Etiology is ascertained through a detailed history from the patient, family members, or other informants, physical examination, neuropsychologic testing, imaging studies, and sometimes biomarkers. For many NCDs, definitive diagnosis is only attainable through tissue pathology. Other causes of NCD-like presentations, such as depressive disorders and untreated sleep apnea, should be ruled out.

• •A thorough general physical, neurologic examination, and brief bedside or office-based neuropsychological screening targeting specific cognitive domains (especially attention, anterograde memory, executive function, language, and visuospatial function) are required. Often, neuropsychologic testing and neuroimaging (structural or functional, depending on the differential diagnosis in question) are indicated. Biomarkers and genetic screening tests are diagnostic in some cases. Attention should be given to excluding underlying medical causes of NCD. Serology and lab tests, including B₁₂, folate, vitamin D₃, CBC, and TSH, may reveal abnormalities that upon treatment improve cognition.^13-15
• •Alzheimer disease: Detailed history and physical examination including neuropsychologic screening or testing often points to the diagnosis. MRI findings include general as well as focal (hippocampal and temporoparietal cortical) atrophy and can reveal alternative or additional diagnoses (e.g., cerebrovascular disease). FDG-PET may show hypometabolism in temporoparietal regions. Amyloid PET scanning may have diagnostic value, as might tau PET imaging in select cases. Cerebrospinal fluid biomarkers include elevated total and phosphorylated tau levels with reduced amyloid beta-42 (Aβ-42) or a low Aβ-42:40 ratio. Recognizing that Alzheimer disease begins 20 yr before symptom onset highlights a significant window for intervention. Advances in plasma-based biomarkers are enabling progress in presymptomatic stages, allowing those affected to address modifiable risk factors to potentially slow or delay cognitive decline.^2,16,17APOE testing may detect APOE4, a risk factor for development of Alzheimer disease. In early onset cases, autosomal dominant inheritance mutations in APP, PSEN1, or PSEN2 may be detected.
• •Frontotemporal degeneration: History and examination should pay specific attention to executive dysfunction, apathy, disinhibition, and aphasia. In cases with early-onset behavior or language disorders, an MRI or computed tomography (CT) scan may show atrophy in frontal lobes and/or corresponding parts of anterior or inferior temporal lobes either bilaterally or asymmetrically. Functional imaging may show hypoperfusion in the corresponding regions. In familial cases, genetic mutations in genes encoding the microtubule-associated protein tau and the granulin gene may confirm the diagnosis.
• •Lewy body disease: History and examination should be particularly attuned to motor (parkinsonism) and fluctuating cognitive symptoms, signs, and temporal course, as well as the associated signs noted above. Neurocognitive impairment precedes or develops within 1 yr of motor symptom onset. A sleep study may help to confirm a diagnosis of REM sleep behavior disorder. Nuclear medicine testing (single-photon emission CT [SPECT]/DaTscan or PET) may reveal reduced perfusion or metabolism in the occipital lobe or decreased dopaminergic activity in the striatum. Parkinson disease dementia and dementia with Lewy bodies are pathologically indistinguishable, and the umbrella term "Lewy body dementia" is now commonly used for both of these clinical syndromes.¹⁸
• •Parkinson disease: The diagnosis of PD is based on distinctive clinical features from history and neurologic examination. At a minimum, bradykinesia plus either tremor or rigidity must be present. A clear beneficial response to dopaminergic therapy supports the diagnosis. MRI is usually unremarkable in patients with PD. It is important to note that imaging studies are not diagnostic methods for PD. However, techniques such as DAT SPECT and MRI with nigrosome are useful for demonstrating dopaminergic dysfunction or parkinsonism.¹⁹
• •Vascular disease: Neurologic assessment often reveals a history of stroke or transient ischemic attack (TIA). Neurologic and cognitive examinations are, as always, essential. MRI or CT scan may show significant parenchymal injury and marked patchy and/or confluent white matter lesions attributable to cerebrovascular disease.
• •TBI: Clinical/injury history and course may be associated with abnormal CT or MRI scan indicative of petechial hemorrhages, diffuse axonal injury, subdural or subarachnoid hemorrhage, or evidence of contusion.
• •Prion disease: May be suspected in patients with appropriate clinical presentation, including rapidly progressive course. MRI may show T2-FLAIR hyperintensities in the striatum, cingulate, and additional neocortical areas. Electroencephalogram (EEG) reveals periodic synchronous biphasic or triphasic sharp wave complexes. Real-time quaking-induced conversion (RT-QuIC) and cerebral spinal fluid (CSF) tau levels are more sensitive than the better known EEG findings and CSF protein 14-3-3 levels.²⁰
• •Huntington disease: Supplementing neurological, cognitive, and psychiatric history and examination, genetic testing for trinucleotide cytosine-adenine-guanine (CAG) repeat expansion in the gene that encodes Huntington protein on chromosome 4 is diagnostic.

