Early detection of Alzheimer’s: what the latest research says

For early diagnosis, in addition to in-depth neurological evaluation, instrumental investigations such as CT and MRI are needed.

Although it remains a non-trivial undertaking even for neurologists and neuropsychiatrists with extensive experience, in recent years the chances of issuing a more precise and earlier diagnosis of Alzheimer’s disease have greatly increased compared to the past.

Contrary to 10-15 years ago, when the detection of this severe form of dementia was linked to the evaluation of overt clinical symptoms, which begin to manifest when memory and cognitive performance are at a level of impairment already quite advanced, today, thanks to the use of brain imaging techniques and the supporting information obtainable from the analysis of some biomarkers, You can recognize the disease more in advance.

This diagnostic improvement is valuable because currently available therapies to combat Alzheimer’s disease can only bring real benefits if undertaken at a very early stage of neuronal degeneration. In addition, the timely differential diagnosis made possible by brain imaging and new laboratory tests makes it possible to treat earlier and more targeted other forms of cognitive decline with onset symptoms similar to those of Alzheimer’s disease, but different in origin and course, for which there are valid therapies.

Initial symptoms and instrumental evaluations

Although research continually suggests new potential diagnostic approaches, to date, in clinical practice, the early recognition of Alzheimer’s disease is essentially based on the evaluation of very early symptoms of cognitive decline and on the execution of some instrumental and laboratory investigations, such as CT, magnetic resonance imaging (MRI), PET (positron emission tomography) or SPECT (single photon emission tomography) brain and fluid analysis Cephalorachidian.

Early symptoms characteristic of cognitive decline in people over 50-60 years include:

• mild difficulty remembering recent events (worsening by usual standards)
• brief episodes of disorientation and mental confusion
• modest difficulty concentrating and speaking (choice of words)
• alterations in mood and behavior (in particular, onset of apathy, irritability, anxiety and depression).

In the face of signals of this type, as a rule, the neurologist deepens the evaluation with neuropsychological and cognitive tests, accompanied by the execution of routine laboratory tests, aimed at excluding organic diseases characterized by overlapping manifestations.

In addition to identifying structural alterations of some brain regions involved in memorization, learning and language processing, brain imaging with CT or MRI is important because it allows to exclude that the initial clinical symptoms of suspected dementia, found during neurological examination and cognitive tests, are actually due to brain tumors or alterations in cerebral blood circulation (atherosclerosis). , micro-ischemia, carotid stenosis, etc.), to be managed with targeted interventions, very different from those used in Alzheimer’s dementia.

PET and SPECT are, on the other hand, “functional” investigations that allow us to understand if the nerve cells present in different parts of the brain function more or less efficiently, through the evaluation of their energy metabolism (glucose consumption). Generally, in people with cognitive decline or very early Alzheimer’s disease, there are reductions in blood circulation and metabolism of the temporal and parietal zone of the cerebral cortex (roughly corresponding to the area behind the forehead, the front top and the sides of the head). These investigations are very sensitive, but provide non-specific information, which must be evaluated together with other clinical and instrumental data to issue a reliable diagnosis.

All patients with cognitive-behavioral symptoms of unclear origin and not associated with the presence of a coded psychiatric illness (major depression, anxiety disorder, psychosis, etc.) should perform at least once a CT scan or a brain MRI to better understand what it is, while PET and SPECT are considered third-level assessments, to be performed if it is necessary to differentiate between different forms of dementia in order to set up an approach more correct therapeutic.

Cerebrospinal fluid analysis

For some years now, the diagnosis of cognitive decline and Alzheimer’s disease can also be supported by the analysis of cerebrospinal fluid: a physiological fluid present in the space surrounding the brain and spinal cord, with the function of protective and “stabilizing” cavity. The examination consists in the sampling of a small amount of cerebrospinal fluid, through a lumbar puncture, and in the evaluation of the amount of ß-amyloid and/or Tau proteins, distinctive of Alzheimer’s disease.

Although its role in the etiopathogenesis of the disease has not yet been fully understood, it has long been known that the ß-amyloid protein tends to accumulate in the areas of the brain mainly affected by neuronal degeneration and it has been shown that in patients with Alzheimer’s dementia, from the earliest stages, the same protein is present in cerebrospinal fluid at lower levels than those of healthy people.

Conversely, in case of illness, the levels of Tau protein in the cerebrospinal fluid tend to increase. This second biomarker is much less useful than the first for a timely diagnosis of Alzheimer’s dementia since its variation in concentration in cerebrospinal fluid occurs at a fairly advanced stage of the disease.

Both tests are available in clinical practice, but are performed only in special cases (especially when the diagnosis is uncertain or the onset is early) since the lumbar puncture necessary for sampling is an invasive action and potentially associated with side effects such as back pain, headache and, rarely, reactive meningitis.

Recently, as an alternative to assessing ß-amyloid levels in cerebrospinal fluid, a variant of PET has been developed that can detect ß-amyloid deposits in the brain. Despite its high sensitivity and specificity, at the moment, this imaging technique has not yet entered the diagnostic routine, mainly due to the high cost. Experts would consider it useful to perform it (at least) in patients with:

• mild cognitive decline associated with memory deficits
• dementia with atypical presentation
• early-onset cases (< 65 years).

The information provided by genes

In the vast majority of cases (about 98%), Alzheimer’s disease occurs sporadically and is not linked to specific inherited genetic alterations, which affect only a minority of very early-onset familial forms (generally, between 30 and 40 years). However, it is known that the presence of certain genetic variants, combined with unfavorable environmental and lifestyle factors, can increase the likelihood of developing the disease and that the latter is higher in people with first-degree relatives who already suffer from it (parents or siblings).

The genetic variant most closely related to an increased risk of Alzheimer’s disease is APOE4: if present in a single copy, it increases the individual’s likelihood of developing Alzheimer’s dementia threefold; If present in double copy, it increases the risk by as much as 15 times. Screening for this genetic alteration is not recommended, since its presence alone does not allow to predict whether a person with a family history of Alzheimer’s dementia, but still without symptoms, will develop the disease or not.

The same applies to about 20 other genetic variants that have more recently been attributed a protective role or risk factor for Alzheimer’s dementia, since the contribution of each DNA sequence is small and not relevant when considered in isolation.

Rather than supporting early diagnosis, the characterization of these and other genetic determinants has confirmed that Alzheimer’s dementia is a disease with a complex and multifactorial genesis, difficult to predict, prevent and treat through therapies aimed at compensating for single molecular defects.