Diagnostic Advancement

Loss or impairment of olfaction (sense of smell) has been identified as an early indicator of Alzheimer’s Disease.  Interestingly, the infectious agents most commonly studied in association with Alzheimer’s and Dementia enter the brain via the olfactory bulbs.   This pertains to the Herpes Viruses as well as Chlamydia pneumonaie, which we believe is an important clue supporting the infection hypothesis.  This also presents a low-cost, non-invasive, easily administered testing option to help identify patients early in the disease process.  Olfactory testing, traditional MMSE (Mini Mental-State examination) and infection testing could identify patients that are candidates for antimicrobial therapy.  Intervening before extensive damage occurs should be the focus going forward.

Olfactory Loss in Alzheimer’s

Odor identification as a biomarker of preclinical AD in older adults at risk
Cohort analysis, n= 274, 101 CSF donations.  Neurology, 2017.
Methods- OI measured using the University of Pennsylvania Smell Identification Test and cognitive performance using the Repeatable Battery for Assessment of Neuropsychological Status.  Assessment of AD pathology with the biomarkers total tau (t-tau), phospho-tau (P181-tau), and their ratios with β-amyloid (Aβ1-42). Adjusted analyses considered age, cognition, APOE ε4 status, education, and sex as covariates.
Results- Reduced OI was associated with lower cognitive score and older age, as well as increased ratios of CSF t-tau and P181-tau to Aβ1-42 (all p < 0.02).
Conclusion- These findings from healthy high-risk older individuals suggest that OI reflects the degree of preclinical AD pathology, while its relationships with age and cognition result from the association of these latter variables with such pathology. Diminished OI may be a practical and affordable biomarker of AD pathology.

Early olfactory involvement in Alzheimer’s disease
Autopsy cases, n= 110.  The Canadian Journal of Neurological Sciences, 2003.
Methods- cortical areas and the olfactory bulb and tract were analyzed using histo- and immunohistochemical techniques.  Based on a semiquantitative analysis of cortical senile plaques, neurofibrillary tangles and curly fibers, the 110 cases were divided into four groups: 19 cases with severe (definite AD), 14 cases with moderate, 58 cases with discrete and 19 control cases without AD-type cortical changes.
Results- The number of cases with olfactory involvement was very high, more than 84% in the three groups with cortical AD-type lesions. Degenerative olfactory changes were present in all 19 definite AD cases, and in two of the 19 controls. The statistical analysis showed a significant association between the peripheral olfactory and cortical degenerative changes with respect to their frequency and severity (P < 0.001). Neurofibrillary tangles and neuropil threads appear in the olfactory system as early as in entorhinal cortex.

Olfactory centres in Alzheimer’s disease: olfactory bulb is involved in early Braak’s stages
post-mortem tissue and case analysis, n= 30 (15 AD cases compared with 15 non-AD cases), Neuroreport, 2001.
Methods- Cases asssessed by psychiatrist using NINCDS-ADRDA criteria, CERAD and Braak and Braak staging.  Brain tissue assessed post-mortem using immunohistochemistry.
Results- statistically significant difference in brain weight between AD and controls suggesting atrophy in AD (p=.002), all but one patient had neurofibrillary tangles, the anterior olfactory nucleus and olfactory bulbs were damaged in AD relative to controls.
Conclusion- Olfactory bulbs damaged earlier in AD than entorhinal cortex.  This supports the belief that olfactory testing is a preclinical marker for AD.

A Brief Olfactory Test for Alzheimer’s Disease
Retrospective, case-control study.  n = 94.  Journal of Neurological Sciences, 2014.
Design- Participants with probable AD (N=18), mild cognitive impairment (MCI, N=24), other causes of dementia (OD, N=26) and matched controls (OC, N=26) were tested, with closed eyes, for their ability to detect an odor, one nostril at a time. A container of 14g of peanut butter was opened, held medially at the bottom of a 30 cm ruler, and moved up 1cm at a time during the participants’ exhale. Upon odor detection, the distance between the subject’s nostril and container was measured.
Results- The mean odor detection distance of AD patients’ left nostril (5.1 cm), and not their right (17.4 cm), was significantly less (F(3,90) = 22.28, p < 0.0001) than the other groups. The mean, standard error, and 95% Confidence Interval of the L R nostril odor detection difference (cm) for AD was −12.4 ±0.5, (−15.0, −9.8); for MCI was −1.9 ±1.2, (−4.2,0.4); for OD was 4.8 ±1.0, (2.6,6.9); and for OC was 0.0 ±1.4 (−2.2,2.1).
Conclusion- This non-invasive and inexpensive left-right nostril odor detection test appears to be a sensitive and specific test for probable AD.

