoplasm that may be occult, although there are an increasing number of antibody-mediated syndromes recognized in individuals both with and without an identifiable cancer. The most common cause of paraneoplastic limbic encephalitis is small cell lung carcinoma (table 3). Response to treatment of the cancer can be dramatic but is highly variable, and overall prognosis is generally poor [44]. Limbic encephalitis can also present without an associated cancer thought referable to autoimmune reaction. It is treated with immune suppression. (See "Autoimmune (including paraneoplastic) encephalitis: Clinical features and diagnosis".)

●Other nonparaneoplastic autoimmune encephalopathies – Autoimmune dementia is a term that has been used to describe a steroid-responsive autoimmune disorder characterized by a rapidly progressive dementia with a fluctuating course. This condition, unlike paraneoplastic encephalopathy, is more common in females. In a large cohort, the median age was 58 years [45]. The condition has been referred to by many names (including Hashimoto encephalopathy), but in the end represents a steroid-responsive autoimmune disorder causing a dementing disorder.

●Encephalopathy associated with systemic autoimmune disease – Progressive cognitive impairment has been described in association with systemic lupus erythematosus, Sjögren's disease, and Behçet syndrome. These conditions typically produce a nonvasculitic encephalitis. (See "Neurologic and neuropsychiatric manifestations of systemic lupus erythematosus", section on 'Cognitive impairment' and "Clinical manifestations of Sjögren’s disease: Extraglandular disease" and "Clinical manifestations and diagnosis of Behçet syndrome".)

Neurometabolic disorders

●Mitochondrial disease – Mitochondrial disease can manifest in younger adults and may be more prevalent than previously thought [46]. Many patients do not fit exactly into the well-described phenotypes of mitochondrial dysfunction and therefore go undiagnosed [47]. Neurologic symptoms are common in mitochondrial disease and can include stroke-like symptoms and encephalopathy consistent with a clinical picture of early-onset dementia. One should always have a high degree of suspicion for mitochondrial disease when a young adult has multiorgan system involvement and cognitive dysfunction. Adult forms of mitochondrial disease include mitochondrial encephalomyopathy with lactic acidosis and stroke-like episodes (MELAS), myoclonic epilepsy with ragged red fibers (MERRF), chronic progressive external ophthalmoplegia (CPEO), Kearns-Sayre syndrome, and many others. (See "Mitochondrial myopathies: Clinical features and diagnosis".)

●Leukodystrophies – Leukodystrophies are inherited metabolic disorders characterized by progressive white matter degeneration or hypomyelination. Although many of the leukodystrophies have profound effects starting in infancy or childhood, the phenotypic spectrum is variable and includes progressive cognitive dysfunction in early adulthood for some [48,49]. Examples include adult-onset metachromatic leukodystrophy, vanishing white matter disease, and X-linked adrenoleukodystrophy. A high index of suspicion, radiographic features (algorithm 1), and genetic testing are key components in the evaluation of leukodystrophies that should obviate brain biopsy in the majority of cases. (See "Metachromatic leukodystrophy" and "Vanishing white matter disease" and "Clinical features, evaluation, and diagnosis of X-linked adrenoleukodystrophy".)

In addition to these disorders, an increasing number of monogenetic leukodystrophies are being identified that almost exclusively present in adulthood; examples include [49]:

•Hereditary diffuse leukoencephalopathy with axonal spheroids, caused by mutations in the colony-stimulating factor 1 receptor (CSF1R) gene [50,51]

•Adult-onset autosomal dominant leukodystrophy due to LMNB1 duplication [52]

•Adult polyglucosan body disease due to mutations in GBE1 [53,54]

•Adult-onset leukodystrophy and ovarian failure in females due to mutations in AARS2 [55]

●Adult neuronal ceroid lipofuscinosis (ANCL) – ANCL is a rare inherited neurodegenerative disease characterized by abnormal liposomal accumulation of lipofuscins in neurons. An adult form of NCL (Kufs disease) presents with dementia and motor system dysfunction with an average age of onset of 30 years [56].

