Two studies from JAMA Neurology raise doubts about whether suspected non-Alzheimer’s pathophysiology – a brain biomarker construct suspected by some to be an Alzheimer’s disease precursor – truly belongs on the Alzheimer’s spectrum.

A team from Washington University in St. Louis concluded that neurodegeneration in isolation without beta-amyloid deposition – the definition of suspected non-Alzheimer’s pathophysiology (SNAP) – “often represents comorbid influences rather than emerging” Alzheimer’s disease (JAMA Neurol. 2016 Aug 22. doi: 10.1001/jamaneurol.2016.2642 ).

A team from Harvard Medical School in Boston came to a similar conclusion, finding that patterns of neurodegeneration in brain regions vulnerable to Alzheimer’s disease (AD) “are not specific to AD processes among [clinically normal] individuals. Instead, multiple causes likely contribute to the biomarker construct of SNAP” (JAMA Neurol. 2016 Aug 22. doi: 10.1001/jamaneurol.2016.2237 ).

The relationship between SNAP and AD is, for now, mostly of concern to researchers. SNAP was originally linked to cerebral vascular disease and other age-related problems, but since it was proposed a few years ago as an addition to the National Institute on Aging (NIA)–Alzheimer’s Association’s research criteria for preclinical AD, it’s been unclear how – or if – it really fits. The two research groups tackled the issue.

Patients in stage 1 of the NIA scheme have biomarker evidence of amyloid deposition without neurodegeneration (ND); stage 2 patients have both. Stage 3 adds cognitive decline to the amyloid and ND signs. SNAP captures cognitively normal patients with ND but no evidence of amyloid deposition.

Over a period of 9 years, the St. Louis team split 174 cognitively normal adults – about equal numbers of men and women with an average age of 66 – into the four groups at baseline, plus a fifth: no evidence of ND or amyloid. Amyloid deposition was assessed by positron emission tomography, and ND was assessed by both hippocampal volume loss on MRI and cerebrospinal fluid levels of the AD-linked tau protein.

Amyloid accumulation and hippocampal loss were greater in the later NIA stages than in either SNAP or biomarker-free subjects. Among the 34 SNAP patients (20%), only about 5 went on to deposit amyloid.

“The rates of [amyloid] accumulation and loss of hippocampal volume in individuals with SNAP were indistinguishable from those without any pathologic features at baseline. … SNAP appears most likely to capture inherent individual variability in brain structure or to represent comorbid pathologic features rather than early emerging AD. Low hippocampal volumes or elevated levels of [tau protein] in isolation may not accurately represent ongoing neurodegenerative processes,” said investigators led by Brian Gordon, PhD.

Meanwhile, in the Harvard study, only “a small subset” of the 64 SNAP patients went on to rapid cognitive decline. SNAP seems to be “heterogeneous, and further biomarker refinement will be necessary to characterize this group,” said investigators led by Elizabeth Mormino, PhD.

The Harvard team split 247 clinically normal individuals – a bit more women than men this time, with an average age of 74 years – into NIA categories, SNAP, and patients with no ND or amyloid biomarkers. Hippocampal volume was again assessed by MRI; positron emission tomography scans were used to assess amyloid deposition, but also regional brain tau protein levels and other pathologies, and there was serial cognitive testing. The study started in 2010 and is ongoing, with subjects evaluated yearly.

SNAP patients had less pathology and better ongoing cognitive function than peers in the accepted NIA categories, and had levels of amyloid deposition no greater than biomarker-free subjects. Tau protein “levels in the medial and inferior temporal lobes were indistinguishable between” the two groups.

SNAP patients did slightly worse on serial cognitive tests, but these findings were driven mostly by two SNAP patients who declined faster than the others. (The study by Dr. Gordon and his associates did not report cognitive outcomes.)

Overall, “clinically normal adults with SNAP,” the Harvard group said, “did not exhibit evidence of elevated tau levels, which suggests that this biomarker construct does not represent amyloid-independent tauopathy,” one of the bridges proposed from SNAP to AD.

“SNAP is likely heterogeneous,” with only a subset of patients at risk “for short-term decline. Future refinement of biomarkers will be necessary to subclassify this group and determine the biologic correlates of ND markers.” SNAP does not “appear to be specific to AD,” and is likely influenced by “age-related pathologic processes, the normal aging process, and [individual] differences,” the investigators said.

When asked to comment on the studies, Richard J. Caselli, MD, professor of neurology at the Mayo Clinic, Scottsdale, Ariz., noted that the Mormino study’s findings of a flattened test-retest effect on the serial cognitive tests seemed to be a sensitive cognitive correlate of SNAP, and consistent with the previously reported increased rate of decline in MCI [mild cognitive impairment] patients with SNAP relative to both preclinical stage 0 and preclinical stage 1 ( Neurology. 2015 Feb 13;84[5]:508-15 ).

Overall, the two studies support SNAP as a “generally non-AD heterogeneous diagnosis that does in fact exhibit greater cognitive decline with age, even if subtle in the Mormino study, with an increased risk of MCI and dementia. If we look at the neuropathology of AD cases, we find similar additional pathologies, so maybe SNAP is that minus the AD piece,” said Dr. Caselli, who was not involved in either study.

The heterogeneity explains “our difficulties understanding” the nature of SNAP, Sylvia Villeneuve, PhD, said in an editorial to the Harvard study (JAMA Neurol. 2016 Aug 22. doi: 10.1001/jamaneurol.2016.2842 ).

“Given that the cognitive and brain profile of most SNAP individuals are stable over time, some authors have suggested that neurodegeneration should not be a defining feature of SNAP. … Part of what we capture as SNAP represents a tail of the normal aging distribution,” said Dr. Villeneuve of McGill University in Montreal. “A better comprehension of the biomarkers used to characterize SNAP will be important, with an awareness of the limitations of bimodal markers” – the yes/no answers used for NIA and SNAP classification – “especially those with cutoffs that do not have a biological basis.”

Both studies were funded at least in part by the National Institutes of Health. Dr. Gordon reported research work with Avid Radiopharmaceuticals; Dr. Mormino had no industry disclosures. Other investigators in both projects reported ties to several companies, including Eli Lilly, Janssen, AbbVie, Roche, and Pfizer. Dr. Villeneuve had no disclosures.