Alzheimer dementia G30.9+F00.9*

Alois Alzheimer, professor of psychiatry and neuropathologist (14.06.1864-19.12.1915) first described the neuropathological changes post mortem in the brain of a patient suffering from severe presenile dementia (first published in 1906/1907). These were subsequently referred to as Alzheimer's disease by his mentor and colleague Emil Kraeplin in his Handbook of Psychiatry of 1910 and are still regarded today as typical of the form of dementia named after Alzheimer. (Hippius H and Neundörfer G 2003).

AD occurs with an average prevalence of approx. 9% at the age of ≥ 65 years, with a general upward trend and increasing prevalence with increasing age (≥90 years approx. one in three affected).

AD is the most common form of dementia, accounting for 60-70% of all dementias. However, there are often overlaps with other forms of dementia such as vascular dementia and frontotemporal dementia in particular.

Around 1 million people in Germany currently suffer from AD, around 100,000 people with AD are under the age of 65 and 65% of sufferers are female. An increase to 2.4 to 2.8 million sufferers is expected by 2050; the rate of new cases is estimated at around 400,000 per year. The care of people with AD will therefore be one of the key challenges facing the healthcare system in the future.

The pathophysiology of Alzheimer's disease (AD) is not fully understood and is still the subject of intensive research. It is presumably a multifactorial process with varying degrees of involvement of genetic, metabolic, immunological and also environmental or lifestyle-specific factors.

Different hypotheses on the pathophysiology of the development of AD are currently leading the way in research (see also: Liu PP et al 2019).

Two of the numerous hypotheses are significant for the currently available drug therapy approaches.

Cholinergic hypothesis: first formulated by P. Davies and A.J.F.Maloney for the first time (Davies 1979; see also Hampel et al 2018) is based on the importance of the neurotransmitter acetylcholine (ACh) in cognitive processes (memory), in affected brain regions and the reduction of ACh biosynthesis (acetylcholine transferase activity), as well as ACh content at synapses in the brain (amygdala, hippocampus and cortex), which has been demonstrated in the brains of AD patients and forms the basis for pharmacological treatment with cholesterol esterase inhibitors such as donezepil, rivastigmine and galantamine.

Amyloid hypothesis/amyloid cascade hypothesis and tau pathology: first published in 1991 by J. Hardy and D. Allsop (Hardy J and Allsop D 1991)(Paroni G et al 2019)(Kametani F and Hasegawa M 2018); for about 25 years the main hypothesis for the pathogenesis of AD and the basis for the development of new pharmacological substances/antibodies directed against amyloid β(Aβ), so-called anti-amyloid antibodies, such as lecanemab and donunemab (approved since the end of 2025). The hypothesis is based on neuropathologically proven typical deposits of Aβ in the brain of Alzheimer's patients (detection originally only possible post mortem, today objectifiable in vivo using PET-CT and determination in cerebrospinal fluid in diagnostics), which opens up the possibility of detecting the potential postulated damage mechanism during the course of the disease process and making it usable for diagnostics and research (Jack CR et al 2018). (Aβ) deposits, however, are not always necessarily associated with AD and therefore, strictly speaking, cannot be regarded as pathognomonic (detection of amyloid deposits in PET examinations in the brains of healthy people, as well as in the brains of deceased people who showed no cognitive impairment during their lifetime).

In extension, the amyloidcascade hypothesis assumes that initial amyloid deposits spread like a chain reaction (similar to prion diseases) and trigger further damage mechanisms, e.g. through inflammation and immune reactions (including disturbed signal transmission at the synapses) within the neurons, leading to the formation of neurofibril conglomerates intracellularly(taupathology) and to increased nerve cell death(neurodegeneration).

In addition, numerous other significant hypotheses such as mitochondrial, neurovascular, Ca homeostasis and other damage mechanisms are the subject of research (Liu PP et al 2019).

Neuropathological changes in AD: extraneural deposits of fibrillar amyloidbeta proteins(amyloid β-peptides(Aβ)) and dystrophic or atrophied neurites, which together form the neuritic or senile amyloid plques. senile amyloid plaques, and intraneural deposits of hyperphosphorylated tau protein, so-called neurofibrillary tangles(NFT)(neurofibrillary conglomerates), as well as the loss of synapses and presumably entire neurons (tau pathology).

These changes are seen as a typical characteristic of AD, but are not pathognomonic for the disease, as they can also be seen in other forms of dementia, in a similar form in MCI and even without clinical symptoms. The causal relationship between these neuropathological changes and the development of the typical cognitive symptoms of AD has not yet been fully elucidated (Kametani F and Hasegawa M. 2018).

Pathological changes can often be detected decades before the onset of clinical symptoms and, to a lesser extent, also in MCI. However, neuropathological changes and disease-related effects on the brain due to a wide variety of causes are generally detected more frequently with increasing age. However, the causal relationship to AD in vivo and the relevance of individual changes has so far been difficult to establish, even with the use of modern imaging techniques, and animal models cannot fully reproduce the pathology of AD specific to humans. Working out these relationships and making them usable in early diagnosis and therapy, as well as for prevention and improving prognosis, remains the challenge for research in the future.