Others

●Chronic traumatic encephalopathy (CTE) – There is accumulating evidence that repeated mild traumatic brain injuries can contribute to a condition termed "chronic traumatic encephalopathy" (CTE). Neuropathology is consistent with a tauopathy, with an anatomic distribution involving superficial cortical layers that is distinct from that seen in AD. CTE has been described in professional sport settings, combat-related injuries, and after motor vehicle accidents. It likely also encompasses what has been referred to as "dementia pugilistica," a late-emerging dementia in boxers. Symptoms typically include progressive cognitive impairment and neuropsychological symptoms (behavior, personality changes, depression, and suicidality); parkinsonism and other speech and gait abnormalities have also been described. (See "Sequelae of mild traumatic brain injury", section on 'Chronic traumatic encephalopathy'.)

●Complications of alcohol abuse – Chronic alcohol use can lead to neurologic dysfunction. This can take several forms, including Korsakoff syndrome, Marchiafava-Bignami disease, and cognitive dysfunction with ventricular enlargement. A common presentation involves dementia and ataxia. (See "Overview of the chronic neurologic complications of alcohol".)

●Normal pressure hydrocephalus (NPH) – NPH is characterized by the clinical triad of dementia, gait disturbance, and urinary incontinence. By definition, there is hydrocephalus with a normal opening pressure during lumbar puncture. Although idiopathic NPH is most common in older adults (>60 years of age), secondary NPH due to a variety of causes (eg, subarachnoid hemorrhage, post-meningitis) can occur at any age. NPH as a cause of dementia is important to recognize, since some symptoms can be reversed with ventricular shunting. (See "Normal pressure hydrocephalus".)

●Frontotemporal brain sagging syndrome (FBSS) – In rare patients, intracranial hypotension can lead to an FTD-like syndrome. In one case series, the median age of onset was 53 years. This acquired condition can occur spontaneously or it can result from a posttraumatic persistent spinal fluid leak. Magnetic resonance imaging (MRI) is often able to make the diagnosis, and treatment is focused on repairing the leak, which can lead to resolution of symptoms in some cases. (See "Spontaneous intracranial hypotension: Pathophysiology, clinical features, and diagnosis", section on 'Associated symptoms'.)

●Wilson disease – Wilson disease, also known as hepatolenticular degeneration, is a neuropsychiatric disorder that usually manifests in young adults, in the late teens and early twenties. The initial neurologic manifestations of Wilson disease are broad and range in severity from subtle to rapidly progressive and severely debilitating. The majority of patients have dysarthria, ataxia, dystonia, or tremor; nearly all patients with neurologic manifestations have Kayser-Fleischer rings. Cognitive impairment may take the form of a frontal syndrome, with impulsivity, impaired judgment, and emotional lability, or a "subcortical dementia," with slowed thinking, memory loss, and executive dysfunction. (See "Wilson disease: Clinical manifestations, diagnosis, and natural history".)

●Huntington disease (HD) – HD is an autosomal dominant, inherited neurodegenerative disease caused by a trinucleotide (cytosine-adenine-guanine [CAG]) repeat expansion in the huntingtin gene that leads to abnormal choreiform movements, personality changes, and early-onset dementia. The dominant cognitive features of HD are executive dysfunction, lack of insight, and slowed processing. Symptoms begin insidiously with movement abnormalities and/or psychiatric and cognitive features. Age of onset and rate of disease progression are inversely related to the number of CAG repeats. (See "Huntington disease: Clinical features and diagnosis".)

DIFFERENTIAL DIAGNOSIS — Dementia should be distinguished from symptoms of memory loss or personality and behavioral change that are nonprogressive or provoked by underlying systemic illness, medication, psychiatric disorder, or structural brain pathology.

