Controversial Past, Splendid Present, Unpredictable Future: A Brief Review of Alzheimer Disease History

Abstract

Background: The concept of Alzheimer disease (AD)-since its histological discovery by Alzheimer to the present day-has undergone substantial modifications. Methods: We conducted a classical narrative review of this field with a bibliography selection (giving preference to Medline best match). Results: The following subjects are reviewed and discussed: Alzheimer's discovery, Kraepelin's creation of a new disease that was a rare condition until the 1970's, the growing interest and investment in AD as a major killer in a society with a large elderly population in the second half of the 20th century, the consolidation of the AD clinicopathological model, and the modern AD nosology based on the dominant amyloid hypothesis among many others. In the 21st century, the development of AD biomarkers has supported a novel biological definition of AD, although the proposed therapies have failed to cure this disease. The incidence of dementia/AD has shown a decrease in affluent countries (possibly due to control of risk factors), and mixed dementia has been established as the most frequent etiology in the oldest old. Conclusions: The current concept of AD lacks unanimity. Many hypotheses attempt to explain its complex physiopathology entwined with aging, and the dominant amyloid cascade has yielded poor therapeutic results. The reduction in the incidence of dementia/AD appears promising but it should be confirmed in the future. A reevaluation of the AD concept is also necessary.

Keywords: Alzheimer disease; elderly dementia; future; hypothesis; nosological concept; past history; pathology; physiopathology; prevention; therapy.

Figure 2

Cajal’s histological images of AD lesions [32]. (A) Neurofibrillary tangles (NFTs) (images (A–F)); neuritic plaques (bottom line). Bielschowsky staining. Courtesy of R. Martínez, Director of Cajal’s Institute in Madrid. (B). Details of neuritic plaques. Neuritic plaques stained with ammoniacal silver oxide (top line), formalin bromide (medium line, left) or sublimated gold chloride staining (medium line, right). Neuritic plaque near a capillary vessel (bottom line, left; reduced silver nitrate staining). Dystrophic neurites (bottom line, right; ammoniacal silver oxide staining). Courtesy of R. Martínez, Director of Cajal’s Institute in Madrid.

Figure 2

Cajal’s histological images of AD lesions [32]. (A) Neurofibrillary tangles (NFTs) (images (A–F)); neuritic plaques (bottom line). Bielschowsky staining. Courtesy of R. Martínez, Director of Cajal’s Institute in Madrid. (B). Details of neuritic plaques. Neuritic plaques stained with ammoniacal silver oxide (top line), formalin bromide (medium line, left) or sublimated gold chloride staining (medium line, right). Neuritic plaque near a capillary vessel (bottom line, left; reduced silver nitrate staining). Dystrophic neurites (bottom line, right; ammoniacal silver oxide staining). Courtesy of R. Martínez, Director of Cajal’s Institute in Madrid.

Figure 1

Pictures taken from de Kraepelin’ book [15]. NFT in the soma of cortical neurons (top line), a high magnification of NFT and neurites (bottom left panel), and NFT throughout the cortex (bottom right panel) of AD cases.

Figure 3

The Alois Alzheimer’s team. Alois Alzheimer and coworkers in Munich. Back (Left to right. Fifth: E. Kraepelin?; Sixth: A. Alzheimer; Seventh: N. Achúcarro, Spanish neurologist; Eighth: F. Lewy). Front (left to right): Frau Grombach; U. Cerletti; unknown; F. Bonfiglio; G. Perusini. Circa 1909–1910. Archive for History of Psychiatry, Department of Psychiatry, University of Munich. (Photography in sepia and permission to reprint by Psychiatrische Klinik für Psychiatrie und Psychotherapie in 2023).

Figure 4

Publications on AD recorded in Medline by year: 1970–2022. (Taken from Medline in 2023).

Figure 5

Putative AD evolution. Possible AD brain and clinical evolution along life. Theoretic evolution of AD cases with increasing pathologic burden along life, going from the early preclinical period to preclinical period plus positive biomarkers (+), predementia (MCI), and progressive stages of dementia. (The time-periods described are an average). Many cases with great AD pathologic burden never exhibit MCI or dementia and die with normal cognition. Pathological burden in the oldest cases is always mixed. Modified from Bermejo-Pareja F [224]; and inspired in Scinto et al. [225].

Figure 6

Possible Physiopathology of AD. This figure represents the AD physiopathological model of the cascade hypothesis (top) and a more complex relationship between many risk factors, dementia, and the hallmark pathologies of AD: Neurofibrillary tangles (NFTs) and senile plaques (SPs). Figure inspired in Herrup [138] and modified by authors. * There are many RF described for dementia/AD.

Figure 7

Pathological burden in the brains of patients with dementia throughout aging. This figure charts the brain pathologies in demented cases according to different periods of aging. Vascular lesions (VaDs) grow almost exponentially from the age of 50. The pathological burden of type AD lesions (SADs) could begin in childhood and possibly decline towards 90–100 years of age according to some studies [455] or increase (grey). LATE and hippocampal sclerosis (HS) increase with aging. Many other neurodegenerative disorders (NDD, e.g., ADAD, LBD) have an early presentation or increase with aging. Modified from Bermejo-Pareja et al. [387] and inspired by Nelson et al. [455] and modified, with data from other authors ([456,457,458,459,460], see text).