Rethinking the diagnostic and treatment approach to Alzheimer disease: A fresh look

The traditional view of dementia experienced in later life has focused on a unitary disease causation, most often Alzheimer disease (AD). Traditional teaching has led to the diagnosis of AD through excluding items in a long and daunting list of other dementia causes. Previously, the outlook for modifying disease onset through the treatment of risk factors was bleak, resulting in diagnostic and therapeutic nihilism. In the past decade, however, with better characterization of the clinical phenotype of the disease and with the approval of cholinesterase inhibitors (ChEIs) for symptom control, much has changed.

Departing from the traditional monolithic view of dementia has allowed us to recognize that in the aging brain there is a critical interaction between degenerative, vascular, and other mechanisms of brain injury that culminate in the clinical expression of dementia. Cerebral infarcts, even when small and incidental, will increase the risk of dementia by 20 times in individuals with some AD senile neuritic plaque and neurofibrillary tangle pathology.[1] In relation to these findings, it has been shown that treating systolic hypertension in asymptomatic individuals in middle to later life is associated with a significant reduction in dementia risk.[2] The goal of preventing and reducing the effects of both symptomatic strokes and asymptomatic cerebrovascular lesions, including white-matter lesions and lacunar infarcts, is now clearly established. Level 1 evidence from randomized controlled trials (RCTs) now supports a recommendation to treat hypertension to prevent both cognitive impairment and dementia.

Estimates suggest that if the onset of AD could be delayed by 5 years, the prevalence would be reduced by 50% within that generation.[3] Emerging data on risk factors and protective factors for AD also suggest that there are other possible intervention strategies beyond controlling hypertension that might be implemented in the primary care setting. In a number of retrospective studies, the use of statins has been associated with a significant dementia risk reduction (>50%).[4-6] Whether this is mediated through LDL cholesterol lowering or through another pleiotropic action of the statins has not been determined. There is also considerable evidence that the use of nonsteroidal anti-inflammatory drugs (NSAIDs) is associated with a reduced incidence of AD.[7] The efficacy of both statins and NSAIDs will need to be tested in prospective randomized clinical trials before these medications can be recommended as a standard of care for either primary prevention or for the treatment of established AD. Researchers are currently directing the necessary RCTs to address these leads. Other pharmacological interventions, including the treatment of hyperhomocystinemia and the use of vitamin supplements and gingko biloba, as well as nonpharmacological programs of cognitive training, are being investigated as approaches to reducing AD risk.

Diagnosis

During the past decade, the traditional exclusionary diagnostic approach to AD has changed to one of positive phenotypic identification. AD is the most common cause of dementia, accounting for 50% to 70% of dementia cases (Table), doubling in prevalence every 5 years after age 65.[8] The key clinical phenotypic features can be elicited with an assessment in an office setting. Collateral informant history is essential, as patients will frequently exhibit anosognosia and deny their symptoms or impairment. There is a characteristic core loss of short-term memory elicited both from the history and on tests of new learning and event recall. This memory deficit is particularly underscored by the patient’s failure to respond to cueing with either a categorical or forced-choice prompt. Long-term memory is initially better preserved but later fails in concert with time-sequencing losses. Other domains of cognition, particularly executive function, become impaired early in AD, with change apparent in decision-making abilities, self-confidence, organizational abilities, and planning skills. Language deficits usually begin with word-finding troubles that often herald a progressive aphasia. Problems with learned motor skills (apraxia) develop and visuospatial abilities become impaired. To reach the threshold of diagnosable dementia, these cognitive impairments (memory loss plus a deficit in at least one other cognitive domain) must interfere with social functioning.

In the office setting, global screening cognitive measures such as the Mini-Mental State Exam (MMSE),[9] the Modified Mini-Mental State Exam (3MS),[10] or the Mattis Dementia Rating Scale (MDRS) allow the objective identification of cognitive deficits and are a necessary part of the diagnostic process. They each have total scores that can indicate a significant cognitive disorder and can be evaluated for evidence of the specific cognitive domains impaired. Both age and education must be taken into account in the interpretation of these global scores. Features of “atypical for AD dementia” include the early presence of any of the following: gait disorder, incontinence, aphasia, or prominent behavioral changes.[12] Focal neurological signs, either motor or sensory, are not expected in AD and should lead to more detailed investigation to determine alternative causes.

