This is part 2 of a two-part series. See Part 1

Since the advent of brain amyloid imaging, researchers have been surprised to find that a substantial minority of people clinically diagnosed with Alzheimer’s disease have no detectable amyloid β deposits in the brain. In some large trials, up to one third of the ApoE4-negative ‘AD’ patients also turned out to be negative on amyloid scans (see, e.g., ARF related news story). “Amyloid-negative neurodegeneration is more common than we would have suspected,” David Wolk, University of Pennsylvania, Philadelphia, told Alzforum at the Alzheimer's Association International Conference, held July 14-18 in Boston, Massachusetts.

What do these people have? Researchers at AAIC presented the latest on these patients. They seem to represent a heterogeneous group. In some studies, half of them show an AD-like pattern of neurodegeneration on MRI scans and analysis of fluid biomarkers, and progress rapidly from cognitive impairment to dementia. In other studies, amyloid-negative participants seem to have a milder, slower-progressing disorder than AD, with distinct patterns of neurodegeneration. Neurodegeneration in the absence of amyloid has been dubbed “suspected non-AD pathology” (SNAP). While the underlying pathologies remains mysterious, researchers agree this will be an important group to understand.

In Boston, Wolk described how about one-quarter of patients with mild cognitive impairment (MCI) in the Alzheimer’s Disease Neuroimaging Initiative (ADNI) cohort (see Part 1) had no sign of brain amyloid. Of these, 40 percent tested positive for markers of neurodegeneration such as elevated cerebrospinal fluid (CSF) phospho-tau and an AD-like pattern of cortical thinning. Of these 16 patients, four, or 25 percent, developed clinical AD in one year, compared to a rate of 4 percent among people without amyloid or markers of neurodegeneration. This is similar to rates reported by the Mayo Clinic for their SNAP group, (see Petersen et al., 2013). “It suggests that amyloid doesn’t tell the whole picture with regard to development of dementia,” Wolk told Alzforum.

Other studies show similar rates of progression. Consider the Australian Imaging, Biomarkers, and Lifestyle (AIBL) Flagship Study of Ageing. Of its 87 participants with MCI who had MRI and PiB PET brain scans, 28 were amyloid-negative. Eight of them developed dementia in three years, and five of these eight appeared to have AD. None were ApoE4 carriers, reported Christopher Rowe from Austin Hospital, Melbourne, Australia. Rowe did not divide the amyloid-negative group into people with and without neurodegeneration, but he did find that having hippocampal atrophy increased the odds of developing AD. By contrast, 77 percent of amyloid-positive participants progressed to AD within three years.

What might be happening in amyloid-negative patients? One possibility is that they have a non-AD dementia that resembles Alzheimer’s clinically, such as frontotemporal dementia or Dementia with Lewy Bodies. However, Wolk pointed out that in ADNI, the pattern of brain shrinkage and its relationship to CSF phospho-tau resembled that of AD, making it less likely that they have a non-AD dementia. He suggested they might have amyloid that current PET tracers cannot detect. PET ligands bind to fibrillar amyloid deposits but not, for example, to diffuse amyloid or soluble Aβ oligomers, which are widely believed to be more toxic. There is also discussion of amyloid strains.

At AAIC, Brad Dickerson at Massachusetts General Hospital, Boston, hinted that tau pathology underlies some cases of amyloid-negative MCI. He reported that in a cohort of 167 MCI patients, higher CSF tau correlated with cortical thinning, particularly in the medial temporal lobe where shrinkage associates with memory loss. In MCI patients without brain amyloid, neurofibrillary tangles in the medial temporal lobe accounted for memory impairments, Dickerson said.

Other Theories on SNAP
Hyo Jung Choi at Seoul National University Hospital, South Korea, proposed that apolipoprotein A1 could play a crucial role in SNAP. ApoA1 is the main component of high-density lipoprotein (HDL), aka the “good cholesterol.” Choi followed 28 people with amnestic MCI for one year. About half of them had a positive amyloid brain scan, and in this group, about 25 percent developed dementia. Nobody who was amyloid-negative progressed within the year. This subset had low serum ApoA1, which correlated with poor cognition and a distinct pattern of brain atrophy. The pattern showed more shrinkage in temporal and frontal lobes and less in medial temporal lobe, compared to brain atrophy in people who did have amyloid. This suggests that a distinct degenerative process occurs in people without brain amyloid, Choi said.

How might ApoA1 contribute to degeneration? ApoA1 has antioxidant properties and can attenuate the inflammation caused by microglia and astrocytes. Therefore loss of ApoA1 might exacerbate neuroinflammation, Choi suggested. In AD mouse models, too little ApoA1 leads to greater buildup of amyloid in blood vessels and poorer cognition, while abundant ApoA1 protects against these problems (see ARF related news story).

Vascular damage in the brain can damage cognition independently of amyloid burden (see ARF related news story). Duygu Tosun from the University of California, San Francisco, examined diffusion-weighted MRI scans, which show axonal integrity, from a small group of MCI patients in ADNI2 and ADNIGo. Amyloid-negative patients had damage in their fornix, the bundle of fibers that connect the hippocampus to the hypothalamus, compared to amyloid-positive patients and controls, she reported. These patients also had more white matter lesions and vascular damage than controls. Moreover, they showed a different pattern of brain atrophy and hypometabolism than the amyloid-positive group. All told, her data suggest that amyloid-negative MCI might represent vascular cognitive impairment, Tosun said.

At this point, the amyloid-negative group appears to represent a mixture of several different types of pathology, researchers agreed. Most of the studies to date have been small, and larger samples will be needed to parse the reasons for amyloid-negative cognitive impairment, they concluded.—Madolyn Bowman Rogers.

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  1. Time to SNAP out of it?

    Many of us have been consistently voicing the opinion that it will be helpful to widen our notion of pathogenesis of late-onset AD and also include non-amyloid agents/mechanisms as potential causative factors. If anything, findings from biomarker studies discussed above and those from genome-wide association studies (GWAS) and systems-biology studies identifying abnormal immune networks in late-onset AD (discussed previously in Alzforum) lend strong support to such thinking. The observations that about 1-in-4 or 1-in-3 people diagnosed with mild cognitive impairment or AD exhibit neurodegeneration, elevated cerebrospinal fluid tau, and cortical thinning in the absence of amyloid plaques (Suspected Non-AD Pathology; SNAP) are too compelling to be swept away as being non-AD cases (which, incidentally, would mean that the prevalence of AD is being overestimated by 25-30 percent). If their presence is confirmed in larger samples, such cohorts of patients, when juxtaposed with PiB-positive cognitively normal individuals, leads to the conclusion that the correlation between amyloid and dementia is even weaker than previously suspected. This is not a polemic but something that needs to be considered as we go forward with therapeutic treatments for AD. This is not a polemic but something that needs to be considered as we go forward with therapeutic treatments for AD.

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References

News Citations

  1. Biomarkers Predict Alzheimer’s, But Shoe Does Not Always Fit
  2. ApoA1: Does Good Cholesterol Protect the Brain?
  3. Vascular Dementia or Alzheimer’s: Is the Delineation Emerging?

Paper Citations

  1. . Criteria for mild cognitive impairment due to alzheimer's disease in the community. Ann Neurol. 2013 May 20; PubMed.

Other Citations

  1. ARF related news story

Further Reading

News

  1. Longitudinal Data Stand Out at AD/PD Imaging Satellite