●Many younger adults complain of memory loss that can be attributed to psychosocial stressors, multitasking, and a distracted thought process. In some cases, there is comorbid depression or anxiety that may be exacerbating the symptoms. Memory complaints in such cases are usually disproportionate to performance on objective testing. These individuals can generally be distinguished from those with dementia by history, examination, cognitive testing, and serial follow-up.

●Psychiatric illnesses, in particular depression, can manifest with cognitive impairment that is sometimes more prominent than mood symptoms. In a longitudinal study of 226 adults <65 years of age referred to a tertiary care clinic for evaluation of suspected dementia and followed for a median of five years, psychiatric disease accounted for 25 percent of primary diagnoses [57]. For most depressed patients (especially younger and middle-aged adults), cognitive dysfunction is readily distinguished from that caused by dementia. Neurocognitive dysfunction in depression is generally mild and marked by a greater number of subjective complaints rather than objective findings. In older adult patients, memory problems may be mistaken for dementia ("pseudodementia"); these problems often abate with successful treatment.

The early stages of certain neurodegenerative diseases, in particular the behavioral variant of frontotemporal dementia (FTD), can be dominated by personality and behavioral changes suggestive of primary psychiatric disease (eg, depression, obsessive compulsive disorder, bipolar disorder). In some cases, treatment trials, formal psychiatric evaluation, neuroimaging, and clinical follow-up are required to distinguish these disorders from each other.

●Delirium is associated with fluctuating, altered level of consciousness and cognitive change. Delirium may be agitated or "quiet," and the latter form is more likely to be confused with dementia (table 4). Most cases are provoked by a medical stressor such as infection, surgery, or medication. Infections should be adequately treated. Medications known to induce delirium should be stopped if possible. Outpatient follow-up may be necessary once the index illness has been adequately treated to determine whether cognitive function has returned to normal; interview of caregivers and other informants about premorbid function is also critical. (See "Diagnosis of delirium and confusional states".)

●Structural brain pathology (eg, tumor, vascular malformation, subacute stroke) can mimic dementia but is easily ruled out by structural neuroimaging. Primary brain tumors, although rare, can present with subacute, progressive cognitive decline that is not always accompanied by other focal neurologic signs and symptoms or headache, depending upon the location and growth rate of the tumor.

●Obstructive sleep apnea (OSA) can manifest with cognitive impairment, often accompanied by complaints of daytime sleepiness, snoring, or morning headaches. Risk factors for OSA (eg, obesity, male sex, large neck circumference, and oropharyngeal crowding) should prompt consideration of a sleep study. Other comorbidities that are often associated with OSA include refractory hypertension, chronic lung disease, and stroke. In the longitudinal study discussed above that included 226 adults <65 years of age referred to a tertiary care center for suspected dementia, OSA was the most common non-neurologic or -psychiatric alternative diagnosis [57]. (See "Clinical presentation and diagnosis of obstructive sleep apnea in adults".)

INITIAL EVALUATION — The clinical assessment of a patient with suspected early-onset dementia is similar to that of an older adult but often needs to be extended to detect a broader range of diseases than the common neurodegenerative dementias. Although Alzheimer disease (AD) is the most common etiology of dementia in adults presenting both under and over the age of 65 years, the younger population with dementia is enriched with a wider range of rare and genetic disorders that may have implications for both family counseling and emerging therapies.

Early in the course of the evaluation, dementia should be distinguished from nonprogressive, reversible, structural, and psychiatric disorders that can mimic dementia [58]. (See 'Differential diagnosis' above.)

The goals of the initial clinical assessment of a patient with suspected early-onset dementia are threefold [59]:

●Determine the pattern of cognitive and behavioral deficits, their time course and progression, and the extent to which they impact daily function

●Determine the involvement of the nervous system more generally, including motor, sensory, and cerebellar systems

●Determine whether there is systemic or multiorgan involvement

The information gained from the initial evaluation, which should also include basic laboratories and structural neuroimaging, will guide further testing.

