Genetic predisposition is another major risk factor for AD, and most cases of AD are polygenic, although no genetic etiologies can be identified in many AD cases.19 The e4 allele of apolipoprotein E is associated with an increased risk of late-onset AD in both familial and sporadic cases; however, carrying 1 or 2 apoe4 alleles does not necessarily translate into the development of AD. Causative mutations in chromosome 21 (amyloid precursor protein gene), chromosome 14 (presenilin 1 gene), and chromosome 1 (presenilin 2 gene) have been identified for early-onset AD, although the proportion of early-onset AD cases caused by these mutations is debatable. Many other genes and chromosomes are under investigation.18,19 AD is a heterogeneous disorder with many etiologies that involve different interactions between various genetic and environmental risk factors.3
Clinical features include an impaired ability to learn new information or to recall previously learned information, with aphasia, apraxia, agnosia, or disturbance in executive functioning. Neuropathological hallmarks of AD include neuritic plaques, neurofibrillary tangles, and loss of neurons in the cholinergic, serotonergic, and dopaminergic neurotransmitter systems.
Management of associated vascular risk factors (such as elevated blood pressure and diabetes) and weight loss, exercise, and a healthy diet are important medical interventions for AD. Nonpharmacological interventions include psychotherapeutic, social, and family interventions (Table 4). Pharmacological interventions for AD approved by the FDA include cholinesterase inhibitors (donepezil, galantamine(Drug information on galantamine), rivastigmine(Drug information on rivastigmine), tacrine(Drug information on tacrine)) and memantine(Drug information on memantine).7 A discussion on evaluation, management, and medication use for associated neuropsychiatric symptoms can be found elsewhere.20,21
Vascular dementia
Vascular dementia accounts for 4% to 22% of all dementias in Western society and up to 50% of all dementias in Japan.22 Risk factors include increasing age, hypertension, diabetes mellitus, obesity, smoking, hyperlipidemia, coronary artery disease, and arrhythmias.
Several criteria have been proposed to diagnose vascular dementia, although none have been definitively validated and the clinical utility of these criteria is questionable.23,24 The National Institute of Neurological Disorders and Stroke–Association Internationale pour la Recherche et l’Enseignement en Neurosciences criteria include neurological signs, levels of certainty, and a list of potential locations for vascular lesions.25 Because vascular dementia is heterogeneous, there are no widely accepted neuropathological markers for vascular dementia and its subtypes.
Clinical features of vascular dementia, as defined by DSM-IV-TR, include focal neurological signs and symptoms or laboratory evidence of cerebrovascular disease that is determined to be etiologically related to the disturbance. Clinical features may be abrupt in onset and show a stepwise progression, although presentation of features may be variable.
Treatment of risk factors can help decrease the risk of vascular dementia. Although limited evidence exists for cholinesterase inhibitors (such as donepezil(Drug information on donepezil) and rivastigmine), there are still no FDA-approved medications for the treatment of vascular dementia.
Frontotemporal dementia
Frontotemporal dementia accounts for 20% to 50% of cases of dementia that occur before age 65. It is the second most common subtype of dementia in patients who have dementia onset before age 65.1,26 Postmortem investigations have shown that the relative frequency of frontotemporal dementia is 3% to 10%.27 Risk factors include a history of head trauma, family history of frontotemporal dementia, and (possibly) thyroid disease. Amyotrophic lateral sclerosis (ALS) can be comorbid with frontotemporal dementia: ALS symptoms may present later in the course of frontotemporal dementia. Alternatively, frontotemporal dementia may present as the ALS progresses.3
Positron emission tomography (PET) has been approved by Medicare to differentiate between AD and frontotemporal dementia, although many private insurers do not pay for PET scans for this purpose.
Frontotemporal lobar degeneration is the generic term for the spectrum of frontotemporal dementia-related pathologies, which are generally divided into 3 groups: frontal-variant or behavioral-variant; progressive nonfluent aphasia; and semantic dementia. The core diagnostic features in the consensus clinical diagnostic criteria for frontotemporal dementia are:
• Insidious onset and gradual progression
• Early decline in social interpersonal conduct
• Early impairment in regulation of personal conduct
• Early emotional blunting, and early loss of insight
Neuropathologically, the report of the Working Group on Frontotemporal Dementia and Pick’s Disease recommended 5 categories for the classification of frontotemporal dementias. These were based on the presence or absence of τ-positive and ubiquitin-positive inclusions, the predominance of microtubule-binding repeats in insoluble t, and the presence of motor neuron disease-type inclusions.28
Various mood abnormalities, such as major depression, affective reactivity and lability, and profound apathy, can be seen in patients with frontotemporal dementia. In older patients who present with mood abnormalities, frontotemporal dementia should be included in the differential diagnosis.29
Nonpharmacological interventions include caregiver support; attending to functional issues, such as driving and home safety; and behavioral management strategies. Pharmacological interventions include SSRIs for such neuropsychiatric symptoms as disinhibition-impulsivity, depression, and repetitive behaviors. Atypical antipsychotics may be needed to control aggressive behaviors. Acetylcholinesterase inhibitors could ex-acerbate disinhibition-impulsivity and repetitive behaviors, and the role of memantine is being investigated.26
