Evidence-Based Reviews

Is it Alzheimer’s? How to pare down the possibilities

Current Psychiatry. 2008 January;7(1):53-66

References

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Possible AD is considered when a patient has an atypical onset, presentation, or course and other secondary illnesses capable of producing dementia are not believed to be the cause.

Clinical Point

Only 1% of dementia causes are considered reversible, but keep them in mind in the Alzheimer’s differential diagnosis

Probable AD is diagnosed when dementia is established by clinical exam and con- firmed with cognitive testing, where ≥2 cognitive domains are progressively affected; includes gradual memory loss not caused by another systemic or brain disease, with age of onset between 40 and 90 years.

Definite AD requires histopathologic evidence of AD in addition to fulfilling criteria for probable AD.20

DSM-IV-TR. Similar but broader DSM-IVTR criteria describe an insidious progressive cognitive decline that affects recent memory and ≥1 other cognitive domain (apraxia, aphasia, agnosia, or executive functioning). This cognitive decline impairs social and occupational function, represents a change from a higher level, and is not due to other causes such as delirium.²¹

NINCDS-ADRDA and DSM-IV-TR criteria have comparable sensitivity and specificity for clinical AD diagnosis. Neither requires neuropathologic or genetic assessment (Box 3).^15,17,22-²⁴ Neuroimaging and other tests may be required to rule out other brain diseases that may cause dementia.

Other causes of dementia

Mild cognitive impairment (MCI) may represent a prodromal state for the earliest clinical manifestations of dementia. Symptoms include memory complaints but generally preserved activities of daily living.

Originally introduced to define a progressive, single-symptom amnestic syndrome, MCI has evolved into a classification of amnestic and non-amnestic MCI with single or multiple domains.²⁵ Amnestic MCI is the most specifically correlated with AD.²⁶ Neurobiologic similarities between amnestic MCI and clinically diagnosed AD include:

neuropsychiatric symptoms, such as apathy, mood disturbance, irritability and anxiety
over-representation of the APOE ε4 allele
volumetric loss in the entorhinal cortex and hippocampus as measured by MRI
Glucose hypometabolism in AD-typical regions as measured by FDG-PET
neuronal loss in vulnerable brain regions.²⁶

Most patients with MCI go on to meet AD criteria within 5 to 10 years, and approximately 80% of those originally diagnosed with MCI prove to have AD at post-mortem histopathologic examination.^26,27

Clinical Point

Vascular dementia was once thought to account for 15% to 20% of dementia illness, but discrete VaD is now viewed as much less common

Dementia with Lewy bodies (DLB) is the second most common dementing disorder in late life—after Alzheimer’s dementia— and two-thirds of DLB cases overlap with AD. Core DLB clinical features include early recurrent visual hallucinations, fluctuating cognition, spontaneous parkinsonism, and sensitivity to conventional antipsychotics.^15,28

Parkinson’s disease (PD) and DLB may represent a clinicopathologic continuum, and substantial overlap exists among AD, DLB, and PD in underlying disease process and clinical presentation.^15,29 Hallucinations, depression, delusions, and delusional misidentification are seen more often in patients with DLB than AD.¹⁵

Vascular dementia (VaD) was once thought to account for 15% to 20% of dementing illnesses, but discrete VaD is now viewed as much less common. Whatever the underlying vasculopathy, vascular lesions often co-exist with other causes of dementia—usually AD (in 77% of presumed VaD cases).³⁰

Compared with AD, patients with VaD have a more subcortical dementia with difficulty retrieving words, organizing and solving complex problems, “absent-mindedness,” and psychomotor slowing with relatively preserved language skills. VaD is thought to have a more abrupt onset than AD and “stepladder” deterioration.

Frontotemporal dementia (FTD)—such as Pick’s disease—is associated with focal atrophy of the frontal and/or temporal lobes. Mean onset is age 52 to 56, and FTD is less common than AD, VaD, or DLB.

FTD often presents with gradual personality changes (with inappropriate responses or activities) or language changes (with severe naming difficulty and problems with word meaning).³¹ Features that may help differentiate FTD from AD include:

disinhibition/apathy with personality change
affect disregulation
behavioral disturbance (frontal type) and expressive/receptive language changes (semantic or primary progressive aphasia) with relatively mild memory loss.^32,33

Unlike AD, memory usually is unaffected in early FTD, with problems largely secondary to poor concentration and relating to difficulties with working (immediate) memory.

Other neurodegenerative diseases that might present with dementia include PD, Huntington’s disease, progressive supra-nuclear palsy, corticobasal degeneration, and Creutzfeldt-Jakob disease.³³

Box 3

Genetic testing for Alzheimer’s?

Genetic testing may become important for high-risk patients or early-stage Alzheimer’s disease (AD) when preventive/ disease-modifying therapy becomes available. At this time, however, the clinical value and implications of genetic tests remain controversial.^17,22

Apolipoprotein E (APOE). The APOE ε4 allele is an established risk factor for AD,^23,24 but limitations of APOE testing include:

inability to predict with sufficient certainty whether or when a person might develop AD
risk of false alarm or false reassurance
no established treatment exists for a person with this genetic risk.

Amyloid precursor protein (APP), presenilin 1 (PS1), presenilin 2 (PS2). Age 15

Mutations are rare (~1% of AD cases).
Increased APP transcriptional activity is an AD risk factor; onset age correlates inversely with levels of APP expression.
PS1 mutation testing may benefit patients with early-onset familial AD. If this mutation is found, other presymptomatic at-risk family members may wish to be tested so they can make important life decisions based on the results.^17,22 Careful pre- and post-test counseling is critical.