History — The initial appointment in a patient with suspected dementia should focus upon the history. Family members or someone who knows the patient well must be available to give an adequate history of cognitive and behavioral changes. The Diagnostic and Statistical Manual of Mental Disorders, Fifth Edition (DSM-5) criteria for the diagnosis of dementia (major neurocognitive disorder) are shown in the table (table 1).

The history should establish the type of cognitive impairment, the most prominent domains affected (eg, learning and memory, language, visuospatial function, executive function, social cognition), any accompanying behavioral or personality changes, the time course of symptoms, and the degree of functional impairment.

Other important historical features include headaches (as often occur in vascular causes of dementia, including cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy [CADASIL]), stroke-like symptoms (as occur in multiple sclerosis [MS], mitochondrial disease, and vascular disease), underlying neoplasm (suggesting possible paraneoplastic disease), multiple organ system dysfunction (mitochondrial and metabolic disorders), and a history of significant head injury (chronic traumatic encephalopathy [CTE]).

A particular focus on family history is important. Many of the causes of early-onset dementia are familial. A history of cognitive decline at an early age in a parent (or perhaps a debilitating psychiatric illness) could indicate the presence of a familial form of AD, frontotemporal dementia (FTD), Huntington disease (HD), other heritable neurodegenerative dementias, or neurometabolic disease, including adult-onset leukodystrophies.

Physical and neurologic examination — Patients with early-onset dementia should undergo a complete physical and neurologic examination. A general physical examination is important, as many forms of early-onset dementia lead to or are associated with multisystem dysfunction (table 5 and table 6).

Eye examination is important to look for Kayser-Fleischer rings (seen in Wilson disease), retinitis pigmentosa (as seen in neuropathy, ataxia, retinitis pigmentosa [NARP], a form of mitochondrial disease), and ophthalmoplegia as seen in many adult-onset mitochondrial disorders. Patients with MS may have an afferent pupillary defect and optic disc pallor from prior optic neuritis.

Cardiac examination may reveal signs of heart failure or arrhythmia, which may be seen in mitochondrial disease and Wilson disease. Abdominal examinations showing hepatomegaly and other sequelae of liver dysfunction can be seen in Wilson disease and mitochondrial disease.

Facial nerve palsy and other cranial neuropathies can be seen in patients with neurosarcoidosis and some infectious causes of encephalopathy. Whipple disease can cause oculomasticatory myorhythmia, ie, characteristic rhythmic rapid muscle contractions around the mouth in coordination with pendular eye movements.

Careful assessment of motor function can be essential to diagnosis. Subtle signs of parkinsonism may be present in dementia with Lewy bodies (DLB) or Parkinson disease (PD) dementia. Asymmetry in motor function, whether frank weakness or subtle upper motor neuron signs, is often present in CADASIL, MS, vascular dementia, and mitochondrial disease (eg, mitochondrial encephalomyopathy with lactic acidosis and stroke-like episodes [MELAS]). Myoclonus can be seen in prion disease and mitochondrial disease (eg, myoclonic epilepsy with ragged red fibers [MERRF]).

Movement disorders are quite common in a variety of diseases that manifest early-onset dementia; suggestive features may include resting tremor (DLB and PD dementia), a wing-beating tremor (Wilson disease), and chorea (HD). Sensory examination can reveal a peripheral neuropathy, which can be present in sarcoidosis and mitochondrial disease, among others.

Cerebellar ataxia in a patient with early-onset dementia requires special attention. Alcoholic dementia should be a primary consideration. Differential diagnosis beyond this includes neurodegenerative diseases such as multiple system atrophy cerebellar subtype (olivopontocerebellar degeneration) and prion disease (eg, Gerstmann-Straussler-Scheinker syndrome). Other associations include AD associated with PSEN1 gene mutations, paraneoplastic disease, and mitochondrial disease.

Cognitive testing — Cognitive testing in a patient with presumed early-onset dementia is similar to that of an older adult, with a lower threshold to obtain complete neuropsychologic testing to exclude other etiologies such as psychiatric disorders and functional presentations. (See "Evaluation of cognitive impairment and dementia", section on 'Cognitive testing'.)

