Biomarkers of Alzheimer Disease FREE

The most successful diagnostic tests for AD are based on advances in molecular genetics, and are limited to early-onset familial AD. Missense mutations in 3 genes—PS1on chromosome 14, PS2on chromosome 1, and APPon chromosome 21—all cause familial AD. In all, only a few hundred families carry these identified mutations that cause autosomal dominant AD. Most of these pedigrees have PS1mutations and onset of dementia at age younger than 50 years; mutations in the APPgene are rare, and there are only 2 pedigrees with PS2mutations. From a practical viewpoint, it is reasonable to search for a PS1mutation in familial AD with very early onset, but searching for missense mutations in individuals with familial AD with onset older than 50 years or in individuals without a family history of AD is rarely worthwhile. In contrast to these deterministic genetic causes of AD, the apolipoprotein E (apoE) ϵ4 allele is a risk factor for AD. Numerous studies^4- 5attest to the fact that the ϵ4 allele is 3 to 4 times more common in AD, including the most common category of late-onset disease without known family history, than in individuals who are not demented. As opposed to the missense mutations, however, the ϵ4allele is not a deterministic cause of AD, only a risk factor. Thus, relying on the apoEgenotype alone to establish a diagnosis of AD is inadequate because this measure by itself has low sensitivity and specificity. Many individuals, perhaps a majority, who inherit ϵ4do not develop AD even at an advanced age. Nonetheless, when used in conjunction with conventional diagnostic workup, finding an ϵ4allele adds a small percentage of confidence to the clinical diagnosis.⁶

Genetics aside, the most convincing diagnostic tests will be those that seek to detect in life the histopathologic hallmarks characteristic of AD that are observed in the brain at death. The neurofibrillary tangle and neuritic plaque are the principal lesions associated with AD. The neurofibrillary tangle is composed primarily of hyperphosphorylated tau, which is a cytoskeletal protein. Diffuse amyloid deposits pepper the AD brain; the mature neuritic plaque contains a compacted core of amyloid protein. Much of this amyloid is a 42-amino acid peptide derived from proteolytic cleavage of a larger amyloid precursor protein molecule. This peptide, called Aβ_1-42, has putative neurotoxic properties that may initiate a cascade of events leading to neuronal dysfunction and death.^7- 8As a result of intense investigation into the mechanism whereby tangles and plaques form, antibodies directed toward epitopes of tau and toward different amyloid fragments have been adapted for clinical use. Under normal conditions, a small amount of soluble Aβ_1-42circulates in the bloodstream. In individuals with the deterministic mutations for AD in PS1, PS2, and APP, Aβ_1-42levels in the blood are increased compared with levels in sporadic AD, which generally do not differ from levels measured in individuals without dementia.⁹Although potentially useful in diagnosing familial AD, measuring Aβ_1-42levels in the blood is limited to research laboratories and is not in widespread use. Even if this test were widely available, information to date indicates plasma Aβ_1-42levels would not be diagnostically useful in most patients with nonfamilial or late-onset AD.

The CSF bathes the brain, and is potentially a more accurate representation of what goes on in the brain than measuring tau or Aβ in the peripheral bloodstream. Both tau and amyloid fragments can be measured in CSF; their detection forms the basis for the development of commercial diagnostic tests for AD. There is general consensus that CSF levels of tau are significantly increased in AD compared with both healthy control subjects and patients with non-AD neurologic diseases.¹⁰Similarly, there is general consensus that levels of Aβ_1-42are characteristically decreased in AD, whereas levels of Aβ total (Aβ_1-42and Aβ_1-40) are no different in patients with AD than in control subjects.¹¹The crucial question is whether the increases in tau and decreases in Aβ_1-42occur with sufficient frequency and magnitude that they offer diagnostic value. To date, the answer has been no. Both measures suffer from poor accuracy: if sensitivity is set at a satisfactory 80% to 90% level, specificity is low, and vice versa. Combining the 2 measures increase accuracy slightly, but many individual values remain in a diagnostically indeterminate range.^10,12A further limitation on using these measures as diagnostic tests is that few cases of dementia with a clinical diagnosis of probable AD and the putative diagnostic profile of low Aβ_1-42and high tau in CSF during life have been confirmed pathologically. Other CSF markers, such as neuronal thread protein, have been proposed as biomarkers for AD,¹³but require independent confirmation. It is likely that refinements on current Aβ_1-42, tau, or neuronal thread protein assays will occur as a result of attempts to improve diagnostic accuracy. At present, these tests can be recommended only as an adjunct to comprehensive diagnostic assessment in difficult cases. Confidence in the diagnosis increases when the CSF profile fits that expected in AD, but indeterminate results should be anticipated.

What can we expect from an ideal biomarker for AD? It is probably unrealistic to expect that any biomarker be 100% specific and sensitive for the diagnosis of AD. At autopsy, the brains of many patients with definite AD have other lesions, including infarcts, gliosis, and Lewy bodies. In any given instance, it is difficult to be certain which of these was etiologically important in producing dementia. Clinicians may eventually follow the lead of pathologists, who have adopted a less dichotomous diagnosis of AD vs no AD than in the past. According to the National Institute on Aging and the Reagan Research Institute of the Alzheimer's Association consensus criteria for the neuropathological diagnosis of AD,¹⁴the diagnosis of AD is probabilistic. That is to say, the diagnosis of AD is based on a likelihood estimate in which all pathologic findings are described, and the extent and intensity of plaques and tangles graded. If pathologists examining the entire brain are cautious in diagnosing AD unequivocally, then perhaps clinicians, armed with indirect molecular and biochemical measures of plaques and tangles, should be even more reserved. Viewed from this perspective, biological markers of AD may turn out to be more useful in tracking the course of illness and documenting the response to treatment than in diagnosis.

Accepted for publication June 20, 1998.

Corresponding author: John H. Growdon, MD, Department of Neurology, Massachusetts General Hospital, Wang Ambulatory Center, Suite 830, John H. 15 Parkman St, Boston, MA 02114.