There is no single diagnostic test for AD. Recommended laboratory investigations include CBC and testing for thyroid-stimulating hormone, calcium, glucose, and electrolytes, which allow for the exclusion of metabolic disorders that may adversely effect cognitive functioning though rarely cause a progressive dementia.[13] Neuroimaging with either CT or MRI allows visualization of key neuroanatomic regions such as hippocampi/medial temporal lobe and allows an estimate of cerebral atrophy and the presence of focal brain abnormalities, particularly cerebrovascular lesions. Unfortunately, neuroimaging lacks diagnostic sensitivity and specificity and must be considered supplementary to the clinical assessment. Both typical AD and atypical dementia can be identified in the primary care setting with the help of a clinical algorithm (Figure).

Treatment

The treatment of typical AD with cholinesterase inhibitors is recommended for all patients without contraindications (see articles referring to ChEIs in this issue: “Current therapy,”and “Treatment Efficacy in Alzheimer Disease (TREAD) conference.”) Where pharmacological management of behavioral symptoms is needed, specific target symptoms should be identified and endpoints established. With the expected approval of memantine, an N-methyl-D-asparate (NMDA) receptor antagonist, clinicians will soon have another treatment agent—one that appears to have additive benefits when used with the cholinesterase inhibitors.

In addition to pharmacological management, all patients with dementia need a multifaceted care plan. Diagnostic disclosure in the early stages of AD or atypical dementia should lead immediately to the necessary legal and financial planning such as arranging for a representation agreement and power of attorney. Social agencies, including the Alzheimer Society of BC and the continuing care units of the regional health authorities in BC, are important contact points for patients and families. Access to community support services, day-care programs and, eventually, institutional care can be organized through a health authority, while caregiver support is available through the Alzheimer Society.

Assessment and advice on fitness to drive are also needed as part of the care plan, since all patients with dementia will usually lose their ability to drive by the mild to moderate stages of impairment. In BC, when an objective measure of driving fitness is required, physicians can refer patients to private driving assessment units at Pearson Hospital and Drive-Able, where on-road driving fitness testing can be safely undertaken. Planning for the anticipated loss of driving is generally much better accepted at the time of diagnosis than at a later disease stage, when confrontation and immediate physician action are required.

Conclusion

There is now proven benefit to treating vascular risk factors in preventing all forms of dementia. The diagnostic approach to Alzheimer disease has shifted from an exclusionary one to a positive phenotypic identification. Current therapies for AD are improving with the use of ChEIs and the anticipated approval of the NMDA receptor antagonist memantine.

Patients with all forms of dementia need a care plan that includes diagnostic disclosure, legal and financial planning, assessment of driving fitness, and community-based programs and support systems. Management of AD and atypical dementia also requires providing educational, medical, and social support for caregivers.

Competing interests
At different times over the past year, Dr Feldman has had a financial interest/arrangement or affiliation with the following organizations: Pfizer, Eisai, Novartis, Janssen-Ortho, Lilly, AstraZeneca, Sanofi Synthelabo, GlaxoSmithKline (grant/research support; external); Pfizer, Eisai, Novartis, Janssen-Ortho, Servier, Sanofi Synthelabo, GlaxoSmithKline, Myriad, Targacept (consultant); Pfizer, Eisai, Janssen-Ortho, Novartis, Forest (speakers' bureau or CME programs).

Table. Common causes of dementia in later life.

Source: Adapted from Feldman H, Levy AR, Hsiung GY, et al. A Canadian cohort study of cognitive impairment and related dementias (ACCORD): Study methods and baseline results. Neuroepidemiology 2003;22:265-274.

This article has been peer reviewed.

Dr Feldman is professor and head of the Division of Neurology at UBC and the director of the UBC Alzheimer Clinical Trials Unit at UBC and Vancouver Hospital.