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Alzheimer’s disease Neuropathological Change (ADNC), i.e. amyloid β (Aβ) and hyperphosphorylated τ (HPτ), is seen in excess in the brains of subjects with AD. Idiopathic Normal Pressure Hydrocephalus (iNPH) lacks defined hallmark lesions, affects the elderly and leads to cognitive impairment, gait disturbance and urinary incontinence that can be treated with a ventriculoperitoneal shunt (VPS). A few centres around the world have obtained a brain biopsy from the area of VPS. It has been reported that the presence of ADNC in the biopsy is associated with progression to AD.

We confirm that majority of iNPH subjects display ADNC, and the ADNC increases in extent with age, in line with AD. The HPτ pathology is sparse in majority of cases. We observed remarkable neuronal survival and loss of matrix/synapses in subjects with iNPH (paper III).

When studying subjects with notable Aβ pathology (paper IV), we observed a stepwise increase of pyroglutamylated Aβ (pyAβ) and phosphorylated Aβ variants in iNPH. These two Aβ variants are associated with symptomatic AD and correlate with HPτ pathology. The pyAβ in the frontal cortex is a predictive marker for AD. Thus, notable Aβ pathology in presence of HPτ in iNPH is suggestive of a moderate level of ADNC.  

When assessing changes in the extent of pathology occurring during 21 months in a frontal cortex of a subject with iNPH and AD (paper II), HPτ pathology increased in parallel with neuronal and synaptic loss, whereas Aβ pathology and astroglial activity were stable over time. In contrast, we observed reduction of microglial markers, which might explain why anti-inflammatory treatment is effective only at an early stage of AD.

When assessing brain tissue, the section thickness must be standardised, as it affects the staining outcome and diagnosis (paper I).

In conclusion, we have demonstrated a progressive neurodegeneration of ADNC type in a population of iNPH subjects, mimicking what is seen in subjects with AD. A brain biopsy obtained from subjects with iNPH should be obligatory. This is because when ADNC is present in the biopsy, representing prodromal AD, contact with memory clinic should be initiated.