• •Though not applicable across all subtypes of NCD, modifiable risk factors remain the primary prevention strategy for reducing incidence of dementia. The greatest attributable modifiable risk factors for Alzheimer (across racial and ethnic groups) include hypertension, obesity, and physical inactivity.⁴ Other preventive strategies applicable to NCDs include social engagement, exercise, improved diet, reduced alcohol intake, smoking cessation, treating hearing loss, managing sleep disorders (e.g., obstructive sleep apnea), and (to the extent possible) avoiding critical illness. Cognitive training and stimulation (e.g., cognitive-behavioral therapy, music-based therapies) can improve mood and memory early in the course of neurocognitive disease.
• •Agitation in NCD is notoriously difficult to treat. Pharmacologic treatments for behavioral disturbance have a limited role in improving overall quality of life for most people with major or minor NCD. Therefore nonpharmacologic approaches (e.g., behavioral strategies) are first-line treatments for most NCD-related behavioral disturbances.
• •Care coordination and family education and support may help reduce the need for a skilled nursing facility and reduce caregiver stress and burnout. Patient safety, including risks associated with driving, wandering, and cooking, should be addressed throughout the course of the illness. Supervised living may ensure appropriate long-term care in late stages of progressive illness.
• •Delirium and its underlying causes should be identified and treated first (e.g., infections, medication toxicities).

• •Sleep disorders and pain (and their pharmacologic treatments, both prescribed and over the counter) also warrant special attention.
• •Antidepressants, especially selective serotonin reuptake inhibitors, have shown mixed benefits. Useful in the management of agitation and paranoia, risk-benefit assessment is warranted due to risks including QT prolongation, orthostasis, and falls.²¹
• •Cognitive enhancers such as donepezil are also used to help manage behavioral symptoms.²²
• •Acetylcholinesterase inhibitors and the NMDA receptor antagonist memantine can be prescribed for cognitive enhancement and behavioral management; however, these treatments are not disease-modifying, and a risk/benefit determination is necessary before initiating treatment.²²
• •Atypical antipsychotics carry multiple risks for the elderly but with judicious use can be helpful for behavioral symptoms of NCDs.²³ A risk/benefit conversation is necessary when initiating neuroleptic treatment, given the possible side effects of increased all-cause mortality, risk for arrhythmias, extrapyramidal symptoms, and stroke.
• •Patients with dementia with Lewy bodies are highly sensitive to antidopaminergic effects of antipsychotics, and agitation in these patients should be managed extremely cautiously with alternative agents used whenever possible.
• •Antiseizure medications have been investigated for the treatment of neuropsychiatric symptoms in dementia due to their mood-stabilizing properties.²³
• •Potentially disease-modifying drugs such as passive antibody infusions (e.g., anti-Aβ and anti-tau) are now approved for treatment of Alzheimer disease. Three have been FDA approved: aducanumab (2021), lecanemab (2023), and donanemab (2024).^24,25 Aducaumab was withdrawn from the market following significant controversy surrounding its regulatory approval.²⁶ Lecanemab (Leqembi®) is approved to slow progression of disease and to be initiated in early AD (mild cognitive impairment) with confirmed brain amyloid pathology. Adverse events such as amyloid-related imaging abnormalities (ARIA) and infusion reactions are usually asymptomatic but can occasionally be severe and in rare cases fatal. Micro/macro hemorrhages, particularly in anticoagulated patients, have resulted in it being contraindicated in this population. Given the elevated ARIA risk in APOE4 carriers, especially homozygotes, APOE genotyping is recommended.²⁵
• •Donanemab, an IgG1 monoclonal antibody, targets N-terminal truncated β-amyloid present specifically in brain amyloid plaques. The TRAILBLAZER-ALZ 2 clinical trial, involving 1736 participants with early Alzheimer and amyloid/tau pathology, demonstrated that donanemab significantly slowed clinical progression at 76 wk. However, experts noted significant risks of cerebral edema and hemorrhage, affecting 24% and 31% of patients, respectively, mostly asymptomatic but resulting in three deaths from brain swelling.^26,27