The diagnosis of AD can only be made in conjunction with clinical symptoms (medical history with family history, general clinical and neurological examination, neuropsychological testing), biomarkers (cerebrospinal fluid for amyloid and tau pathology; laboratory concomitant diseases, secondary causes, etc.), imaging (cMRI as basic diagnostics, possibly PET) and, with increasing importance, genetic typing.

The diagnosis is made in stages, initially on the basis of the patient's medical history and assessment of cognitive symptoms using neuropsychological test procedures and subsequently additional diagnostic procedures to clarify other causes (secondary dementia symptoms), as well as differential diagnosis, in particular differentiation from other forms of dementia, and should preferably be made by a specialist experienced in dementia-related diseases.

Due to the paradigm shift with the necessity of early diagnosis for early planning and optimization of treatment and care options, it will become increasingly important for general medical practice to carry out an initial orientation assessment by means of simple standardized cognitive tests in the presence of cognitive abnormalities and, if there are findings, to arrange for early referral to the memory consultation or special neurological departments for further diagnostics. It should be noted here that MCI (mild cognitive impairment) must at least be present as a symptom in order to initiate further diagnostics and that screening without the presence of symptoms should not be carried out as a matter of principle, as diagnostics at the current scientific level are not validated pre-symptomatically and are not meaningful.

The diagnosis of AD can only be made in conjunction with clinical symptoms, biomarkers (CSF amyloid, tau pathology), cMRI, possibly PET, possibly genetic testing.

Minimum criteria for the diagnosis of AD: symptoms (at least MCI), clear biomarker patterns for amyloid and tau pathology in the CSF (if biomarker pattern is not clear, amyloid PET is also necessary, if necessary also FDG PET, tau PET for DD of other forms of dementia), typical structural changes in cMRI (exclusion of secondary causes of dementia or other pathology/other forms of dementia).

In accordance with the annually updated living guideline of the S3 Dementia Guideline:

Detailed neuropsychological testing to record cognitive, neuropsychological/psychiatric impairments and impairments in everyday life as accurately as possible;

The aim is to identify MCI as early as possible to enable early treatment and planning of care services, etc. An orientation test using simple test procedures should and can be carried out at an early stage in the general practitioner's practice if there are corresponding complaints and indications (own or external medical history); further detailed neuropsychological testing should then be carried out by experienced neurologists/psychiatrists/neuropsychologists in a specialized memory consultation if necessary.

Biomarker diagnostics from the cerebrospinal fluid:

A-T-Nclassification: amyloid, tau, neurodegeneration; biomarker combination is considered a well-established diagnostic tool for clinical symptoms (Jack C et al 2018).

Beta-amyloid 42 (Aβ42) (also Aβ42/40 quotient) (reduced in AD)

Total tau (hTau, non-specific for neuronal degeneration) and phosphorylated tau (pTau181, indicative of AD) (both elevated in AD)

CSF biomarkers should be determined in MCI and symptoms of mild dementia for early diagnosis of AD and DD of other forms of dementia. General screening without indicative symptoms (own or external medical history) is not recommended (biomarkers are not meaningful enough without context and are therefore unsuitable).

Biomarker diagnostics from the blood (new, not yet fully established procedure): p-Tau 181 and 217 determination from the blood. According to studies to date, changes are not sufficiently specific for AD (e.g. also elevated in ALS) and therefore not suitable for early diagnosis alone and generally not suitable for general pre-symptomatic screening (too high rate of false positive and false negative results), therefore at best in addition to the previously established biomarker diagnostics from CSF or PET and only in combination with clinical symptoms (e.g. progression).

Imaging:

Amyloid - PET anatomical imaging of the amyloid deposits (not absolutely necessary if there is clear evidence of biomarkers in the CSF)

FDG - PET anatomical imaging of glucose metabolism in the brain, which correlates with energy consumption of the neurons; in AD, reduced glucose metabolism in specific brain regions can be detected at an early stage (mainly used in cases of unclear DD or comorbidity).

Tau - PET anatomical imaging of tau deposits (not yet established as routine but only in specialized centers, not required for diagnosis).

cMRI: basic diagnostics, detection and description of the anatomical extent of neurodegeneration, to exclude other causes, in particular causes of secondary, i.e. treatable, dementia; DD other forms of dementia; may be necessary in the context of drug therapy with anti-amyloid antibodies according to a special examination protocol (NW monitoring).

Basic diagnostics in general medicine/family practice in the presence of personal or external medical history:

General clinical examination,

Simple standardized cognitive test procedures for screening and detection of MCI: preferably Montreal Cognitive Assessment (MoCA), alternatively Mini-Mental Status Examination (MMSE) (but less sensitive than MoCA) or DemTect (dementia detection test).

Laboratory to rule out secondary causes of cognitive impairment and taking into account underlying diseases

cMRI

To date, there is no therapy available for AD that can stop the progression of the disease or even lead to a cure. At best, the progression of the disease can be slowed down!