Routine laboratories — Laboratories such as a complete blood count, basic metabolic panel, liver function tests, thyroid studies, vitamin B12, and urinalysis should be obtained to exclude potentially causative systemic illnesses.

Structural neuroimaging — MRI of the brain is an important component of the initial evaluation of suspected early-onset dementia, both to exclude structural pathologies and to look for clues to the underlying dementia etiology (table 7). Computed tomography (CT) can be substituted in patients who have a contraindication to MRI, but the sensitivity is lower.

Some findings on initial MRI that provide clues to an etiologic diagnosis include:

●The pattern of cerebral atrophy, which may help distinguish among various neurodegenerative diseases (table 8)

●The presence of prior cortical or subcortical strokes and subcortical ischemic changes, commonly seen in vascular dementia (see "Etiology, clinical manifestations, and diagnosis of vascular dementia", section on 'Neuroimaging')

●White matter lesions, which may be seen in acquired demyelinating diseases such as MS (usually asymmetrical) or an adult-onset leukoencephalopathy or other neurometabolic disorder (often symmetrical) (algorithm 1)

●Cortical ribboning and subcortical gray matter diffusion-weighted changes typical of Creutzfeldt-Jakob disease (CJD) (see "Creutzfeldt-Jakob disease", section on 'Brain MRI')

●Hydrocephalus, as seen in both idiopathic and secondary normal pressure hydrocephalus (NPH) (see "Normal pressure hydrocephalus", section on 'Magnetic resonance imaging')

Neuroimaging in the evaluation of patients with cognitive impairment is discussed in detail separately. (See "Evaluation of cognitive impairment and dementia", section on 'Neuroimaging'.)

ADDITIONAL TESTING

General approach — Information gained from the initial evaluation guides further testing:

●The majority of patients with a slow, insidious disease course and "pure" cognitive decline by history and examination will have a neurodegenerative dementia, particularly if routine MRI is unremarkable or shows only mild atrophy. The primary goal of further testing in such patients is to improve diagnostic certainty as to the type of dementia. As in older adults, the most common etiologies are Alzheimer disease (AD), vascular dementia, and frontotemporal dementia (FTD). Additional testing may include cerebrospinal fluid (CSF) for amyloid and tau, functional neuroimaging (eg, amyloid positron emission tomography [PET,] 18-F fluorodeoxyglucose-PET [FDG-PET]), and focused genetic testing.

●Patients with a rapidly progressive course should routinely undergo lumbar puncture, electroencephalography (EEG) if there is clinical suspicion for seizures, and selected laboratory studies (table 9). A search for occult neoplasm is indicated if limbic encephalitis is suspected. Prion and other infectious diseases must also be considered.

●In patients with cognitive decline and evidence of additional neurologic or multisystem dysfunction, the range of tests to consider is broader and should be directed by the additional physical and neurologic signs and symptoms, as well as any clues from structural neuroimaging. (See 'Structural neuroimaging' above.)

Lumbar puncture and other laboratories — Lumbar puncture is suggested in most patients presenting with early-onset dementia after appropriate brain imaging has been obtained [58,60]. CSF analysis can help identify infectious and autoimmune conditions; cell count and protein are often elevated in these settings. Early-onset AD is supported by a CSF profile of low Aβ42 and elevated tau and phospho-tau levels. (See "Clinical features and diagnosis of Alzheimer disease", section on 'Role of biomarkers'.)

Additional laboratories to consider depending upon the specifics of the individual case include CSF for either 14-3-3 or total tau (elevated in Creutzfeldt-Jakob disease [CJD]); serum copper, ceruloplasmin, and 24-hour urine copper (for Wilson disease); plasma HIV immunoassay; CSF herpes simplex virus 1/2 polymerase chain reaction (PCR); CSF varicella PCR; CSF Whipple PCR; and a serum paraneoplastic panel.