• Alzheimer Disease (Related Key Topic)
• Delirium (Related Key Topic)
• Human Immunodeficiency Virus (Related Key Topic)
• Huntington Disease (Related Key Topic)
• Parkinson Disease (Related Key Topic)
• Progressive Supranuclear Palsy (Related Key Topic)
• Traumatic Brain Injury (Related Key Topic)
• Wernicke Syndrome (Related Key Topic)

The American Psychiatric Association’s Diagnostic and Statistical Manual of Mental Disorders, 5th edition, text revision (DSM-5-TR), includes delirium and major and mild neurocognitive disorders, as well as their subtypes, under the grouping neurocognitive disorders.¹

The core features of neurocognitive disorders (NCDs) are deficits in one or more cognitive domains (learning and memory, language, executive function, complex attention, perceptual-motor, social cognition).¹ The cognitive dysfunction is acquired rather than developmental and thus represents a decline from a previously attained level of functioning. The NCDs are subtyped according to known or presumed etiologic/pathologic entities underlying the decline. The subtypes may be distinguished by clinical characteristics such as time course, physical examination, and cognitive domains affected.

The initial evidence is based on concern brought forth by the patient, a knowledgeable informant, or the clinician. It is often supported by performance on objective standardized assessments such as neuropsychologic testing.

The DSM-5-TR collects the entities, major and minor NCDs under one broad heading. Major NCD replaces the DSM-IV term dementia, denoting a significant cognitive decline that interferes with independence that is not due to delirium. Minor NCD refers to a presentation in which cognitive deficits do not interfere with independence and the capacity to perform activities of daily living (ADLs), often because of the use of compensatory strategies and supports. Subtypes of both major and minor NCDs are specified, including Alzheimer disease, frontotemporal degeneration, vascular disease, dementia, Lewy body disease, and many others, with unknown etiology available, though perhaps better reserved for more frequent use in minor NCD. For both categories, specifiers include the presence/absence of behavioral disturbance.¹

ICD-11 codings classify NCDs under Dementia 6D8. These are subcoded for the presence of behavioral or psychological disturbances and causality (e.g., Alzheimer disease, cerebrovascular, Lewy body, frontotemporal dementia, psychoactive substance/medication, and diseases classified elsewhere).

The prevalence of NCDs varies depending on the etiology of the neurocognitive disorder and age of the patient. Among patients 75 yr of age and older, the prevalence tends to increase sharply with age for the most common neurocognitive disorders. According to the 2024 Alzheimer’s Association Report, the prevalence of Alzheimer disease among U.S. Medicare beneficiaries is 5% for those aged 65 to 74, increases to 13.2% for those aged 75 to 84, and reaches 33.4% for those aged 85 and older.² Sixty to eighty percent of those with dementia have Alzheimer disease and have concomitant cerebrovascular disease.³ Compared with non-Hispanic White individuals, dementia is twice as prevalent among non-Hispanic Black and 1.5 times as prevalent among Hispanic individuals.⁴

Neurocognitive domains that are affected in NCDs include:

• •Complex attention, including sustained attention, divided attention, selective attention, and processing speed
• •Executive functioning, such as planning, decision making, working memory, and mental flexibility
• •Learning and memory, including immediate memory, recent memory
• •Language expression and reception, including word recall, grammar, and syntax
• •Perceptual motor skills, including visual construction, praxis, and gnosis
• •Social cognition, including recognition of emotions

Associated physical findings, time course of illness, and response to treatment depend on the etiology of the NCD. Mood disturbance, psychosis, and behavioral disturbances are recognized as common neuropsychiatric symptoms associated with NCDs.

