Many Alzheimer's Patients Have Minimal Amyloid Plaque

Pauline Anderson

August 25, 2015

More than a third of apolipoprotein E (APOE) ε4 noncarriers diagnosed with mild to moderate Alzheimer's dementia have minimal amyloid plaque in the cerebral cortex, autopsies performed on these patients show.

The results confirm earlier amyloid positron emission tomography (PET) studies and reports from the National Alzheimer's Coordinating Center database.

This means that those earlier findings "aren't just an artefact of the PET scan" and that there may be implications for research into Alzheimer's treatments, said study author Eric Reiman, MD, executive director, Banner Alzheimer's Institute, director, PET Center, Banner Good Samaritan Medical Center (both in Phoenix, Arizona), and director, Arizona Alzheimer's Disease Consortium.

"The next question is, is this a misdiagnosis or is there something else going on" in patients with dementia but few amyloid plaques, he said.

Dr Eric Reiman

In any case, the new research findings don't mean that the amyloid hypothesis in Alzheimer's disease (AD) is dead, according to Dr Reiman. That, he said, will have to wait for results of prevention trials now under way.

Their results were published online August 24 in JAMA Neurology.

Another Pathology

The study included 100 carriers and 100 noncarriers of the APOE ε4 Alzheimer's genetic risk allele who had a clinical diagnosis of mild to moderate Alzheimer dementia at their last clinic visit and who had died and come to autopsy within 2 years.

Carriers were slightly younger at the onset of symptoms (75.8 years vs 78.5 for noncarriers), at their last clinical evaluation, and at the time of death. Scores at the last clinical evaluation for the Mini-Mental State Examination and clinical dementia rating–sum of boxes were 20.3 and 8.5, respectively, for noncarriers and 20.6 and 8.0, respectively, for carriers.

The researchers found that 13% of carriers and 37% of noncarriers had no more than a minimal amount of amyloid plaque. Among the noncarriers, 28% had both minimal neuritic plaques and minimal diffuse plaques.

The researchers wondered whether dementia in patients with minimal plaques could be due to another form of pathology, for example, tangle pathology, which along with amyloid is a cardinal feature of AD.

Whereas amyloid accumulates outside of neurons and so can be more easily targeted with therapies, tau accumulates primarily inside neurons, where it's more difficult for an antibody to target.

The study showed that noncarriers with minimal neuritic plaques had on average lower Braak stages for neurofibrillary tau pathology compared with those with moderate to frequent neuritic plaques (43.2% vs 95.2% with Braak stages II to VI; P < .001).

Dr Reiman pointed out that although close to 45% of individuals with minimal plaque had evidence of somewhat extensive tau pathology, a similar percentage of older adults without dementia had the same amount of tau pathology.

Of the 50 persons with no more than sparse neuritic plaques, 5 had a normal brain and 33 had a non-AD pathologic diagnosis, including 8 with vascular disease, 6 with Lewy body disease, 5 with hippocampal sclerosis, 4 with frontotemporal lobar degeneration, and 3 with tangle-only dementia.

These new results suggest that there's a group of patients without amyloid or another form of pathology who have dementia "and we don't know why just yet," said Dr Reiman.

He would like to learn more about these patients, he said. "It would be helpful to know, for instance, if there are any differences in their clinical presentation or clinical course," he notes. "It would also be good to learn about risk factors for that less common form of dementia and molecular mechanisms that would provide a clue to what`s going on."

Several clinical trials are investigating various approaches to preventing AD in those at risk, including a study in amyloid-positive older adults and another in APOE ε4 mutation carriers who have an elevated chance of developing amyloid. Such studies use PET and cerebrospinal fluid as amyloid biomarkers.

These studies should help cement the amyloid hypothesis or bury it for good, according to Dr Reiman.

"We think that these prevention trials, particularly those studies with individuals at genetic risk that include about a third of subjects who don't yet meet criteria for moderate to frequent plaques, will provide a better test of the amyloid hypothesis than failed trials of those in the latter preclinical or clinical stages of Alzheimer disease when the failure begs the question of whether it was too little too late."

The idea, said Dr Reiman, is to "set the stage for the field to rapidly evaluate the range of promising prevention therapies ultimately with biomarker endpoints, not waiting to see who goes on to develop symptoms so that we could have chance to find one that works within 10 years."

Dr Reiman is convinced that "there's something related to amyloid or some byproduct of the amyloid precursor protein" that contributes to dementia. The genetics of AD alone support that, "but at moment it remains a hypothesis," he said.

One theory is that AD starts with amyloid deposition relatively early, triggering several events, including inflammation, tangle formation, and loss of synapses in neurons. "If the amyloid hypothesis is correct and it is just too little, too late to exert an effect, maybe there's an opportunity in patients with Alzheimer dementia to simultaneously target earlier and later stages of the disease," said Dr Reiman.

He used the analogy of a campfire where amyloid is the kindling (the earlier stages) and tau pathology and synaptic loss are the ensuing raging fire (the later stages).

But if the prevention trials are negative, "it will encourage the field to redirect their efforts to other elements of the disease," said Dr Reiman. "One could argue that in the drug discovery process, we need a more diversified approach to treatment in any case."

"Strong Rationale" for Biomarkers

In an accompanying editorial, Stephen Salloway, MD, Department of Neurology, Albert Medical School of Brown University, Providence, Rhode Island, and Reisa Sperling, MD, Department of Neurology, Brigham and Women's College, Massachusetts General Hospital and Harvard Medical School, Boston, said the findings provide "a strong rationale" for using amyloid biomarkers in AD clinical trials to recruit more homogenous populations most likely to respond to amyloid-based treatments.

"The question we will ultimately face is when should APOE and amyloid PET be performed in the clinic," they write.

Dr Salloway and Dr Sperling noted that a consensus panel of the Alzheimer's Association and the Society of Nuclear Medicine and Molecular Imaging has developed recommendations on the appropriate use of amyloid PET in clinical practice but that APOE testing isn't included in the appropriate use recommendations.

"Given that APOE carrier status is a strong predictor of amyloid and AD pathology, it may be prudent to consider a hierarchical approach to amyloid biomarkers based on APOE genotyping."

They concluded that distinguishing between AD and non-AD pathologies will become increasingly important as more targeted treatments become available for preclinical and early stages of the disease.

The National Alzheimer Coordinating Center (NACC) database is funded by a grant from the National Institute on Aging (NIA)/National Institutes of Health. NACC data are contributed by the NIA-funded Alzheimer disease center grants that support data collection. Additional support was provided by the Arizona Alzheimer's Consortium and NACC. Dr Reiman has disclosed no relevant financial relationships. Dr Salloway reported receiving research support from Functional Neuromodulation, Biogen, Merck, Genentech, Roche, Lilly, and Avid Radiopharmaceuticals and receiving consultation fees from Biogen, Merck, Piramal, Lilly, Genentech, and Roche. Dr Sperling reported receiving research support from Janssen and Eli Lilly and Co and serving as a consultant to Biogen, Bracket, Genentech, Isis Pharmaceuticals, Janssen, Lundbeck, and Roche.

JAMA Neurol. Published online August 24, 2015. Abstract Editorial

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