In patients with evidence of a leukoencephalopathy on MRI raising suspicion for adult-onset leukodystrophy or other neurometabolic disorder, additional laboratories to consider include serum very long chain fatty acids and lysosomal enzyme screening (eg, arylsulfatase A, hexosaminidase A, galactocerebrosidase, β-galactosidase).

Electroencephalography — EEG is likely of low yield as a routine study in the evaluation of all patients presenting with suspected early-onset dementia, but it may be helpful in selected cases. Examples include patients with rapidly progressive dementia syndromes, particularly when there is suspicion for prion disease. (See "Creutzfeldt-Jakob disease", section on 'Electroencephalogram'.)

Advanced neuroimaging — Additional tests that may be helpful in patients with suggestive clinical symptoms include CT angiogram or magnetic resonance angiogram for evaluation of suspected vasculitis, FDG-PET to assess any pattern of abnormal metabolism in suspected FTD or other neurodegenerative dementias, and amyloid PET to identify early-onset dementia caused by AD [61]. Single-photon emission computed tomography (SPECT) is an alternate form of metabolic brain imaging that may help differentiate and corroborate a clinical diagnosis of early-onset dementia [62]. Amyloid PET is commercially available but often not reimbursed. Given that spinal fluid analysis is often performed, biomarkers for AD are often sent at that time in lieu of this imaging. (See "Clinical features and diagnosis of Alzheimer disease", section on 'Neuroimaging' and "Evaluation of cognitive impairment and dementia", section on 'Advanced neuroimaging'.)

Brain and other tissue biopsies — Brain biopsy is reserved for patients in whom all diagnostic tests have been exhausted and failed to identify a cause. This includes careful consideration of neurometabolic diseases, which can be diagnosed by metabolic and genetic testing in the vast majority of cases and do not require brain biopsy for diagnosis. Neuropathologic tissue diagnosis is most warranted when a reversible or treatable condition is suspected, or if a potentially harmful treatment is being considered [59]. The risk of complications with brain biopsy is around 8 to 9 percent, with approximately 5 percent or less having permanent neurologic sequelae; the risk of death is approximately 1 percent or less [63,64].

In selected diseases, a less invasive tissue diagnosis may be useful for diagnostic purposes. Examples include a skin biopsy for confirmation of cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL) or muscle biopsy in certain mitochondrial diseases (although genetic testing may supersede biopsy in many cases). (See "Mitochondrial myopathies: Clinical features and diagnosis", section on 'Evaluation and diagnosis' and "Cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL)", section on 'Evaluation'.)

Genetic testing — Genetic testing may be helpful in establishing a cause for early-onset dementia in selected patients. The cost of testing has come down substantially, and many panels for common AD and FTD mutations are affordable (hundreds of dollars or less in many cases). Other comprehensive panels can come at high cost. A clear family history should be documented in suspected cases, with the caveat that a family history might not always be apparent or available because of censoring by premature death, small family size, uncertain parentage, de novo mutations, and incomplete penetrance.

The decision to pursue genetic testing is highly individualized and depends on a variety of factors, including the age of the patient, the presence or absence of additional family members who might be at risk, the cost of the test and insurance coverage, and whether there are other affected family members. Among the neurodegenerative dementias, genetic testing is most often pursued for CADASIL, Huntington disease (HD), autosomal-dominant forms of AD, and patients with FTD, particularly when there is concomitant motor neuron disease. Genetic testing is also available and useful in the diagnosis of an increasing number of adult-onset leukodystrophies and other neurometabolic diseases. (See "Cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL)", section on 'Genetic analysis' and "Huntington disease: Clinical features and diagnosis", section on 'Genetic testing' and "Genetics of Alzheimer disease", section on 'Genetic testing' and "Frontotemporal dementia: Clinical features and diagnosis", section on 'Genetic testing'.)

Since the results of genetic testing commonly have implications for asymptomatic family members, genetic testing should be done in conjunction with genetic counseling. (See "Genetic testing", section on 'Ethical, legal, and psychosocial issues'.)