• •Standardized cognitive screening instruments can be used for an initial assessment, such as the Mini-Mental State Examination (MMSE), Montreal Cognitive Assessment (MoCA), and Addenbrooke’s Cognitive Examination (ACE). These tests should be implemented, scored, and interpreted within a culturally responsive frame, including factors like language, social and economic background, scholarship, and cultural idiosyncrasies.
• •Formal neuropsychological testing (i.e., ambulatory) to assess the different cognitive domains (i.e., memory, language, attention, executive, and visuospatial) can be employed to objectively measure cognitive function.

Mood disturbances (e.g., depression), apathy, sleep disturbances, behavioral dysregulation, aggression, and psychosis are recognized as common neuropsychiatric symptoms associated with NCDs.² Mood symptoms are common early in the clinical course of NCDs due to Alzheimer’s disease, NCD with Lewy bodies, and vascular NCD. Psychosis may present across the spectrum of illness but is more common in mild to moderate stages of NCD with Lewy bodies and in moderate to severe stages of NCD due to Alzheimer disease. Psychosis, agitation, and other behavioral disturbances lead to increased rates of hospitalization, early admission to assisted living environments or nursing homes, and increased level of caregiver depression and distress. Apathy manifests early in NCDs and is the most common neuropsychiatric symptom of NCD due to Alzheimer disease across the spectrum of the disease.

(For each etiology, the criteria are met for major or mild neurocognitive disorder.)

