that herpes simplex virus (HSV) type 1 plays a role as a possible cause of AD in people carrying the susceptible versions of the ApoE gene. But it fails to explain why there are increasing numbers of AD patients despite HSV being an old, known virus.
Diagnosis
Core clinical criteria proposed by the National Institute on Aging (NIA) and the Alzheimer’s Association (AA) are intended to facilitate research and the diagnosis of mild cognitive impairment (MCI) by health care providers who do not have access to advanced medical imaging or testing.
In summary, presence of the following are highly suspicious of AD:
2 or more areas of cognitive defects
Progressively worsening memory and other cognitive functions
No disturbance of consciousness
Onset after age 60
Absence of other systemic or neurological disorders associated with progressive cognitive defects
Lab studies are performed only to rule out other possible causes for dementia (e.g., cerebrovascular disease, cobalamin deficiency, syphilis, thyroid disease). There is a possible link between vitamin D deficiency and cognitive impairment. However, vitamin D deficiency has not been identified as a reversible cause of dementia.
The American Academy of Neurology (AAN) recommendations suggest that structural neuroimaging with either a noncontrast computed tomography (CT) scan or magnetic resonance image (MRI) is appropriate in the initial evaluation of patients with dementia. In patients with AD, brain MRIs or CT scans can show diffuse cortical and/or cerebral atrophy, but these findings are not diagnostic. Atrophy of the hippocampi (structures important in mediating memory processes) on coronal MRI is considered a valid biomarker of AD neuropathology but some studies suggest that resting-state functional MRI can help better classify AD, mild cognitive impairment, and healthy brains. Another study suggests that MRI can effectively replace invasive studies on CSF biomarkers. Electroencephalography (EEG) is valuable when prion-related diseases are suspected on differential diagnoses. For example, a common finding in Creutzfeldt-Jakob disease is periodic high-amplitude sharp waves. EEG is also useful to distinguish pseudodementia, wherein a normal EEG is found in a patient who appears profoundly demented.
Cerebrospinal fluid (CSF) biomarkers are determined after performing a lumbar puncture. CSF levels of tau and phosphorylated tau are often found to be elevated, whereas amyloid levels are usually found to be low. A reasonable explanation for these low levels is the evidence of amyloid deposition in the brain rather than CSF. The CSF biomarkers provide a statistical sensitivity of 80% and a specificity of approximately 90%. However, routine CSF testing is not a recommendation outside of research settings. Genotyping for ApoE alleles is another research tool to screen populations at risk, but until recently has been considered of little relevance in diagnosis and management of AD.
Before undergoing testing, patients should receive appropriate counseling on the predictive value of genetic testing for AD. Afterward, patients should receive counseling on the implications of the results. Recommendations on pre- and post-test counseling are detailed in the guidelines from the American College of Medical Genetics and the National Society of Genetic Counselors.
Management and Treatment
For effective management, the patients and families must be involved early; this strategy will help the patient/family to assess and arrange for the treatment and support services. The leading cause of morbidity and mortality in AD are the concomitant medical conditions and adjuvant therapy that should be put to best medical practices for the welfare of the patient.
By and large the management of AD has been aimed at symptomatic relief. The major drug groups used for treatment include:
Neurotransmitter (acetylcholine and glutamate) modulators; cholinesterase inhibitors (ChEIs) like donepezil, rivastigmine, and galantamine; and the partial N-methyl-D-Aspartate (NMDA) antagonist memantine is of significance especially in mild to moderate disease.
Secondary neuropsychiatric symptoms (e.g., depression, agitation, aggression, hallucinations, delusions, sleep disorders) are associated with cognitive and functional impairment. The psychotropic medications used to treat these secondary symptoms include:
Antidepressants (citalopram, sertraline) enhance the social functioning and relieve depression, however, the adverse effects of orthostatic hypotension and adverse drug effects mandate frequent dose adjustments.
Atypical antipsychotics (risperidone, quetiapine, olanzapine, aripiprazole) may be useful in managing behavioral problems, although a 2006 study in the New England Journal of Medicine found them to be only as effective as placebo.
Anticonvulsants (carbamazepine) effectively control agitation and aggression in randomized trials.
Anxiolytics help to relieve sundowning and insomnia.
Antiparkinsonian agents and beta blockers are also used in AD treatment.
Proposed Disease-Modifying Therapies
Immunotherapy (bapineuzumab). Most target beta amyloid. Transgenic mice models showed improvement in behavior and clearance of plaques in some AD patients after administration of Aβ immunoglobulin, but there was an increased incidence of encephalitis in some study groups, thus, this therapy is of limited utility. Passive immunotherapy with Aβ antibodies is an ongoing research, however, its relevance is questionable because only a limited quantity can cross the blood–brain barrier.
Secretase inhibitors (tarenflurbil, semagacestat) aim to increase the concentration of Aβ 1–40 and to reduce Aβ 1–42.
Amyloid aggregators (tramiprosate) failed in three trials, thus they are of questionable benefit.
Copper or zinc modulators (PBT2). Experimental evidence exists that copper and zinc are found in abundance in amyloid plaques and interfere with NMDA receptor responses. Clinical benefit has been observed as decreased CSF Aβ following administration of PBT2/clioquinol.
Tau aggregation inhibitors (methylthioninium chloride, lithium and sodium valproate) have been known to target tau phosphorylation and aggregation in animal models.
Natural products and vitamins (vitamin E, ginkgo biloba, omega 3 fatty acids, and docosahexaenoic acid) have been of questionable efficacy in randomized controlled trials.
Diagram of how microtubules disintegrate with Alzheimer’s disease. Abnormal clusters of protein fragments, called plaque, build up between nerve cells. Dying nerve cells contain tangles, which are made up of twisted strands of another protein. Scientists are unsure what causes cell death and tissue loss in the Alzheimer’s brain, but plaques and tangles are prime suspects. (National Institute on Aging)
Suppression of brain inflammation. Epidemiologic studies suggest that some patients on long-term anti-inflammatory therapy have a decreased risk of developing AD. Nonetheless, no randomized clinical trial longer than 6 months has demonstrated efficacy of anti-inflammatory drugs in slowing the rate of progression of AD.
Nerve