TREATMENT — Treatment for early-onset dementia is not generalizable given the heterogeneity of causes. Many illnesses have specific treatments available, which underscores the importance of a thorough diagnostic evaluation. For patients with a rapidly progressive dementia and an unrevealing diagnostic evaluation, many experts recommend consideration of high-dose steroids as empiric treatment for a possible autoimmune process, even if testing has been negative [44].

Symptomatic treatment for dementia includes cholinesterase inhibitors and/or memantine for Alzheimer disease (AD) and other forms of dementia (eg, vascular dementia, dementia with Lewy bodies [DLB]), treatment of behavioral disturbances, environmental manipulations to support function, and counseling with respect to safety issues. These aspects of dementia therapy are reviewed in detail elsewhere:

●Treatment of dementia (see "Management of the patient with dementia")

●Cholinesterase inhibitors (see "Cholinesterase inhibitors in the treatment of dementia")

●Neuropsychiatric symptoms of dementia (see "Management of neuropsychiatric symptoms of dementia")

●Palliative care for advanced dementia (see "Care of patients with advanced dementia")

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".)

SUMMARY AND RECOMMENDATIONS

●Definitions – Dementia refers to progressive cognitive impairment in one or more cognitive domains, most often memory, that represents a significant decline from previous baseline and interferes with functional independence.

Early-onset dementia refers to cases of dementia occurring in adults ranging from 18 to 65 years of age. (See 'Definitions' above.)

●Causes – Although genetic etiologies are more common in early-onset dementia compared with late-onset dementia, the majority of cases of both early-onset dementia and late-onset dementia do not have an identifiable monogenetic cause. (See 'Causes of early-onset dementia' above.)

Similar to older adults, the most common etiologies in younger patients are Alzheimer disease (AD), vascular dementia, and frontotemporal dementia (FTD). (See 'Epidemiology' above.)

In addition to neurodegenerative dementia, vascular disease, infectious disease, inflammatory and autoimmune disease, and neurometabolic disease can cause dementia (table 2). (See 'Causes of early-onset dementia' above.)

●Dementia mimics – Dementia should be distinguished from symptoms of memory loss or personality and behavioral change that are nonprogressive or provoked by underlying systemic illness, medication, psychiatric disorder, or structural brain pathology. (See 'Differential diagnosis' above.)

●Initial evaluation – The clinical assessment of a patient with early-onset dementia is similar to that of an older adult but often needs to be extended to detect a broader range of diseases than the common neurodegenerative dementias.

The information gained from the initial evaluation, which should include a detailed history, physical and neurologic examination, cognitive assessment, basic laboratories, and structural neuroimaging, will guide further testing. (See 'Initial evaluation' above.)

●Additional testing – The pace of the illness and the presence or absence of additional neurologic and systemic features determine which additional tests are indicated. (See 'Additional testing' above.)

•Most patients with a slow disease course and "pure" cognitive decline will have a neurodegenerative dementia, particularly if MRI is unremarkable. Further testing in such patients may improve diagnostic certainty as to the type of dementia and may include cerebrospinal fluid (CSF) for amyloid and tau, functional neuroimaging (eg, amyloid positron emission tomography [PET,] 18-F fluorodeoxyglucose-PET [FDG-PET]), and focused genetic testing.

•Patients with a rapidly progressive course should routinely undergo lumbar puncture, EEG if there is clinical suspicion for seizures, and selected laboratory studies. A search for occult neoplasm is indicated if limbic encephalitis is suspected. Prion and other infectious diseases are also considerations.

•In patients with cognitive decline and evidence of additional neurologic or multisystem dysfunction, testing should be directed by the additional physical and neurologic signs and symptoms (table 5 and table 6).

●Treatment – Treatment for early-onset dementia is not generalizable given the heterogeneity of causes. Many illnesses have specific treatments available, which underscores the importance of a thorough diagnostic evaluation. (See 'Treatment' above.)