Volume 61, Number 1 - Winter 2010

 

By Allan Bernstein, MD

Alzheimer’s disease (AD) is a progressive neurodegenerative disorder characterized clinically by memory impairment and cognitive dysfunction. The AD brain shows prominent cerebral atrophy and neuron loss, especially involving the medial temporal lobe; but these findings are non-specific. The signature neuropathology of AD is defined by two lesions: (1) senile plaques composed of ß-amyloid (Aß), a cleavage product of the amyloid precursor protein, and (2) neurofibrillary tangles composed of aberrantly phosphorylated tau, a microtubule-associated protein. Clinical diagnosis is about 87% accurate for AD, though it may take years to arrive at the correct determination. 

Clinical symptoms of AD unfold slowly and at widely varying rates. Thus, identifying biomarkers that track with AD progression is critical to enabling early decision-making regarding disease-modifying therapies. Although not a biomarker per se, amnestic mild cognitive impairment (aMCI) is known to be an early precursor to AD, with conversion to AD occurring in 15% of the affected individuals, per year. Accurately identifying aMCI would allow an even earlier window for treatment, potentially minimizing the disability already in place by the time the clinical diagnosis of AD is made. 

Biomarkers for AD can be divided into three major areas: genetics, chemistry and imaging. All have been available for many years, but refinements in interpretations have improved their validity.

Most AD is not familial and occurs sporadically after age 65. Five percent of AD is early onset (before age 60), and 62% of those cases are familial. One susceptibility gene, apolipoproteinE, has been identified, along with three causative genes: amyloid precursor protein, presenilin 1 and presenilin 2. The three causative genes account for 50% of early-onset familial Alzheimer’s dementia (EOFAD). First-degree relatives have a 50% risk of EOFAD. 

ApolipoproteinE (APOE), on chromosome 19, has three alleles, E2, E3 and E4. One of the functions of APOE is to break down amyloid. Of the alleles, E2 is the most effective at this task, and E4 the least effective. Not surprisingly, E4 is most often associated with AD, but only in the late-onset type. Homozygotes for E4 are identified in 2% of normal elderly and 17% of autopsy-proven AD. Heterozygotes (E2/E4 and E3/E4) also show a slightly higher association with AD than non-E4s. There is no E4 association seen in non-amyloid dementias such as fronto-temporal or Lewy body dementia. 

Amyloid precursor protein (APP), on chromosome 21, has multiple mutations associated with AD. For example, Down’s syndrome, a trisomy 21 condition, has a very high incidence of AD in middle age. 

Presenilin 1 (PSEN1), on chromosome 14, plays a role in cleaving amyloid beta, with mutations of PSEN1 producing longer forms of Aß that are prone to aggregation and neurotoxicity. One hundred fifty mutations of PSEN1 have been identified to date. These mutations can cause early-onset AD; up to 70% of EOFAD is associated with PSEN1. 

PSEN2, on chromosome 1, has a 5% association with EOFAD. Two additional AD-associated genes (CLU and CR1) were identified in 2009. CR1 appears to be involved in inflammation of the central nervous system, and CLU is another type of apolipoprotein-related gene. Their roles and risks are not yet fully understood. 

Attempts to identify serum markers of AD have not been successful. The most promising studies, involving c-reactive protein (CRP) have shown modest association with dementia, but not specific for AD. There is a higher association of CRP in patients with mild cognitive impairment. 

The most promising markers have all come from cerebrospinal fluid (CSF). Amyloid monomers are reduced in CSF as more and more of the substance is converted to insoluble oligomers and deposited in the central nervous system as plaques. Specifically, Aß 42 is reduced in CSF in Alzheimer’s patients, though it is also reduced in those with vascular dementia, Lewy body dementia or fronto-temporal dementia. Tau protein (t-tau) is increased in CSF, though this can be found in stroke, multiple sclerosis and other dementias. Phosphorylated tau protein (p-tau) is more specific for AD and is also elevated in the CSF. 

Recent studies have calculated the ratio between Aß and p-tau, arriving at a better correlation with clinical and imaging studies. Future studies of therapeutics are likely to include CSF analysis for both diagnosis and outcome measures.