Until now, treatment has mainly focused on symptomatic treatment to slow down cognitive decline and maintain everyday functions and quality of life for longer; since the end of 2025, anti-amyloid antibodies have also been approved for the first time, which intervene causally in the disease process and are thus intended to slow down progression at a very early stage:

Cholinesterase inhibitors (improvement of ACh signaling by inhibiting the degradation of ACh): Donepezil (e.g. Aricept®); Rivastigmine (e.g. Exelon®); Galantamine (e.g. Reminyl®) can be used for mild and moderate dementia. No general application but individual indication taking into account concomitant diseases. Efficacy and benefit-risk must be regularly re-evaluated individually, as efficacy is not generally proven but non-minor side effects can occur.

NMDAreceptorantagonists, glutamate antagonists (improvement of signal transmission and protection of neurons by reducing overstimulation by glutamate): Memantine can be tried for moderate and severe dementia; here too, a strict individual indication is recommended, taking into account concomitant diseases, as well as regular individual risk-benefit assessment and re-evaluation to avoid undesirable effects.

Ginkgo biloba can be used well for mild and moderate dementia and is well tolerated without significant side effects. It increases cerebral blood flow and can therefore also have a positive effect on brain function. Efficacy has been investigated in RCTs: high-dose (240 mg) ginkgo extracts classified as medicinal products showed efficacy in individual studies in terms of improving everyday functions, cognitive performance and neuropsychiatric symptoms (depression, behavioral problems, restlessness, hallucinations), but only with long-term use (at least 8-12 weeks) and not generally in every patient. Medicines are available from pharmacies and are also reimbursable if prescribed by a doctor. (important: use only after consultation with a doctor, as herbal substances must always be used in conjunction with concomitant medication, in this case especially cardiovascular medication such as anticoagulation, etc.)!

Anti-amyloid antibodies(lecanemab, donanemab) cause the degradation of amyloid deposits in the brain and should thus lead to a slowing of cognitive decline, treatment must be carried out very early in MCI and very early forms of mild dementia, infusion treatment should be used in individual cases and under the appropriate conditions (e.g. genetics of apolipoproteins). E, Apo E4 homozygosity is an exclusion criterion, etc.) and may only be carried out by specialists in neurology/psychiatry with the appropriate infrastructure for special MRI monitoring of the potentially serious NW (prescription restriction). Here too, regular re-evaluation is part of the treatment protocol; individual effectiveness is not guaranteed.

Neuropsychiatric symptoms (severe behavioral abnormalities such as agitation, aggression) should generally not be treated with medication. Psychotropic drugs should not generally be used, as severe (including life-threatening cardiovascular) side effects must be expected and paradoxical reactions and worsening of neuropsychiatric symptoms may occur! Use psychotropic drugs only in exceptional cases, only temporarily and in the lowest possible dosage and, if necessary, only increase them slowly (go low and slow), preferably atypical antipsychotics (2nd generation substances).

In the case of neuropsychiatric symptoms, especially aggression and severe restlessness, the patient should be provided with supportive care measures and a reduction in stressors (pain, thirst/dehydration, hunger, noise, restlessness, etc.) as well as exercise and occupational therapy, music therapy, biography work, cognitive challenges and social activities to improve cognitive reserve and quality of life, and a regular, reliable daily routine to calm the patient and improve the sleep-wake rhythm, among other things.

Recent studies show evidence that regular exercise not only has a preventive effect but can also have a beneficial effect on the course of the disease (improvement of cerebral blood flow, metabolism and plasticity) (Marino FR et al 2025)

In addition, patients should also be made aware of risk factors at an early stage as part of preventive examinations, the avoidance of which is important for the prevention of AD throughout life (Lancet Commission 2024). This could prevent up to 45% of AD diseases!

Therapy and care concepts as well as palliative care should be discussed with patients and relatives early on in the course of the disease to ensure the best possible care!

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2. Hampel H, Mesulam M-M, Cuello A et. al. (2018) The cholinergic system in the pathophysiology and treatment of Alzheimer's disease, Brain 141(7): 1917-1933 doi.org/10.1093/brain/awy132
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10. Liu P-P, Xie Y, Meng X-Y et al (2019). History and progress of hypotheses and clinical trials for Alzheimer's disease. Signal Transduct Target Ther 4:29. doi.org/10.1038/s41392-019-0063-8
11. Marino FR, Lyu C, Li Y et al (2025). Physical Activity Over the Adult Life Course and Risk of Dementia in the Framingham Heart Study. JAMA Netw Open. 2025;8(11):e2544439. doi:10.1001/jamanetworkopen.2025.44439
12. Paroni G, Bisceglia P, Seripa D (2019).Understanding the Amyloid Hypothesis in Alzheimer's Disease. J Alzheimers Dis. 68(2):493-510. doi: 10.3233/JAD-180802
13. Zlokovic BV (2013). Cerebrovascular Effects of Apolipoprotein E: Implications for Alzheimer Disease. JAMA Neurol. 70(4):440-444. doi: 10.1001/jamaneurol.2013.2152

S3 guideline 'living guideline' last update 2025