• •Major or mild neurocognitive disorder due to Alzheimer disease: Insidious onset and gradual progression, occasionally with brief plateaus characterize the course of Alzheimer disease. Impairments in anterograde memory, visuospatial functioning, and to a subtler degree, executive function, are prominent early in the disease process. In moderate to severe disease, language deficits manifest and problematic behaviors, including agitation, combativeness, and psychosis, may arise. Apathy, agitation, and psychosis are often more distressing to caregivers than are the cognitive deficits. Psychosis commonly takes the form of delusions of theft, though this is difficult to distinguish from misattributions of cause for items lost because of anterograde memory impairment.
• •Major or mild neurocognitive disorder due to frontotemporal degeneration (FTD): Prominent changes in social behavior and personality or progressive aphasia, both associated with degeneration of the frontal and/or temporal lobes. Typical onset in the sixth decade of life can be a useful discriminating characteristic in many cases, and some individuals even manifest symptoms in the fifth decade. Three clinical presentations are described: Behavioral variant (also called "frontal variant"), nonfluent primary progressive aphasia (PPA; also referred to as "agrammatic PPA"), and semantic variant PPA (also called "temporal variant").⁵ Behavior changes in FTD are characterized by progressive development of personality changes, behavior changes including disinhibition, and/or language impairment. Patients with behavior variant FTD may present with impaired insight, socially inappropriate behaviors, apathy, hyperorality, or compulsive behaviors. Maniform features may also be present. A significant overlap has been noted between behavioral variant FTD and amyotrophic lateral sclerosis, revealing the latter to not be an exclusively motor neuron disease.⁶ Learning and memory dysfunction may be spared in the early stages. Nonfluent PPA resembles a gradual-onset Broca/expressive aphasia, while semantic variant PPA involves loss of understanding and access to word meaning and naming.
• •Major or mild neurocognitive disorder due to Lewy body disease (LBD): Core features are parkinsonism, cognitive fluctuations, complex visual hallucinations, and REM sleep behavior disorder.⁷ Though there is some debate, the temporal proximity of onset of clinically significant parkinsonism and cognitive deficits is shorter in LBD than in Parkinson disease with dementia.⁸ Cognitive deficits are fluctuating in nature and typically feature visuospatial and executive function impairments, contrasting with the memory deficits in AD. Mood disturbances, autonomic dysfunction, falls, and exquisite sensitivity to dopamine-blocking drugs are also highly suggestive of this diagnosis. Individuals with major or mild neurocognitive disorder with Lewy bodies are typically more functionally impaired than would be expected for their cognitive deficits because of the motor and autonomic impairments.
• •Major or mild neurocognitive disorder due to Parkinson disease: The primary motor features, collectively referred to as "parkinsonism," include bradykinesia, rigidity, tremor, and impaired gait and postural reflexes. Mild cognitive impairment, particularly executive dysfunction, can accompany prodromal PD and is present in up to 20% of patients at diagnosis.⁹ While the onset of clinically significant cognitive impairment in Parkinson disease is generally believed to occur much later than in LBD, there is considerable variability here. Within 20 yr, up to 80% of individuals with PD develop dementia.¹⁰ Other nonmotor features such as reduced olfaction, apathy, depression, hallucinations, and REM sleep disorder are suggestive of this diagnosis. The atypical parkinsonian syndrome, progressive supranuclear palsy, presents with early postural instability and retropulsion, supranuclear gaze palsy, and early cognitive impairment marked by prominent executive dysfunction, along with depression, apathy, and anxiety.
• •Major or mild neurocognitive disorder due to vascular disease: The onset of cognitive decline with cerebrovascular disease is temporally related to one or more ischemic or hemorrhagic events. The diagnosis is supported by neuroimaging evidence of parenchymal injury, including large vessel infarcts or hemorrhages, two or more lacunar infarcts outside the brainstem, or confluent white matter lesions attributed to cerebrovascular disease. Patients typically present with a decline in processing speed, complex attention, and executive dysfunction, though other presentations are possible depending on stroke localization. Stepwise and/or fluctuating decline is described. Prominent depression, apathy, and personality changes are common.
• •Major or mild neurocognitive disorder due to traumatic brain injury (TBI): This NCD presents immediately after the occurrence of a TBI or can be attributed to a TBI that causes loss of consciousness, posttraumatic amnesia, disorientation, or neurologic signs such as seizure or hemiparesis. Cognitive presentation is variable but may include difficulty with complex attention, executive dysfunction, or deficits in learning and memory. Associated findings include disturbances in emotional function and personality change. The features of major or mild NCD due to TBI vary by age of patient and specifics of the injury as well as other factors, such as premorbid functioning of the patient. Chronic traumatic encephalopathy results from multiple concussive episodes (e.g., sports-related injuries). It is a pathological diagnosis with traumatic encephalopathy syndrome being its clinical correlate diagnosed based on history of repetitive head impacts, episodic memory and/or executive function impairment(s), and progressive course.¹¹
• •Major or mild neurocognitive disorder due to substance/medication use: See Substance/Medication-Induced Neurocognitive Disorder chapter.
• •Major or mild neurocognitive disorder due to prion disease: Neurocognitive deficits associated with prion disease arise and progress rapidly, typically over 6 mo, as in Creutzfeldt-Jakob disease. In some variants, prominent psychiatric symptoms such as dysphoria, anxiety, hallucinations, and behavioral disturbance may precede neurocognitive deficits.¹² Ataxia, myoclonus, chorea, and a prominent startle reflex are typically present.
• •Major or mild neurocognitive disorder due to Huntington disease: Early prominent changes in processing speed, organization, and planning rather than learning and memory are common in Huntington disease. Behavior changes, changes in mood, anxiety, obsessive-compulsive symptoms, irritability, and apathy often precede motor symptoms. Suicidality is common.
• •Major or mild neurocognitive disorder due to another medical condition: Many general medical conditions can cause NCDs. Examples include structural brain lesions such as primary or secondary brain tumors, subdural hematomas, normal pressure hydrocephalus (NPH), hypoxia, infections (e.g., HIV), endocrine conditions, immune disorders, and metabolic conditions. The temporal association between the onset or exacerbation of the medical condition and the development of neuropsychiatric impairment supports the diagnosis.