The main role of imaging in studying AD is to rule out “something else.” CT scans are adequate to identify normal pressure hydrocephalus, large strokes, intracranial bleeds, tumors and subdural hematomas. CTs are also fast and relatively inexpensive. 

MRIs have increased our ability to diagnose smaller strokes and demyelinating conditions; to calculate volume loss in multiple parts of the brain; and to calculate blood flow to various structures. Magnetic resonance angiography (MRA) can identify large and medium-sized vessels and further define areas of reduced flow. 

MRI can also show atrophy of the hippocampus using volume calculations. These show a 10% atrophy in mild AD and a 30% atrophy in moderate AD. Hippocampal atrophy progresses at 2-6% per year in AD patients, compared to <2% in age-matched controls. 

Serial measurements may help determine the risk of mild cognitive impairment converting to AD. Perfusion MRI shows decreased blood flow in parietal and cingulate regions. Functional MRI demonstrates reduced activation at encoding stages and increased activation at retrieval stages, which is consistent with encoding failure and compensatory attempts in other areas. Functional MRI also shows abnormal activity in APOE E4 carriers, suggesting pathologic changes years before clinical changes appear. 

A recent MRI study created gray-matter maps and correlated them to blood-flow maps.[1] Patients with AD exhibit atrophy of gray matter and increased blood flow to the remaining tissue, suggesting a compensatory increase in metabolism in the remaining tissue. This condition may also represent inflammation in the remaining tissue, reflecting underlying inflammatory aspects of progressive AD.

Regional cerebral perfusion studies with single photon emission computed tomography (SPECT) were some of the earliest to distinguish AD patients from controls. Using tracers, regional perfusion was found to be decreased in AD in similar regions as that detected by fluorine-18 fluorodeoxyglucose positron emission tomography (FDG-PET), including parieto-temporal and posterior cingulate cortices and medial temporal lobe structures. Decreased cerebral perfusion by SPECT studies in presymptomatic individuals also predicted progression to dementia. 

FDG-PET represents one of the most studied imaging biomarkers for AD, with dozens of studies reported to date. FDG-PET measures alterations in the metabolic rate of glucose consumption (MRglc) by using FDG as a tracer. The imaging gives a quantitative estimate of the local cerebral rate of glucose metabolism, thereby providing information on neuronal and synaptic dysfunction. AD patients have widespread reductions in brain MRglc as compared to normal elderly. In early AD, specific regional metabolic decreases have been observed in parieto-temporal and posterior cingulate cortices, as well as the hippocampal formation. 

Various amyloid-binding PET radiotracers have been developed. The most widely studied is Pittsburgh compound B (PiB) which binds to fibrillary Aß. PiB will accumulate in neocortical regions known to contain a high concentration of plaques. In studies on mild AD patients, PiB binding was 40-90% higher than controls.[2] 

One surprising observation using PiB is that many patients in their 30s and 40s have high amyloid loads. Because PiB imaging is only 10 years old, this cohort has not yet been followed into ages more typical for developing AD.

Multiple biomarkers have been studied for predicting and quantifying AD, including diagnostic markers and markers to track treatments, both current and future. All of these biomarkers seem better than the currently available evaluation and tracking systems, but each has significant limitations. Serum markers still do not accurately define AD. CSF markers, while more specific to AD, are technically difficult to obtain on large populations. FDG-PET and PiB imaging is expensive, not widely available and often not specific to the type of dementia being studied.

Genetic markers are likely to be used as predictors of disease rather than in tracking disease. If we can develop a preventive treatment, we may be able to identify high-risk patients and decrease their likelihood of developing clinical AD. Until we have preventive treatments, however, gathering genetic data on patients is probably not warranted. 

The most promising technology appears to be MRI, using the widely available 1.5 Tesla units, along with the 3, 5 and 7 Tesla units used for university research. MRIs can calculate blood flow, gray-matter maps and tissue density, as well as track areas of atrophy. While they are noisy, claustrophobic, uncomfortable, moderately expensive and difficult to use with some AD patients, they use no ionizing radiation or radioactive tracers. Moreover, they can be repeated multiple times as a means of tracking progression of disease or effect of treatment.