Pathologic changes in olfactory neurons in Alzheimer’s disease
Annals New York Academy of Sciences, 1991.
Abstract- “We speculated that the peripheral olfactory neurons in the nose, which are readily available for biopsy, might be affected in AD and might be a valuable source of tissue for examination and studies of the mechanism and progression of the disease process. The importance of identifying a peripheral site that is affected in AD is clear because our ability to study the development of degenerative events and to diagnose AD is severely restricted by the inaccessibility of the affected brain tissue, which lies within the cranium and is not easily obtained for the purposes of biopsy.”

SMELL-S and SMELL-R: Olfactory tests not influenced by odor-specific insensitivity or prior olfactory experience
PNAS, 2017.
Abstract- “Smell dysfunction is a common and underdiagnosed medical condition that can have serious consequences. It is also an early biomarker of neurodegenerative diseases, including Alzheimer’s disease, where olfactory deficits precede detectable memory loss. Clinical tests that evaluate the sense of smell face two major challenges. First, human sensitivity to individual odorants varies significantly, so test results may be unreliable in people with low sensitivity to a test odorant but an otherwise normal sense of smell.”

Olfactory Identification Deficits, Cognitive Decline, and Dementia in Older Adults
American Journal of Geriatric Psychiatry, 2016.
Abstract- “Several recently developed biomarkers of Alzheimer disease (AD) are invasive, expensive, and difficult to obtain in most clinical settings. Olfactory identification test performance represents a noninvasive, inexpensive biomarker of AD that may have predictive accuracy comparable with neuroimaging measures and biomarkers assessed in cerebrospinal fluid. Neurofibrillary tangles in the olfactory bulb are among the earliest pathologic features of AD and are also seen in the projection pathways from the olfactory bulb to secondary olfactory brain regions, including the piriform and medial temporal cortex, orbitofrontal cortex, and other limbic regions. Odor identification impairment characterizes AD and predicts the clinical transition from mild cognitive impairment to AD in both clinical and community samples.”

Evaluation of olfactory dysfunction in neurodegenerative diseases
Review Article, Journal of the Neurological Sciences, 2012.
Parkinson’s disease, Alzheimer’s disease, multiple sclerosis, Huntington’s disease and motor neuron disease have all been associated with olfactory dysfunction.  The review discusses the use of olfactory event-related potentials (OERPs) and functional magnetic resonance imaging (fMRI) measurements as markers to assist in earlier diagnosis of the aforementioned diseases.

Olfactory dysfunction in the pathophysiological continuum of dementia

Ageing Research Reviews, 2019.
Abstract- “Sensory capacities like smell, taste, hearing, vision decline with aging, but increasing evidence show that sensory dysfunctions are one of the early signs diagnosing the conversion from physiological to pathological brain state. Smell loss represents the best-characterized sense in clinical practice and is considered as one of the first preclinical signs of Alzheimer’s and Parkinson’s disease, occurring a decade or more before the onset of cognitive and motor symptoms. Despite the numerous scientific reports and the adoption in clinical practice, the etiology of sensory damage as prodromal of dementia remains largely unexplored and more studies are needed to resolve the mechanisms underlying sensory network dysfunction. Although both cognitive and sensory domains are progressively affected, loss of sensory experience in early stages plays a major role in reducing the autonomy of demented people in their daily tasks or even possibly contributing to their cognitive decline. Interestingly, the chemosensory circuitry is devoid of a blood-brain barrier, representing a vulnerable port of entry for neurotoxic species that can spread to the brain. Furthermore, the exposure of the olfactory system to the external environment make it more susceptible to mechanical injury and trauma, which can cause degenerative neuroinflammation. In this review, we will summarize several findings about chemosensory impairment signing the conversion from healthy to pathological brain aging and we will try to connect those observations to the promising research linking environmental influences to sporadic dementia. The scientific body of knowledge will support the use of chemosensory diagnostics in the presymptomatic stages of AD and other biomarkers with the scope of finding treatment strategies before the onset of the disease.”